According to the latest report by IMARC Group, titled Stem Cell Banking Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2021-2026 the global market reached a value of US$ 10.4 Billion in 2020. Stem cell banking refers to the process of collecting, storing and freezing stem cells for potential future use. Embryo, placenta, umbilical cord, bone marrow and cord blood are some of the common sources for obtaining stem cells. These cells are cryopreserved and are used to replace damaged organs, tissues and treat various diseases, such as leukemia, diabetes, thalassemia and cardiac disorders. Moreover, stem cells can regenerate and produce red blood cells (RBCs), platelets and white blood cells to protect the body in case of an infection. As a result, they are widely used for clinical, personalized and research applications.

Request Free Report Sample:https://www.imarcgroup.com/stem-cell-banking-market/requestsample

The global stem cell banking market is primarily being driven by the rising geriatric population. Due to the increasing prevalence of fatal chronic diseases, preserved stem cells are used in various medical therapies for the treatment of immune, blood, degenerative and metabolic disorders. Moreover, various technological advancements, such as the utilization of artificial intelligence (AI) solutions to identify productive and healthy stem cells, are providing a thrust to the market growth. Other factors, including the implementation of various government initiatives promoting public health, along with significant improvements in the medical infrastructure, are creating a positive outlook for the market. Looking forward, IMARC Group expects the market to reach a value of US$ 21.5Billion by 2026.

Checkout Now:https://www.imarcgroup.com/checkout?id=1152&method=1

As the novel coronavirus (COVID-19) crisis takes over the world, we are continuously tracking the changes in the markets, as well as the industry behaviors of the consumers globally and our estimates about the latest market trends and forecasts are being done after considering the impact of this pandemic.

Competitive Landscape with Key Players:

Key Highlights of the Market Segmentation:

Breakup by Product Type:

Breakup by Service Type:

Breakup by Bank Type:

Breakup by Utilization:

Breakup by Application:

Breakup by Region:

Ask Analyst for Customization and Explore full report with TOC & List of Figures:https://bit.ly/3o1uQZI

Note:We are updating our reports, If you want the report with the latest primary and secondary data (2021-2026) including industry trends, market size and Competitive landscape, etc. Click request free sample report, published report will be delivered to you in PDF format via email within 24 to 48 hours.

Key highlights of the report:

If you need specific information that is not currently within the scope of the report, we will provide it to you as a part of the customization.

About Us:

IMARC Group is a leading market research company that offers management strategy and market research worldwide. We partner with clients in all sectors and regions to identify their highest-value opportunities, address their most critical challenges, and transform their businesses.

IMARCs information products include major market, scientific, economic and technological developments for business leaders in pharmaceutical, industrial, and high technology organizations. Market forecasts and industry analysis for biotechnology, advanced materials, pharmaceuticals, food and beverage, travel and tourism, nanotechnology and novel processing methods are at the top of the companys expertise.

Contact Us:

IMARC Group

30 N Gould St Ste R

Sheridan, WY 82801 USA Wyoming

Email:Sales@imarcgroup.com

Tel No:(D) +91 120 433 0800

Americas: +1 631 791 1145 | Africa and Europe: +44-702-409-7331 | Asia: +91-120-433-0800, +91-120-433-0800

Continue reading here:
Stem Cell Banking Market: Top Companies, Investment Trend, Growth & Innovation Trends 2021-2026 The Bite - The Bite

Cardiac Stem Cells Comments Off on Stem Cell Banking Market: Top Companies, Investment Trend, Growth & Innovation Trends 2021-2026 The Bite – The Bite | March 22nd, 2022

March 17, 2022 2:15 pm ET

First Phase 3 Study To Demonstrate Statistically Significant Improvement in DFS in the Adjuvant Setting for Patients With Stage IB-IIIA NSCLC Regardless of PD-L1 Expression

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, the European Organisation for Research and Treatment of Cancer (EORTC) and the European Thoracic Oncology Platform (ETOP) today announced results from the pivotal Phase 3 KEYNOTE-091 trial, also known as EORTC-1416-LCG/ETOP-8-15 PEARLS. The study found that adjuvant treatment with KEYTRUDA significantly improved disease-free survival (DFS), one of the dual primary endpoints, reducing the risk of disease recurrence or death by 24% compared to placebo (hazard ratio [HR]=0.76 [95% CI, 0.63-0.91]; p=0.0014) in patients with stage IB (4 centimeters) to IIIA non-small cell lung cancer (NSCLC) following surgical resection regardless of PD-L1 expression. Median DFS was 53.6 months for KEYTRUDA versus 42.0 months for placebo, an improvement of nearly one year. These data are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary and will be shared with regulatory authorities worldwide.

These are the first positive results for KEYTRUDA in the adjuvant setting for non-small cell lung cancer, and represent the sixth positive pivotal study evaluating a KEYTRUDA-based regimen in earlier stages of cancer, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. KEYTRUDA has become foundational in the treatment of metastatic non-small cell lung cancer, and we are pleased to present these data showing the potential of KEYTRUDA to help more patients with lung cancer in earlier stages of disease. We thank the patients, their caregivers and investigators for participating in this study.

As previously announced, there was also an improvement in DFS for patients whose tumors express PD-L1 (tumor proportion score [TPS] 50%) treated with KEYTRUDA compared to placebo, the other dual primary endpoint; these results did not reach statistical significance per the pre-specified statistical plan (HR=0.82 [95% CI, 0.57-1.18]; p=0.14). Among these patients, median DFS was not reached in either arm. Additionally, a favorable trend in overall survival (OS), a key secondary endpoint, was observed for KEYTRUDA versus placebo regardless of PD-L1 expression (HR=0.87 [95% CI, 0.67-1.15]; p=0.17); these OS data are not mature and did not reach statistical significance at the time of this interim analysis. The trial will continue to evaluate DFS in patients whose tumors express high levels of PD-L1 (TPS 50%) and OS. The safety profile of KEYTRUDA in this study was consistent with that observed in previously reported studies.

Lung cancer is most treatable at earlier stages, and adding treatment after surgery may help reduce the risk of recurrence, said Professor Mary O'Brien, consultant medical oncologist and head of the Lung Unit at The Royal Marsden NHS Foundation Trust and professor of practice (medical oncology) at Imperial College London, as well as co-principal investigator. We are encouraged by these new Phase 3 data, as they represent the first time adjuvant immunotherapy has demonstrated a statistically significant and clinically meaningful improvement in disease-free survival for patients with stage IB-IIIA non-small cell lung cancer.

While significant advancements have been made in the treatment of metastatic non-small cell lung cancer, there remains an unmet need for patients with earlier stages of this disease, as up to 43% of them will experience disease recurrence following surgery, said Dr. Luis Paz-Ares, chair of the medical oncology department, Hospital Universitario Doce de Octubre, Madrid, Spain and co-principal investigator. The positive disease-free survival data observed in this study with the use of KEYTRUDA in the adjuvant setting has the potential to have important implications for how we treat patients with stage IB-IIIA non-small cell lung cancer.

In addition to KEYNOTE-091, five other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials included: KEYNOTE-716 in stage IIB and IIC melanoma; KEYNOTE-054 in stage III melanoma; KEYNOTE-564 in renal cell carcinoma; KEYNOTE-522 in triple-negative breast cancer; and KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer.

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies in earlier stages of NSCLC include KEYNOTE-091, KEYNOTE-671, KEYNOTE-867 and KEYLYNK-012.

Study Design and Additional Data From KEYNOTE-091

KEYNOTE-091, also known as EORTC-1416-LCG/ETOP-8-15 PEARLS, is a randomized, Phase 3 trial (ClinicalTrials.gov, NCT02504372) sponsored by Merck and conducted in collaboration with EORTC and ETOP evaluating KEYTRUDA compared to placebo for the adjuvant treatment of patients with stage IB (4 centimeters) to IIIA NSCLC following surgical resection (lobectomy or pneumonectomy) and with adjuvant chemotherapy when indicated. The dual primary endpoints are DFS in the overall population and in patients whose tumors express PD-L1 (TPS 50%). Disease-free survival is calculated as the time from randomization to the date of disease recurrence, occurrence of second primary lung cancer, occurrence of second malignancy, or death from any cause, whichever occurs first. The secondary endpoints include OS and lung cancer-specific survival (the time from randomization to date of death due to lung cancer specifically). The study randomized 1,177 patients (1:1) to receive either KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for one year or maximum 18 doses; n=590); or placebo (IV Q3W for one year or maximum 18 doses; n=587). The median number of doses was 17 for KEYTRUDA and 18 for placebo. As of data cut-off for this interim analysis (September 20, 2021), median time from randomization to data cut-off was 35.6 months (range, 16.5-68.0 months).

Grade 3 adverse events occurred in 34.1% of patients receiving KEYTRUDA and 25.8% of patients receiving placebo. Adverse events resulting in discontinuation of any treatment occurred in 19.8% of patients receiving KEYTRUDA and 5.9% of patients receiving placebo; there were four treatment-related deaths in the KEYTRUDA arm and no treatment-related deaths in the placebo arm.

About EORTC

The European Organisation for Research and Treatment of Cancer (EORTC) is a non-governmental, non-profit organisation, which unites clinical cancer research experts, throughout Europe, to define better treatments for cancer patients to prolong survival and improve quality of life. Spanning from translational to large, prospective, multi-centre, phase III clinical trials that evaluate new therapies and treatment strategies as well as patient quality of life, its activities are coordinated from EORTC Headquarters, a unique international clinical research infrastructure, based in Brussels, Belgium.

For further information, please visit the EORTC website: http://www.eortc.org.

About ETOP

The European Thoracic Oncology Platform (ETOP) is a foundation promoting exchange and research in the field of thoracic malignancies in Europe. It is a not-for-profit organization, domiciled in Bern, Switzerland. Since 2009 ETOP been able to bring together international leaders in field of thoracic malignancies from all disciplines and has continuously enlarged its clinical trial and translational research activity in collaboration with many groups and institutions from 20 countries from Europe and beyond.

For further information, please visit the ETOP website: http://www.etop-eu.org.

About Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 82% of all cases. In the U.S., the overall five-year survival rate for patients diagnosed with lung cancer is 24%, a 14% improvement over the last five years. Improving survival rates are due in part to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures as well as the introduction of new therapies.

About Mercks Research in Lung Cancer

Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In advanced NSCLC, KEYTRUDA has four approved U.S. indications (see indications below), and is approved in advanced NSCLC in more than 95 countries. Among Mercks research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA.

About Mercks Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected Indications for KEYTRUDA (pembrolizumab) in the U.S.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

First-line treatment of advanced RCC in combination therapy with axitinib (KEYNOTE-426)

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those 1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of 5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in 20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those 3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (1%) was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

More here:
Significantly Improved Disease-Free Survival (DFS) Versus Placebo as Adjuvant Therapy in Patients With Stage IB-IIIA Non-Small Cell Lung Cancer...

Cardiac Stem Cells Comments Off on Significantly Improved Disease-Free Survival (DFS) Versus Placebo as Adjuvant Therapy in Patients With Stage IB-IIIA Non-Small Cell Lung Cancer… | March 22nd, 2022

Relatlimab is the third immune checkpoint inhibitor from Bristol Myers Squibb, adding to the Company's growing and differentiated oncology portfolio

Bristol Myers Squibb (NYSE: BMY) today announced that Opdualag TM (nivolumab and relatlimab-rmbw), a new, first-in-class, fixed-dose combination of nivolumab and relatlimab, administered as a single intravenous infusion, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. 1 The approval is based on the Phase 2/3 RELATIVITY-047 trial, which compared Opdualag (n=355) to nivolumab alone (n=359). 1,2

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220304005561/en/

Opdualag Logo, Bristol Myers Squibb

The trial met its primary endpoint, progression-free survival (PFS), and Opdualag more than doubled the median PFS when compared to nivolumab monotherapy, 10.1 months (95% Confidence Interval [CI]: 6.4 to 15.7) versus 4.6 months (95% CI: 3.4 to 5.6); (Hazard Ratio [HR] 0.75; 95% CI: 0.62 to 0.92, P =0.0055). 1 The Opdualag safety profile was similar to that previously reported for nivolumab. 1,2 No new safety events were identified with the combination when compared to nivolumab monotherapy. 1,2 Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. 2 Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm. 2

"Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we've seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma," said F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute. 3 "Today's approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints LAG-3 and PD-1." 1,2

Opdualag is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity. 1 Please see Important Safety Information below.

"While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients," said Samit Hirawat, chief medical officer, global drug development, Bristol Myers Squibb. 3 "Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment."

Lymphocyte activation gene-3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes, thus contributing to tumor-mediated T-cell exhaustion. 2 The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. 1 Relatlimab (in combination with nivolumab) is the first LAG-3-blocking antibody to demonstrate a benefit in a Phase 3 study. 1 It is the third checkpoint inhibitor (along with anti-PD-1 and anti-CTLA-4) for Bristol Myers Squibb.

"Today's approval is exciting news and offers new hope to the melanoma community. The availability of this treatment combination may enable patients to potentially benefit from a new, first-in-class dual immunotherapy," said Michael Kaplan, president and CEO, Melanoma Research Alliance.

The FDA-approved dosing for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every four weeks. 1 The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg, and pediatric patients younger than 12 years of age, has not been established. 1

This application was approved under the FDA's Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. 4 The review was also conducted under the FDA's Project Orbis initiative, which enabled concurrent review by the health authorities in Australia, Brazil and Switzerland, where the application remains under review.

About RELATIVITY-047

RELATIVITY-047 is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of nivolumab and relatlimab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. 1,2 The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. 1 The primary endpoint of the trial is progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). 1 The secondary endpoints are overall survival (OS) and objective response rate (ORR). 1 A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of nivolumab (480 mg) and relatlimab (160 mg) or nivolumab (480 mg) by intravenous infusion every four weeks until disease progression or unacceptable toxicity. 1

Select Safety Profile From RELATIVITY-047

Adverse reactions leading to permanent discontinuation of Opdualag occurred in 18% of patients. 1 Opdualag was interrupted due to an adverse reaction in 43% of patients. 1 Serious adverse reactions occurred in 36% of patients treated with Opdualag. 1 The most frequent (1%) serious adverse reactions were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%). 1 Fatal adverse reactions occurred in three (0.8%) patients treated with Opdualag and included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. 1 The most common (20%) adverse reactions were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). 1 The Opdualag safety profile was similar to that previously reported for nivolumab. 1,2 No new safety events were identified with the combination when compared to nivolumab monotherapy. 1,2 Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. 2 Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm. 2

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. 5 Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. 5,6 The incidence of melanoma has been increasing steadily for the last 30 years. 5,6 In the United States, approximately 99,780 new diagnoses of melanoma and about 7,650 related deaths are estimated for 2022. 5 Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses. 6

OPDUALAG INDICATION

Opdualag TM (nivolumab and relatlimab-rmbw) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

OPDUALAG IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis

Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis

Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies

Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction

Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions

Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis

Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant IMARs occurred at an incidence of ardiac/Vascular: pericarditis, vasculitis; Nervous System: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica; Endocrine: hypoparathyroidism; Other (Hematologic/Immune) : hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation

There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions

In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in 1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities

The most common adverse reactions reported in 20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in 20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see U.S. Full Prescribing Information for Opdualag .

OPDIVO + YERVOY INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO + YERVOY IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%).

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Here is the original post:
Bristol Myers Squibb to Demonstrate the Strength of its Growing Cardiovascular Portfolio at the American College of Cardiology's 71st Annual...

Cardiac Stem Cells Comments Off on Bristol Myers Squibb to Demonstrate the Strength of its Growing Cardiovascular Portfolio at the American College of Cardiology’s 71st Annual… | March 22nd, 2022

On January 7, a 57-year-old male patient received a genetically-modified pig heart transplant at the University of Maryland Medical Center (UMMC). The surgery was a world-first and deemed the patients only chance for survival after he was declared unsuitable for a human donor transplant or an artificial heart pump. On January 10, the University of Maryland School of Medicine (UMSOM) published a news release stating that the patient was doing well, and is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits.

Dr. Bartley P. Griffith the surgeon responsible for transplanting the porcine heart into the patient and a professor in transplant surgery at UMSOM said, We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future. Dr. Griffith leads the Cardiac Xenotransplantation Program at UMSOM alongside Dr. Muhammad M. Mohiuddin, professor of surgery at UMSOM.

The operation at the UMMC is an example of xenotransplantation. Xenotransplantation refers to any procedure involving the transplantation, infusion or implantation of cells, tissue or organs from a nonhuman, animal source into a human.

While the surgery was the first-of-its-kind, the concept of xenotransplantation is not novel. Chris Denning, professor of stem cell biology at the University of Nottingham told the UK Science Media Centre, Only in the late 1990s did the technologies become available and have steadily been improved ever since. Various academic and industrial teams have worked in this area for over 20 years, so it is not surprising that this has now been tested.

In the 20th century, non-human primates (NHP) were explored as potentially suitable donors for xenotransplantation due to the genetic similarities between primates and humans. However, concerns such as ethical issues, transmission of infection across species and breeding difficulties halted this research. Consequently, pigs are now considered to be the most appropriate candidate species for xenotransplantation.

"Pigs are considered for several reasons, Denning said. The size and anatomy of the pig heart is roughly the same as a humans, though there are considerable differences:

He added that, despite public perception, it is also relatively easy to keep pigs in a sterile condition.

Despite these advantages, transplanting a porcine heart into a human is considerably more challenging than transplanting a human heart. There are genetic differences between pigs and humans, which can lead to immunological rejection of the organ. Pigs have a gene that produces a molecule called (1,3)galactosyl transferase, which humans do not. This triggers an immediate and aggressive immune response, called hyperacute rejection, said Denning, ultimately causing the body to reject the organ.

The xenotransplantation conducted at UMMC involved a pig that had reportedly received 10 genetic modifications in total. Its unclear at this stage exactly what genes were modified, however the news release from UMSOM states three genes responsible for rapid antibody-mediated rejection of pig organs by humans were knocked out in the pig, and six human genes responsible for immune acceptance were inserted. An additional gene was also knocked out to stop excessive growth of the heart tissue.

Knockout means that an organism has been genetically altered such that it lacks either a single base, a whole gene or several genes. Often, genetic knockouts are utilized in laboratory research to understand how certain genes function, by monitoring changes in the organism when the gene is not expressed.

The porcine heart was provided by Revivicor, a subsidiary of United Therapeutics. You might recall Revivicor as the spin-out company of PPL Therapeutics, the UK-based biotech firm behind the first cloned mammal, Dolly the sheep. In December 2021, Revivicor also supplied New York University Langone Health with a kidney from a genetically-modified pig for an investigational procedure in a deceased human donor. The donor remained on ventilator support, and was closely monitored throughout the procedure and a subsequent observation period, during which the researchers said there were no signs of rejection.

According to the UMSOM news release, it received a $15.7 million research grant to evaluate Revivicor genetically-modified pig UHearts in baboon studies. Mohiuddin and colleagues reportedly applied for permission to conduct human clinical trials of the porcine heart from the US Food and Drug Administration (FDA), but were rejected. Under normal circumstances, IMPs must be evaluated in animal studies prior to human clinical trials this is standard protocol.

However, in the instance of the 57-year-old patient, an exception was made. The FDA granted emergency authorization for the procedure under its expanded access provision. This allows for an individual to access an investigational medicinal product (IMP) outside of clinical trials when there is no alternative therapy option available.

Will it be successful? asked Denning. The fact that the human patient is alive after a few days indicates that immediate hyperacute rejection has been avoided, which is the first hurdle. Only time will tell whether there are issues with chronic rejection, caused by e.g., incompatibility of major and minor histocompatibility complexes. Continuous monitoring will be needed to monitor transmission of potential pathogens, such as porcine endogenous retroviruses or hybrid porcine/human endogenous retroviruses.

Should the patient survive and the xenotransplant prove successful, it will likely raise a lot of questions as to how regulatory bodies move forward. Individual emergency authorization procedures do not generate sufficient data for the widespread implementation of xenotransplantation clinical trials are crucial for demonstrating efficacy.

However, there are logistical hurdles associated with even trialing the procedure. Seventeen people die every day waiting for an organ transplant, according to the Health Resources & Services Administration. There is a severe shortage of organs, and a steep decline in donation has been observed during the COVID-19 global pandemic. While a proposed advantage of xenotransplants is that they could provide on-demand organs, the procedure and its unknowns make it a very high-risk surgery. How does a clinician, or regulatory body, decide that a patient has waited long enough for a human organ that they qualify for inclusion in a trial?

Furthermore, if xenotransplant clinical trials support widespread adoption of xenotransplant procedures, how do we regulate a system whereby organs are widely available? Policies on patient selection and organ allocation currently exist in healthcare systems across the world. Navigating changes to these policies will require global conversations across different regulatory bodies.

Finally, a hurdle that Denning said could be the biggest of them all is: What do the general public think? Is it acceptable to harvest organs from animals? One thing that is for sure, is the outcomes of this [patient] will be watched closely by many, Denning concluded.

Read this article:
What the World's First Pig to Human Heart Transplant Could Mean for the Future of Transplants - Technology Networks

Cardiac Stem Cells Comments Off on What the World’s First Pig to Human Heart Transplant Could Mean for the Future of Transplants – Technology Networks | January 18th, 2022

Sharing is caring!

Cardiac muscle cells or cardiomyocytes (also known as cardiac myocytes) are the muscle cells (myocytes) that make up the heart muscle. Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body.

[In this image] Immunostaining of human cardiomyocytes with antibodies for actin (red), myomesin (green), and nuclei (blue).Photo source: https://www.fujifilmcdi.com/products/cardiac-cells/icell-cardiomyocytes

Cardiomyocytes are highly specialized cell types in terms of their structures and functions. Each cardiomyocyte contains myofibrils, unique organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells.

[In this image] Cardiomyocyte geometry and cellular architecture are controlled by micropatterned ECM substrate. Scientists used this technique to study how cells sense and respond to mechanical forces.Photo source: https://diseasebiophysics.seas.harvard.edu/research/mechanotransduction/

The heart is a muscular organ that pumps blood through the blood vessels of the circulatory system. It is composed of individual heart muscle cells (cardiomyocytes) and several other cell types.

[In this figure] The anatomy of the human heart showing 4 heart chambers (left atrium, left ventricle, right atrium, right ventricle) and the blood flow. The myocardium is referred to the cardiac muscle layers building the wall of each chamber.

[In this figure] The thickness of the heart wall (or myocardium) consists of cardiac muscle cells.Photo source: biologydictionary

[In this video] Structure of the human heart.

Cardiovascular disease is a leading cause of death worldwide. Nearly 2,400 Americans die of cardiac causes each day, one death every 37 seconds.

As the chief cell type of the heart, cardiac muscle cells primarily dedicate to the contractile function of the heart and enable the pumping of blood around the body. If anything goes wrong in the heart, it can lead to a catastrophic outcome. A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow ceases to a part of the heart, causing massive cardiomyocyte death in that area. Severe cases can, ultimately, lead to heart failure and death.

[In this figure] The progress of myocardial infarction or heart attack. At time post-infarction:

0-12 hours: Beginning of necrotic coagulation due to the blockage of coronary arteries Cardiomyocytes suffer the lack of oxygen (hypoxia)

12-72 hours: Culmination of necrotic coagulation Neutrophils infiltrate by an inflammatory response.

1-3 weeks: Disintegration of death myocytes and formation of granulation tissue (collagenous fibers, macrophages, and fibroblasts)

> 1 month: Formation of fibrous scar (fewer cells with an abundance of collagenous fibers)

A human heart contains an estimated 23 billion cardiomyocytes. There are several non-myocyte populations in the heart, including endothelial cells, smooth muscle cells, myofibroblasts, epicardial cells, endocardial cells, valve interstitial cells, resident macrophages, and other immune system-related cells, and potentially, adult stem cells (mesenchymal stem cells and cardiac stem cells). These distinct cell pools are not isolated from one another within the heart but interact physically to maintain the function of the whole organ. Overall, cardiomyocytes only account for less than a third of the total cell number in the heart.

[In this image] Immunostaining showing highly vascularized heart muscle.Cardiomyocytes are labeled by the striated pattern of sarcomeric -actinin (green). Capillaries are red and nuclei are blue.Photo source: biocompare.

The three main types of muscle include: Cardiac muscle, Skeletal muscle, and Smooth muscle.

[In this figure] Morphology and comparison of cardiac, skeleton, and smooth muscles.

Note: Involuntary muscles are the muscles that cannot be controlled by will or conscious.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells.

The heart is composed of cardiac muscle cells that have specialized features that relate to their function:

These structural features contribute to the unique functional properties of the cardiac tissue:

Like other animal cells, cardiomyocytes contain all the cell organelles that are essential for normal cell physiology. Moreover, cardiomyocytes have several unique cellular structures that allow them to perform their function effectively. Here are five main characteristics of mature cardiomyocytes: (1) striated; (2) uninucleated; (3) branched; (4) connected by intercalated discs; (5) high mitochondrial content.

[In this figure] Main characteristics of cardiac myocytes.Modified from lumen Anatomy and Physiology I.

Lets get closer to look inside a cardiomyocyte and learn its unique ultrastructure.

All cardiomyocytes and pacemaker cells are linked by cellular bridges. Intercalated discs, which form porous junctions, bring the membranes of adjacent cardiomyocytes very close together. These pores (gap junctions) permit ions, such as sodium, potassium, and calcium, to easily diffuse from cell to cell, establishing a cell-cell communication. This joining is called electric coupling, and it allows the quick transmission of action potentials and the coordinated contraction of the entire heart.

Intercalated discs also function as mechanical anchor points that enable the transmission of contractile force from one cardiomyocyte to another (by desmosomes and adherens junctions). This allows for the heart to work as a single coordinated unit.

[In this figure] Cardiac muscle cells are connected together to coordinate the cardiac contraction. This joining is called electric coupling and is achieved by the presence of irregularly-spaced dark bands between cardiomyocytes. These bands are known as intercalated discs.Photo source: bioninja.

[In this figure] Cardiac myocytes are branched and interconnected from end to end by structures called intercalated disks, visible as dark lines in the light microscope.Photo source: https://doctorlib.info/physiology/medical/49.html

There are 3 main types of junctional complexes within the intercalated discs. They work in different ways to maintain cardiac tissue integrity and cardiomyocyte synchrony.

The term desmosome came from Greek words of bonding (desmo) and body (soma). Desmosomes serve as the anchor points to bring the cardiac muscle fibers together. Desmosomes can withstand mechanical stress, which allows them to hold cells together. Without desmosomes, the cells of the cardiac muscles will fall apart during contraction.

The ability of desmosome to resist mechanical stress comes from its unique 3-D structure. Desmosome is an asymmetrical protein complex bridging between two adjacent cardiomyocytes, with each end residing in the cytoplasm. The intracellular part anchors intermediate filaments in the cytoskeleton to the cell surface. The middle part bridges the intercellular space between two cytoplasmic membranes.

[In this figure] Desmosomes connect intermediate filaments from two adjust cardiomyocytes. This job is accomplished by the formation of a dense protein complex or plaque in the intercalated discs. Major protein players include transmembrane cadherins: desmogleins (Dsgs) and desmocollins (Dscs), cytoplasmic anchors: plakophilins (PKPs) and plakoglobin (PG), and cytoskeleton adaptor: desmoplakin (DP). Cadherins link cells together, and other proteins form a dense complex called plaque.

In addition to desmosomes, adherens junctions (Ajs) are another type of mechanical intercellular junctions in cardiomyocytes. The difference is that adherens junctions link the intercalated disc to the actin cytoskeleton and desmosomes attach to intermediate filaments.

Adherens junctions keep the cardiac muscle cells tightly together as the heart pump. Adherens junctions are also the anchor point where myofibrils are attached, enabling transmission of contractile force from one cell to another.

[In this figure] Adherens junctions link actin cytoskeleton from two adjust cardiomyocytes together.Adherens junctions are constructed from cadherins and catenins. Cadherins (in cardiomyocytes N-Cadherin is the main cadherin) are transmembrane proteins that zip together adjacent cells in a homophilic manner. The transmembrane cadherins form complexes with cytosolic catenins, thereby establishing the connection to the actin cytoskeleton. At the adherens junctions, the opposing membranes become separated by 20nm.

Gap junctions are essential for the chemical and electrical coupling of neighboring cells. Gap junctions work like intercellular channels connecting the cytoplasm of neighboring cells, enabling passive diffusion of various compounds, like metabolites, water, and ions, up to a molecular mass of 1000 Da. Thereby they establish direct communication between adjacent cells.

[In this figure] Neonatal rat cardiac myocytes in cell culture.Cells were immunostained for actinin (green), gap junctions (red), and counterstained with DAPI (blue).Photo source: bioscience

Gap junctions are present in nearly all tissues and cells throughout the entire body. In cardiac muscle, gap junctions ensure proper propagation of the electrical impulse (from pacemaker cells to neighboring cardiomyocytes). This electrical wave triggers sequential and coordinated contraction of the cardiomyocytes as a whole.

[In this figure] A gap junction channel consists of twelve connexin proteins, six of which are contributed by each cell. The six connexin subunits form a hemi-channel in the plasma membrane, which is called a connexon. A connexon docks to another connexon in the intercellular space to create a complete gap junction channel. The intercellular space between adjacent cells at the site of a gap junction is 2-4 nm.

A second feature of cardiomyocytes is the sarcomeres, which are also present in skeletal muscles. The sarcomeres give cardiac muscle their striated appearance and are the repeating sections that make up myofibrils.

[In this image] Freshly isolated heart muscle cells showing intercalated discs (green), sarcomeres (red), and nuclei (blue).Photo source: https://christianz.artstation.com/

Cardiac muscle cells are equipped with bundles of myofibrils that contain myofilaments. These fiber-like structures can occupy 45-60% of the volume of cardiomyocytes. The myofibrils are formed of distinct, repeating units, termed sarcomeres. The sarcomeres, which are composed of thick and thin myofilaments, represent the basic contractile units of a muscle cell and are defined as the region of myofilament structures between two Z-lines (see image below). The distance between Z-lines in human hearts ranges from around 1.6 to 2.2 m.

[In this figure] Labeled diagram of myofibril showing the unit of a sarcomere. A sarcomere is defined as a segment between two neighboring Z-discs.

[In this image] Immunofluorescence image of adult mouse cardiomyocytes showing the Z-lines of the sarcomeres. 3D color projection of alpha-actinin 2 acquired with a confocal microscope.Photo source: Dylan Burnette.

The thick filaments are composed of myosin II. Each myosin contains two ATPase sites on its head. ATPase hydrolyzes ATP and this process is required for actin and myosin cross-bridge formation. These heads bind to actin on the thin filaments. There are about 300 molecules of myosin per thick filament.

The thin filaments are composed of single units of actin known as globular actin (G-actin). Two strands of actin filaments form a helix, which is stabilized by rod-shaped proteins termed tropomyosin. Troponin proteins, which function as regulators, bind to the tropomyosin at regular intervals. Whereas troponin lies in the grooves between the actin filaments, tropomyosin covers the sites on which actin binds to myosin. Their respective actions, therefore, control the binding of myosin to actin and consequently in the contraction and relaxation of cardiac muscles.

To generate muscular contraction, the myosin heads bind to actin filaments, allowing myosin to function as a motor that drives filament sliding. The actin filaments slide past the myosin filaments toward the middle of the sarcomere. This results in the shortening of the sarcomere without any change in filament length.

[In this figure] Sliding-filament model of muscle contraction.

Sarcolemma (also called myolemma) is a specialized cell membrane of cardiomyocytes and skeletal muscle cells. It consists of a lipid bilayer and a thin outer coat of polysaccharide material (glycocalyx) that contacts the basement membrane. The sarcolemma is also part of the intercalated disks as well as the T-tubules of the cardiac muscle.

Basement membrane is an extracellular matrix (ECM) coat that cover individual cardiomyocytes. Its composed of glycoproteins laminin and fibronectin, type IV collagen as well as proteoglycans that contribute to its overall width of about 50nm. Basement membrane provides a scaffold to which the muscle fiber can adhere.

[In this figure] A cross-section of a mouse heart showing the basement membrane (green) wrapping around an individual myocyte.

In cardiomyocytes and skeletal muscle cells, the sarcolemma (i.e. the plasma membrane) forms deep invaginations known as T-tubules (or transverse tubules). These invaginations increase the total surface area and allow depolarization of the membrane to penetrate quickly to the interior of the cell.

Without t-tubules, the wave of calcium ions (Ca2+) takes time to propagate from the periphery of the cell into the center. This time lag will first activate the peripheral sarcomeres and then the deeper sarcomeres, resulting in sub-maximal force production.

The t-tubules make it possible that current is simultaneously relayed to the core of the cell, and trigger near to all sarcomeres simultaneously, resulting in a maximal force output. T-tubules also stay close to sarcoplasmic reticulum (SR) networks, which is the modified endoplasmic reticulum (ER) of calcium storage in myocytes.

[In this figure] T-tubules (transverse tubules) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. T-tubules permit the rapid transmission of the action potential into the cell and also play an important role in regulating cellular calcium concentration.

Mitochondria are the powerhouse of the cell because they generate most of the cells energy supply of adenosine triphosphate (ATP). It is no doubt that the normal functions of cardiomyocytes require a lot of energy. Effective heart pumping is primarily dependent on oxidative energy production by mitochondria. Cardiomyocytes have a densely packed mitochondrial network, which allows them to produce ATP quickly, making them highly resistant to fatigue.

Different types of mitochondria can be distinguished within cardiomyocytes, and their morphological features are usually defined according to their location: intermyofibrillar mitochondria, subsarcolemmal mitochondria, and perinuclear mitochondria.

[In this figure] Mitochondrial morphology in cardiomyocytes.(Top) The anatomy of a mitochondrion. (Bottom left) Schematic diagram of the location of subsarcolemmal mitochondria (SSM), interfibrillar mitochondria (IFM), and perinuclear mitochondria (PNM). (Bottom right) TEM images of mitochondria in cardiomyocytes.Photo source: researchgate, wiki

Intermyofibrilar Mitochondria are found deeper within the cells and strictly ordered between rows of contractile proteins, apparently isolated from each other by repeated arrays. They play a huge role in producing enough energy for muscle contractions.

[In this figure] Immunofluorescent confocal imaging showing the densely packed mitochondria in cardiomyocytes. (A): Z-line (actinin); (B): Mitochondria; (C): Merge image.Photo source: MDPI

Subsarcolemmal Mitochondria reside beneath the sarcolemma. They collect oxygen from the circulating blood in the arteries and are responsible for providing the energy needed for conserving the integrity of the sarcolemma.

Perinuclear mitochondria are organized in clusters around the nucleus to provide energy for transcription and translation processes.

The cardiac function requires high energy demands; therefore, the adult cardiomyocytes contain numerous mitochondria, which can occupy at least 30% of cell volume. They meet >90% of the energy requirements by oxidative phosphorylation (OXPHOS) in the mitochondria, which requires a huge demand for oxygen consumption.

In humans, at a heart rate of 6070 beats per minute, the oxygen consumption of the myocardium is 20-fold higher than that of skeletal muscle at rest (compared by a normalization per gram of cell mass). In order to meet this high oxygen demand, the capillary density in the heart is 2-8 times higher than that in skeletal muscle (3,0004,000/mm2 compared to 5002,000 capillaries/mm2, respectively). Also, cardiomyocytes maintain a very high level of oxygen extraction (from blood) of 7080% compared with 3040% in skeletal muscle.

[In this image] Myofibrils in cultured cardiomyocytes.Photo source: https://christianz.artstation.com/

Cardiomyocytes go through a contraction-relaxation cycle that enables cardiac muscles to pump blood throughout the body. This is achieved through a process known as excitation-contraction coupling (ECC) that converts action potential (an electric stimulus) into muscle contraction.

[In this figure] Schematic diagram of the process of cardiac excitation-contraction coupling.Key steps in the cardiac excitation-contraction coupling:

Step 1: An action potential is induced by pacemaker cells. It travels along the sarcolemma and down into the T-tubule system to depolarize the cell membrane.

Step 2: Calcium channels in the T-tubules are activated by the action potential and permit calcium entry into the cell.

Step 3: Calcium influx triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR).

Step 4: Free calcium binds troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments. Calcium binding moves the troponin complex from the actin binding site. As a result, actin is free to bind myosin. The actin and myosin filaments slide past each other thereby shortening the sarcomere length, thus initiating contraction.

Step 5: At the end of a contraction, calcium entry into the cell slows and calcium is sequestered by the SR by calcium pumps. Lowering the cytosolic calcium concentration releases myosin-actin binding and the initial sarcomere length is restored.

In human beings (and many other animals), cardiomyocytes are the first cells to terminally differentiate, thus making the heart one of the first organs to form in a developing fetus. This makes sense because the function of the circulatory system is so crucial for a growing embryo so that the heart is the top priority.

In the embryo of a mouse, for instance, precursor cells of the cardiac muscles have been shown to start developing about 6 days after fertilization. In human embryos, the heart begins to beat at about 22-23 days, with blood flow beginning in the 4th week. The heart is therefore one of the earliest differentiating and functioning organs.

The heart forms initially in the embryonic disc as a simple paired tube (heart tube formation; week 3) derived from mesoderm. Then, the heart tubes loop and begin segmenting to separate chambers primitive atrium, and primitive ventricle. During this period, the first heartbeat begins.

[In this figure] The timeline of heart development.LA means left atrium; RA means right atrium. For more details, seehttps://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Heart_Development

Here, cardiomyocytes grow into a spongy-like tissue (cardiac jelly), called trabeculation, to build up the thickness of myocardial muscles. Thus, the heart begins to resemble the adult heart in that it has two atria, two ventricles, and the aorta forming a connection with the left ventricle while the pulmonary trunk forms a connection with the right ventricle.

As you can see that our hearts went through a complex developmental process. Inevitably, heart developmental abnormalities could happen (affect 8-10 of every 1000 births in the United States).

Can cardiomyocytes divide? Scientists used to believe that damaged human cardiac muscles cannot regenerate themselves by cell division in adults. In other words, all cardiomyocytes are terminally differentiated. In humans, our cardiomyocytes lose the ability to divide at around 7 days after birth. However, studies have recently shown that myocytes renew at a significantly low rate throughout the life of an individual. For instance, for younger people, about 25 years of age, the annual turnover of cardiomyocytes is about 1 percent. This, however, decreases to about 0.45 percent for older individuals (75 and above). Over the lifespan of an individual, less than 50 percent of these cells are renewed. Comparing to many of the other cells, cardiomyocytes have a very long lifespan. In contrast, small intestine epithelium renews every 2-7 days and hepatocytes (liver cells) renew every 0.5-1 year.

[In this figure] Radiocarbon dating establishes the age of human cardiomyocytes.Scientists used a pretty smart way to estimate the turnover of human heart cells. Generally speaking, the half-life of 14C is too long to date a lifetime of less than a century. However, the dramatic increase in the atmospheric 14C caused by nuclear bomb tests (during the Cool War) in the 1950s and 1960s increased the sensitivity of radiocarbon dating to a temporal resolution of 1-2years.Photo source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837331/

Low turnover of human cardiomyocytes suggests that the regenerative ability of cardiac muscles may be poor (another example is neural cells in the brain). In the event of injuries or myocardial infarction, the injured heart muscles of human beings do not regenerate sufficiently to allow the heart to heal itself. Instead, fibrotic scar tissue forms in the injured site (fibrosis), and the heart functions are compromised, leading to heart failure.

Currently, a number of methods have been studied to repair a broken heart by regenerating cardiomyocytes. These new inventions benefit from the recent advances in biotechnology, especially stem cell biology, regenerative medicine, and tissue engineering. Hopefully, this can bring new therapeutic options to patients with cardiovascular diseases in the near future.

Studies suggested that even in adults, a very small population of progenitor cells reside in the heart and are capable of producing new cardiac myocytes. These cells, known as cardiac stem cells, may not be able to regenerate fast enough to repair a large area of damaged myocardium naturally in humans. However, these cells have shown to be powerful in regenerative capability in other species, like zebrafish.

Scientists believe that once we understand these cardiac progenitors more, we may isolate and expand these cells in quantity, and transplant them to repair damaged heart tissues. For example, we already learned that these cardiac stem cells express cell surface markers like c-Kit (sca-1 in mouse) and aggregate into cardiac spheres.

[In this figure] Multiple different stem cell populations have been described in the adult heart, including c-Kit and Sca-1 cells that were shown to be cardiac progenitors.Photo source: https://dev.biologists.org/content/143/8/1242

Induced pluripotent stem cell (iPSC) technology is a huge revolution in biotechnology. Patients cells (easily obtained from skin biopsy or even urine) can be converted into powerful pluripotent stem cells that have unlimited proliferation capacity and can differentiate any cell type of our body. This eliminates the need to use human embryos for this purpose. Furthermore, these cells are autologous, meaning they wont be rejected by the immune system after transplantation.

Using iPSC technology, researchers have been able to obtain unlimited amounts of functional cardiomyocytes for cell transplantation. Basically, they control the Wnt pathway to convert iPSCs to mesodermal progenitor cells, then play with several growth factors to direct the cardiac vascular progenitors (Flk1+). Following glucose starvation, pure cardiomyocytes can be selected. You can even see these cells beating in the dish.

Therapeutic implantation of iPSC-derived cardiomyocytes progresses pretty fast. We already witnessed successful cell engraftment and cardiac repairing in non-human primates and human patients.

[In this video] Heart cells derived from iPSC stem cells beating in a cell culture dish.

Cardiac fibroblasts make up a significant portion of the total cardiac cells. In the injured heart, these fibroblasts will become active myofibroblasts and form scar tissue. Myofibroblasts survive very well and have ability to coupled with neighboring cells; therefore, myofibroblasts have been shown to be particularly ideal for direct reprogramming to convert them into cells that resemble cardiomyocytes.

Over the past decade, a number of studies have been successfully conducted, reprogramming fibroblasts into cardiomyocyte-like cells. In principle, scientists expressed transcription factors (i.e., Gata4, Mef2c, and Tbx5) that play critical roles in cardiomyocyte differentiation to force the conversion of fibroblasts. Ideally, these genes can be delivered directly to the injured heart via viruses or nanoparticles to perform in situ reprogramming.

Scientists also put their efforts into how to stimulate mature cardiomyocytes to proliferate again (Mature cardiomyocytes typically do not proliferate.) This strategy, called cell cycle re-entry, recently gained success by screening many cell-cycle regulators. Scientists found a combination of cyclin-dependent kinases (CDK) and cyclins, or regulators of the Hippo-YAP signaling pathway can do so. These findings reveal the possibility to efficiently unlock the proliferative potential in cells that had terminally exited the cell cycle.

[In this figure] Potential cardiac regenerative therapies.Photo source: https://www.nature.com/articles/s41536-017-0024-1

Cardiomyocytes can be observed by staining of histological sections of the heart. Since the heart is a 3-D organ, make sure you cut the heart at the right angle.

[In this figure] (Left) A longitudinal section through both ventricles should be made from the base to the apex of the heart. (Right) A cross-section of the heart. H&E staining.(Ao: aorta, At: atrium, Lv: left ventricle, Rv: right ventricle)

Common histological staining for heart tissues includes Hematoxylin and eosin (H&E) and Massons trichrome staining.

[In this figure] A cross section of mouse heart stained by Massons trichrome. Blue color indicates the formation of fibrous scar tissues in the infarction area.

Read more from the original source:
Cardiomyocytes (Cardiac Muscle Cells) - Structure ...

Cardiac Stem Cells Comments Off on Cardiomyocytes (Cardiac Muscle Cells) – Structure … | January 3rd, 2022

The International Space Station is the world's most extreme and expensive scientific laboratory. In its more than 20 years of operations it has housed thousands of experiments, providing fascinating insights into the effects of microgravity on the human body, cultured cells or various materials and chemical processes. Here are the most interesting findings that the space station delivered in 2021.

Stem cells are sometimes seen as the holy grail of future medicine. Capable of almost endlessly regenerating and turning themselves into all sorts of cells, stem cells are abundant in young bodies but lose their vigor as we age. There are various types of stem cells. Those found in embryos, also called the pluripotent stem cells, can give rise to all kinds of cells in the human body. But stem cells exist in adult bodies too, ensuring the ability of various organs to repair themselves.

A recent experiment flown on the International Space Station found that in the weightless environment, stem cells from the human heart improved their ability to regenerate, survive and proliferate.

The effects were observed in both adult and neonatal stem cells. The discovery, part of NASA's Cardiac Stem Cells research project, is good news for the future of regenerative medicine as it shows that it is possible to kick adult heart stem cells into better action. That is to increase their 'stemness', their ability to regenerate, proliferate and create new types of cells that a damaged organ might need. Regenerative medicine hopes to one day be able to engineer tissue to repair and replace failing organs and cells. The study was published in the International Journal of Molecular Sciences.

Related: What does space do to the human body? 29 studies investigate the effects of exploration

Microgravity is bad news for bones. The lack of mechanical loading tells the body to stop maintaining these important support structures since they don't seem to be needed. When astronauts return to Earth, they suffer from serious bone loss.

The good news is, that just like on Earth, exercising in space seems to keep the body fit, including the bones. A new study published in the British Journal of Sports Medicine revealed that crew members who increased their resistance training during their space missions were more likely to preserve their bone strength.

The study, part of NASA's Biochem Profile and the Canadian Space Agency's TBone investigations, also found that bone loss in some astronauts could be predicted by the elevation of certain biomarkers before their flight. These biomarkers, found in the astronauts' blood and urine, together with the astronauts' exercise history could help space surgeons identify astronauts at greater risk for bone loss.

Microbes can efficiently extract valuable metals from lunar and martian rocks in space, a recent experiment by the European Space Agency (ESA) revealed. The experiment, called Biorock, used microorganisms to extract the metal element vanadium from basalt, which can be commonly found on the moon and Mars.

The microbes extracted 283% more vanadium while on the space station than on Earth. Biomining is a cheaper and more environmentally friendly alternative to chemical extraction of important materials from ores, a process that usually relies on harsh chemicals and requires a lot of energy. Using biomining in space will surely come handy to future Mars and moon colonists as they will be able to get raw materials for making tools, spacecraft parts and other equipment.

A European instrument called the Atmosphere-Space Interactions Monitor (ASIM) has provided new insights into the genesis of some little understood phenomena in Earth's atmosphere. Used to study severe thunderstorms and their atmospheric effects, ASIM previously helped shed light on the generation of high-energy terrestrial gamma-ray flashes (TGFs), the most energetic natural phenomena on Earth that accompany lightings during thunderstorms.

But more recently, the instrument studied the so-called blue jets, which are essentially upward shooting bursts of lighting generated by disturbances of positively and negatively charged regions in the tops of the clouds. Blue jets, which get their characteristic blue color from nitrogen ions, can shoot up to altitudes of 30 miles (50 kilometers) in less than a second.

Scientists found that the blue jets are generated by "blue bangs," short discharges in the upper layers of storm clouds. The mechanism behind these blue jets appears to be somewhat different from that behind normal lightning that we can observe on the ground.

Astronauts on the International Space Station experimented with making cement in space and found that although it creates somewhat different microstructures than on Earth, it works. The experiment, called Microgravity Investigation of Cement Solidification (MICS), involved mixing cement powders with various additives and different amounts of water.

In the latest round of experiments, a mixture of tricalcium aluminate and gypsum showed interesting results.

In the future, these "made in space" cement blends could be used to build stations on Mars or the moon. Cement is used to make concrete, which has excellent shielding properties against cosmic radiation. It is also strong enough to protect against impacting meteorites.

And to make things easy, future Mars and moon colonists could actually 3D-print structures from concrete made from lunar and martian soils in a 3D printer similar to the Additive Manufacturing Facility that is currently on the space station.

New space station research has shown that the technology used to shield astronauts from dangerous space radiation can be made even more efficient in the future using a mineral called colemanite. This boron-rich mineral is a type of borax that forms as a deposit during evaporation of alkaline water.

An experiment by the Japan Aerospace Exploration Agency (JAXA) exposed several pieces of a polymer material to space conditions outside the International Space Station. The polymer sample treated with colemanite suffered almost no radiation damage and looked nearly indistinguishable from a sample that was not exposed to space. The researchers published their results in the Journal of Applied Polymer Science in July.

In the future, colemanite could be used to treat satellites, space station exteriors or even high altitude planes, NASA said in a statement.

Astronauts and cosmonauts in space frequently suffer from changes to the structure of their veins, especially in their legs. A study by the Russian space agency Roscosmos, however, found that these changes can be somewhat prevented by exercise and can be reversed post-flight if the space travellers have enough time off between missions.

The veins of the 11 cosmonauts that participated in this study, published in the journal Experimental and Theoretical Research, didn't show worse damage after the second flight compared to the first. The spacefarers had breaks of about 4 years between their missions.

Follow Tereza Pultarova on Twitter @TerezaPultarova. Follow us on Twitter @Spacedotcom and on Facebook.

Original post:
Here's 7 things the International Space Station taught us in 2021 - Space.com

Cardiac Stem Cells Comments Off on Here’s 7 things the International Space Station taught us in 2021 – Space.com | January 3rd, 2022

Successful stem cell therapies are no science fiction anymore

Stem cells from the umbilical cord are special. They are young, potent, and viable. Numerous clinical studies are being conducted worldwide researching the suitability of stem cells for the regeneration of damaged tissues after accidents, degenerative diseases like e.g. slipped intervertebral discs, or cancer treatment. Like Vita 34, many health professionals and scientists believe in the potential of stem cells: Umbilical cord blood and tissue that is rich in stem cells will be an important therapeutic option in future medicine.

Stem cell therapies give hope to many patients and are an important therapeutic option.

Vita 34 actively participates in this development. We are involved with our in-house department of research and development and in collaboration with leading universities and research institutions all over Europe in basic and application research. Vita 34-customers benefit from this knowhow: The expanding knowledge in stem cell research makes your childs stem cell deposits more valuable every day.

Applications of stem cells in modern medicine

Stem cells have been applied in the treatment of serious diseases for more than 55 years. They are applied especially to treat cancers, which require high-dose chemotherapy within the scope of medical care. The patients own stem cells are extracted from bone marrow or peripheral blood prior to high-dose chemotherapy, stored temporarily and transplanted after the treatment in order to minimize the side effects of the aggressive chemotherapy and to support the regeneration of destroyed cells.

Applications of stem cells in modern medicine

Stem cells have been applied in the treatment of serious diseases for more than 55 years. They are applied especially to treat cancers, which require high-dose chemotherapy within the scope of medical care. The patients own stem cells are extracted from bone marrow or peripheral blood prior to high-dose chemotherapy, stored temporarily and transplanted after the treatment in order to minimize the side effects of the aggressive chemotherapy and to support the regeneration of destroyed cells.

Besides cancer, several 100,000 people come down with common diseases like dementia, which belongs to the neurodegenerative diseases, cardiac infarction, stroke, arthritis, or diabetes every year. The lifelong therapy causes enormous costs in the health care system. Stem cell therapy offers great potential for the treatment of such diseases. Experts expect that every seventh person up to the age of 70 will need a therapy based on stem cells in the future to regenerate sick or aged cells and tissues.

To be able to store stem cells does not automatically mean to apply stem cells. The transplantation of stem cells requires enormous knowledge and experience. So far, 51 stem cell deposits stored with Vita 34 have been applied in practice. They were already applied in the treatment of cancers (like leukemia and neuroblastoma), hematopoietic disorders (like aplastic anemia or beta thalassemia), immune defects (like SCID or Wiskott Aldrich syndrome), infantile brain damage, and infantile diabetes type 1.

"Stem cells are called the building blocks of life, because an entire human being develops from the very first stem cell. The potential of stem cells therefore is enormous and already provides for entirely new therapeutic options in the field of individualized, regenerative medicine.

By the way, as measured by applications in clinical treatment attempts and studies, Vita 34 is the most experienced private stem cell bank in Europe.

Scientists expect further findings and developments in the field of stem cell therapy in the next years.

Areas of application of stem cells.

Stem cells have already been applied successfully for:

In clinical studies and treatment attempts, stem cell therapies are tested with the following indications:

More about the topic

Is each stem cell like the other? No, experts know different types of stem cells. Embryonic stem cells differ in their properties from adult stem cells, and omnipotent stem cells can do more than unipotent stem cells. And what is the difference again between mesenchymal stem cells and hematopoietic stem cells? Read the overview to learn all that.

Stem cells age with us and can suffer damages from diseases and environmental influences. Stem cells from the umbilical cord are different. They are extracted safely and easily right after birth and frozen by means of cryo-preservation. They do not age and remain untroubled by environmental influences and diseases.

Umbilical cord blood is much too good to throw away. That is why many parents want to store their offsprings umbilical cord blood for the future. They are often faced with the question, whether to donate their childs stem cells publicly or store them privately to take individual precautions. Vita 34 offers parents the option VitaPlusDonation to combine both possibilities.

As a precaution, store either the umbilical cord blood or the umbilical cord tissue after the birth of your child. We offer both at different prices and terms. Also a financing is possible. Optionally, you can also donate the umbilical cord blood.

Storing cord blood and cord tissue

Our guidebook for parents contains comprehensive information on the subject of cord blood storage. Order the guidebook by mail at no charge and without any obligation.

Free consultation

Mo Fr 8.00 am 7.00 pm

We use cookies to store your login data, to log in securely, to collect statistical data, to optimize website functions, as well as for online marketing and remarketing, in order to offer you a more pleasant experience overall. Click on "Accept" to accept cookies or click on "Further information" to get a detailed description of the types of cookies we use and information about the corresponding functions. Via the link "Cookies" at the end of each website you can revoke or reset your settings at any time. You can find more information in our data privacy statement.

Accept all

Save Selection

Accept only necessary cookies

More information

Cookie details Data privacy satement Imprint

Read this article:
Application of stem cells Vita 34

Cardiac Stem Cells Comments Off on Application of stem cells Vita 34 | December 23rd, 2021

Stem cells are special human cells that can develop into many different types of cells, from muscle cells to brain cells.

Stem cells also have the ability to repair the damaged cells.These cells have strong healing power. They can evolve into any types of cell.

Researches are going on and it is believed that stem cell therapies can cure ailments like paralysis and Alzheimers as well. Let us have a detailed look at stem cells, its types and functions.

Also Read: Gene Therapy

Stem cells are of the following different types:

The fertilized egg begins to divide immediately. All the cells in the young embryo are totipotent cells. These cells form a hollow structure within a few days. Cells in one region group together to form the inner cell mass. This contains pluripotent cells that make up the developing foetus.

The embryonic stem cells can be further classified as:

These stem cells are obtained from developed organs and tissues. They can repair and replace the damaged tissues in the region where they are located. For eg., hematopoietic stem cells are found in the bone marrow. These stem cells are used in bone marrow transplants to treat specific types of cancers.

These cells have been tested and arranged by converting tissue-specific cells into embryonic cells in the lab. These cells are accepted as an important tool to learn about normal development, onset and progression of the disease and also helpful in testing various drugs. These stem cells share the same characteristics as embryonic cells do. They also have the potential to give rise to all the different types of cells in the human body.

These cells are mainly formed from the connective tissues surrounding other tissues and organs known as the stroma. These mesenchymal stem cells are accurately called stromal cells. The first mesenchymal stem cells were found in the bone marrow that is capable of developing bones, fat cells, and cartilage.

There are different mesenchymal stem cells that are used to treat various diseases as they have been developed from different tissues of the human body. The characteristics of mesenchymal stem cells depend on the organ from where they originate.

Following are the important applications of stem cells:

This is the most important application of stem cells. The stem cells can be used to grow a specific type of tissue or organ. This can be helpful in kidney and liver transplants. The doctors have already used the stem cells from beneath the epidermis to develop skin tissue that can repair severe burns or other injuries by tissue grafting.

A team of researchers have developed blood vessels in mice using human stem cells. Within two weeks of implantation, the blood vessels formed their network and were as efficient as the natural vessels.

Stem cells can also treat diseases such as Parkinsons disease and Alzheimers. These can help to replenish the damaged brain cells. The researchers have tried to differentiate embryonic stem cells into these type of cells and make it possible to treat diseases.

The adult hematopoietic stem cells are used to treat cancers, sickle cell anaemia, and other immunodeficiency diseases. These stem cells can be used to produce red blood cells and white blood cells in the body.

Stem Cells originate from different parts of the body. Adult stem cells can be found in specific tissues in the human body. Matured cells are specialized to conduct various functions. Generally, these cells can develop the kind of cells found in tissues where they reside.

Embryonic Stem Cells are derived from 5-day old blastocysts that develop into embryos and are pluripotent in nature. These cells can develop any type of cell and tissue in the body. These cells have the potential to regenerate all the cells and tissues that have been lost because of any kind of injury or disease.

To know more about stem cells, its types, applications and sources, keep visiting BYJUS website.

Read the original post:
What are Stem Cells? - Types, Applications and Sources

Cardiac Stem Cells Comments Off on What are Stem Cells? – Types, Applications and Sources | December 23rd, 2021

While stem cell therapies have been touted as miracle cures, data indicates that there are still hurdles keeping them out of the clinic.

Image credit: Getty Images/Hero Images

Stem cells have the unique ability to develop into a number of different and specialized cells. They can be thought of as the bodys raw material, ready for use when needed. With this comes their potential use in medicine as a means of repairing diseased or damaged tissue.

Consequently, stem cell therapy has generated intense interest, with a staggering 2600 clinical studies registered in the last 10 years alone. However, while these studies performed in both humans and animals have provided insight into potential benefits, the overall consensus is that they have yet to live up to their initial promise.

Currently, the only stem cell treatments that have FDA approval consist of blood-forming stem cells or hematopoietic progenitor cells derived from umbilical cord blood. These help restore blood-forming stem cells in cancer patients whose bone marrow cells have been destroyed by high doses of chemo-or radiation therapy.

Outside of this, clinical translation has seemingly been hampered. Its therefore important to ask: Are stem cells a source of hope or are they just hype?

The problem within this realm of scientific literature is conflicting study outcomes, says Hang Thu Ta, professor at Griffith University in Queensland, Australia and expert in biomedical engineering in the context of diagnosing and treating life-threatening diseases. Many studies demonstrate the desired, beneficial outcomes, but many others also demonstrate only modest or even negligible benefits.

For example, a review from 2016 exploring progress in cardiac stem cell regenerative therapy using adult stem cells found a lack of significant benefit. The analysis included 29 randomized clinical trials and seven systematic reviews and meta-analyses.

This could be explained by variations in trial methodology or discrepancies in reporting, but a major issue within the field is a lingering inability to track stem cells once they enter the body.

In a typical procedure, a large number of cells are infused through a single injection and repeated doses are given accordingly to maintain optimal therapeutic levels. Guided by biological cues or signals (like specific cytokines or growth factors), stem cells are expected to travel towards the diseased or injured location where they would stimulate regeneration of healthy tissue.

This happens naturally in the body, however, more often than not, researchers cannot definitively track their cells distribution and accumulation after they are transplanted artificially, said Shehzahdi Shebbrin Moonshi, a research fellow at the Queensland Micro- and Nanotechnology Centre at Griffith University and co-author of a recent study with Ta exploring the challenges that stem cell research is facing.

This puts a lot of guesswork into optimizing regimens and troubleshooting problems. Researchers are hard pressed to answer questions such as, where do the cells actually go? Do they migrate to the expected location? How long does this take? How many cells reach the target location?

The answers to all these questions cannot be known unless stem cells are monitored in real time after implantation. If stem cells arent where they need to be, then therapeutic effects aside, they cannot be properly exploited.

To solve this problem, clinicians and researchers need to be able to track stem cells in the body safely over prolonged periods of time.

Developments in this area have been growing in recent years. To this end, MRI is emerging as one of the safest and most suitable medical imaging techniques for this purpose. This is made possible using chemical tracers that make labelled stem cells visible in an MRI scan.

While there are many clinical trials being designed to monitor stem cells in the treatment of various diseases, MRI is [currently being] utilized in these studies as an imaging modality to monitor treatment efficacy and not to track implanted cells, said Ta. Therefore, it is crucial that we develop reliable and safe MRI tracers so we can get to the bottom of this.

There have been several preclinical studies involving the development of novel MRI cell tracers. These have included iron oxide nanoparticles and fluorinated nanoparticles that are attached to the cells.

Only one has really shown promise and has progressed to Phase I clinical trials, where iron-oxide labelled mesenchymal stromal cells were successfully tracked in patients with chronic heart disease, said Moonshi. The treatment was found to be safe, and cells were detectable at injection sites up to 14 days after transplantation.

MRI is even being combined with new technologies, such as optogenetics, which employs laser light to stimulate specific cells that have been rendered sensitive to particular frequencies of light.

Whilst MRI itself presents as a suitable imaging technique that allows visualization and monitoring of stem cells, a single modality is insufficient to obtain all vital data of implanted cells, said Moonshi. Therefore, combining different imaging modalities to track stem cells can overcome shortcomings involved with individual techniques.

This would provide scientists with a better understanding of effective dose, number of cells injected, and how effective they are at reaching their target location, added Ta. Going forward, this will allow researchers to explore best practices for achieving the greatest therapeutic outcome.

This article was contributed to by Shehzahdi Moonshi and Hang Ta

Reference: Shehzahdi Shebbrin Moonshi, Yuao Wu, Hang Thu Ta. Visualising Stem Cells In Vivo using Magnetic Resonance Imaging, WIRES Nanomed. Nanobiotechnol (2021). DOI: 10.1002/wnan.1760

See the rest here:
Are stem cells just hype? - Advanced Science News

Cardiac Stem Cells Comments Off on Are stem cells just hype? – Advanced Science News | December 23rd, 2021

Int J Cell Biol. 2016; 2016: 6940283.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Academic Editor: Paul J. Higgins

Received 2016 Mar 13; Accepted 2016 Jun 5.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of specific tissue and/or organ of the patients suffering with severe injuries or chronic disease conditions, in the state where bodies own regenerative responses do not suffice [1]. In the present scenario donated tissues and organs cannot meet the transplantation demands of aged and diseased populations that have driven the thrust for search for the alternatives. Stem cells are endorsed with indefinite cell division potential, can transdifferentiate into other types of cells, and have emerged as frontline regenerative medicine source in recent time, for reparation of tissues and organs anomalies occurring due to congenital defects, disease, and age associated effects [1]. Stem cells pave foundation for all tissue and organ system of the body and mediates diverse role in disease progression, development, and tissue repair processes in host. On the basis of transdifferentiation potential, stem cells are of four types, that is, (1) unipotent, (2) multipotent, (3) pluripotent, and (4) totipotent [2]. Zygote, the only totipotent stem cell in human body, can give rise to whole organism through the process of transdifferentiation, while cells from inner cells mass (ICM) of embryo are pluripotent in their nature and can differentiate into cells representing three germ layers but do not differentiate into cells of extraembryonic tissue [2]. Stemness and transdifferentiation potential of the embryonic, extraembryonic, fetal, or adult stem cells depend on functional status of pluripotency factors like OCT4, cMYC, KLF44, NANOG, SOX2, and so forth [35]. Ectopic expression or functional restoration of endogenous pluripotency factors epigenetically transforms terminally differentiated cells into ESCs-like cells [3], known as induced pluripotent stem cells (iPSCs) [3, 4]. On the basis of regenerative applications, stem cells can be categorized as embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and iPSCs (; ). The transplantation of stem cells can be autologous, allogenic, and syngeneic for induction of tissue regeneration and immunolysis of pathogen or malignant cells. For avoiding the consequences of host-versus-graft rejections, tissue typing of human leucocyte antigens (HLA) for tissue and organ transplant as well as use of immune suppressant is recommended [6]. Stem cells express major histocompatibility complex (MHC) receptor in low and secret chemokine that recruitment of endothelial and immune cells is enabling tissue tolerance at graft site [6]. The current stem cell regenerative medicine approaches are founded onto tissue engineering technologies that combine the principles of cell transplantation, material science, and microengineering for development of organoid; those can be used for physiological restoration of damaged tissue and organs. The tissue engineering technology generates nascent tissue on biodegradable 3D-scaffolds [7, 8]. The ideal scaffolds support cell adhesion and ingrowths, mimic mechanics of target tissue, support angiogenesis and neovascularisation for appropriate tissue perfusion, and, being nonimmunogenic to host, do not require systemic immune suppressant [9]. Stem cells number in tissue transplant impacts upon regenerative outcome [10]; in that case prior ex vivo expansion of transplantable stem cells is required [11]. For successful regenerative outcomes, transplanted stem cells must survive, proliferate, and differentiate in site specific manner and integrate into host circulatory system [12]. This review provides framework of most recent (; Figures ) advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells as the tool of regenerative applications in wildlife conservation.

Promises of stem cells in regenerative medicine: the six classes of stem cells, that is, embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and induced pluripotent stem cells (iPSCs), have many promises in regenerative medicine and disease therapeutics.

ESCs in regenerative medicine: ESCs, sourced from ICM of gastrula, have tremendous promises in regenerative medicine. These cells can differentiate into more than 200 types of cells representing three germ layers. With defined culture conditions, ESCs can be transformed into hepatocytes, retinal ganglion cells, chondrocytes, pancreatic progenitor cells, cone cells, cardiomyocytes, pacemaker cells, eggs, and sperms which can be used in regeneration of tissue and treatment of disease in tissue specific manner.

TSPSCs in regenerative medicine: tissue specific stem and progenitor cells have potential to differentiate into other cells of the tissue. Characteristically inner ear stem cells can be transformed into auditory hair cells, skin progenitors into vascular smooth muscle cells, mesoangioblasts into tibialis anterior muscles, and dental pulp stem cells into serotonin cells. The 3D-culture of TSPSCs in complex biomaterial gives rise to tissue organoids, such as pancreatic organoid from pancreatic progenitor, intestinal tissue organoids from intestinal progenitor cells, and fallopian tube organoids from fallopian tube epithelial cells. Transplantation of TSPSCs regenerates targets tissue such as regeneration of tibialis muscles from mesoangioblasts, cardiac tissue from AdSCs, and corneal tissue from limbal stem cells. Cell growth and transformation factors secreted by TSPSCs can change cells fate to become other types of cell, such that SSCs coculture with skin, prostate, and intestine mesenchyme transforms these cells from MSCs into epithelial cells fate.

MSCs in regenerative medicine: mesenchymal stem cells are CD73+, CD90+, CD105+, CD34, CD45, CD11b, CD14, CD19, and CD79a cells, also known as stromal cells. These bodily MSCs represented here do not account for MSCs of bone marrow and umbilical cord. Upon transplantation and transdifferentiation these bodily MSCs regenerate into cartilage, bones, and muscles tissue. Heart scar formed after heart attack and liver cirrhosis can be treated from MSCs. ECM coating provides the niche environment for MSCs to regenerate into hair follicle, stimulating hair growth.

UCSCs in regenerative medicine: umbilical cord, the readily available source of stem cells, has emerged as futuristic source for personalized stem cell therapy. Transplantation of UCSCs to Krabbe's disease patients regenerates myelin tissue and recovers neuroblastoma patients through restoring tissue homeostasis. The UCSCs organoids are readily available tissue source for treatment of neurodegenerative disease. Peritoneal fibrosis caused by long term dialysis, tendon tissue degeneration, and defective hyaline cartilage can be regenerated by UCSCs. Intravenous injection of UCSCs enables treatment of diabetes, spinal myelitis, systemic lupus erythematosus, Hodgkin's lymphoma, and congenital neuropathies. Cord blood stem cells banking avails long lasting source of stem cells for personalized therapy and regenerative medicine.

BMSCs in regenerative medicine: bone marrow, the soft sponge bone tissue that consisted of stromal, hematopoietic, and mesenchymal and progenitor stem cells, is responsible for blood formation. Even halo-HLA matched BMSCs can cure from disease and regenerate tissue. BMSCs can regenerate craniofacial tissue, brain tissue, diaphragm tissue, and liver tissue and restore erectile function and transdifferentiation monocytes. These multipotent stem cells can cure host from cancer and infection of HIV and HCV.

iPSCs in regenerative medicine: using the edge of iPSCs technology, skin fibroblasts and other adult tissues derived, terminally differentiated cells can be transformed into ESCs-like cells. It is possible that adult cells can be transformed into cells of distinct lineages bypassing the phase of pluripotency. The tissue specific defined culture can transform skin cells to become trophoblast, heart valve cells, photoreceptor cells, immune cells, melanocytes, and so forth. ECM complexation with iPSCs enables generation of tissue organoids for lung, kidney, brain, and other organs of the body. Similar to ESCs, iPSCs also can be transformed into cells representing three germ layers such as pacemaker cells and serotonin cells.

Stem cells in wildlife conservation: tissue biopsies obtained from dead and live wild animals can be either cryopreserved or transdifferentiated to other types of cells, through culture in defined culture medium or in vivo maturation. Stem cells and adult tissue derived iPSCs have great potential of regenerative medicine and disease therapeutics. Gonadal tissue procured from dead wild animals can be matured, ex vivo and in vivo for generation of sperm and egg, which can be used for assistive reproductive technology oriented captive breeding of wild animals or even for resurrection of wildlife.

Application of stem cells in regenerative medicine: stem cells (ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs) have diverse applications in tissue regeneration and disease therapeutics.

For the first time in 1998, Thomson isolated human ESCs (hESCs) [13]. ESCs are pluripotent in their nature and can give rise to more than 200 types of cells and promises for the treatment of any kinds of disease [13]. The pluripotency fate of ESCs is governed by functional dynamics of transcription factors OCT4, SOX2, NANOG, and so forth, which are termed as pluripotency factors. The two alleles of the OCT4 are held apart in pluripotency state in ESCs; phase through homologues pairing during embryogenesis and transdifferentiation processes [14] has been considered as critical regulatory switch for lineage commitment of ESCs. The diverse lineage commitment potential represents ESCs as ideal model for regenerative therapeutics of disease and tissue anomalies. This section of review on ESCs discusses transplantation and transdifferentiation of ESCs into retinal ganglion, hepatocytes, cardiomyocytes, pancreatic progenitors, chondrocytes, cones, egg sperm, and pacemaker cells (; ). Infection, cancer treatment, and accidents can cause spinal cord injuries (SCIs). The transplantation of hESCs to paraplegic or quadriplegic SCI patients improves body control, balance, sensation, and limbal movements [15], where transplanted stem cells do homing to injury sites. By birth, humans have fixed numbers of cone cells; degeneration of retinal pigment epithelium (RPE) of macula in central retina causes age-related macular degeneration (ARMD). The genomic incorporation of COCO gene (expressed during embryogenesis) in the developing embryo leads lineage commitment of ESCs into cone cells, through suppression of TGF, BMP, and Wnt signalling pathways. Transplantation of these cone cells to eye recovers individual from ARMD phenomenon, where transplanted cone cells migrate and form sheet-like structure in host retina [16]. However, establishment of missing neuronal connection of retinal ganglion cells (RGCs), cones, and PRE is the most challenging aspect of ARMD therapeutics. Recently, Donald Z Jacks group at John Hopkins University School of Medicine has generated RGCs from CRISPER-Cas9-m-Cherry reporter ESCs [17]. During ESCs transdifferentiation process, CRIPER-Cas9 directs the knock-in of m-Cherry reporter into 3UTR of BRN3B gene, which is specifically expressed in RGCs and can be used for purification of generated RGCs from other cells [17]. Furthermore, incorporation of forskolin in transdifferentiation regime boosts generation of RGCs. Coaxing of these RGCs into biomaterial scaffolds directs axonal differentiation of RGCs. Further modification in RGCs generation regime and composition of biomaterial scaffolds might enable restoration of vision for ARMD and glaucoma patients [17]. Globally, especially in India, cardiovascular problems are a more common cause of human death, where biomedical therapeutics require immediate restoration of heart functions for the very survival of the patient. Regeneration of cardiac tissue can be achieved by transplantation of cardiomyocytes, ESCs-derived cardiovascular progenitors, and bone marrow derived mononuclear cells (BMDMNCs); however healing by cardiomyocytes and progenitor cells is superior to BMDMNCs but mature cardiomyocytes have higher tissue healing potential, suppress heart arrhythmias, couple electromagnetically into hearts functions, and provide mechanical and electrical repair without any associated tumorigenic effects [18, 19]. Like CM differentiation, ESCs derived liver stem cells can be transformed into Cytp450-hepatocytes, mediating chemical modification and catabolism of toxic xenobiotic drugs [20]. Even today, availability and variability of functional hepatocytes are a major a challenge for testing drug toxicity [20]. Stimulation of ESCs and ex vivo VitK12 and lithocholic acid (a by-product of intestinal flora regulating drug metabolism during infancy) activates pregnane X receptor (PXR), CYP3A4, and CYP2C9, which leads to differentiation of ESCs into hepatocytes; those are functionally similar to primary hepatocytes, for their ability to produce albumin and apolipoprotein B100 [20]. These hepatocytes are excellent source for the endpoint screening of drugs for accurate prediction of clinical outcomes [20]. Generation of hepatic cells from ESCs can be achieved in multiple ways, as serum-free differentiation [21], chemical approaches [20, 22], and genetic transformation [23, 24]. These ESCs-derived hepatocytes are long lasting source for treatment of liver injuries and high throughput screening of drugs [20, 23, 24]. Transplantation of the inert biomaterial encapsulated hESCs-derived pancreatic progenitors (CD24+, CD49+, and CD133+) differentiates into -cells, minimizing high fat diet induced glycemic and obesity effects in mice [25] (). Addition of antidiabetic drugs into transdifferentiation regime can boost ESCs conservation into -cells [25], which theoretically can cure T2DM permanently [25]. ESCs can be differentiated directly into insulin secreting -cells (marked with GLUT2, INS1, GCK, and PDX1) which can be achieved through PDX1 mediated epigenetic reprogramming [26]. Globally, osteoarthritis affects millions of people and occurs when cartilage at joints wears away, causing stiffness of the joints. The available therapeutics for arthritis relieve symptoms but do not initiate reverse generation of cartilage. For young individuals and athletes replacement of joints is not feasible like old populations; in that case transplantation of stem cells represents an alternative for healing cartilage injuries [27]. Chondrocytes, the cartilage forming cells derived from hESC, embedded in fibrin gel effectively heal defective cartilage within 12 weeks, when transplanted to focal cartilage defects of knee joints in mice without any negative effect [27]. Transplanted chondrocytes form cell aggregates, positive for SOX9 and collagen II, and defined chondrocytes are active for more than 12wks at transplantation site, advocating clinical suitability of chondrocytes for treatment of cartilage lesions [27]. The integrity of ESCs to integrate and differentiate into electrophysiologically active cells provides a means for natural regulation of heart rhythm as biological pacemaker. Coaxing of ESCs into inert biomaterial as well as propagation in defined culture conditions leads to transdifferentiation of ESCs to become sinoatrial node (SAN) pacemaker cells (PCs) [28]. Genomic incorporation TBox3 into ESCs ex vivo leads to generation of PCs-like cells; those express activated leukocyte cells adhesion molecules (ALCAM) and exhibit similarity to PCs for gene expression and immune functions [28]. Transplantation of PCs can restore pacemaker functions of the ailing heart [28]. In summary, ESCs can be transdifferentiated into any kinds of cells representing three germ layers of the body, being most promising source of regenerative medicine for tissue regeneration and disease therapy (). Ethical concerns limit the applications of ESCs, where set guidelines need to be followed; in that case TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs can be explored as alternatives.

TSPSCs maintain tissue homeostasis through continuous cell division, but, unlike ESCs, TSPSCs retain stem cells plasticity and differentiation in tissue specific manner, giving rise to few types of cells (). The number of TSPSCs population to total cells population is too low; in that case their harvesting as well as in vitro manipulation is really a tricky task [29], to explore them for therapeutic scale. Human body has foundation from various types of TSPSCs; discussing the therapeutic application for all types is not feasible. This section of review discusses therapeutic application of pancreatic progenitor cells (PPCs), dental pulp stem cells (DPSCs), inner ear stem cells (IESCs), intestinal progenitor cells (IPCs), limbal progenitor stem cells (LPSCs), epithelial progenitor stem cells (EPSCs), mesoangioblasts (MABs), spermatogonial stem cells (SSCs), the skin derived precursors (SKPs), and adipose derived stem cells (AdSCs) (; ). During embryogenesis PPCs give rise to insulin-producing -cells. The differentiation of PPCs to become -cells is negatively regulated by insulin [30]. PPCs require active FGF and Notch signalling; growing more rapidly in community than in single cell populations advocates the functional importance of niche effect in self-renewal and transdifferentiation processes. In 3D-scaffold culture system, mice embryo derived PPCs grow into hollow organoid spheres; those finally differentiate into insulin-producing -cell clusters [29]. The DSPSCs, responsible for maintenance of teeth health status, can be sourced from apical papilla, deciduous teeth, dental follicle, and periodontal ligaments, have emerged as regenerative medicine candidate, and might be explored for treatment of various kinds of disease including restoration neurogenic functions in teeth [31, 32]. Expansion of DSPSCs in chemically defined neuronal culture medium transforms them into a mixed population of cholinergic, GABAergic, and glutaminergic neurons; those are known to respond towards acetylcholine, GABA, and glutamine stimulations in vivo. These transformed neuronal cells express nestin, glial fibrillary acidic protein (GFAP), III-tubulin, and voltage gated L-type Ca2+ channels [32]. However, absence of Na+ and K+ channels does not support spontaneous action potential generation, necessary for response generation against environmental stimulus. All together, these primordial neuronal stem cells have possible therapeutic potential for treatment of neurodental problems [32]. Sometimes, brain tumor chemotherapy can cause neurodegeneration mediated cognitive impairment, a condition known as chemobrain [33]. The intrahippocampal transplantation of human derived neuronal stem cells to cyclophosphamide behavioural decremented mice restores cognitive functions in a month time. Here the transplanted stem cells differentiate into neuronal and astroglial lineage, reduce neuroinflammation, and restore microglial functions [33]. Furthermore, transplantation of stem cells, followed by chemotherapy, directs pyramidal and granule-cell neurons of the gyrus and CA1 subfields of hippocampus which leads to reduction in spine and dendritic cell density in the brain. These findings suggest that transplantation of stem cells to cranium restores cognitive functions of the chemobrain [33]. The hair cells of the auditory system produced during development are not postmitotic; loss of hair cells cannot be replaced by inner ear stem cells, due to active state of the Notch signalling [34]. Stimulation of inner ear progenitors with -secretase inhibitor ({"type":"entrez-nucleotide","attrs":{"text":"LY411575","term_id":"1257853995","term_text":"LY411575"}}LY411575) abrogates Notch signalling through activation of transcription factor atonal homologue 1 (Atoh1) and directs transdifferentiation of progenitors into cochlear hair cells [34]. Transplantation of in vitro generated hair cells restores acoustic functions in mice, which can be the potential regenerative medicine candidates for the treatment of deafness [34]. Generation of the hair cells also can be achieved through overexpression of -catenin and Atoh1 in Lrg5+ cells in vivo [35]. Similar to ear progenitors, intestine of the digestive tract also has its own tissue specific progenitor stem cells, mediating regeneration of the intestinal tissue [34, 36]. Dysregulation of the common stem cells signalling pathways, Notch/BMP/TGF-/Wnt, in the intestinal tissue leads to disease. Information on these signalling pathways [37] is critically important in designing therapeutics. Coaxing of the intestinal tissue specific progenitors with immune cells (macrophages), connective tissue cells (myofibroblasts), and probiotic bacteria into 3D-scaffolds of inert biomaterial, crafting biological environment, is suitable for differentiation of progenitors to occupy the crypt-villi structures into these scaffolds [36]. Omental implementation of these crypt-villi structures to dogs enhances intestinal mucosa through regeneration of goblet cells containing intestinal tissue [36]. These intestinal scaffolds are close approach for generation of implantable intestinal tissue, divested by infection, trauma, cancer, necrotizing enterocolitis (NEC), and so forth [36]. In vitro culture conditions cause differentiation of intestinal stem cells to become other types of cells, whereas incorporation of valproic acid and CHIR-99021 in culture conditions avoids differentiation of intestinal stem cells, enabling generation of indefinite pool of stem cells to be used for regenerative applications [38]. The limbal stem cells of the basal limbal epithelium, marked with ABCB5, are essential for regeneration and maintenance of corneal tissue [39]. Functional status of ABCB5 is critical for survival and functional integrity of limbal stem cells, protecting them from apoptotic cell death [39]. Limbal stem cells deficiency leads to replacement of corneal epithelium with visually dead conjunctival tissue, which can be contributed by burns, inflammation, and genetic factors [40]. Transplanted human cornea stem cells to mice regrown into fully functional human cornea, possibly supported by blood eye barrier phenomena, can be used for treatment of eye diseases, where regeneration of corneal tissue is critically required for vision restoration [39]. Muscle degenerative disease like duchenne muscular dystrophy (DMD) can cause extensive thrashing of muscle tissue, where tissue engineering technology can be deployed for functional restoration of tissue through regeneration [41]. Encapsulation of mouse or human derived MABs (engineered to express placental derived growth factor (PDGF)) into polyethylene glycol (PEG) fibrinogen hydrogel and their transplantation beneath the skin at ablated tibialis anterior form artificial muscles, which are functionally similar to those of normal tibialis anterior muscles [41]. The PDGF attracts various cell types of vasculogenic and neurogenic potential to the site of transplantation, supporting transdifferentiation of mesoangioblasts to become muscle fibrils [41]. The therapeutic application of MABs in skeletal muscle regeneration and other therapeutic outcomes has been reviewed by others [42]. One of the most important tissue specific stem cells, the male germline stem cells or spermatogonial stem cells (SSCs), produces spermatogenic lineage through mesenchymal and epithets cells [43] which itself creates niche effect on other cells. In vivo transplantation of SSCs with prostate, skin, and uterine mesenchyme leads to differentiation of these cells to become epithelia of the tissue of origin [43]. These newly formed tissues exhibit all physical and physiological characteristics of prostate and skin and the physical characteristics of prostate, skin, and uterus, express tissue specific markers, and suggest that factors secreted from SSCs lead to lineage conservation which defines the importance of niche effect in regenerative medicine [43]. According to an estimate, more than 100 million people are suffering from the condition of diabetic retinopathy, a progressive dropout of vascularisation in retina that leads to loss of vision [44]. The intravitreal injection of adipose derived stem cells (AdSCs) to the eye restores microvascular capillary bed in mice. The AdSCs from healthy donor produce higher amounts of vasoprotective factors compared to glycemic mice, enabling superior vascularisation [44]. However use of AdSCs for disease therapeutics needs further standardization for cell counts in dose of transplant and monitoring of therapeutic outcomes at population scale [44]. Apart from AdSCs, other kinds of stem cells also have therapeutic potential in regenerative medicine for treatment of eye defects, which has been reviewed by others [45]. Fallopian tubes, connecting ovaries to uterus, are the sites where fertilization of the egg takes place. Infection in fallopian tubes can lead to inflammation, tissue scarring, and closure of the fallopian tube which often leads to infertility and ectopic pregnancies. Fallopian is also the site where onset of ovarian cancer takes place. The studies on origin and etiology of ovarian cancer are restricted due to lack of technical advancement for culture of epithelial cells. The in vitro 3D organoid culture of clinically obtained fallopian tube epithelial cells retains their tissue specificity, keeps cells alive, which differentiate into typical ciliated and secretory cells of fallopian tube, and advocates that ectopic examination of fallopian tube in organoid culture settings might be the ideal approach for screening of cancer [46]. The sustained growth and differentiation of fallopian TSPSCs into fallopian tube organoid depend both on the active state of the Wnt and on paracrine Notch signalling [46]. Similar to fallopian tube stem cells, subcutaneous visceral tissue specific cardiac adipose (CA) derived stem cells (AdSCs) have the potential of differentiation into cardiovascular tissue [47]. Systemic infusion of CA-AdSCs into ischemic myocardium of mice regenerates heart tissue and improves cardiac function through differentiation to endothelial cells, vascular smooth cells, and cardiomyocytes and vascular smooth cells. The differentiation and heart regeneration potential of CA-AdSCs are higher than AdSCs [48], representing CA-AdSCs as potent regenerative medicine candidates for myocardial ischemic therapy [47]. The skin derived precursors (SKPs), the progenitors of dermal papilla/hair/hair sheath, give rise to multiple tissues of mesodermal and/or ectodermal origin such as neurons, Schwann cells, adipocytes, chondrocytes, and vascular smooth muscle cells (VSMCs). VSMCs mediate wound healing and angiogenesis process can be derived from human foreskin progenitor SKPs, suggesting that SKPs derived VSMCs are potential regenerative medicine candidates for wound healing and vasculature injuries treatments [49]. In summary, TSPSCs are potentiated with tissue regeneration, where advancement in organoid culture (; ) technologies defines the importance of niche effect in tissue regeneration and therapeutic outcomes of ex vivo expanded stem cells.

MSCs, the multilineage stem cells, differentiate only to tissue of mesodermal origin, which includes tendons, bone, cartilage, ligaments, muscles, and neurons [50]. MSCs are the cells which express combination of markers: CD73+, CD90+, CD105+, CD11b, CD14, CD19, CD34, CD45, CD79a, and HLA-DR, reviewed elsewhere [50]. The application of MSCs in regenerative medicine can be generalized from ongoing clinical trials, phasing through different state of completions, reviewed elsewhere [90]. This section of review outlines the most recent representative applications of MSCs (; ). The anatomical and physiological characteristics of both donor and receiver have equal impact on therapeutic outcomes. The bone marrow derived MSCs (BMDMSCs) from baboon are morphologically and phenotypically similar to those of bladder stem cells and can be used in regeneration of bladder tissue. The BMDMSCs (CD105+, CD73+, CD34, and CD45), expressing GFP reporter, coaxed with small intestinal submucosa (SIS) scaffolds, augment healing of degenerated bladder tissue within 10wks of the transplantation [51]. The combinatorial CD characterized MACs are functionally active at transplantation site, which suggests that CD characterization of donor MSCs yields superior regenerative outcomes [51]. MSCs also have potential to regenerate liver tissue and treat liver cirrhosis, reviewed elsewhere [91]. The regenerative medicinal application of MSCs utilizes cells in two formats as direct transplantation or first transdifferentiation and then transplantation; ex vivo transdifferentiation of MSCs deploys retroviral delivery system that can cause oncogenic effect on cells. Nonviral, NanoScript technology, comprising utility of transcription factors (TFs) functionalized gold nanoparticles, can target specific regulatory site in the genome effectively and direct differentiation of MSCs into another cell fate, depending on regime of TFs. For example, myogenic regulatory factor containing NanoScript-MRF differentiates the adipose tissue derived MSCs into muscle cells [92]. The multipotency characteristics represent MSCs as promising candidate for obtaining stable tissue constructs through coaxed 3D organoid culture; however heterogeneous distribution of MSCs slows down cell proliferation, rendering therapeutic applications of MSCs. Adopting two-step culture system for MSCs can yield homogeneous distribution of MSCs in biomaterial scaffolds. For example, fetal-MSCs coaxed in biomaterial when cultured first in rotating bioreactor followed with static culture lead to homogeneous distribution of MSCs in ECM components [7]. Occurrence of dental carries, periodontal disease, and tooth injury can impact individual's health, where bioengineering of teeth can be the alternative option. Coaxing of epithelial-MSCs with dental stem cells into synthetic polymer gives rise to mature teeth unit, which consisted of mature teeth and oral tissue, offering multiple regenerative therapeutics, reviewed elsewhere [52]. Like the tooth decay, both human and animals are prone to orthopedic injuries, affecting bones, joint, tendon, muscles, cartilage, and so forth. Although natural healing potential of bone is sufficient to heal the common injuries, severe trauma and tumor-recession can abrogate germinal potential of bone-forming stem cells. In vitro chondrogenic, osteogenic, and adipogenic potential of MSCs advocates therapeutic applications of MSCs in orthopedic injuries [53]. Seeding of MSCs, coaxed into biomaterial scaffolds, at defective bone tissue, regenerates defective bone tissues, within fourwks of transplantation; by the end of 32wks newly formed tissues integrate into old bone [54]. Osteoblasts, the bone-forming cells, have lesser actin cytoskeleton compared to adipocytes and MSCs. Treatment of MSCs with cytochalasin-D causes rapid transportation of G-actin, leading to osteogenic transformation of MSCs. Furthermore, injection of cytochalasin-D to mice tibia also promotes bone formation within a wk time frame [55]. The bone formation processes in mice, dog, and human are fundamentally similar, so outcomes of research on mice and dogs can be directional for regenerative application to human. Injection of MSCs to femur head of Legg-Calve-Perthes suffering dog heals the bone very fast and reduces the injury associated pain [55]. Degeneration of skeletal muscle and muscle cramps are very common to sledge dogs, animals, and individuals involved in adventurous athletics activities. Direct injection of adipose tissue derived MSCs to tear-site of semitendinosus muscle in dogs heals injuries much faster than traditional therapies [56]. Damage effect treatment for heart muscle regeneration is much more complex than regeneration of skeletal muscles, which needs high grade fine-tuned coordination of neurons with muscles. Coaxing of MSCs into alginate gel increases cell retention time that leads to releasing of tissue repairing factors in controlled manner. Transplantation of alginate encapsulated cells to mice heart reduces scar size and increases vascularisation, which leads to restoration of heart functions. Furthermore, transplanted MSCs face host inhospitable inflammatory immune responses and other mechanical forces at transplantation site, where encapsulation of cells keeps them away from all sorts of mechanical forces and enables sensing of host tissue microenvironment, and respond accordingly [57]. Ageing, disease, and medicine consumption can cause hair loss, known as alopecia. Although alopecia has no life threatening effects, emotional catchments can lead to psychological disturbance. The available treatments for alopecia include hair transplantation and use of drugs, where drugs are expensive to afford and generation of new hair follicle is challenging. Dermal papillary cells (DPCs), the specialized MSCs localized in hair follicle, are responsible for morphogenesis of hair follicle and hair cycling. The layer-by-layer coating of DPCs, called GAG coating, consists of coating of geletin as outer layer, middle layer of fibroblast growth factor 2 (FGF2) loaded alginate, and innermost layer of geletin. GAG coating creates tissue microenvironment for DPCs that can sustain immunological and mechanical obstacles, supporting generation of hair follicle. Transplantation of GAG-coated DPCs leads to abundant hair growth and maturation of hair follicle, where GAG coating serves as ECM, enhancing intrinsic therapeutic potential of DPCs [58]. During infection, the inflammatory cytokines secreted from host immune cells attract MSCs to the site of inflammation, which modulates inflammatory responses, representing MSCs as key candidate of regenerative medicine for infectious disease therapeutics. Coculture of macrophages (M) and adipose derived MSCs from Leishmania major (LM) susceptible and resistant mice demonstrates that AD-MSCs educate M against LM infection, differentially inducing M1 and M2 phenotype that represents AD-MSC as therapeutic agent for leishmanial therapy [93]. In summary, the multilineage differentiation potential of MSCs, as well as adoption of next-generation organoid culture system, avails MSCs as ideal regenerative medicine candidate.

Umbilical cord, generally thrown at the time of child birth, is the best known source for stem cells, procured in noninvasive manner, having lesser ethical constraints than ESCs. Umbilical cord is rich source of hematopoietic stem cells (HSCs) and MSCs, which possess enormous regeneration potential [94] (; ). The HSCs of cord blood are responsible for constant renewal of all types of blood cells and protective immune cells. The proliferation of HSCs is regulated by Musashi-2 protein mediated attenuation of Aryl hydrocarbon receptor (AHR) signalling in stem cells [95]. UCSCs can be cryopreserved at stem cells banks (; ), in operation by both private and public sector organization. Public stem cells banks operate on donation formats and perform rigorous screening for HLA typing and donated UCSCs remain available to anyone in need, whereas private stem cell banks operation is more personalized, availing cells according to donor consent. Stem cell banking is not so common, even in developed countries. Survey studies find that educated women are more eager to donate UCSCs, but willingness for donation decreases with subsequent deliveries, due to associated cost and safety concerns for preservation [96]. FDA has approved five HSCs for treatment of blood and other immunological complications [97]. The amniotic fluid, drawn during pregnancy for standard diagnostic purposes, is generally discarded without considering its vasculogenic potential. UCSCs are the best alternatives for those patients who lack donors with fully matched HLA typing for peripheral blood and PBMCs and bone marrow [98]. One major issue with UCSCs is number of cells in transplant, fewer cells in transplant require more time for engraftment to mature, and there are also risks of infection and mortality; in that case ex vivo propagation of UCSCs can meet the demand of desired outcomes. There are diverse protocols, available for ex vivo expansion of UCSCs, reviewed elsewhere [99]. Amniotic fluid stem cells (AFSCs), coaxed to fibrin (required for blood clotting, ECM interactions, wound healing, and angiogenesis) hydrogel and PEG supplemented with vascular endothelial growth factor (VEGF), give rise to vascularised tissue, when grafted to mice, suggesting that organoid cultures of UCSCs have promise for generation of biocompatible tissue patches, for treating infants born with congenital heart defects [59]. Retroviral integration of OCT4, KLF4, cMYC, and SOX2 transforms AFSCs into pluripotency stem cells known as AFiPSCs which can be directed to differentiate into extraembryonic trophoblast by BMP2 and BMP4 stimulation, which can be used for regeneration of placental tissues [60]. Wharton's jelly (WJ), the gelatinous substance inside umbilical cord, is rich in mucopolysaccharides, fibroblast, macrophages, and stem cells. The stem cells from UCB and WJ can be transdifferentiated into -cells. Homogeneous nature of WJ-SCs enables better differentiation into -cells; transplantation of these cells to streptozotocin induced diabetic mice efficiently brings glucose level to normal [7]. Easy access and expansion potential and plasticity to differentiate into multiple cell lineages represent WJ as an ideal candidate for regenerative medicine but cells viability changes with passages with maximum viable population at 5th-6th passages. So it is suggested to perform controlled expansion of WJ-MSCS for desired regenerative outcomes [9]. Study suggests that CD34+ expression leads to the best regenerative outcomes, with less chance of host-versus-graft rejection. In vitro expansion of UCSCs, in presence of StemRegenin-1 (SR-1), conditionally expands CD34+ cells [61]. In type I diabetic mellitus (T1DM), T-cell mediated autoimmune destruction of pancreatic -cells occurs, which has been considered as tough to treat. Transplantation of WJ-SCs to recent onset-T1DM patients restores pancreatic function, suggesting that WJ-MSCs are effective in regeneration of pancreatic tissue anomalies [62]. WJ-MSCs also have therapeutic importance for treatment of T2DM. A non-placebo controlled phase I/II clinical trial demonstrates that intravenous and intrapancreatic endovascular injection of WJ-MSCs to T2DM patients controls fasting glucose and glycated haemoglobin through improvement of -cells functions, evidenced by enhanced c-peptides and reduced inflammatory cytokines (IL-1 and IL-6) and T-cells counts [63]. Like diabetes, systematic lupus erythematosus (SLE) also can be treated with WJ-MSCs transplantation. During progression of SLE host immune system targets its own tissue leading to degeneration of renal, cardiovascular, neuronal, and musculoskeletal tissues. A non-placebo controlled follow-up study on 40 SLE patients demonstrates that intravenous infusion of WJ-MSC improves renal functions and decreases systematic lupus erythematosus disease activity index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), and repeated infusion of WJ-MSCs protects the patient from relapse of the disease [64]. Sometimes, host inflammatory immune responses can be detrimental for HSCs transplantation and blood transfusion procedures. Infusion of WJ-MSC to patients, who had allogenic HSCs transplantation, reduces haemorrhage inflammation (HI) of bladder, suggesting that WJ-MSCs are potential stem cells adjuvant in HSCs transplantation and blood transfusion based therapies [100]. Apart from WJ, umbilical cord perivascular space and cord vein are also rich source for obtaining MSCs. The perivascular MSCs of umbilical cord are more primitive than WJ-MSCs and other MSCs from cord suggest that perivascular MSCs might be used as alternatives for WJ-MSCs for regenerative therapeutics outcome [101]. Based on origin, MSCs exhibit differential in vitro and in vivo properties and advocate functional characterization of MSCs, prior to regenerative applications. Emerging evidence suggests that UCSCs can heal brain injuries, caused by neurodegenerative diseases like Alzheimer's, Krabbe's disease, and so forth. Krabbe's disease, the infantile lysosomal storage disease, occurs due to deficiency of myelin synthesizing enzyme (MSE), affecting brain development and cognitive functions. Progression of neurodegeneration finally leads to death of babies aged two. Investigation shows that healing of peripheral nervous system (PNS) and central nervous system (CNS) tissues with Krabbe's disease can be achieved by allogenic UCSCs. UCSCs transplantation to asymptomatic infants with subsequent monitoring for 46 years reveals that UCSCs recover babies from MSE deficiency, improving myelination and cognitive functions, compared to those of symptomatic babies. The survival rate of transplanted UCSCs in asymptomatic and symptomatic infants was 100% and 43%, respectively, suggesting that early diagnosis and timely treatment are critical for UCSCs acceptance for desired therapeutic outcomes. UCSCs are more primitive than BMSCs, so perfect HLA typing is not critically required, representing UCSCs as an excellent source for treatment of all the diseases involving lysosomal defects, like Krabbe's disease, hurler syndrome, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Tay-Sachs disease (TSD), and Sandhoff disease [65]. Brain injuries often lead to cavities formation, which can be treated from neuronal parenchyma, generated ex vivo from UCSCs. Coaxing of UCSCs into human originated biodegradable matrix scaffold and in vitro expansion of cells in defined culture conditions lead to formation of neuronal organoids, within threewks' time frame. These organoids structurally resemble brain tissue and consisted of neuroblasts (GFAP+, Nestin+, and Ki67+) and immature stem cells (OCT4+ and SOX2+). The neuroblasts of these organoids further can be differentiated into mature neurons (MAP2+ and TUJ1+) [66]. Administration of high dose of drugs in divesting neuroblastoma therapeutics requires immediate restoration of hematopoiesis. Although BMSCs had been promising in restoration of hematopoiesis UCSCs are sparely used in clinical settings. A case study demonstrates that neuroblastoma patients who received autologous UCSCs survive without any associated side effects [12]. During radiation therapy of neoplasm, spinal cord myelitis can occur, although occurrence of myelitis is a rare event and usually such neurodegenerative complication of spinal cord occurs 624 years after exposure to radiations. Transplantation of allogenic UC-MSCs in laryngeal patients undergoing radiation therapy restores myelination [102]. For treatment of neurodegenerative disease like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), traumatic brain injuries (TBI), Parkinson's, SCI, stroke, and so forth, distribution of transplanted UCSCs is critical for therapeutic outcomes. In mice and rat, injection of UCSCs and subsequent MRI scanning show that transplanted UCSCs migrate to CNS and multiple peripheral organs [67]. For immunomodulation of tumor cells disease recovery, transplantation of allogenic DCs is required. The CD11c+DCs, derived from UCB, are morphologically and phenotypically similar to those of peripheral blood derived CTLs-DCs, suggesting that UCB-DCs can be used for personalized medicine of cancer patient, in need for DCs transplantation [103]. Coculture of UCSCs with radiation exposed human lung fibroblast stops their transdifferentiation, which suggests that factors secreted from UCSCs may restore niche identity of fibroblast, if they are transplanted to lung after radiation therapy [104]. Tearing of shoulder cuff tendon can cause severe pain and functional disability, whereas ultrasound guided transplantation of UCB-MSCs in rabbit regenerates subscapularis tendon in fourwks' time frame, suggesting that UCB-MSCs are effective enough to treat tendons injuries when injected to focal points of tear-site [68]. Furthermore, transplantation of UCB-MSCs to chondral cartilage injuries site in pig knee along with HA hydrogel composite regenerates hyaline cartilage [69], suggesting that UCB-MSCs are effective regenerative medicine candidate for treating cartilage and ligament injuries. Physiologically circulatory systems of brain, placenta, and lungs are similar. Infusion of UCB-MSCs to preeclampsia (PE) induced hypertension mice reduces the endotoxic effect, suggesting that UC-MSCs are potential source for treatment of endotoxin induced hypertension during pregnancy, drug abuse, and other kinds of inflammatory shocks [105]. Transplantation of UCSCs to severe congenital neutropenia (SCN) patients restores neutrophils count from donor cells without any side effect, representing UCSCs as potential alternative for SCN therapy, when HLA matched bone marrow donors are not accessible [106]. In clinical settings, the success of myocardial infarction (MI) treatment depends on ageing, systemic inflammation in host, and processing of cells for infusion. Infusion of human hyaluronan hydrogel coaxed UCSCs in pigs induces angiogenesis, decreases scar area, improves cardiac function at preclinical level, and suggests that the same strategy might be effective for human [107]. In stem cells therapeutics, UCSCs transplantation can be either autologous or allogenic. Sometimes, the autologous UCSCs transplants cannot combat over tumor relapse, observed in Hodgkin's lymphoma (HL), which might require second dose transplantation of allogenic stem cells, but efficacy and tolerance of stem cells transplant need to be addressed, where tumor replace occurs. A case study demonstrates that second dose allogenic transplants of UCSCs effective for HL patients, who had heavy dose in prior transplant, increase the long term survival chances by 30% [10]. Patients undergoing long term peritoneal renal dialysis are prone to peritoneal fibrosis and can change peritoneal structure and failure of ultrafiltration processes. The intraperitoneal (IP) injection of WJ-MSCs prevents methylglyoxal induced programmed cell death and peritoneal wall thickening and fibrosis, suggesting that WJ-MSCs are effective in therapeutics of encapsulating peritoneal fibrosis [70]. In summary, UCB-HSCs, WJ-MSCs, perivascular MSCs, and UCB-MSCs have tissue regeneration potential.

Bone marrow found in soft spongy bones is responsible for formation of all peripheral blood and comprises hematopoietic stem cells (producing blood cells) and stromal cells (producing fat, cartilage, and bones) [108] (; ). Visually bone marrow has two types, red marrow (myeloid tissue; producing RBC, platelets, and most of WBC) and yellow marrow (producing fat cells and some WBC) [108]. Imbalance in marrow composition can culminate to the diseased condition. Since 1980, bone marrow transplantation is widely accepted for cancer therapeutics [109]. In order to avoid graft rejection, HLA typing of donors is a must, but completely matched donors are limited to family members, which hampers allogenic transplantation applications. Since matching of all HLA antigens is not critically required, in that case defining the critical antigens for haploidentical allogenic donor for patients, who cannot find fully matched donor, might relieve from donor constraints. Two-step administration of lymphoid and myeloid BMSCs from haploidentical donor to the patients of aplastic anaemia and haematological malignancies reconstructs host immune system and the outcomes are almost similar to fully matched transplants, which recommends that profiling of critically important HLA is sufficient for successful outcomes of BMSCs transplantation. Haploidentical HLA matching protocol is the major process for minorities and others who do not have access to matched donor [71]. Furthermore, antigen profiling is not the sole concern for BMSCs based therapeutics. For example, restriction of HIV1 (human immune deficiency virus) infection is not feasible through BMSCs transplantation because HIV1 infection is mediated through CD4+ receptors, chemokine CXC motif receptor 4 (CXCR4), and chemokine receptor 5 (CCR5) for infecting and propagating into T helper (Th), monocytes, macrophages, and dendritic cells (DCs). Genetic variation in CCR2 and CCR5 receptors is also a contributory factor; mediating protection against infection has been reviewed elsewhere [110]. Engineering of hematopoietic stem and progenitor cells (HSPCs) derived CD4+ cells to express HIV1 antagonistic RNA, specifically designed for targeting HIV1 genome, can restrict HIV1 infection, through immune elimination of latently infected CD4+ cells. A single dose infusion of genetically modified (GM), HIV1 resistant HSPCs can be the alternative of HIV1 retroviral therapy. In the present scenario stem cells source, patient selection, transplantation-conditioning regimen, and postinfusion follow-up studies are the major factors, which can limit application of HIV1 resistant GM-HSPCs (CD4+) cells application in AIDS therapy [72, 73]. Platelets, essential for blood clotting, are formed from megakaryocytes inside the bone marrow [74]. Due to infection, trauma, and cancer, there are chances of bone marrow failure. To an extent, spongy bone marrow microenvironment responsible for lineage commitment can be reconstructed ex vivo [75]. The ex vivo constructed 3D-scaffolds consisted of microtubule and silk sponge, flooded with chemically defined organ culture medium, which mimics bone marrow environment. The coculture of megakaryocytes and embryonic stem cells (ESCs) in this microenvironment leads to generation of functional platelets from megakaryocytes [75]. The ex vivo 3D-scaffolds of bone microenvironment can stride the path for generation of platelets in therapeutic quantities for regenerative medication of burns [75] and blood clotting associated defects. Accidents, traumatic injuries, and brain stroke can deplete neuronal stem cells (NSCs), responsible for generation of neurons, astrocytes, and oligodendrocytes. Brain does not repopulate NSCs and heal traumatic injuries itself and transplantation of BMSCs also can heal neurodegeneration alone. Lipoic acid (LA), a known pharmacological antioxidant compound used in treatment of diabetic and multiple sclerosis neuropathy when combined with BMSCs, induces neovascularisation at focal cerebral injuries, within 8wks of transplantation. Vascularisation further attracts microglia and induces their colonization into scaffold, which leads to differentiation of BMSCs to become brain tissue, within 16wks of transplantation. In this approach, healing of tissue directly depends on number of BMSCs in transplantation dose [76]. Dental caries and periodontal disease are common craniofacial disease, often requiring jaw bone reconstruction after removal of the teeth. Traditional therapy focuses on functional and structural restoration of oral tissue, bone, and teeth rather than biological restoration, but BMSCs based therapies promise for regeneration of craniofacial bone defects, enabling replacement of missing teeth in restored bones with dental implants. Bone marrow derived CD14+ and CD90+ stem and progenitor cells, termed as tissue repair cells (TRC), accelerate alveolar bone regeneration and reconstruction of jaw bone when transplanted in damaged craniofacial tissue, earlier to oral implants. Hence, TRC therapy reduces the need of secondary bone grafts, best suited for severe defects in oral bone, skin, and gum, resulting from trauma, disease, or birth defects [77]. Overall, HSCs have great value in regenerative medicine, where stem cells transplantation strategies explore importance of niche in tissue regeneration. Prior to transplantation of BMSCs, clearance of original niche from target tissue is necessary for generation of organoid and organs without host-versus-graft rejection events. Some genetic defects can lead to disorganization of niche, leading to developmental errors. Complementation with human blastocyst derived primary cells can restore niche function of pancreas in pigs and rats, which defines the concept for generation of clinical grade human pancreas in mice and pigs [111]. Similar to other organs, diaphragm also has its own niche. Congenital defects in diaphragm can affect diaphragm functions. In the present scenario functional restoration of congenital diaphragm defects by surgical repair has risk of reoccurrence of defects or incomplete restoration [8]. Decellularization of donor derived diaphragm offers a way for reconstruction of new and functionally compatible diaphragm through niche modulation. Tissue engineering technology based decellularization of diaphragm and simultaneous perfusion of bone marrow mesenchymal stem cells (BM-MSCs) facilitates regeneration of functional scaffolds of diaphragm tissues [8]. In vivo replacement of hemidiaphragm in rats with reseeded scaffolds possesses similar myography and spirometry as it has in vivo in donor rats. These scaffolds retaining natural architecture are devoid of immune cells, retaining intact extracellular matrix that supports adhesion, proliferation, and differentiation of seeded cells [8]. These findings suggest that cadaver obtained diaphragm, seeded with BM-MSCs, can be used for curing patients in need for restoration of diaphragm functions (; ). However, BMSCs are heterogeneous population, which might result in differential outcomes in clinical settings; however clonal expansion of BMSCs yields homogenous cells population for therapeutic application [8]. One study also finds that intracavernous delivery of single clone BMSCs can restore erectile function in diabetic mice [112] and the same strategy might be explored for adult human individuals. The infection of hepatitis C virus (HCV) can cause liver cirrhosis and degeneration of hepatic tissue. The intraparenchymal transplantation of bone marrow mononuclear cells (BMMNCs) into liver tissue decreases aspartate aminotransferase (AST), alanine transaminase (ALT), bilirubin, CD34, and -SMA, suggesting that transplanted BMSCs restore hepatic functions through regeneration of hepatic tissues [113]. In order to meet the growing demand for stem cells transplantation therapy, donor encouragement is always required [8]. The stem cells donation procedure is very simple; with consent donor gets an injection of granulocyte-colony stimulating factor (G-CSF) that increases BMSCs population. Bone marrow collection is done from hip bone using syringe in 4-5hrs, requiring local anaesthesia and within a wk time frame donor gets recovered donation associated weakness.

The field of iPSCs technology and research is new to all other stem cells research, emerging in 2006 when, for the first time, Takahashi and Yamanaka generated ESCs-like cells through genetic incorporation of four factors, Sox2, Oct3/4, Klf4, and c-Myc, into skin fibroblast [3]. Due to extensive nuclear reprogramming, generated iPSCs are indistinguishable from ESCs, for their transcriptome profiling, epigenetic markings, and functional competence [3], but use of retrovirus in transdifferentiation approach has questioned iPSCs technology. Technological advancement has enabled generation of iPSCs from various kinds of adult cells phasing through ESCs or direct transdifferentiation. This section of review outlines most recent advancement in iPSC technology and regenerative applications (; ). Using the new edge of iPSCs technology, terminally differentiated skin cells directly can be transformed into kidney organoids [114], which are functionally and structurally similar to those of kidney tissue in vivo. Up to certain extent kidneys heal themselves; however natural regeneration potential cannot meet healing for severe injuries. During kidneys healing process, a progenitor stem cell needs to become 20 types of cells, required for waste excretion, pH regulation, and restoration of water and electrolytic ions. The procedure for generation of kidney organoids ex vivo, containing functional nephrons, has been identified for human. These ex vivo kidney organoids are similar to fetal first-trimester kidneys for their structure and physiology. Such kidney organoids can serve as model for nephrotoxicity screening of drugs, disease modelling, and organ transplantation. However generation of fully functional kidneys is a far seen event with today's scientific technologies [114]. Loss of neurons in age-related macular degeneration (ARMD) is the common cause of blindness. At preclinical level, transplantation of iPSCs derived neuronal progenitor cells (NPCs) in rat limits progression of disease through generation of 5-6 layers of photoreceptor nuclei, restoring visual acuity [78]. The various approaches of iPSCs mediated retinal regeneration including ARMD have been reviewed elsewhere [79]. Placenta, the cordial connection between mother and developing fetus, gets degenerated in certain pathophysiological conditions. Nuclear programming of OCT4 knock-out (KO) and wild type (WT) mice fibroblast through transient expression of GATA3, EOMES, TFAP2C, and +/ cMYC generates transgene independent trophoblast stem-like cells (iTSCs), which are highly similar to blastocyst derived TSCs for DNA methylation, H3K7ac, nucleosome deposition of H2A.X, and other epigenetic markings. Chimeric differentiation of iTSCs specifically gives rise to haemorrhagic lineages and placental tissue, bypassing pluripotency phase, opening an avenue for generation of fully functional placenta for human [115]. Neurodegenerative disease like Alzheimer's and obstinate epilepsies can degenerate cerebrum, controlling excitatory and inhibitory signals of the brain. The inhibitory tones in cerebral cortex and hippocampus are accounted by -amino butyric acid secreting (GABAergic) interneurons (INs). Loss of these neurons often leads to progressive neurodegeneration. Genomic integration of Ascl1, Dlx5, Foxg1, and Lhx6 to mice and human fibroblast transforms these adult cells into GABAergic-INs (iGABA-INs). These cells have molecular signature of telencephalic INs, release GABA, and show inhibition to host granule neuronal activity [81]. Transplantation of these INs in developing embryo cures from genetic and acquired seizures, where transplanted cells disperse and mature into functional neuronal circuits as local INs [82]. Dorsomorphin and SB-431542 mediated inhibition of TGF- and BMP signalling direct transformation of human iPSCs into cortical spheroids. These cortical spheroids consisted of both peripheral and cortical neurons, surrounded by astrocytes, displaying transcription profiling and electrophysiology similarity with developing fetal brain and mature neurons, respectively [83]. The underlying complex biology and lack of clear etiology and genetic reprogramming and difficulty in recapitulation of brain development have barred understanding of pathophysiology of autism spectrum disorder (ASD) and schizophrenia. 3D organoid cultures of ASD patient derived iPSC generate miniature brain organoid, resembling fetal brain few months after gestation. The idiopathic conditions of these organoids are similar with brain of ASD patients; both possess higher inhibitory GABAergic neurons with imbalanced neuronal connection. Furthermore these organoids express forkhead Box G1 (FOXG1) much higher than normal brain tissue, which explains that FOXG1 might be the leading cause of ASD [84]. Degeneration of other organs and tissues also has been reported, like degeneration of lungs which might occur due to tuberculosis infection, fibrosis, and cancer. The underlying etiology for lung degeneration can be explained through organoid culture. Coaxing of iPSC into inert biomaterial and defined culture leads to formation of lung organoids that consisted of epithelial and mesenchymal cells, which can survive in culture for months. These organoids are miniature lung, resemble tissues of large airways and alveoli, and can be used for lung developmental studies and screening of antituberculosis and anticancer drugs [87]. The conventional multistep reprogramming for iPSCs consumes months of time, while CRISPER-Cas9 system based episomal reprogramming system that combines two steps together enables generation of ESCs-like cells in less than twowks, reducing the chances of culture associated genetic abrasions and unwanted epigenetic [80]. This approach can yield single step ESCs-like cells in more personalized way from adults with retinal degradation and infants with severe immunodeficiency, involving correction for genetic mutation of OCT4 and DNMT3B [80]. The iPSCs expressing anti-CCR5-RNA, which can be differentiated into HIV1 resistant macrophages, have applications in AIDS therapeutics [88]. The diversified immunotherapeutic application of iPSCs has been reviewed elsewhere [89]. The -1 antitrypsin deficiency (A1AD) encoded by serpin peptidase inhibitor clade A member 1 (SERPINA1) protein synthesized in liver protects lungs from neutrophils elastase, the enzyme causing disruption of lungs connective tissue. A1AD deficiency is common cause of both lung and liver disease like chronic obstructive pulmonary disease (COPD) and liver cirrhosis. Patient specific iPSCs from lung and liver cells might explain pathophysiology of A1AD deficiency. COPD patient derived iPSCs show sensitivity to toxic drugs which explains that actual patient might be sensitive in similar fashion. It is known that A1AD deficiency is caused by single base pair mutation and correction of this mutation fixes the A1AD deficiency in hepatic-iPSCs [85]. The high order brain functions, like emotions, anxiety, sleep, depression, appetite, breathing heartbeats, and so forth, are regulated by serotonin neurons. Generation of serotonin neurons occurs prior to birth, which are postmitotic in their nature. Any sort of developmental defect and degeneration of serotonin neurons might lead to neuronal disorders like bipolar disorder, depression, and schizophrenia-like psychiatric conditions. Manipulation of Wnt signalling in human iPSCs in defined culture conditions leads to an in vitro differentiation of iPSCs to serotonin-like neurons. These iPSCs-neurons primarily localize to rhombomere 2-3 segment of rostral raphe nucleus, exhibit electrophysiological properties similar to serotonin neurons, express hydroxylase 2, the developmental marker, and release serotonin in dose and time dependent manner. Transplantation of these neurons might cure from schizophrenia, bipolar disorder, and other neuropathological conditions [116]. The iPSCs technology mediated somatic cell reprogramming of ventricular monocytes results in generation of cells, similar in morphology and functionality with PCs. SA note transplantation of PCs to large animals improves rhythmic heart functions. Pacemaker needs very reliable and robust performance so understanding of transformation process and site of transplantation are the critical aspect for therapeutic validation of iPSCs derived PCs [28]. Diabetes is a major health concern in modern world, and generation of -cells from adult tissue is challenging. Direct reprogramming of skin cells into pancreatic cells, bypassing pluripotency phase, can yield clinical grade -cells. This reprogramming strategy involves transformation of skin cells into definitive endodermal progenitors (cDE) and foregut like progenitor cells (cPF) intermediates and subsequent in vitro expansion of these intermediates to become pancreatic -cells (cPB). The first step is chemically complex and can be understood as nonepisomal reprogramming on day one with pluripotency factors (OCT4, SOX2, KLF4, and hair pin RNA against p53), then supplementation with GFs and chemical supplements on day seven (EGF, bFGF, CHIR, NECA, NaB, Par, and RG), and two weeks later (Activin-A, CHIR, NECA, NaB, and RG) yielding DE and cPF [86]. Transplantation of cPB yields into glucose stimulated secretion of insulin in diabetic mice defines that such cells can be explored for treatment of T1DM and T2DM in more personalized manner [86]. iPSCs represent underrated opportunities for drug industries and clinical research laboratories for development of therapeutics, but safety concerns might limit transplantation applications (; ) [117]. Transplantation of human iPSCs into mice gastrula leads to colonization and differentiation of cells into three germ layers, evidenced with clinical developmental fat measurements. The acceptance of human iPSCs by mice gastrula suggests that correct timing and appropriate reprogramming regime might delimit human mice species barrier. Using this fact of species barrier, generation of human organs in closely associated primates might be possible, which can be used for treatment of genetic factors governed disease at embryo level itself [118]. In summary, iPSCs are safe and effective for treatment of regenerative medicine.

The unstable growth of human population threatens the existence of wildlife, through overexploitation of natural habitats and illegal killing of wild animals, leading many species to face the fate of being endangered and go for extinction. For wildlife conservation, the concept of creation of frozen zoo involves preservation of gene pool and germ plasm from threatened and endangered species (). The frozen zoo tissue samples collection from dead or live animal can be DNA, sperms, eggs, embryos, gonads, skin, or any other tissue of the body [119]. Preserved tissue can be reprogrammed or transdifferentiated to become other types of tissues and cells, which opens an avenue for conservation of endangered species and resurrection of life (). The gonadal tissue from young individuals harbouring immature tissue can be matured in vivo and ex vivo for generation of functional gametes. Transplantation of SSCs to testis of male from the same different species can give rise to spermatozoa of donor cells [120], which might be used for IVF based captive breeding of wild animals. The most dangerous fact in wildlife conservation is low genetic diversity, too few reproductively capable animals which cannot maintain adequate genetic diversity in wild or captivity. Using the edge of iPSC technology, pluripotent stem cells can be generated from skin cells. For endangered drill, Mandrillus leucophaeus, and nearly extinct white rhinoceros, Ceratotherium simum cottoni, iPSC has been generated in 2011 [121]. The endangered animal drill (Mandrillus leucophaeus) is genetically very close to human and often suffers from diabetes, while rhinos are genetically far removed from other primates. The progress in iPSCs, from the human point of view, might be transformed for animal research for recapturing reproductive potential and health in wild animals. However, stem cells based interventions in wild animals are much more complex than classical conservation planning and biomedical research has to face. Conversion of iPSC into egg or sperm can open the door for generation of IVF based embryo; those might be transplanted in womb of live counterparts for propagation of population. Recently, iPSCs have been generated for snow leopard (Panthera uncia), native to mountain ranges of central Asia, which belongs to cat family; this breakthrough has raised the possibilities for cryopreservation of genetic material for future cloning and other assisted reproductive technology (ART) applications, for the conservation of cat species and biodiversity. Generation of leopard iPSCs has been achieved through retroviral-system based genomic integration of OCT4, SOX2, KLF4, cMYC, and NANOG. These iPSCs from snow leopard also open an avenue for further transformation of iPSCs into gametes [122]. The in vivo maturation of grafted tissue depends both on age and on hormonal status of donor tissue. These facts are equally applicable to accepting host. Ectopic xenografts of cryopreserved testis tissue from Indian spotted deer (Moschiola indica) to nude mice yielded generation of spermatocytes [123], suggesting that one-day procurement of functional sperm from premature tissue might become a general technique in wildlife conservation. In summary, tissue biopsies from dead or live animals can be used for generation of iPSCs and functional gametes; those can be used in assisted reproductive technology (ART) for wildlife conservation.

The spectacular progress in the field of stem cells research represents great scope of stem cells regenerative therapeutics. It can be estimated that by 2020 or so we will be able to produce wide array of tissue, organoid, and organs from adult stem cells. Inductions of pluripotency phenotypes in terminally differentiated adult cells have better therapeutic future than ESCs, due to least ethical constraints with adult cells. In the coming future, there might be new pharmaceutical compounds; those can activate tissue specific stem cells, promote stem cells to migrate to the side of tissue injury, and promote their differentiation to tissue specific cells. Except few countries, the ongoing financial and ethical hindrance on ESCs application in regenerative medicine have more chance for funding agencies to distribute funding for the least risky projects on UCSCs, BMSCs, and TSPSCs from biopsies. The existing stem cells therapeutics advancements are more experimental and high in cost; due to that application on broad scale is not feasible in current scenario. In the near future, the advancements of medical science presume using stem cells to treat cancer, muscles damage, autoimmune disease, and spinal cord injuries among a number of impairments and diseases. It is expected that stem cells therapies will bring considerable benefits to the patients suffering from wide range of injuries and disease. There is high optimism for use of BMSCs, TSPSCs, and iPSCs for treatment of various diseases to overcome the contradictions associated with ESCs. For advancement of translational application of stem cells, there is a need of clinical trials, which needs funding rejoinder from both public and private organizations. The critical evaluation of regulatory guidelines at each phase of clinical trial is a must to comprehend the success and efficacy in time frame.

Dr. Anuradha Reddy from Centre for Cellular and Molecular Biology Hyderabad and Mrs. Sarita Kumari from Department of Yoga Science, BU, Bhopal, India, are acknowledged for their critical suggestions and comments on paper.

There are no competing interests associated with this paper.

View post:
Stem Cells Applications in Regenerative Medicine and ...

Cardiac Stem Cells Comments Off on Stem Cells Applications in Regenerative Medicine and … | December 23rd, 2021

DUBLIN, Dec. 20, 2021 /PRNewswire/ -- The "22q11.2 Deletion Syndrome - Global Market Insights, Epidemiology and Forecast to 2030" report has been added to ResearchAndMarkets.com's offering.

This report delivers an in-depth understanding of the 22q11.2 deletion syndrome, historical and forecasted epidemiology as well as the 22q11.2 deletion syndrome market trends in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan.

Epidemiology

The 22q11.2 deletion syndrome epidemiology division provides the insights about historical and current 22q11.2 deletion syndrome patient pool and forecasted trend for each seven major countries. It helps to recognize the causes of current and forecasted trends by exploring numerous studies and views of key opinion leaders. This part of The report also provides the diagnosed patient pool and their trends along with assumptions undertaken.

Key Findings

The disease epidemiology covered in the report provides historical as well as forecasted 22q11.2 deletion syndrome epidemiology [segmented as Total Prevalent Cases of 22q11.2 deletion syndrome, Total Diagnosed Prevalent Cases of 22q11.2 deletion syndrome, Total diagnosed prevalent cases of 22q11.2 deletion syndrome by age group, Total diagnosed prevalent cases of 22q11.2 deletion syndrome with Behavioral and Psychiatric phenotypes, and Total treated cases of 22q11.2 deletion syndrome with behavioral and psychiatric phenotypes scenario of 22q11.2 deletion syndrome in the 7MM covering United States, EU5 countries (Germany, France, Italy, Spain, and United Kingdom), and Japan from 2018 to 2030.

Country-Wise Epidemiology

In 2020, the total prevalent cases of 22q11.2 deletion syndrome were 196,476 in the 7MM. The United States, in the same year, accounted for 83,326 cases, the highest prevalence of 22q11.2 deletion syndrome cases in the 7MM, accounting for approximately 42% of the total 7MM cases in 2020.

Among the EU-5 countries, the highest number of cases of 22q11.2 deletion syndrome were in Germany and the least in Spain in 2020.

22q11.2 deletion syndrome is often underdiagnosed and misdiagnosed, as the symptoms vary from patient to patient. In the EU-5 countries, the total diagnosed prevalent cases of 22q11.2 deletion syndrome were 35,203 in 2020.

In the year 2020, Japan accounted for 1,409, 1,160, 2,196, 582, and 850 cases for the age groups Infant, 1-5, 6-12, 13-17, and ?18 years, respectively, for 22q11.2 deletion syndrome which are expected to rise during the forecast period.

22q11.2 deletion syndrome is a multisystem disorder characterized by several physical, behavioral and psychiatric disorders. In the 7MM, of the focused age-group 6 to 12 and 13 to 17 years, the diagnosed prevalent cases of 22q11.2 deletion syndrome with Behavioral and Psychiatric Phenotypes were 36,702, in 2020.

Drug Chapters

Drug chapter segment of the 22q11.2 deletion syndrome report encloses the detailed analysis of 22q11.2 deletion syndrome pipeline drugs. It also helps to understand the 22q11.2 deletion syndrome clinical trial details, expressive pharmacological action, agreements and collaborations, approval and patent details, advantages and disadvantages of each included drug and the latest news and press releases.

Emerging Drugs

Zygel (ZYN002; Cannabidiol): Zynerba Pharmaceuticals

Zygel (ZYN002), developed by Zynerba Pharmaceuticals, is the first and only pharmaceutically produced Cannabidiol (CBD). Zygel is formulated as a patent-protected permeation-enhanced gel for transdermal delivery through skin and then into the circulatory system. Zynerba Pharmaceuticals is currently developing the Zygel in Phase II (ACTRN12619000673145; INSPIRE) of the clinical development in Children and Adolescents with 22q11.2 Deletion Syndrome. The trial is currently registered with the Australian New Zealand Clinical Trials Registry (ANZCTR).

RVT-802: Enzyvant/Roivant Sciences/Sumitomo Dainippon Pharma

RVT-802 is a one-time regenerative therapy and is a cultured human thymus tissue engineered to generate a functioning immune response when implanted in pediatric patients with congenital athymia. RVT-802 is a human thymus tissue that has been removed during pediatric cardiac surgery for unrelated conditions. In a healthy, functioning immune system, T cells that start as stem cells in the bone marrow become fully developed in the thymus. Currently, RVT-802 is being developed by Sumitomo Dainippon Pharma (Parent company of Sumitovant Biopharma for Pediatric Congenital Athymia) associated with multiple conditions, including complete DiGeorge Anomaly (cDGA).

Key Findings

The 22q11.2 deletion syndrome market size in the 7MM is expected to change during the forecast period (2021-2030), at a CAGR of 41.9%. According to the estimates, the highest market size of 22q11.2 deletion syndrome is found in the United States.

US: Market Outlook

In United States, the total market size of 22q11.2 deletion syndrome is expected to increase at a CAGR of 43.9% during the study period (2018-2030).

EU-5 Countries: Market Outlook

In the EU-5 countries, the total market size of 22q11.2 deletion syndrome is expected to increase at a CAGR of 37.1% during the study period (2018-2030).

Japan: Market Outlook

In the Japan, the total market size of 22q11.2 deletion syndrome is expected to increase at a CAGR of 41.6% during the study period (2018-2030).

Pipeline Activities

The drugs which are in pipeline include:

Analysts Insight

At present, like many other rare diseases, there is no cure for 22q11.2 deletion syndrome. It is worth mentioning that as a result of the early diagnosis in cases like heart and palate defects, evidence-based protocols can be followed in the early stages of diagnosis to improve the quality of life for children. In such cases, surgery is the major option. The major treatment challenge is seen in patients with psychopathologies (such as Autism, Anxiety disorders, Psychotic disorder [Schizophrenia], Attention deficit hyperactivity disorder [ADHD], and Mood Disorders). In such cases diagnosis is also a major challenge. Antidepressants, antipsychotics, and stimulants are used as off-label therapeutic choices to address all of the aforementioned behavioral and psychiatric traits. Behavioral therapy, on the other hand, is another important part of the treatment process. The pipeline for 22q11.2 deletion syndrome is not competitive, and if Zygel (ZYN002) gets approved by regulatory authorities in the coming years, the overall market size in the seven major markets is likely to grow, as there will be no expected competition.

Access and Reimbursement Scenario

Children are born with this disorder, they require a lifetime of expenditure over diagnosis, treatment, and other supportive care. In a study by Peter et al. (2017), the average pediatric medical care cost associated with the diagnosis of 22q11.2 deletion syndrome in the general population was estimated to be USD 727,178. Costs were highest for patients ascertained prenatally (USD 2,599,955) or in the first year of life (USD 1,043,096), those with cardiac abnormalities or referred for cardiac evaluation (USD 751,535), and patients with low T-cell counts (USD 1,382,222), presumably reflecting the fact that more severely affected cases are more likely to have come to attention early, and that they have a larger number of years of accumulated costs.

KOL Views

To keep up with current market trends, the publisher takes KOLs and SME's opinion working in 22q11.2 deletion syndrome domain through primary research to fill the data gaps and validate our secondary research. Their opinion helps to understand and validate current and emerging therapies treatment patterns o r22q11.2 deletion syndrome market trend. This will support the clients in potential upcoming novel treatment by identifying the overall scenario of the market and the unmet needs.

Competitive Intelligence Analysis

The publisher performs Competitive and Market Intelligence analysis of the 22q11.2 deletion syndrome Market by using various Competitive Intelligence tools that includes - SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies etc. The inclusion of the analysis entirely depends upon the data availability.

For more information about this report visit https://www.researchandmarkets.com/r/bs6hd4

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716

SOURCE Research and Markets

Original post:
In-depth Analysis of the 22q11.2 Deletion Syndrome Market, 2017-2030 - If Zygel (ZYN002) Gets Approved, the Market Will Grow as There Will Be No...

Cardiac Stem Cells Comments Off on In-depth Analysis of the 22q11.2 Deletion Syndrome Market, 2017-2030 – If Zygel (ZYN002) Gets Approved, the Market Will Grow as There Will Be No… | December 23rd, 2021

Event summary produced by The Globe and Mail Events team. The Globes editorial department was not involved.

Canada was a pioneer of stem cell research and today, innovators are developing clinical trials to test regenerative treatments for a range of illnesses including cardiac disease and Parkinsons. At the same time, theyre navigating risks and considerations that often surround medical innovations.

The Globe and Mail hosted a webcast on November 30 to explore the promise and potential of stem cells. Speakers also discussed ethical issues, misinformation and the importance of rigorous evaluation in bringing new treatments to market.

Missed the live event or would like to view it again? Scroll down to the video player, below.

Andr Picard, health reporter and columnist with The Globe and Mail moderated the event and hosted the following speakers:

Read a summary of the event here

View the full webcast, below:

The Globe and Mail presented the webcast with sponsor support from Bayer.

Go here to see the original:
Stem cells and the future of health care - The Globe and Mail

Cardiac Stem Cells Comments Off on Stem cells and the future of health care – The Globe and Mail | December 10th, 2021

All articles published by MDPI are made immediately available worldwide under an open access license. No specialpermission is required to reuse all or part of the article published by MDPI, including figures and tables. Forarticles published under an open access Creative Common CC BY license, any part of the article may be reused withoutpermission provided that the original article is clearly cited.

Feature Papers represent the most advanced research with significant potential for high impact in the field. FeaturePapers are submitted upon individual invitation or recommendation by the scientific editors and undergo peer reviewprior to publication.

The Feature Paper can be either an original research article, a substantial novel research study that often involvesseveral techniques or approaches, or a comprehensive review paper with concise and precise updates on the latestprogress in the field that systematically reviews the most exciting advances in scientific literature. This type ofpaper provides an outlook on future directions of research or possible applications.

Editors Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world.Editors select a small number of articles recently published in the journal that they believe will be particularlyinteresting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting workpublished in the various research areas of the journal.

See the original post here:
Cells | Free Full-Text | Improving Cardiac Reprogramming ...

Cardiac Stem Cells Comments Off on Cells | Free Full-Text | Improving Cardiac Reprogramming … | December 10th, 2021

LAWRENCE The human body contains trillions of cells at any given moment, each doing highly specialized work to help us function but they dont operate in isolation. Imagine a sophisticated FedEx or UPS delivery network empowering communication between our cells. The nano-sized delivery vehicles in this scenario are called exosomes, and a company born from technology developed at the University of Kansas is harnessing the power of these tiny vessels to enable tomorrows medical breakthroughs.

Clara Biotech, founded by KU engineering alumnus Jim West and former KU professor of chemical & petroleum engineering and chemistry Mei He, has spent the last three years refining a novel technology to isolate and purify exosomes, which can be used for early disease diagnosis, targeted drug delivery, cancer immunotherapy and other forms of regenerative medicine.

Now, the company is poised to commercialize its first product after recently finalizing $1.5 million in seed funding and being recognized in a national competition. Clara Biotech was the only Midwest company singled out in MedTech Innovators Biotools Innovator program, which recognizes the 10 best life science tools startups. The company received $10,000 for securing a spot in the 2021 cohort and a $5,000 best-video award for a one-minute spot introducing the company and detailing what sets it apart.

Clara Biotech was founded to help move exosomes from the bench to the bedside, said West, who serves as Claras CEO. Our company is about building a platform that everybody can leverage to bring their products to market and help solve challenges around isolation and purification, which today is one of the number one issues in the field.

Exosomes deliver genetic information to cells throughout the body. Exosomes from regenerative cells, such as stem cells, can help the body heal and repair itself. Exosomes released from diseased cells might be used for early detection and diagnosis of cancer and other conditions.

But at 100 nanometers in diameter less than the wavelength of visible light exosomes are difficult to handle.

Clara Biotechs patented ExoRelease platform is unique in the industry. Current processes rely on bulk isolation, whereas Claras capture and release technology isolates pure exosomes. This allows researchers to easily isolate and target specific exosomes including cardiac, neurological, cancer and others and use them for therapeutic treatments and drug delivery platforms.

Im very excited about the work that Clara Biotech is doing to improve exosome purification, said Kathryn Zavala, managing director of BioTools Innovator. Their technology has the potential to significantly impact how we diagnose and treat diseases by advancing the field of exosome research and development.

Clara Biotech launched in 2018 with a Small Business Innovation Research grant from the National Cancer Institute and received training through the National Science Foundations Innovation Corps (I-Corps) program on how to transfer knowledge into products and processes that benefit society. It has seven full-time employees, and its lab is housed in the KU Innovation Park.

Clara Biotech is an example of how KU innovation provides the foundation to form a company that addresses societal needs and creates Kansas jobs, said Tricia Bergman, KUs director of strategic partnerships. It also illustrates how technology developed in KU labs can transition into the KU Innovation Park, where the company can continue to develop through ongoing partnerships with the university.

Until now, Clara Biotech has provided lab services to its customers. Now, its moving toward packaging its technology so other companies, labs and researchers can leverage it to complete the isolation process themselves.

Were trying to democratize access to these exosomes, West said.

Clara Biotech is beta-testing kits containing its isolation technology with promising results from early adopters and hopes to launch its first product by the end of the year.

Building a company is probably the hardest thing Ive ever done in my life, but its also super rewarding, West said. The work were doing is really important.

Photo: Jim West, CEO of Clara Biotech, holds the two checks his company won at MedTech Innovators Biotools Innovator program in San Diego in October.

Read the original:
Biotech company with KU roots wins national competition, secures funding to help move research 'from bench to bedside' | The University of Kansas - KU...

Cardiac Stem Cells Comments Off on Biotech company with KU roots wins national competition, secures funding to help move research ‘from bench to bedside’ | The University of Kansas – KU… | December 10th, 2021

Findings Continue to Change the Treatment of Blood Cancers

HACKENSACK, N.J., Dec. 9, 2021 /PRNewswire/ -- Researchers from Hackensack Meridian Health John Theurer Cancer Center (JTCC), a part of the Georgetown Lombardi Comprehensive Cancer Center, will present updates on treatment advances in multiple myeloma, lymphoma, leukemia, and bone marrow transplantation at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, to be held virtually and live at the Georgia World Congress Center in Atlanta from December 11-14, 2021.

"John Theurer Cancer Center is a world leader in the care of people with hematologic malignancies and a pioneer in clinical research related to blood cancers. The acceptance of 47 studies from our investigators demonstrates our expertise in this area and our commitment to improving outcomes not only for our own patients, but people affected by these diseases everywhere," said Andre Goy, MD, MS, chairman and executive director of the John Theurer Cancer Center.

This year's presentations will include a plenary session as the #2 ranked abstract for the entire conference with data that will change the paradigm in the treatment of relapsed aggressive lymphoma for the FIRST TIME in 40 years. Dr. Lori Leslie, MD, director of the Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs at JTCC will be co-presenter of the phase III international ZUMA-7 clinical trial (abstract #2), which compared axicabtagene ciloleucel (axi-cel) CAR T-cell therapy with standard of care (SOC) in patients with relapsed / refractory diffuse large B-cell lymphoma (DLBCL) after initial therapy. For decades the SOC has been high dose therapy followed by autologous stem cell transplant (ASCT) but patients with high risk disease and / or early relapse still do very poorly. Axi-cel is now used to treat DLBCL that have failed two prior regimens of treatment, including standard salvage chemoimmunotherapy (CIT) followed by ASCT.

Story continues

Bringing axi-cel earlier as second line therapy resulted in a 2.5-fold increase in median event-free survival (defined as the time without any cancer progression or any related complications) and doubled the complete response rate (65% vs 32%).

"This study is the first to change the paradigm for relapsed and refractory DLBCL that was established decades ago, demonstrating significant and clinically meaningful improvements in outcome," said Dr. Leslie. "Axi-cel may replace chemoimmunotherapy and autologous stem cell transplantation as the standard of care for people with DLBCL that relapses or persists after initial treatment. It is a game-changer."

The JTCC presentations address new developments in the treatment of multiple myeloma, lymphoma, leukemia, and bone marrow transplantation, as well as a study assessing gene therapy for sickle cell disease in pediatric patients.

Multiple Myeloma Research

Adding a PI3K inhibitor improved duration of CAR T-cell response. (Abstract #548, David S. Siegel, MD, PhD) In this phase I clinical trial, researchers showed that adding a PI3 kinase inhibitor called bb007 to bb2121 CAR T-cell therapy (forming a combined therapy called bb21217) in relapsed/refractory multiple myeloma (MM) patients who had three or more regimens of treatment resulted in a duration of response of 17 months (compared with 10 months for bb2121 alone in a prior study), and CAR T cells were detectable longer.

Study shows feasibility of "off the shelf" donated CAR T cells. (Abstract #651, David S. Siegel, MD, PhD). Current CAR T-cell therapies involve expensive modification of a patient's own T cells. Allogeneic (donated) CAR T cells represent a potentially more accessible, less expensive option but carry the risk of rejection and complications such as graft-vs-host disease. The phase I UNIVERSAL study demonstrated the safety of donated anti-BCMA CAR T cells in heavily pretreated MM patients, with mild to moderate side effects as expected for this type of immunotherapy.

Novel targeted MM therapies. Three abstracts provided additional data on novel targeted agents for relapsed/refractory MM. Selinexor was FDA approved in December 2020 and is being assessed in combination with other agents. A study of once-weekly oral selinexor with pomalidomide and dexamethasone (abstract #2748, Noa Biran, MD) showed an overall response rate of more than 60% in relapsed/refractory MM, including patients whose disease persisted after CAR T-cell therapy or after anti-CD38 antibody treatment. This is important because patients with MM after CAR T-cell therapy usually do not respond to additional treatment.

Study shows patients fare better if treated in high-volume academic medical centers. (Abstract #2996, David Vesole, MD, PhD, with Lombardi Comprehensive Cancer Center researchers) An analysis of data from the National Cancer Database of nearly 175,000 patients with MM treated at all types of facilities showed that the median overall survival was 75.5 months at high-volume centers versus 50.2 months at low-volume centers. Academic/research cancer programs with high volumes have the best outcomes in MM and are more likely to use chemotherapy, immunotherapy, and autologous stem cell transplantation than low-volume centers, particularly community cancer centers.

Lymphoma Research

Long-term data confirm durability of CAR T-cell benefit in indolent lymphoma. (Abstract #93, Lori Leslie, MD) An update of the pivotal ZUMA-5 clinical trial, which led to the approval of axi-cel CAR T-cell therapy for relapsed/refractory follicular lymphoma, confirmed continued benefit in patients with indolent lymphoma. In follicular lymphoma (most common subtype of indolent lymphoma), high response rates translated to durable responses, with a median duration of response of 38.6 months and 57% of patients free of cancer progression at last follow-up.

Study confirms benefit of CAR T-cell therapy for mantle cell lymphoma (MCL). (Abstract #744, Andre Goy, MD) ZUMA-2 led to the first approval of CAR T-cell therapy for MCL. An analysis of real-world data of MCL patients who received this treatment, 73% of whom would not have been eligible for ZUMA-2, demonstrated similar effectiveness, with an overall response rate of 86% and 64% achieving a complete response. The results support the paradigm-shifting benefit of this therapy in a heavily pretreated patient population where the median overall survival would have otherwise been very poor.

Molecular biomarkers predictive of CAR T-cell response. (Abstract #165, Andrew Ip, MD, Andre Goy, MD) Researchers performed whole exome and transcriptome sequencing to show that patients with DLBCL who had genetic signatures of high-risk disease with standard initial therapy do well with CAR T-cell therapy. Some mutations predicted good versus poor outcomes after CAR T-cell therapyreflecting differences in the tumor or its microenvironmentand may provide the rationale for choosing the most appropriate treatment for each patient and augmenting the response to CAR T-cell therapy.

Value of adding brentuximab to standard chemotherapy for peripheral T-cell lymphoma (Abstract #133, Tatyana Feldman, MD, Lori Leslie, MD) Non-anaplastic subtypes of T-cell lymphoma have poor outcomes and require new options. This study showed that adding brentuximab to conventional combination chemotherapy was tolerable and effective in patients with non-anaplastic CD30-positive peripheral T-cell lymphoma.

Machine learning useful for stratifying lymphoma patients. (Abstract #2395, Andre Goy, MD) Using machine learning and data on 380 patients with DLBCL with expression levels of 180 genes, researchers used machine learning to develop a model to reliably stratify patients with DLBCL treated with R-CHOP combination therapy into four survival subgroups. The model can be used to identify which patients may not respond well to R-CHOPa standard DLBCL treatmentand instead be considered for other therapies or clinical trials.

Lymphoma/CLL adversely affects COVID-19 outcomes. (Abstract #184, Lori Leslie, MD) A study of electronic medical record data on 500 patients with lymphoma, chronic lymphocytic leukemia (CLL), or other lymphoid cancers who tested positive for SARS-CoV-2 showed that those with aggressive non-Hodgkin lymphoma and CLL and patients who had received recent cytotoxic chemotherapy or anti-CD20 antibody treatment (such as rituximab) may be at risk for poor COVID-19 outcomes. JTCC researchers are now working with investigators in the Center for Discovery and Innovation to study T-cell immunity in people with cancer.

Other studies focused on adding ublituximab and umbralisib to ibrutinib in people with CLL (Abstract #395, Lori Leslie, MD) and assessing cerdulatinib as monotherapy for patients with relapsed/refractory peripheral T-cell lymphoma (Abstract #622, Tatayana Feldman, MD).

Leukemia Research

Oral therapy for low-risk myelodysplastic syndrome (MDS) (Abstract #66, James McCloskey, MD) People with MDS are at risk for developing acute leukemia. Those with low-risk MDS may receive supportive care for low blood counts. Patients with high-risk MDS have received inconvenient injections with drugs such as azacitidine and decitabine. This study showed that oral decitabine and cedazuridine was pharmacokinetically equivalent to intravenous decitabine; in patients with low-risk MDS, the oral treatment was well tolerated with prolonged treatment and may be useful for preventing the progression of this disease to leukemia.

Effectiveness of adding venetoclax to gilteritinib effective for FLT3-mutated acute leukemia (Abstract #691, James McCloskey, MD) Acute myeloid leukemia (AML) with FLT3 mutations initially responds to FLT3 inhibitors but frequently becomes resistant to these drugs. This study showed that giving venetoclax (a BCL2 inhibitor) with the FLT3 inhibitor gilteritinib was very effective, clearing the FLT3 mutation in most patients, and was associated with longer overall survivaleven in patients with high-risk subtypes.

Liquid biopsy for detecting molecular abnormalities in AML (Abstract #3463, Jamie Koprivnikar, MD, James McCloskey, MD, and others) This study assessed next-generation sequencing (NGS) to detect molecular abnormalities in AML using liquid biopsies. The data show that this approach is reliable for detecting structural chromosomal abnormalities in myeloid neoplasms. It could potentially replace the need for conventional cytogenetic testing, be much more convenient (replacing bone marrow biopsies for materials), and be more cost-effective.

Bone Marrow Transplantation Research

Next-generation sequencing and liquid biopsy valuable for detecting early relapse after stem cell transplantation. (Abstract #1828, Scott Rowley, MD, Michele Donato, MD, Maher Albitar, MD, and others) Cell-free DNA was isolated from the peripheral blood post-allogeneic transplant in patients treated for AML, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, MDS, MM, and lymphoma. Researchers showed that NGS and liquid biopsy are useful for detecting residual disease. The data suggest that this approach, which examines cancer DNA in peripheral blood rather than a sample from a bone marrow biopsy, may be effective for detecting and managing minimal residual disease (MRD)the next frontier in oncologyenabling doctors to modify therapy to achieve MRD negative status or, during transplantation, to adjust immunosuppressors or use additional T cells to prevent relapse.

Use of NGS and machine learning after transplant to predict graft-vs-host disease (GVHD) (Abstract #2892, Scott Rowley, MD, Michele Donato, MD, Maher Albitar, MD, and others) Using NGS RNA sequencing plus a machine learning approach, researchers looked at over 1,400 genes in 46 patients who had an allogeneic bone marrow transplant and developed a model based on 7 genes to predict acute GVHD, one of the most significant complications of receiving a transplant from a bone marrow donor. There are currently no valid ways to predict acute GVHD and intervene early until patients become symptomatic. The ability to identify molecular markers of this complication while patients are asymptomatic may allow for early intervention to prevent GVHD.

Sickle Cell Disease Research

Sustained quality of life in patients receiving gene therapy for sickle cell disease (Abstract #7, Stacey Rifkin-Zenenberg, DO, Hackensack University Medical Center) LentiGlobin gene therapy (bb1111) has been under study in a clinical trial as a one-time treatment and cure for sickle cell disease. This study presented long-term quality of life data for one group in the study, demonstrating an improvement in hematologic parameters and complete resolution of veno-occlusive events and related pain as well as sustained and clinically meaningful improvement in quality of life 6 and 24 months post-treatment. Even patients with the worst baseline quality of life scores experienced a benefit. LentiGlobin is the first gene therapy for sickle cell disease and the results of this study are very promising, with the potential to change patient outcomes for this chronic debilitating disease.

The full set of ASH data presentations by JTCC researchers is as follows:

Abstract #

Type

Title

Authors

Presenting (PST)

2

Plenary Scientific Session

Primary Analysis of ZUMA-7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Lori A. Leslie

Sunday, December 12, 2021: 2:00 PM-4:00 PM

7

Oral

Sustained Improvements in Patient-Reported Quality of Life up to 24 Months Post-Treatment with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Stacey Rifkin

Saturday, December 11, 2021: 9:30 AM-11:00 AM

50

Oral

A Large Multicenter Real-World Evidence (RWE) Analysis of Autoimmune (AI) Diseases and Lymphoma: Histologic Associations, Disease Characteristics, Survival, and Prognostication

Tatyana A. Feldman, Jason Lofters

Saturday, December 11, 2021: 9:45 AM

66

Oral

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

James K McCloskey

Saturday, December 11, 2021: 10:45 AM

93

Oral

Long-Term Follow-up Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Pashna N. Munshi, Lori A. Leslie,

Saturday, December 11, 2021: 10:00 AM

133

Oral

Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (CHEP-BV) Followed By BV Consolidation in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Tatyana A. Feldman, Lori A. Leslie

Saturday, December 11, 2021: 12:00 PM-1:30 PM

165

Oral

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Andrew Ip, MD, Andre Goy

Saturday, December 11, 2021: 12:30 PM

184

Oral

A Multi-Center Retrospective Review of COVID-19 Outcomes in Patients with Lymphoid Malignancy

Lori A. Leslie

Saturday, December 11, 2021: 12:00 PM-1:30 PM

307

Oral

Post Hoc Analysis of Responses to Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) By Baseline BCR-ABL1 Level and Baseline Mutation Status in the Optic Trial

James K McCloskey

Saturday, December 11, 2021: 4:00 PM-5:30 PM

395

Oral

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

Lori A. Leslie

Sunday, December 12, 2021: 10:30 AM

548

Oral

Updated Clinical and Correlative Results from the Phase I CRB-402 Study of the BCMA-Targeted CAR T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma

David S. Siegel

Sunday, December 12, 2021: 4:30 PM-6:00 PM

561

Oral

Polyclonality Strongly Correlates with Biological Outcomes and Is Significantly Increased Following Improvements to the Phase 1/2 HGB-206 Protocol and Manufacturing of LentiGlobin for Sickle Cell Disease (SCD; bb1111) Gene Therapy (GT)

Stacey Rifkin-Zenenberg

Sunday, December 12, 2021: 4:30 PM-6:00 PM

622

Oral

Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma

Feldman

More:
John Theurer Cancer Center Investigators Present Pioneering Research at the American Society of Hematology Annual Conference - Yahoo Finance

Cardiac Stem Cells Comments Off on John Theurer Cancer Center Investigators Present Pioneering Research at the American Society of Hematology Annual Conference – Yahoo Finance | December 10th, 2021

On International Day of Disabled Persons, TheHealthSite spoke to Dr. Sunil Bhat, Director and Clinical Lead, Pediatric Hematology, Oncology, and Blood & Marrow Transplantation, Mazumdar Shaw Cancer Centre, Narayana Health City, to discuss the condition and understand the ways one can manage it.

Written by Satata Karmakar | Updated : December 3, 2021 5:31 PM IST

3rd December every year is observed as UN-designated International Day for persons with disabilities. The observance of the Day aims to promote an understanding of disability issues and mobilize support for the dignity, rights, and well-being of persons with disabilities. This year's theme is "not all disabilities are visible" since some of the disabilities are non-visible but they cause significant challenges for people living with such conditions for day-to-day participation in society.

Such non-visible disabilities include some of the rare blood disorders such as Thalassemia, Aplastic Anemia, Sickle cell Anemia, Fanconi Anemia, Hemophilia, and so on. The Rights of People with Disability Bill passed by the Parliament of India in December 2016 included newer disabilities like blood disorders sickle cell anemia, thalassemia, and hemophilia. Today, on International Day of Disabled Persons, TheHealthSite spoke to Dr. Sunil Bhat, Director and Clinical Lead, Pediatric Hematology, Oncology, and Blood & Marrow Transplantation, Mazumdar Shaw Cancer Centre, Narayana Health City, to discuss the condition and understand the ways one can manage it.

In India, the burden of blood disorders and blood cancer is huge. India is even called as Thalassemia capital of the world with over 10,000 new cases every year. Thalassemia is a disabling condition not just because of chronic anemia but other co-morbidities like organ damage, bone damage, and cardiac complications.

People with thalassemia may need lifelong blood transfusions and other therapies (like iron removal medications). With the advances in the medical field, blood stem cell transplant plays an important role in the treatment of various blood disorders like thalassemia, aplastic anemia, and blood cancers as well. For a blood stem cell transplant to be deemed successful, the human leukocyte antigens (HLA) of the donor should match the antigens present in the cells of the patient. Only 30% of the patients find a matching donor in the family and the rest 70% depending on an unrelated donor. Such unrelated donors are being registered by stem cell registries like DKMS BMST Foundation India.

However, despite such a huge disease burden, Indian stem cell donors only form a tiny fraction, about 0.04% of the total listed unrelated donors globally. The main reason is the lack of awareness and prevailing myths around the stem cell donation process deny many patients a second chance at their lives in the country. It is high time that healthy people understand blood stem cell donation is a safe process and come forward to register as a donor. There is only a 1 in a million chance that someone comes as a match for a patient!

Follow us on

Read more here:
Rare Blood Disorders In India: How It Can Lead To Disabilities In People Expert Explains | TheHealthSite. - TheHealthSite

Cardiac Stem Cells Comments Off on Rare Blood Disorders In India: How It Can Lead To Disabilities In People Expert Explains | TheHealthSite. – TheHealthSite | December 10th, 2021

BURLINGTON, Mass.--(BUSINESS WIRE)--PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that BESREMi (ropeginterferon alfa-2b-njft) is now commercially available in the U.S. to eligible patients with polycythemia vera (PV). BESREMi was approved by the FDA in November as the only interferon for adults with polycythemia vera. BESREMi was approved with a boxed warning for risk of serious disorders including aggravation of neuropsychiatric, autoimmune, ischemic and infectious disorders.

Today marks the beginning of a new chapter in the treatment of PV. Our team is delivering on our goal to bring an innovative solution that may help more people manage not only the symptoms of PV, but target the disease itself to gain durable control with potential to reduce progression over time, said Meredith Manning, U.S. General Manager. We look forward to working closely with U.S. providers to raise awareness of this therapy and help advance treatment goals.

PharmaEssentia SOURCE Now Available to Support People with PV in the U.S.

With the commercial availability of BESREMi, PharmaEssentia is also launching a comprehensive patient support program, which can be found at http://www.pharmaessentiaSOURCE.com.

The SOURCE program is available for patients prescribed BESREMi and offers a full suite of services designed to help patients start and stay on therapy. Services include insurance navigation support, titration and injection training, and ongoing adherence guidance. The program also includes physician resources, including guides to help patients get started on treatment and ordering processes.

As part of this program, PharmaEssentia will help patients with financial barriers to starting therapy. The company is offering co-pay and co-insurance programs to assist eligible patients who experience financial need. Programs include a $0 copay card for commercially insured patients, temporary product supply in case of insurance delays and/or gaps in coverage, free drug for the uninsured and under-insured as well as assistance identifying additional support as needed.

Weve designed SOURCE with active input from the PV community to simplify the process for appropriate patients to initiate and maintain access to BESREMi and to benefit from its effects over the long-term, added Manning. Our goal is to ensure that any appropriate person with PV who is prescribed BESREMi is able to receive the therapy.

About Polycythemia Vera

Polycythemia Vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.1

About BESREMi

BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients. After one year, patients with stable complete hematologic response (CHR) can be treated with BESREMi every four weeks.

BESREMi has orphan drug designation for treatment of PV in the United States. The product was approved by the European Medicines Agency (EMA) in 2019 and has received approval in Taiwan and South Korea. BESREMi was invented and is manufactured by PharmaEssentia.

Important Safety Information

IMPORTANT SAFETY INFORMATION AND INDICATIONS

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products.

Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy.

ADVERSE REACTIONS

The most common adverse reactions reported in > 40% of patients in the PEGINVERA study (n=51) were influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. In the pooled safety population (n=178), the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%).

DRUG INTERACTIONS

Patients on BESREMi who are receiving concomitant drugs which are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs. Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression. Avoid use with narcotics, hypnotics or sedatives and monitor patients receiving the combination for effects of excessive CNS toxicity.

USE IN SPECIFIC POPULATIONS

Please see accompanying full Prescribing Information, including Boxed Warning.

About PharmaEssentia

PharmaEssentia Corporation (TPEx: 6446), based in Taipei, Taiwan, is a rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, the company aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today the company is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung. For more information, visit our website or find us on LinkedIn and Twitter.

Forward Looking Statement

This press release contains forward looking statements, including statements regarding the timing of BESREMis availability in the United States, the commercialization plans and expectations for commercializing BESREMi in the United States, and the potential benefits or competitive position of BESREMi. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and similar legislation and regulations under Taiwanese law. These forward-looking statements are based on management expectations and assumptions as of the date of this press release, and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include PharmaEssentias ability to launch BESREMi in the United States, whether BESREMi is successfully commercialized and adopted by physicians and patients, the extent to which reimbursement is available for BESREMi, and the ability to receive FDA and other regulatory approvals for additional indications for BESREMi. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. The information found on our website, and the FDA website, is not incorporated by reference into this press release and is included for reference purposes only.

1 Cerquozzi S, Tefferi A. Blast Transformation and Fibrotic Progression in Polycythemia Vera and Essential Thrombocythemia: A Literature Review of Incidence and Risk Factors. Blood Cancer Journal (2015) 5, e366; doi:10.1038/bcj.2015.95.

2021 PharmaEssentia Corporation. All rights reserved. US-BSRM-2100225 11/21

BESREMi and PharmaEssentia are registered trademarks of PharmaEssentia Corporation, and the PharmaEssentia logo and PharmaEssentia SOURCE are trademarks of PharmaEssentia Corporation.

More here:
PharmaEssentia's BESREMi (ropeginterferon alfa-2b-njft) Now Available for the Treatment of People With Polycythemia Vera in the United States -...

Cardiac Stem Cells Comments Off on PharmaEssentia’s BESREMi (ropeginterferon alfa-2b-njft) Now Available for the Treatment of People With Polycythemia Vera in the United States -… | December 10th, 2021

Shahid Akhter, editor, ETHealthworld, spoke to Ramesh Ramadurai, MD, 3M India, to know more 3M collaborations that can improve and impact cancer care, besides cutting down on the costs in a big way.

How has the technological and infrastructural facilities impacted Bone Marrow Transplantation in India ?Every year nearly 20,000 Indian patients, including many children, who suffer from blood and solid cancers require bone marrow transplantation (BMT). However, only 2,000 of these patients are fortunate enough to receive this therapy, as the cost of bone marrow transplantation can vary from INR 10 Lakhs to 30 Lakhs. It is imperative to reduce the cost of cancer treatment while maintaining a stringent focus on sterilization and quality. It is indeed the need of the hour for us to address this issue.

What are the various technological advancement required for the better functioning of the facilities?Despite the increasing demand for bone marrow transplantation, the number of bone marrow doners in India is astonishingly low. India conducts stem cell transplant procedure for approximately 2,000 every year, while around 80,000 to 100,000 annual transplants are required to tackle the burden of blood cancers and fatal blood disorders. Finding a matching donor is very difficult. This option is exercised only after the alternative options have failed.

India has only about 400,000 donors registered on the bone marrow registry. Chances of finding a donor match are as low as 10% to 15% compared to the West where the chances of matching are as high as 60% to 70% due to higher rates of donations.

What are the major and significant developments in treating bone marrow cancer in the country?A bone marrow registry collects information on individuals willing and able to donate bone marrow and gathers the donor information into a database. In India, organisations like Datri are helping to create a pool of donors to help people who do not have blood-related donors by finding an unrelated match for life-saving treatment.

Infusion of a memory cell is another advancement. This involves taking out the cells, sorting the good cells and the memory cells or the fighting cells, which can fight infections, sorting them out, capturing them and putting them back into the body after giving the requisite chemotherapy. This is also called T-cell depletion with memory cell infusion. It is now available in India and is affordable.

Through this partnership with United Way Bengaluru and Sri Shankara Cancer Hospital and Research Centre (SSCHRC), how does 3M aim to foster accessibility for people from different sections of the society in treating cancer. 3M India was brought into the SSCHRC family through United Way of Bengaluru, and this is our second round of engagement with the hospital. Last year, 3M India had donated equipment for cancer research and diagnostics like the Sanger sequencer and QPCR, made enhancements to the childrens play area at the long-stay Lakshmi Childrens center with child-friendly wall graphics, and provided kitchen utensils and cooking counters for the resident families of paediatric cancer patients.

We have donated several critical equipments for the research labs which contribute to the successful treatment of the BMT patients. As on date the BMT unit at SSCHRC has treated and discharged 5 patients and currently 4 are undergoing treatment. This wing of the hospital is accessible by few staff nurses and specialists like Dr K N Nataraj who is the Chief of Adult and Paediatric Haematology at the hospital. For a successful bone marrow transplantation, there are several requisites, some of which include, successful donor matching, extremely technique-sensitive harvesting and transplantation processes and robust infection control. With this essential, life-saving equipment, the cost of the treatment will reduce to approximately 50% (between Rs 8-12 Lacs as against the actual cost of Rs 15- 30 lacs) and help the hospital treat many more cancer patients.

How do 3M India and Sri Shankara Hospital plan to take this initiative ahead in the future for the growth and enhancement of bone marrow transplantation in the facility? It is matter of pride for 3M India and United Way of Bengaluru that we are associated with SSCHRC, an institution at the forefront of providing comprehensive cancer treatment to the needy, through CSR interventions.

By complying with the Foundation for the Accreditation of Cellular Therapy (FACT) Guidelines, the BMT Centre will be a one-of-a-kind medical facility where people of all economic status can receive treatment. Being a growing facility, the hospital is committed to continuing its responsibility towards expansion of multiple hospital beds and medical care. We are inspired by the commitment of the doctors and Sri Shankara Board of Trustees, led by Dr. B.S. Srinath and other dedicated professionals who developed a multifaceted approach to establishment a state of the art, affordable cancer hospital that is accessible to all irrespective of caste, creed, religion, gender or socioeconomic status.

More:
It is imperative to reduce the cost of cancer treatment: Ramesh Ramadurai, MD, 3M India - ETHealthworld.com

Cardiac Stem Cells Comments Off on It is imperative to reduce the cost of cancer treatment: Ramesh Ramadurai, MD, 3M India – ETHealthworld.com | December 10th, 2021

November 19, 2021 Stem cell therapy helped to reduce the number of heart attacks, strokes and death among people with chronic, high-risk, NYHA class II or III heart failure with reduced ejection fraction (HFrEF), especially among those who have higher levels of inflammation, yet hospitalization was not reduced, according to late-breaking research presented at the American Heart Associations Scientific Sessions 2021.

Heart failure is a condition when the heart is unable to adequately pump blood to meet the bodys need for oxygen and nutrients. In heart failure with reduced ejection fraction (HFrEF), the heart muscle enlarges and weakens, resulting in a decrease in pumping ability and fluid buildup in the bodys tissues. Inflammation plays a significant role in the progression of heart failure over time.

This study set out to examine the effects of using stem cells (mesenchymal precursor cells) injected into the heart to target inflammation and treat chronic heart failure. Researchers hypothesized that a single injection of stem cells from healthy adult donors in addition to guideline-directed medical therapy (GDMT) for heart failure would affect the number of times participants were hospitalized for heart failure events and reduce heart attacks, strokes, and/or death.

Cell therapy has the potential to change how we treat heart failure, said Emerson C. Perin, M.D., Ph.D., the studys lead author, the director of the Center for Clinical Research and medical director of the Texas Heart Institute in Houston. This study addresses the inflammatory aspects of heart failure, which go mostly untreated, despite significant pharmaceutical and device therapy development. Our findings indicate stem cell therapy may be considered for use in addition to standard guideline therapies.

The Randomized Trial of Targeted Transendocardial Delivery of Mesenchymal Precursor Cells in High-Risk Chronic Heart Failure Patients with Reduced Ejection Fraction study also called the DREAM-HF trial, is the largest stem cell therapy study to date among people with heart failure. In this multi-center, randomized, sham-controlled, double-blind trial, researchers enrolled 537 participants (average age 63, 20% female) with heart failure and reduced ejection fraction, which is when the left side of the heart, its main pumping chamber, is significantly weakened.

Heart failure was defined using the New York Heart Association (NYHA) functional classification system. This classification system places patients in one of four categories based on how much they are limited during physical activity. Class I heart failure means no limitation of physical activity, with class IV heart failure meaning an inability to have any physical activity without discomfort.

Participants were randomly divided into two groups: 261 adults received an injection of 150 million mesenchymal precursor cells, commonly known as stem cells, directly into the heart using a catheter. The remaining 276 adults received a scripted, or sham, procedure. Healthy adult donors provided the mesenchymal precursor cells.

The study participants were discharged from the hospital the day after the procedure, and researchers followed these participants for an average of 30 months. The studys focus was to examine if the stem cell treatment affected the likelihood of participants returning to the hospital for treatment of worsening heart failure. They also tracked whether participants had a heart attack or stroke, or died, and measured levels of high-sensitivity C-reactive protein (CRP), a measure in the blood indicating inflammation.

While researchers did not see a decrease in hospitalizations due to the stem cell treatment, they did notice several other significant results. The findings include:

We were impressed to learn that stem cell treatment effects were additive to current standard heart failure treatments, Perin said. For the first time, the known anti-inflammatory mechanism of action of these cells may be linked to a cause-and-effect benefit in heart failure. The stem cells acted locally in the heart, and they also helped in blood vessels throughout the body.

Perin and colleagues believe further research is needed to better understand how these stem cells may affect the course of progression of heart failure and how these therapies may be directed to the patient groups that could see the most benefits.

Limitations to the research include the selection of endpoints commonly used in heart failure studies. The studys results suggest that traditional endpoints associated with recurrent heart failure hospitalization do not fully reveal the benefits or mechanisms of these stem cells on heart attack, stroke and death in patients with chronic heart failure.

Co-authors are Barry H. Greenberg, M.D.; Kenneth M. Borow, M.D.; Timothy D. Henry II, M.D.; Farrell O. Mendelsohn, M.D.; Les R. Miller, M.D.; Elizabeth Swiggum, M.D.; Eric D. Adler, M.D.; Christopher A. James, P.A.; and Silviu Itescu, M.D. Authors disclosures are listed in the abstract.

The study was funded by Mesoblast Inc.

https://www.dicardiology.com/article/late-breaking-science-presentations-aha-2021-meeting

Read the rest here:
Stem Cell Therapy for Heart Failure Reduced Major Cardiac Events and Death - Diagnostic and Interventional Cardiology

Cardiac Stem Cells Comments Off on Stem Cell Therapy for Heart Failure Reduced Major Cardiac Events and Death – Diagnostic and Interventional Cardiology | November 22nd, 2021

DUBLIN--(BUSINESS WIRE)--The "Induced Pluripotent Stem Cell (iPSC) Market Share, Size, Trends, Industry Analysis Report By Application (Manufacturing, Academic Research, Drug Development & Discovery, Toxicity Screening, Regenerative Medicine); By Derived Cell; By Region, Segment & Forecast, 2021 - 2028" report has been added to ResearchAndMarkets.com's offering.

The global Induced Pluripotent Stem Cell (iPSC) market size is expected to reach $2,893.3 million by 2028

The ability to model human diseases in vitro as well as high-throughput screening has greatly propelled market growth. Companies have effectively overcome market hurdles faced in the recent past such as proper culturing and differentiation of derived cells at a commercial scale and have developed state-of-the-art manufacturing processes that can achieve scalability and can achieve stringent quality parameters. Such trends are propelling the overall industry growth.

Companies have also developed advanced platforms for Induced pluripotent stem cells that guarantee close connection with a host of in-house technologies that are useful in the proper definition of disease signatures as well as relationships between genetic mutations as well as that properly describe perturbation of specific molecular pathways. This has resulted in the creation of human translational models that are aiding better target identification of diseases that have high unmet medical needs.

Many companies have developed transfection kits, reprogramming vectors, differentiation media, live staining kits, immunocytochemistry, among others to aid the smooth workflow of iPSC production.

However, it has been observed in the recent past that the demand for cells for screening and other purposes is significant and that there are significant challenges that pose a significant hurdle in large-scale iPSC production and differentiation.

Heavy investment in R&D activities pertaining to the development and optimization of iPSC reprogramming process in order to achieve sufficient production is a key industry trend. In the recent past, companies focused more on hepatic, cardiac, pancreatic cells, among others.

However, with the advent of a number of new participants as well as advancements and breakthroughs achieved, it is anticipated that the application portfolio will further increase in the near future.

Industry participants operating in the industry are:

Key Topics Covered:

1. Introduction

2. Executive Summary

3. Research Methodology

4. iPSC Market Insights

4.1. iPSC - Industry Snapshot

4.2. iPSC Market Dynamics

4.2.1. Drivers and Opportunities

4.2.1.1. Increasing demand for body reconstruction procedures and tissue engineering

4.2.1.2. Rising Investments across the globe

4.2.2. Restraints and Challenges

4.2.2.1. Scalability Issues

4.3. Porter's Five Forces Analysis

4.4. PESTLE Analysis

4.5. iPSC Market Industry trends

4.6. COVID-19 Impact Analysis

5. Global iPSC Market, by Derived Cell

5.1. Key Findings

5.2. Introduction

5.3. Hepatocytes

5.4. Fibroblasts

5.5. Amniotic Cells

5.6. Cardiomyocytes

6. Global iPSC Market, by Application

6.1. Key Findings

6.2. Introduction

6.2.1. Global iPSC Market, by Application, 2017 - 2028 (USD Million)

6.3. Manufacturing

6.4. Academic Research

6.5. Drug Development & Discovery

6.6. Toxicity Screening

6.7. Regenerative Medicine

7. Global iPSC Market, by Geography

7.1. Key findings

7.2. Introduction

7.2.1. iPSC Market Assessment, By Geography, 2017 - 2028 (USD Million)

8. Competitive Landscape

8.1. Expansion and Acquisition Analysis

8.1.1. Expansion

8.1.2. Acquisitions

8.2. Partnerships/Collaborations/Agreements/Exhibitions

9. Company Profiles

9.1. Company Overview

9.2. Financial Performance

9.3. Product Benchmarking

9.4. Recent Development

For more information about this report visit https://www.researchandmarkets.com/r/ykewbe

See original here:
Global Induced Pluripotent Stem Cell (iPSC) Market Report 2021-2028 - Increasing Demand for Body Reconstruction Procedures and Tissue Engineering -...

Cardiac Stem Cells Comments Off on Global Induced Pluripotent Stem Cell (iPSC) Market Report 2021-2028 – Increasing Demand for Body Reconstruction Procedures and Tissue Engineering -… | November 22nd, 2021