Are ‘robot massages’ the future of muscle repair? – Medical News Today

By daniellenierenberg

Skeletal muscle enables the body to move and maintain posture. Direct injury for instance, from trauma can impair a persons movement and quality of life.

People have been using massage and other mechanotherapies for thousands of years to soothe aching and injured muscles. However, the science behind the effects of massage has not been examined in detail.

Lots of people have been trying to study the beneficial effects of massage and other mechanotherapies on the body, but up to this point, it hadnt been done in a systematic, reproducible way, explains lead author of the current study Dr. Bo Ri Seo, Ph.D.

Our work shows a very clear connection between mechanical stimulation and immune function, he continues.

Like much of the human body, skeletal muscle can repair itself. The process involves three stages:

When muscle injury occurs, muscle fibers rupture and die. White blood cells invade the injury site, removing the dead muscle cells and activating cells that help mount an immune response. This includes the release of growth factors, cytokines, and chemokines.

During the repair phase, satellite cells, or muscle precursor cells, grow and differentiate into muscle cells. These then replace injured cells in the muscle fiber, and scar tissue forms.

In the remodeling phase, muscle fibers mature, and scar tissue contracts. However, extensive injuries may cause dense scar tissue formation, impeding muscle repair and resulting in incomplete recovery of muscle function.

Despite its complications, surgical treatment remains the current standard of care for severe muscle injury.

Recognizing the need for an effective noninvasive treatment for severe skeletal muscle injury, researchers from Harvard University in Cambridge, MA, conducted a study investigating the use of mechanotherapy as a potential treatment.

Their findings appear in the journal Science Translational Medicine.

Dr. Seo, who is a postdoctoral fellow at the Wyss Institute at Harvard, explained to Medical News Today:

Our previous study has shown the beneficial impacts of compressive loading for skeletal muscle regeneration. Based on the finding, we wanted to develop a [scientifically] validated, optimal protocol for mechanotherapy and to understand the mechanisms associated with the therapeutic impacts.

The researchers developed an external robotic device to deliver a precise, controlled, and measurable pressure to the leg muscle in mice. The scientists also used ultrasound to measure tissue response to the stress applied.

One to 14 days after injury, the scientists gave the mice in the treatment group mechanotherapy with pressure corresponding to muscle strains of 10, 20, or 40% for 5 minutes every 1012 hours. The scientists did not treat mice in the control group.

Compared with the control mice, the mice in the treatment group demonstrated a significant reduction in muscle fiber damage and scarring. The authors also note increased muscle fiber diameter, which is an indicator of repair and strength recovery.

Since muscle repair improvements were similar across the 10, 20, and 40% groups, the study continued using the 20% muscle strain pressure setting for the remaining experiments.

To uncover how mechanotherapy promoted muscle repair, the researchers also measured levels of inflammatory factors cytokines and chemokines over time.

The study identified that mechanotherapy reduced levels of a cytokine responsible for the movement of neutrophils by more than half by day 3. Neutrophils help clear damaged cells and communicate with other cells to promote repair and immune response. Neutrophils also play a role in inflammation.

To understand why neutrophils and cytokines were moving out of the muscle, the researchers injected a fluorescent compound into the muscle. They observed that mechanotherapy was directly causing this exodus from the muscle.

Next, the scientists cultured satellite cells which are essentially muscle stem cells with factors that neutrophils secrete. They wanted to assess their effects on muscle repair.

The study authors found that neutrophil-secreted factors initially promoted repair, but when they were present for a longer time, they impaired muscle fiber production.

After analyzing the muscle fibers produced in the two groups after 14 days, the researchers found that the leg muscle cells treated with mechanotherapy contained more type IIX fibers.

Type IIX fibers have a larger diameter and can produce increased force, consistent with the results the researchers saw in the mice that received mechanotherapy.

In the final experiment, the scientists used an antibody treatment to remove neutrophils in the mice during the first 3 days after injury. They found that the muscles of the treated mice recovered more quickly.

They discovered that both mechanotherapy and antibody treatment led to significantly reduced muscle damage and the development of larger muscle fibers.

Dr. Bert Mandelbaum, who was not involved in the study, also spoke with MNT. Dr. Mandelbaum is an orthopedic surgeon at Cedars-Sinai Kerlan-Jobe Institute and co-director of the Cedars-Sinai Regenerative Orthobiologics Center in Los Angeles.

He was intrigued by the experimental design particularly the use of robotics to prescribe specific muscle loads and then assessing the biological factors that the loads produce.

Speaking about the results, lead author Dr. Seo told MNT:

It was super exciting to see that the severely injured muscle treated with biologic-free/noninvasive compressive loading shows comparable functional outcomes to the ones treated with biologics-based therapies found from other studies.

Also, we were surprised by the fact that neutrophils were significantly involved in this process by directly influencing muscle progenitor cell activities, he continued.

In addition, we found that compressive loading rapidly reduces neutrophils and their associated factors by day 3 after injury with this change [] confined to the injured site. This makes mechanotherapy a great therapeutic candidate for patients who are already using other medical interventions or existing health complications for example, inflammatory diseases.

He went on to say: Our findings are based on [studies in] mice, so further studies are needed to confirm its impacts for larger animals and humans. Furthermore, since the kinetics and amplitudes of immune response can differ depending on types of injuries, how and what to be delivered should be optimized accordingly.

In conclusion, Dr. Mandelbaum told MNT, I think its a great hypothesis, something needing to be proven over time.

Skin Stem Cells commento

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October 16th, 2021

Merck and Eisai Receive Positive EU CHMP Opinions for KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) in Two Different Types of Cancer – Business…

By daniellenierenberg

KENILWORTH, N.J. & TOKYO--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted positive opinions recommending approval of the combination of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA (marketed as KISPLYX in the European Union [EU] for the treatment of advanced renal cell carcinoma [RCC]), the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for two different indications. One positive opinion is for the first-line treatment of adult patients with advanced RCC, and the other is for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation. Decisions on the CHMPs recommendations will be given by the European Commission for marketing authorization in the EU, and are expected in the fourth quarter of 2021. If approved, this would be the first combination of an anti-PD-1 therapy with a tyrosine kinase inhibitor approved for the treatment of two different types of cancer in the EU.

The positive CHMP opinions are based on data from two pivotal Phase 3 trials: CLEAR (Study 307)/KEYNOTE-581 evaluating the combination in adult patients with advanced RCC and KEYNOTE-775/Study 309 evaluating the combination in certain patients with advanced EC.

In CLEAR/KEYNOTE-581, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements versus sunitinib in the efficacy outcome measures of overall survival (OS), reducing the risk of death by 34% (HR=0.66 [95% CI, 0.49-0.88]; p=0.0049) versus sunitinib, and progression-free survival (PFS), reducing the risk of disease progression or death by 61% (HR=0.39 [95% CI, 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months versus 9.2 months for sunitinib. Additionally, the confirmed objective response rate was 71% (95% CI: 66-76) (n=252) for patients who received KEYTRUDA plus LENVIMA versus 36% with sunitinib (95% CI: 31-41) (n=129).

In KEYNOTE-775/Study 309, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements in the studys dual efficacy outcome measures of OS, reducing the risk of death by 38% (HR=0.62 [95% CI, 0.51-0.75]; p<0.0001) with a median OS of 18.3 months versus 11.4 months for chemotherapy (investigators choice of doxorubicin or paclitaxel), and PFS, reducing the risk of disease progression or death by 44% (HR=0.56 [95% CI, 0.47-0.66]; p<0.0001), with a median PFS of 7.2 months versus 3.8 months for chemotherapy (investigators choice of doxorubicin or paclitaxel).

KEYTRUDA plus LENVIMA demonstrated a survival benefit for advanced renal cell carcinoma in the first-line setting and represents an important potential new treatment option for these patients. Additionally, KEYTRUDA plus LENVIMA is the first anti-PD-1 and tyrosine kinase inhibitor combination to demonstrate a survival benefit in advanced endometrial carcinoma patients, and the benefit was shown regardless of mismatch repair status, said Dr. Gregory Lubiniecki, Vice President, Clinical Research, Merck Research Laboratories. We are pleased that the CHMP has recognized the important role of the combination therapy in these difficult-to-treat cancers.

We appreciate the positive opinions rendered by the EU CHMP recommending approval of KEYTRUDA plus LENVIMA in advanced renal cell carcinoma and advanced endometrial carcinoma, underscoring the potential significance of the outcomes observed in the CLEAR/KEYNOTE-581 and KEYNOTE-775/Study 309 trials, said Dr. Takashi Owa, President, Oncology Business Group at Eisai. We are grateful to the patients who participated in these studies, their families and clinicians. Their commitment made these meaningful milestones possible.

The safety of KEYTRUDA in combination with axitinib or LENVIMA in advanced RCC, and in combination with LENVIMA in advanced EC has been evaluated in a total of 1,456 patients with advanced RCC or advanced EC. In these patient populations, the most frequent adverse reactions were diarrhea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite and nausea (40% each), arthralgia (30%), vomiting, weight decreased, dysphonia and abdominal pain (28% each), proteinuria (27%), palmar plantar erythrodysesthesia syndrome and rash (26% each), stomatitis and constipation (25% each), musculoskeletal pain and headache (23% each) and cough (21%).

About Renal Cell Carcinoma (RCC)

Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In Europe, it is estimated there were more than 138,000 new cases of kidney cancer diagnosed and more than 54,000 deaths from the disease in 2020. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCC. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis. Survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 13% for patients diagnosed with metastatic disease.

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases and more than 97,000 deaths from uterine body cancers in 2020 (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In Europe, it is estimated there were more than 130,000 new cases and more than 29,000 deaths in 2020. The five-year relative survival rate for metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

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 1,600 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 KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

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.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS 1)] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any settings and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

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 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

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 (20%) and increased aspartate aminotransferase (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)

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Merck and Eisai Receive Positive EU CHMP Opinions for KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) in Two Different Types of Cancer - Business...

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October 16th, 2021

Autologous Stem Cell Based Therapies Market Consumption Status and Prospects Professional Market Research Report 2025 – Northwest Diamond Notes

By daniellenierenberg

The Autologous Stem Cell Based Therapies market report delivers a complete analysis of critical aspects such as the predominant trends and growth opportunities that will assure considerable returns in the ensuing years. Also, it offers various solutions to tackle the present and upcoming challenges in the industry vertical. Besides, the document expounds the size and share of market segments including the product landscape, application spectrum, and geographical ambit. Furthermore, it discusses the after-effects of COVID-19 pandemic on this domain, uncovering the top revenue generating strategies for the approaching years.

Key pointers from case studies on COVID-19 impact:

Overview of the regional assessment:

Request Sample Copy of this Report @ https://www.nwdiamondnotes.com/request-sample/37424

Other vital inclusions in the Autologous Stem Cell Based Therapies market report:

Research Objective:

Why to Select This Report:

Key questions answered in the report:

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Autologous Stem Cell Based Therapies Market Consumption Status and Prospects Professional Market Research Report 2025 - Northwest Diamond Notes

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October 16th, 2021

Horizon Therapeutics Public : plc – New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the…

By daniellenierenberg

DUBLIN - Horizon Therapeutics plc (Nasdaq: HZNP) announced the publication of a post-hoc analysis from the N-MOmentum phase 2/3 pivotal trial of UPLIZNA, which highlights a sustained effect on attack risk with no new safety signals in people with NMOSD who received the treatment for four or more years. These data are published in the Multiple Sclerosis Journal.

NMOSD is a rare, severe autoimmune disease that attacks the optic nerve, spinal cord and brain stem. The attacks are often recurrent and can cause irreversible damage to the nerves, leading to cumulative visual and motor disabilities over time. UPLIZNA is the first and only FDA-approved anti-CD19 B-cell-depleting humanized monoclonal antibody for the treatment of adult patients with anti-aquaporin-4 (AQP4) antibody positive NMOSD.

'This long-term study is important because NMOSD is a chronic disease that requires lifelong management. Physicians need to understand the implications of prolonged treatment,' said Bruce Cree, M.D., Ph.D., MAS, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences and primary study investigator. 'It is highly encouraging to see that most patients in this study were attack-free after the first year of UPLIZNA treatment and that new safety concerns were not observed. The data demonstrate that long-term UPLIZNA use is associated with a reduced risk of NMOSD attacks - possibly due to the depth and extent of B-cell depletion with repeated doses.'

The post-hoc analysis represents the experience of 75 people with AQP4 antibody positive NMOSD who were treated with UPLIZNA for four or more years during the open-label extension period of the N-MOmentum trial.

Key study findings include the following:

A total of 18 attacks occurred in 13 people, with an annualized attack rate of 0.052 attacks per person year.

The small number of total attacks decreased significantly after the first year of treatment with UPLIZNA.

67% of attacks occurred within the first year (12 attacks).

92% of patients were attack-free in subsequent years (two attacks each during years two to four).

The infection rate did not increase over time on treatment with UPLIZNA.

UPLIZNA was generally well tolerated, with few treatment-related dose interruptions and no treatment discontinuations.

'NMOSD is a complex and often unpredictable B-cell-mediated disease that presents significant challenges to both patients and physicians,' said Kristina Patterson, M.D., Ph.D., medical director, neuroimmunology, Horizon. 'With recent treatment advancements, the NMOSD community now has more options than ever before - including UPLIZNA, which is engineered for broad, deep and durable B-cell depletion. We are fully committed to increasing our understanding of this disease so we can continue to improve patient care.'

About Neuromyelitis Optica Spectrum Disorder (NMOSD)

NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.1,2 Approximately 80 percent of all patients with NMOSD test positive for anti-AQP4 antibodies.3 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.4

Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.5 Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.7 Each NMOSD attack can lead to further cumulative damage and disability.8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.10,11

About UPLIZNA

INDICATION

UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

IMPORTANT SAFETY INFORMATION

UPLIZNA is contraindicated in patients with:

A history of life-threatening infusion reaction to UPLIZNA

Active hepatitis B infection

Active or untreated latent tuberculosis

WARNINGS AND PRECAUTIONS

Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic.

Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

The risk of hepatitis B virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.

Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.

Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.

Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

For additional information on UPLIZNA, please see Prescribing Information at http://www.UPLIZNA.com.

About Horizon

Horizon is focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: we apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, please visit http://www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA and Horizon's research and development plans. These forward-looking statements are based on management's 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, but are not limited to, risks regarding whether future results of clinical trials will be consistent with preliminary results or results of prior trials or other data or Horizon's expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizon's filings with the United States Securities and Exchange Commission, including those factors discussed under the caption 'Risk Factors' in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law.

Contact:

Rachel Vann

Director

Product Communications

E: media@horizontherapeutics.com

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Horizon Therapeutics Public : plc - New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the...

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October 5th, 2021

New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the Treatment of Neuromyelitis Optica…

By daniellenierenberg

DUBLIN--(BUSINESS WIRE)--Horizon Therapeutics plc (Nasdaq: HZNP) today announced the publication of a post-hoc analysis from the N-MOmentum phase 2/3 pivotal trial of UPLIZNA, which highlights a sustained effect on attack risk with no new safety signals in people with NMOSD who received the treatment for four or more years. These data are published in the Multiple Sclerosis Journal.

This long-term study is important because NMOSD is a chronic disease that requires lifelong management. Physicians need to understand the implications of prolonged treatment, said Bruce Cree, M.D., Ph.D., MAS, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences and primary study investigator. It is highly encouraging to see that most patients in this study were attack-free after the first year of UPLIZNA treatment and that new safety concerns were not observed. The data demonstrate that long-term UPLIZNA use is associated with a reduced risk of NMOSD attacks possibly due to the depth and extent of B-cell depletion with repeated doses.

Key study findings include the following:

NMOSD is a complex and often unpredictable B-cell-mediated disease that presents significant challenges to both patients and physicians, said Kristina Patterson, M.D., Ph.D., medical director, neuroimmunology, Horizon. With recent treatment advancements, the NMOSD community now has more options than ever before including UPLIZNA, which is engineered for broad, deep and durable B-cell depletion. We are fully committed to increasing our understanding of this disease so we can continue to improve patient care.

About Neuromyelitis Optica Spectrum Disorder (NMOSD)

About UPLIZNA

INDICATION

UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

IMPORTANT SAFETY INFORMATION

UPLIZNA is contraindicated in patients with:

WARNINGS AND PRECAUTIONS

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

For additional information on UPLIZNA, please see Prescribing Information at http://www.UPLIZNA.com.

About Horizon

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA and Horizons research and development plans. These forward-looking statements are based on management's 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, but are not limited to, risks regarding whether future results of clinical trials will be consistent with preliminary results or results of prior trials or other data or Horizons expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizons filings with the United States Securities and Exchange Commission, including those factors discussed under the caption Risk Factors in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law.

References

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New Analysis Published in Multiple Sclerosis Journal Assesses Long-Term Use of UPLIZNA (inebilizumab-cdon) for the Treatment of Neuromyelitis Optica...

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October 5th, 2021

Stem cells: Therapy, controversy, and research

By daniellenierenberg

Researchers have been looking for something that can help the body heal itself. Although studies are ongoing, stem cell research brings this notion of regenerative medicine a step closer. However, many of its ideas and concepts remain controversial. So, what are stem cells, and why are they so important?

Stem cells are cells that can develop into other types of cells. For example, they can become muscle or brain cells. They can also renew themselves by dividing, even after they have been inactive for a long time.

Stem cell research is helping scientists understand how an organism develops from a single cell and how healthy cells could be useful in replacing cells that are not working correctly in people and animals.

Researchers are now studying stem cells to see if they could help treat a variety of conditions that impact different body systems and parts.

This article looks at types of stem cells, their potential uses, and some ethical concerns about their use.

The human body requires many different types of cells to function, but it does not produce every cell type fully formed and ready to use.

Scientists call a stem cell an undifferentiated cell because it can become any cell. In contrast, a blood cell, for example, is a differentiated cell because it has already formed into a specific kind of cell.

The sections below look at some types of stem cells in more detail.

Scientists extract embryonic stem cells from unused embryos left over from in vitro fertilization procedures. They do this by taking the cells from the embryos at the blastocyst stage, which is the phase in development before the embryo implants in the uterus.

These cells are undifferentiated cells that divide and replicate. However, they are also able to differentiate into specific types of cells.

There are two main types of adult stem cells: those in developed bodily tissues and induced pluripotent stem (iPS) cells.

Developed bodily tissues such as organs, muscles, skin, and bone include some stem cells. These cells can typically become differentiated cells based on where they exist. For example, a brain stem cell can only become a brain cell.

On the other hand, scientists manipulate iPS cells to make them behave more like embryonic stem cells for use in regenerative medicine. After collecting the stem cells, scientists usually store them in liquid nitrogen for future use. However, researchers have not yet been able to turn these cells into any kind of bodily cell.

Scientists are researching how to use stem cells to regenerate or treat the human body.

The list of conditions that stem cell therapy could help treat may be endless. Among other things, it could include conditions such as Alzheimers disease, heart disease, diabetes, and rheumatoid arthritis. Doctors may also be able to use stem cells to treat injuries in the spinal cord or other parts of the body.

They may do this in several ways, including the following.

In some tissues, stem cells play an essential role in regeneration, as they can divide easily to replace dead cells. Scientists believe that knowing how stem cells work can help treat damaged tissue.

For instance, if someones heart contains damaged tissue, doctors might be able to stimulate healthy tissue to grow by transplanting laboratory-grown stem cells into the persons heart. This could cause the heart tissue to renew itself.

One study suggested that people with heart failure showed some improvement 2 years after a single-dose administration of stem cell therapy. However, the effect of stem cell therapy on the heart is still not fully clear, and research is still ongoing.

Another investigation suggested that stem cell therapies could be the basis of personalized diabetes treatment. In mice and laboratory-grown cultures, researchers successfully produced insulin-secreting cells from stem cells derived from the skin of people with type 1 diabetes.

Study author Jeffrey R. Millman an assistant professor of medicine and biomedical engineering at the Washington University School of Medicine in St. Louis, MO said, What were envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin.

Millman hopes that these stem cell-derived beta cells could be ready for research in humans within 35 years.

Stem cells could also have vast potential in developing other new therapies.

Another way that scientists could use stem cells is in developing and testing new drugs.

The type of stem cell that scientists commonly use for this purpose is the iPS cell. These are cells that have already undergone differentiation but which scientists have genetically reprogrammed using genetic manipulation, sometimes using viruses.

In theory, this allows iPS cells to divide and become any cell. In this way, they could act like undifferentiated stem cells.

For example, scientists want to grow differentiated cells from iPS cells to resemble cancer cells and use them to test anticancer drugs. This could be possible because conditions such as cancer, as well as some congenital disabilities, happen because cells divide abnormally.

However, more research is taking place to determine whether or not scientists really can turn iPS cells into any kind of differentiated cell and how they can use this process to help treat these conditions.

In recent years, clinics have opened that offer different types of stem cell treatments. One 2016 study counted 570 of these clinics in the United States alone. They appear to offer stem cell-based therapies for conditions ranging from sports injuries to cancer.

However, most stem cell therapies are still theoretical rather than evidence-based. For example, researchers are studying how to use stem cells from amniotic fluid which experts can save after an amniocentesis test to treat various conditions.

The Food and Drug Administration (FDA) does allow clinics to inject people with their own stem cells as long as the cells are intended to perform only their normal function.

Aside from that, however, the FDA has only approved the use of blood-forming stem cells known as hematopoietic progenitor cells. Doctors derive these from umbilical cord blood and use them to treat conditions that affect the production of blood. Currently, for example, a doctor can preserve blood from an umbilical cord after a babys birth to save for this purpose in the future.

The FDA lists specific approved stem cell products, such as cord blood, and the medical facilities that use them on its website. It also warns people to be wary of undergoing any unproven treatments because very few stem cell treatments have actually reached the earliest phase of a clinical trial.

Historically, the use of stem cells in medical research has been controversial. This is because when the therapeutic use of stem cells first came to the publics attention in the late 1990s, scientists were only deriving human stem cells from embryos.

Many people disagree with using human embryonic cells for medical research because extracting them means destroying the embryo. This creates complex issues, as people have different beliefs about what constitutes the start of human life.

For some people, life starts when a baby is born, while for others, it starts when an embryo develops into a fetus. Meanwhile, other people believe that human life begins at conception, so an embryo has the same moral status and rights as a human child.

Former U.S. president George W. Bush had strong antiabortion views. He believed that an embryo should be considered a life and not be used for scientific experiments. Bush banned government funding for human stem cell research in 2001, but former U.S. president Barack Obama then revoked this order. Former U.S. president Donald Trump and current U.S. president Joe Biden have also gone back and forth with legislation on this.

However, by 2006, researchers had already started using iPS cells. Scientists do not derive these stem cells from embryonic stem cells. As a result, this technique does not have the same ethical concerns. With this and other recent advances in stem cell technology, attitudes toward stem cell research are slowly beginning to change.

However, other concerns related to using iPS cells still exist. This includes ensuring that donors of biological material give proper consent to have iPS cells extracted and carefully designing any clinical studies.

Researchers also have some concerns that manipulating these cells as part of stem cell therapy could lead to the growth of cancerous tumors.

Although scientists need to do much more research before stem cell therapies can become part of regular medical practice, the science around stem cells is developing all the time.

Scientists still conduct embryonic stem cell research, but research into iPS cells could help reduce some of the ethical concerns around regenerative medicine. This could lead to much more personalized treatment for many conditions and the ability to regenerate parts of the human body.

Learn more about stem cells, where they come from, and their possible uses here.

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Stem cells: Therapy, controversy, and research

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October 5th, 2021

How much does stem cell therapy cost in 2021? – The Niche

By daniellenierenberg

One of the most common questions Ive gotten over the last decade is, how much does stem cell therapy cost? They actually seem most often to want to know more specifically how much itshould cost.

To try to authoritatively answer this now in 2021 we need data from the present and past along with expert perspectives.

These kinds of questions on what are common and reasonable prices have continued in 2021. However, the types of queries have also evolved as things have gotten more complicated. There are many layers to the question of cost, which I cover here in todays article. In the big picture, the most worrisome potential cost is to your health if you proceed with unproven stem cell injections.

This post is the most comprehensive look at stem cell treatment cost and costs of related therapies that Ive seen on the web, especially factoring in our inclusion of historical polling data from past years here on The Niche. The above bullet point list is what is covered in todays post and you can jump to sections that interest you most by clicking on those table of contents bullet points.

You can also watch the video I made summarizing the key points of this post below.

Furthermore, it encompasses other important issues related to insurance, fundraising, and approaches to being a smart consumer. Keep in mind that almost all stem cell therapies outside the bone marrow/hematopoietic sphere are not FDA-approved. They mostly lack rigorous data to back them up too. So this post is definitely not recommending you get them. I advise against it, but many people still want info on cost.

Lets get started.

After more than a decade of blogging about stem cells from just about every angle, its interesting to consider trends in the types of questions I get asked. Beyond cost, I also often get asked How much of a stem cell treatment price does insurance cover?

Of course, insurance (or lack thereof) directly bears on cost too. Ill get more into insurance later in the post.

In a way its not so surprising that cost is so much on peoples minds now for a few reasons.

First, as compared to many years back, people now view stem cell injections as a more everyday thing. Stem cell therapy is often available just down the street at a local strip mall.

Back in 2010 and in the 5 or so years after that, people instead more often viewed stem cells as some amazing thing out of reach to them at that time. Now people view stem cell offerings through the lens of consumers.

Sadly, another major part of the reason for the change in perceptions of stem cell treatments is the tidal wave of stem cell clinics from coast to coast in the US selling unproven and sometimes dangerous offerings.

At the same time, some universities and large medical centers also sell stem cell or similar offerings that arent proven. Im worried that that number may be increasing too and patients who may be paying there for unproven stem cells way at the very high end of the cost spectrum, sometimes above $100K.

Other stem cell suppliers and clinics market stem cell-related stuff that isnt real stem cells such as platelet rich plasma or PRP (see my comprehensive guide to PRP including a helpful infographic here) or injections of often dead perinatal stem cell products.

For all these reasons about once every year or two, I do polling asking the readers of The Niche here about their experiences.

Ive done the polling again now in 2020 in a more comprehensive form.

To have a sense of cost, we need to ask patients certain questions. How much did you pay per injection? How many injections did you get? Where did you get them?

Keep in mind that the total cost of stem cell therapy is the product of the cost per injection times the # of injections. For instance, if a stem cell injection costs $8,000 and you get 10 injections, your total cost is $80,000.

Unfortunately, the unproven stem cell clinics generally do not volunteer data on how much they charge. They also often encourage patients to get many injections.

Our 2020 polling data (you can still participate and I will update this) for stem cell treatments are in the graphic above. Here are some highlights.

The self-reported responses on cost for stem cell treatments, as indicated by respondents to our 2020 polling, suggest the price has gone up.

While the most common answer in 2019 was $2,501-$5,000, in 2020 the most common response was $10,001-$20,000, while $2,501-$5,000 was close behind.

The percentage of people paying the most, more than $100,000, was only slightly (probably non-significantly) higher in 2020, but both in 2019 and 2020 the percentage of people paying over $100K was much higher than in 2018 polling.

Keep in mind this is the cost per injection so how many injections do patients typically get? While the number of injections reported most commonly was 1 in both 2019 and 2020, in 2020, the second most common answer was 6-10 injections, a big boost from 2019. Again, more injections end up multiplying things up to boost the total cost. Only a few people in the polling had many injections, but in my view it is still striking to see anyone say theyve received more than 20 stem cell injections.

For comparison, the 2019 polling can be found here, but some of the key results are captured in a combo screenshot Ive included here. I got a lot more responses to the polling in 2019 so that makes me more confident in the data than in the 2020 polling so far, but I hope well get more responses moving forward in 2020 and if we do, again Ill update the info in this post.

What you can see from 2019 is that a plurality of respondents reported getting one stem cell injection, but 60% of people nonetheless got more than one stem cell injection.

Remarkably about 1 in 20-25 people received more than 20 stem cell injections.

About another 1 in 20 people got 6-20 injections. I find this amount of repeat injections to be surprising and concerning as it amplifies health and financial risks.

In terms of cost per injection, the results are pretty similar to 2018 (see at right below) on the whole.

This kind of polling isnt super scientific, but can gauge trends. Unfortunately, I havent really seen much other published data on stem cell clinic costs in actual journals.

I dont know if its noise or not, but the percentage of people paying over $100K is about 2-fold higher in 2019 versus 2018.

There are more people may be paying $10K-$20K as well now in 2020 vs. 2019 or 2018.

There is growing interest from the public in stem cell supplements. I did a post on this earlier in 2020 so take a look here, which was essentially a review of stem cell supplements like Regenokine. In terms of cost, while supplements are far less expensive than getting stem cell, PRP, or exosome injections, supplements are still pricey for what you get. Its not unusual to pay $100 for a small bottle of stem cell supplements, the other factor to consider is that these supplements generally have no solid, published data behind them so you might as well be paying $100 for water. Its unclear what risks taking these supplements might bring as well.

On the economic side, you might think that the feds like the FTC would be actively pursuing false or even fraudulent marketing of stem cells via the web and other kinds of advertising, but in total so far the FTC to my knowledge has only taken relatively few actions such as this one. and then some letters for COVID-related marketing of stem cells and other biologics earlier this year in 2020.

Oddly, there were just that a couple blips of FTC activity, especially considering the sea of questionable stem cell clinic-related ads out there. This ranges from major newspapers to inflight magazines to mobile ads on a stem-cell-mobile to television. Then of course there are the infomercial seminars.

Patients should also view themselves as consumers. Savvy customers considering paying money to stem cell clinics should do their homework. I often tell patients to use at a minimum the kinds of tough standards they bring to the car-buying process. Over the last few years Consumer Reports has been interested in the stem cell treatment world and done some reporting that is worth reading.

A common question I hear is the following: is stem cell therapy covered by insurance? Unfortunately for patients desperate to try stem cells, insurance generally does not provide any coverage, which often leads them to take extreme financial measures. These steps can include fundraising (more below).

In my view, the Regenexx brand has made a big deal out of how some employers contribute towards costs of their clinics offerings. Im not so clear on where that stands today in 2020.

Does Medicare cover stem cell therapies? Medicare will generally cover the cost of established bone marrow transplantation type therapies. However it does not cover unproven stem cell therapies.

Patients are often reaching out to me so I know that many of them have gone to extraordinary measures to raise the money to pay to unproven stem cell clinics. Its painful to think about what little they get in return. Since we are by definition talking about unproven medical procedures here, in my view this money is largely down the drain.

If you have other data on stem cell economic issues such as what patients pay please let me know. Then theres the issue of what it actually costs the clinics per injection and in turn: whats their profit margin?

What ends up happening is that patients take out second mortgages on their houses, try to collect funds from friends and relatives, or turn to online fundraising. The internet fundraising efforts most often end up on GoFundMe. This is a trend Ive been noticing for years. Some colleagues even published a paper on this trend, a very interesting and an important read. The paper is Crowdfunding for Unproven Stem CellBased Interventions in JAMA by Jeremy Snyder,Leigh Turner , and Valorie A. Crooks. Heres a key passage:

As of December 3, 2017, our search identified 408 campaigns (GoFundMe=358; YouCaring=50) seeking donations for stem cell interventions advertised by 50 individual businesses. These campaigns requested $7439308 and received pledges for $1450011 from 13050 donors. The campaigns were shared 111044 times on social media. Two campaigns were duplicated across platforms but shared separately on social media. Of the 408 campaigns, 178 (43.6%) made statements that were definitive or certain about the interventions efficacy, 124 (30.4%) made statements optimistic or hopeful about efficacy, 63 (15.4%) made statements of both kinds, and 43 (10.5%) did not make efficacy claims. All mentions of risks (n=36) claimed the intervention had low/no risks compared with alternative treatments.

Supposedly GoFundMe has taken some steps to lower the often ethically thorny stem cell fundraising on its site, but Im not sure how much it has changed.

There is pressure on stem cell clinics now in 2021 in large part due to two factors. These could drive costs down or up depending on how things play out. First, the FDA is much more active against unproven stem cell clinics. This may mean more money from the clinics going toward paying attorneys or FDA compliance experts. Youd think this might drive costs up. However, the still large number of clinics may keep pressure to stay with keeping price tags lower.

The second factor is the COVID-19 pandemic, which has forced many clinics to stop injections temporarily. While a surprising number of clinicsI did by phone were still open in a small informal survey, others were in a holding pattern. This may lower supply which could raise prices. But I think demand is likely way down as many patients stay home to avoid COVID risks. This could be temporary though. As things start re-opening, as they are now, the clinics may be able to capitalize on pent-up demand.

To sum up, the answer to the question, How do stem cells cost? is largely driven by clinic firms aiming to profit. Overall, clinics will charge what they think patients will pay them, which will always be a moving target. I urge patients to be cautious both medically, talking to their doctors, and financially.

Link:
How much does stem cell therapy cost in 2021? - The Niche

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October 5th, 2021

"Stem cell-based therapeutics poised to become mainstream option – BSA bureau

By daniellenierenberg

In conversation with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., The United States/Japan

To make the trial investments more meaningful and to avoid ambivalence in animal models, medical science is adopting novel in vitro models of specialised human pluripotent cell lines. Pluripotent stem cells(PSCs) have the agility to expand indefinitely and differentiate into almost any organ-specific cell type. iPSC-derived organs andorganoidsare currently being evaluated in multiple medical research arena like drug development, toxicity testing, drug screening, drug repurposing, regenerative therapies, transgenic studies, disease modeling and more across clinical developments. Innovative pharmacovigilance methodologies are preferring induced pluripotent stem cells (iPSCs) for pre-clinical and clinical investigational studies. Global Induced Pluripotent Stem Cell (iPSC) market is expected to reach $2.3 B by 2026. The iPSC market inAsia-Pacificis estimated to witness fast growth due to increasing R&D projects across countries likeAustralia,JapanandSingapore.

I Peace, Inc. a Palo Alto-based global biotech company with its manufacturing base in Japan, has succeeded in developing and mass-producing clinical grade iPS cells through its proprietary iPS cell manufacturing services. The human iPSC (hiPSC) lines at I Peace leverage differentiated cells across clinical research and medical applications. Biopsectrum Asia discovered more about Japan's stem cell manufacturing ecosystem with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., (The United States/Japan). Tanabe earned his doctorate under Dr Shinya Yamanaka, a Kyoto University researcher who received the 2012 Nobel Prize in Physiology or Medicine for discovery of reprogramming adult somatic cells to pluripotent cells. I Peace is focusing on this Nobel Prize-winning iPSCs technology where Tanabe had played a key role in generating the worlds first successful human iPSCs as one of the team members and is currently industrialising it in the US and Japan.

How do you define Japans Stem cell manufacturing dynamics aligning with regional and APAC market potential?

We believe that human cells play a pivotal role in next-generation drug therapy. Clinical trials of iPSC applications are in full swing not only in Japan, but worldwide as well. In the US, the momentum of clinical trial research is astounding. Yet, mass production of GMP compliant cell products remains a challenge. Entry into this venture is no easy task. As a contract development and manufacturing organisation (CDMO), I Peace is geared to tackle that challenge and become the pioneer of mass production technology of clinical grade cell products.

Can you elaborate I Peaces cost-effective proprietary stem cell synthesis solution and its manufacturing scale?

The key advantage of iPSCs is the ability to create pluripotent cells from an individuals own cells. Furthermore, iPSCs can multiply indefinitely and evolve into any type of cell, making iPSCs an ideal tool for transplant and regenerative medicine and drug research. However, clinical applications of iPSCs to date, utilise heterogenic transplantation. It is because manufacturing of just one line of iPSCs requires a cost intensive clean room to be occupied for several months. Manufacturing process complexities also pose a barrier to cost reduction and mass production.

In contrast, I Peace has developed a proprietary, fully automated closed system for iPS manufacturing, enabling cost-effective production of multiple lines of iPSCs from multiple donors in a single room. Within a few years, we expect to manufacture several thousand lines of iPSCs simultaneously in a single room. With this technology, I Peace can efficiently generate an ample supply of various iPSCs for heterogenic transplant, while also fostering a society where everyone can bank their own iPSCs for potential medical use.

How does I-Peace better position its businesses objectives and go-to-market strategies?

I Peaces manufacturing facility and its processes have undergone rigorous audits and are certified to be in compliance with GMP guidelines of the US, Japan, and Europe. We have the capacity to manufacture clinical-grade iPSCs and iPSC-derived cells for clinical use in the global market. Our manufacturing staff have unparalleled expertise in the manufacturing of iPSCs, and their knowledge and experience make it possible to mass produce high quality clinical-grade iPSCs in the shortest possible time. Additionally, we streamlined the iPSC use licensing scheme to expedite collaborative ventures with downstream partners. We believe these strategies position I Peace as a global leader in iPSC technology.

How do you outline the concept of democratising access to iPSC manufacturing?

At I Peace, we envision a world in which everyone would possess their own iPSCs and if needed, receive autologous transplant medication using their own iPSC. We believe in the importance of raising awareness of Nobel Prize winning iPSC technology and we think much more needs to be done. We need to enlighten the public about iPSCs - what they are, how they are created, and how they play a role in next-generation medical therapies. We also need to underscore the benefits of early banking ones own iPSCs, such as autologous transplant and the fact that cells taken in the early stages of life are preferable over cells collected later in life.

To democratise iPSC access, it is also important to expedite application research. We work closely with downstream partners, and support their iPSC-derived drug therapy development efforts by providing iPSCs to meet their needs. We also collaborate with downstream partners in the development of promising therapies including the use of T-cells for cancer therapy, cardiomyocytes for the treatment of heart disease, and neurocytes for neurological disease.

What is your outlook around boosting public-private stakeholders initiatives to encourage awareness on stem-cell-based therapeutics?

iPSC research has advanced tremendously over the past 16 years, and even more so since Dr Shinya Yamanakas Nobel Prize award in 2012. The acceleration of applied research is paving the way for stem cell-based therapeutics to become a common treatment modality in the near future. As human cell manufacturing requires specialised professional skills and knowledge, it is important to promote functional specialisation. These specialisations include donor recruiting, cell manufacturing (where I Peace is the key player), and implementing cell transplant as a medical practice. We believe that creating a systematic industry structure will build awareness and further drive the growth of stem cell-based therapy.

Can you brief Japans licensing key notes to manufacture and process clinical-grade cells in the region?

Japan enacted three laws to promote the use of regenerative medicine as a national policy:

1) The Regenerative Medicine Promotion Act -- representing the country's determination to promote regenerative medicine;

2) The Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act); and

3) The Act on the Safety of Regenerative Medicine (RM Act). The U.S. also has various tracks such as the Regenerative Medicine Advanced Therapy (RMAT) Designation, Breakthrough Therapy designation, and Fast Track designation.

Of significance, the PMD Act enables a fast-track for regulatory approval of regenerative medicalproducts in Japan. In compliance with the RM Act, I Peace was audited by the PMDA and licensed by the Ministry of Health, Labour, and Welfare to manufacture specific cell products.

Because cell product manufacturing regulations are not standardised globally, cell therapy developers are forced to source GMP iPSCs for each market. I Peace however, has overcome this hurdle. We have built in compliance with global GMP regulations, including FDA's cGMP regulations per 21 CFR 210/211 in our operation. As a result, we can provide cells for global use in multiple markets, accelerating both product development and regulatory approval.

Hithaishi C Bhaskar

hithaishi.cb@mmactiv.com

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"Stem cell-based therapeutics poised to become mainstream option - BSA bureau

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October 5th, 2021

The Best Skincare Treatments For Time-Crunched Moms (Or Anyone Else Who Only Has Five Minutes To Spare) – Forbes

By daniellenierenberg

As a beauty writer and longtime skincare fanatic, Ive subscribed to various multi-step routines. Fast forward to having a baby and the general day-to-day life upheaval that comes along with it, and my definition of a worthwhile personal beauty regimen has changed a bit. While I still enjoy trying new products and learning about innovations in the beauty space, I find myself with less time (and patience) for the more laborious treatments and layering routines, and more interest in noticeable efficacy and multitasking capabilities.

The most effective skincare products and tools are great for paring down your routineand also ... [+] saving you some precious minutes in your day.

And whether youre a busy mom or simply short on me time these days (who isnt?), there are a myriad of tried-and-true products that get the job done without requiring a ton of effort on your part. From Herauxs next-level anti-inflammaging serum to NuFaces skin-smoothing device, these standout skincare products and tools are ideal for a results-driven regimen thats effective enough to knock a few steps off your routineand save you some precious minutes in your day.

Since its launch seven years ago, this antioxidant-rich hydrating facial oil has remained a cult favorite for anyone who wants an instant glow, with the added benefit of skin soothing, balancing and repair. Infused with 22 active botanical and essential oils, the lightweight yet potent treatment can help with everything from acne to sun damage. And when applied using founder April Gargiulos signature push-press technique, it feels like a simple yet luxurious way to start and end the day.

Like the brands Trinity device, the NuFace Fix uses microcurrent technology at a gentler level to help reduce the look of fine lines and wrinkles on the more delicate areas of the face: on the forehead, between brows and around the eyes and lips (filler-free plumping, anyone?). Its sleek, compact shape combined with ease of use makes it a no-brainer for skin smoothing results in a matter of minutes. Plus, it holds an ample 120-minute charge, which amounts to a couple months worth of use before needing to plug it ini.e. no fumbling with cords or a hefty device on a regular basis.

The latest product in Kate McLeods sustainably packaged, handcrafted self care collection and the first to focus on skincare, the Face Stone is essentially a waterless moisturizer that melts on contact with skin. A rich blend of nourishing and antioxidant ingredients like blue tansy, kokum butter and plum kernal borage helps even and soothe stressed skinsomething we could all use these days. An added bonus? Its solid form and shape makes it a natural massaging tool, making it ideal for a morning pick-me-up or the start of an evening wind-down ritual.

While it covers your mineral-based broad spectrum sunscreen needs, this multitasker does much more than that. The unique product uses the U Beautys proprietary Sun-Siren Capsule Technology to help reduce hyperpigmentation, discoloration and dark spots (whether from pregnancy melasma or suntanning sins of the past) while also shielding against UVA, UVB, infrared and blue light exposure. A little goes a long way with this rich balm-cream formula, and its hydrating enough to double as a moisturizer or primer by day and also great as an overnight spot treatment.

An excellent (and cleaner) dupe for Biologique Recherches oft-elusive Lotion P50, this Moon Juice exfoliator is a skin savior in its own right. The liquid formula includes glycolic, lactic and salicylic acids for gentle, pore-minimizing exfoliation paired with niacinamide and adaptogenic reishi to help boost the skins natural barrier. And besides looking pretty, the packaging is completely recyclable, from the sculptural cap and glass bottle to the outer carton.

January Labs is a clean beauty favorite for its science-backed, results-driven products that have long been favored by top aestheticians. Even those with more sensitive (or dry) skin can use this retinol serum without dealing with typical downsides (like redness, drying or peeling) thanks to its use of Retistar, a .5% retinol thats super effective yet non-irritating.

This at-home peel is as easy as can be, requiring a single once-over with the pre-soaked pad to revive dull skin. The duo of glycolic and salicylic acids provide skin-smoothing exfoliation while ingredients like chamomile and bilberry extract calm, soothe and help even skin tone. Pro tip: Use up excess product on any dry, flakey patches on arms and legs.

Created by stem cell biologists at the University of Southern California, this innovative serum features an anti-inflammaging HX-1 molecule thats combined with tried-and-tested ingredients like vitamin C, hyaluronic acid, peptides and red maple bark. The result? A silky, lightweight formula thats both rejuvenating (designed to help reduce the effects of stress and aging factors on skin) and preventative (strengthening stem cells on a molecular level).

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The Best Skincare Treatments For Time-Crunched Moms (Or Anyone Else Who Only Has Five Minutes To Spare) - Forbes

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October 5th, 2021

Losing Your Hair? You Might Blame the Great Stem Cell Escape. – The New York Times

By daniellenierenberg

Every person, every mouse, every dog, has one unmistakable sign of aging: hair loss. But why does that happen?

Rui Yi, a professor of pathology at Northwestern University, set out to answer the question.

A generally accepted hypothesis about stem cells says they replenish tissues and organs, including hair, but they will eventually be exhausted and then die in place. This process is seen as an integral part of aging.

Instead Dr. Yi and his colleagues made a surprising discovery that, at least in the hair of aging animals, stem cells escape from the structures that house them.

Its a new way of thinking about aging, said Dr. Cheng-Ming Chuong, a skin cell researcher and professor of pathology at the University of Southern California, who was not involved in Dr. Yis study, which was published on Monday in the journal Nature Aging.

The study also identifies two genes involved in the aging of hair, opening up new possibilities for stopping the process by preventing stem cells from escaping.

Charles K.F. Chan, a stem cell researcher at Stanford University, called the paper very important, noting that in science, everything about aging seems so complicated we dont know where to start. By showing a pathway and a mechanism for explaining aging hair, Dr. Yi and colleagues may have provided a toehold.

Stem cells play a crucial role in the growth of hair in mice and in humans. Hair follicles, the tunnel-shaped miniature organs from which hairs grow, go through cyclical periods of growth in which a population of stem cells living in a specialized region called the bulge divide and become rapidly growing hair cells.

Sarah Millar, director of the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai, who was not involved in Dr. Yis paper, explained that those cells give rise to the hair shaft and its sheath. Then, after a period of time, which is short for human body hair and much longer for hair on a persons head, the follicle becomes inactive and its lower part degenerates. The hair shaft stops growing and is shed, only to be replaced by a new strand of hair as the cycle repeats.

But while the rest of the follicle dies, a collection of stem cells remains in the bulge, ready to start turning into hair cells to grow a new strand of hair.

Dr. Yi, like most scientists, had assumed that with age the stem cells died in a process known as stem cell exhaustion. He expected that the death of a hair follicles stem cells meant that the hair would turn white and, when enough stem cells were lost, the strand of hair would die. But this hypothesis had not been fully tested.

Together with a graduate student, Chi Zhang, Dr. Yi decided that to understand the aging process in hair, he needed to watch individual strands of hair as they grew and aged.

Ordinarily, researchers who study aging take chunks of tissue from animals of different ages and examine the changes. There are two drawbacks to this approach, Dr. Yi said. First, the tissue is already dead. And it is not clear what led to the changes that are observed or what will come after them.

He decided his team would use a different method. They watched the growth of individual hair follicles in the ears of mice using a long wavelength laser that can penetrate deep into tissue. They labeled hair follicles with a green fluorescent protein, anesthetized the animals so they did not move, put their ear under the microscope and went back again and again to watch what was happening to the same hair follicle.

What they saw was a surprise: When the animals started to grow old and gray and lose their hair, their stem cells started to escape their little homes in the bulge. The cells changed their shapes from round to amoeba-like and squeezed out of tiny holes in the follicle. Then they recovered their normal shapes and darted away.

Sometimes, the escaping stem cells leapt long distances, in cellular terms, from the niche where they lived.

If I did not see it for myself I would not have believed it, Dr. Yi said. Its almost crazy in my mind.

The stem cells then vanished, perhaps consumed by the immune system.

Dr. Chan compared an animal's body to a car. If you run it long enough and dont replace parts, things wear out, he said. In the body, stem cells are like a mechanic, providing replacement parts, and in some organs like hair, blood and bone, the replacement is continual.

But with hair, it now looks as if the mechanic the stem cells simply walks off the job one day.

But why? Dr. Yi and his colleagues next step was to ask if genes are controlling the process. They discovered two FOXC1 and NFATC1 that were less active in older hair follicle cells. Their role was to imprison stem cells in the bulge. So the researchers bred mice that lacked those genes to see if they were the master controllers.

By the time the mice were 4 to 5 months old, they started losing hair. By age 16 months, when the animals were middle-aged, they looked ancient: They had lost a lot of hair and the sparse strands remaining were gray.

Now the researchers want to save the hair stem cells in aging mice.

This story of the discovery of a completely unexpected natural process makes Dr. Chuong wonder what remains to be learned about living creatures.

Nature has endless surprises waiting for us, he said. You can see fantastic things.

Excerpt from:
Losing Your Hair? You Might Blame the Great Stem Cell Escape. - The New York Times

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October 5th, 2021

3 of the Best Fall Beauty Buys – Pursuitist

By daniellenierenberg

Fall is here, and now is the perfect time to upgrade your beauty routine for the cooler temperatures. Here are a few of our favorite products:

Parfums de Marly

The famed perfume house founded by Julien Sprecher will launch sensual Oriana on September 12th. Packaged in a hot pink bottle, the airy and dreamy fragrance is captivating withnotes of orange blossom, marshmallow, and Chantilly cream. Available on parfums-de-marly.com and Saks Fifth Avenue. $320.

ILONA

This innovative skincare brand continuously seeks out innovative ingredients and technologies from around the world and incorporates them into premium high-performance formulas like the BEYOND C Corrective Serum. This reincarnating serum is housed in a beautiful dual vessel package. One side is black, the other gold with each containing corrective technologies that reach maximum potency at the moment of unity.

The black side contains a novel probiotic and micronized niacin that fortifies skin defenses, intensifies cellular activity, quells inflammation, and amends blotchiness. The gold vessel contains a patented, hyper-potent, permeable form of vitamin C that helps brighten, fade age spots, even skin tone, and protect against oxidation. $132.

Heraux

This innovative product was created by Heraux Co-Founder Dr. Ben Van Handel, a Stem Cell Biologist at the University of Southern California and leading inflammaging researcher. Dr. Handel notes that Retinols are anti-inflammatory at the molecular level, acting as antioxidants and blocking hyperactivation of the immune system. HX-1, the proprietary ingredient in HerauxsMolecular Anti-Inflammaging Serum, acts to shield skin stem cells from pro-inflammaging stressors and concurrently supports the youthful function of stem cells. The regenerative program enabled by HX-1 promotes the secretion of collagen and elastin as well as improved skin barrier function.

Kimberly Fisher is a Pursuitist contributor. As a freelance writer and on-camera host, Kimberly has traveled the world and has published over 400 articles in over 44 publications including Sherman's Travel, Huffington Post, Just Luxe, Luxury Lifestyles UK, eHow, Examiner, Food Wine Travel Magazine, Luxe Beat, NiteGuide, Ocean View, and USA Today. Disclosure: Kimberly is employed by Remy Cointreau Americas.

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3 of the Best Fall Beauty Buys - Pursuitist

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October 5th, 2021

Stanford neuroscientist’s ‘assembloids’ pave the way for innovative brain research – Scope

By daniellenierenberg

A recent article in the journal Nature credits Stanford physician-neuroscientist Sergiu Pasca, MD, with blazing a trail toward a more profound understanding of early brain development, and of what can go wrong in the process, using a cell-based research innovation he named "assembloids."

In 2015, Pasca and his colleagues published a paper in Nature Methods describing a fascinating feat: His tinkering with induced pluripotent stem cells, or iPS cells -- former skin cells transformed so that they've acquired an almost magical capacity to generate all the tissues in the body -- had borne a three-dimensional product. From these "magic" iPS cells grew a complex conglomerate of cells capable of modeling specific organs.

Pasca's particular interest was in the brain, and in the experiments detailed in the study, his lab had caused human iPS cells to multiply and differentiate into small spherical clusters of brain tissue suspended in laboratory glassware.

These clusters recapitulated the architecture and physiology of the human cerebral cortex -- the outermost layer of brain tissue, critical to perception, cognition and action. Pasca named these clusters, which grew to several millimeters in diameter and contained millions of cells, "cortical spheroids." Today, researchers around the world are using similar methodology to create models, broadly known as "organoids," to study other parts of the human body.

Two years later, in a study published in Nature, Pasca upped the ante by, first, generating a second kind of neural spheroid -- this time, representative of a deeper part of the developing forebrain called the subpallium -- and, second, by growing this kind of spheroid in conjunction with cortical spheroids, in the same dish.

To the researchers' amazement, spheroids of both types fused together, with nerve cells from subpallial spheroids migrating and poking extensions into the cortical spheroids and establishing working connections with nerve cells of a different type in the latter spheroids, just as occurs in fetal development.

"It's amazing that these cells already self-organize and know what they need to do," Pasca marveled in "Brain Balls," an article I wrote for our magazine, Stanford Medicine, a few years ago.

Pasca sensibly dubbed the two-fused-spheroid combos "assembloids," the Nature recap notes.

But why stop at two? Pasca has since created three-element assembloids composed of spheroids representative of cerebral cortex, spinal cord and skeletal muscle in order to model the circuitry of voluntary movement. He's also shown that stimulating the "cerebral cortex" spheroid can result in contraction of the "muscle" spheroid. (This accomplishment was published in Cell in late 2020.) He has explored other assembloid combinations, as well, such as the fusing of cortical spheroids with spheroids representing the striatum, a brain structure implicated in regulating our movements and responses to rewarding and aversive stimuli.

Because each spheroid begins with skin cells, they can be grown on a personalized basis -- and can therefore be extracted from patients with neurological disorders known or suspected to spring from early developmental aberrations (such as autism or schizophrenia). The cells can then be used to create models to probe these disorders' molecular, cellular and circuit-based deviations from the pathways of normal brain development, allowing scientists to study the brain in way they could never do with a living patient.

From the Nature article:

Assembloids are now at the leading edge of stem-cell research. Scientists are using them to investigate early events in organ development as tools for studying not only psychiatric disorders, but other types of disease as well.

An assembloid is by no means a complete, working brain. But, the article notes, "Pasca stands by the aphorism that all models are wrong, and some are useful. 'There's been important progress in the field in a short period of time,' he says."

Photo courtesy of the Pasca laboratory

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Stanford neuroscientist's 'assembloids' pave the way for innovative brain research - Scope

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October 5th, 2021

12 of the best face serums 2021 – Medical News Today

By daniellenierenberg

Facial serums are skin care products that the skin can absorb rapidly. They are formulated to contain high doses of ingredients, including actives such as vitamin C and retinol. They are not moisturizers. Instead, they are an additional step in a skin care routine selected to address specific skin concerns.

While many facial serums make claims about their benefits, limited scientific data is available to support these claims. The potential uses and benefits of a serum will depend on the ingredients and their concentration.

Many serums use active ingredients such as:

Common issues face serums claim to address include acne, rosacea, and signs of aging such as wrinkles.

One study of a facial serum targeting fine lines and wrinkles found that after 12 weeks, women showed statistically significant improvements in:

Face serums are generally considered safe. They are available without a prescription. However, because face serums deliver concentrated doses of active ingredients such as vitamin C or hyaluronic acid, people should exercise caution when trying them for the first time.

Pregnant people should exercise caution when selecting skin care products. Using products made with concentrated forms of vitamin A, such as retinol, can harm a developing fetus. Pregnant people should avoid skin care products that contain retinoids or other harmful ingredients.

People who are already using prescription or high dosage skin care products should check with their healthcare providers before using face serums to ensure they are not taking in unhealthy levels of powerful ingredients, such as retinoids.

When introducing a new active ingredient to the skin, there is a possibility of side effects such as:

If a person experiences these symptoms, they should reduce the frequency and dosage of the serum or stop using it altogether if symptoms do not reduce.

The American Academy of Dermatology recommends trying just one new product, like a facial serum, at a time. Starting several new products all at once, particularly anti-aging products, can irritate the skin and make it difficult to determine which products are beneficial.

It is also helpful to perform a patch test for a week before using a new product on facial skin. A patch test involves applying small amounts of the new product on the inner forearm for a few days to check for reactions.

A skin serum will not be effective if it is not used properly. The best time to apply face serum is after cleaning the skin and before applying moisturizer.

Facial serums are concentrated, so people should only use a small amount to cover the facial skin.

Learn more about skin care routines here.

No single skin care product can address all skin health needs. To pick out the best face serum, a person should first decide what skin concern they want to address, such as wrinkles or acne.

Look for a face serum that is a good fit for individual concerns and needs. For example, a person should choose a face serum that suits their skin type, such as oily, dry, combination, or aging.

Some people may wish to find products that are hypoallergenic and noncomedogenic, which means they are less likely to cause allergic reactions or acne.

Products do not have to be expensive to be effective, and serums are available to suit various budgets.

Please note that the writer of this article has not tried these products. All information presented is purely research-based.

This is an oil-free vitamin C face serum designed for people with oily or blemish-prone skin.

SkinCeuticals claims this serum can reduce skin oiliness and wrinkles, and improve skin texture.

The ingredients include:

This serum costs $166 for a 30ml bottle.

Made with Avene Thermal Spring Water, this water-gel serum is safe for adolescents and adults.

It is suitable for oily skin and should be used after cleansing in the morning and evening.

Avena claims that this product can be used safely alongside other acne treatments and can reduce the appearance of pores.

This serum costs $28.00 for 30ml.

This antioxidant face serum is fragrance- and oil-free, and certified cruelty-free.

Drunk Elephant claims it can reduce the signs of sun damage and aging while hydrating the skin. It stays active on the skin for up to 72 hours and should be applied in the morning.

Customers must mix a powder and liquid to create the fresh activated serum.

This serum costs $78.00 for 28ml.

This face serum contains aloe, vitamin A, niacinamide, vitamin C, vitamin E, tea tree oil, and other vitamin and herbal ingredients.

Klur states that this serum may even out skin texture, helps calms inflammation, and increases skin clarity.

People should use it at night and no more than 3 times a week.

This serum costs $110.00 for 30ml.

This serum uses forms of retinoid that The Ordinary states may reduce the signs of aging better than other retinoid products, without causing irritation.

The company recommends people patch test the serum, before using it on facial skin. People should not use it in combination with other retinoid products.

Use only in the evening after cleansing, and refrigerate after opening.

This serum is vegan and free from oil, silicones, nuts, and gluten.

This low-cost serum sells for $9.80 for 60ml.

This cruelty-free skin serum contains milk protein, seaweed extract, and arnica. Ren claims it may calm and soothe the skin while reducing redness and irritation.

It should be used morning and/or night before moisturizing.

This serum costs $58.00 for 30ml.

True Botanicals claims that this anti-aging serum may reduce the appearance of fine lines and wrinkles.

It uses natural antioxidants such as chebula, elderberry, ginger, and echinacea to help strengthen the skins immunity to signs of aging.

After morning and evening cleansing, users can apply one half or full drop to their faces.

This serum costs $90.00 for 30ml.

Skin Authority claims that this lightweight serum reduces the appearance of fine lines, by plumping skin folds and smoothing skin texture.

This serum is designed for use after morning cleansing.

This serum costs $155.00 for 15ml.

Peach and Lily claims that this serum can brighten the skin and reduce the appearance of dark spots.

It contains various ingredients from botanical sources, including green tea extracts, mushrooms, and arbutin. It also contains niacinamide.

It is suitable for all skin types.

This serum costs $39.00 for 50ml.

SkinCeuticals claims that this serum may reduce the appearance of dark spots and improves skin tone.

Ingredients include:

It is suitable for people with all skin types.

This serum costs $98.00 for 30ml.

Bioderma claims that this face serum may increase the skins ability to retain moisture. Made specifically for people with dry skin, it is noncomedogenic, meaning it will not block pores.

People can use this serum in the morning and evening.

This serum costs $27.99 for 40ml.

This serum is suitable for use by people with all skin types. Eminence claims that this face serum helps reduce the appearance of sun-induced skin damage.

Its active ingredients include vitamin C and other antioxidants, which work together to brighten the skin and improve the appearance of fine lines and wrinkles.

This serum costs $110.00 for 30ml.

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12 of the best face serums 2021 - Medical News Today

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October 5th, 2021

Man discovers nasty red rash on his hands and elbows is potentially fatal – The Mirror

By daniellenierenberg

A man went to a clinic in Mannheim, Germany, where tests found that the rash on his hands and elbows was in fact leukaemia cutis, where the cancer cells are in the skin tissue

Image: NEJM)

A man suffering from a nasty skin rash on his hands and elbows that looked like psoriasis found that it was actually a form of leukaemia.

The 65-year-old went to a dermatologist in Mannheim, Germany, due to the red patches that had developed on the back of his hands and arms and he later found the worrying diagnosis that it was leukaemia cutis.

Tests done at the hospital showed that he had a high white-cell count along with a low number of platelets, it is reported.

The case was published in the New England Medical Journal where it said that a diagnosis of leukaemia cutis was made.

While extremely rare, the condition means that the leukaemia cells are in the skin tissue.

It is found to happen in around three percent of leukaemia cases where the rash has been found on skin including the arms, back or face.

Image:

Other leukaemia symptoms include fever, tiredness and susceptibility to infections.

But in the case of the 65-year-old in Germany, he only had the rash on his hands and elbow.

The New England Medical Journal stated: "A diagnosis of leukemia cutis was made, and the patient was urgently referred to the oncology clinic.

"The patient received a diagnosis of chronic myelomonocytic leukaemia and underwent stem-cell transplantation.

"Two weeks after the transplantation, the patients skin changes had resolved, and the cancer has been in remission since."

Leukaemia Care UK said that usually patients who have the cancer and find rashes do not have this particular condition.

It stated: Leukaemia cutis is very rare, occurring in only about three percent of total cases of leukaemia.

"With this in mind, it is unsurprising that most lesions seen in leukaemia patients are not leukaemia cutis.

In fact, most lesions (40%) seen in leukaemia patients are caused by other complications of leukaemia.

It continued: In the rare occasion that leukaemia cutis occurs, the patient will normally have already been diagnosed with leukaemia.

"However, in seven percent of cases of leukaemia cutis, the skin lesion is the very first symptom of a blood cancer. This is sometimes referred to as aleukaemic leukaemia cutis.

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Man discovers nasty red rash on his hands and elbows is potentially fatal - The Mirror

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October 5th, 2021

Drug that stops ALS progression found using iPS cells from patients – The Japan Times

By daniellenierenberg

Kyoto A drug discovered through a method using induced pluripotent stem cells, or iPS cells, from sufferers of amyotrophic lateral sclerosis (ALS) was effective in stopping the progression of the neurological disease in five out of nine patients in a clinical trial, a research team at Kyoto University said Thursday.

While drugs that slow down the progression of amyotrophic lateral sclerosis, also known as Lou Gehrigs disease, have been used in the past, this is the first time that a chronic myeloid leukemia drug called bosutinib has been found to stop its progression, according to the team.

Haruhisa Inoue, a professor of neurology at Kyoto University leading the team, said that larger clinical trials will be needed to determine if the drug can be put to practical use, but We are now looking at the possibility of being able to control ALS with the power of science.

The team reproduced the disease by culturing iPS cells derived from the skin of patients into motor neurons. They then tested a series of drug compounds on the cells to find that bosutinib was effective in slowing down the progression of ALS.

The drug was administered for around three months to nine patients who were in the early stages of the disease and showing signs of deterioration. Progression of the disease stopped in five patients during the treatment period, while four patients continued to deteriorate at the same pace as before.

A comparison of the blood samples from both sets of patients showed that they had differing amounts of a protein unique to nerve cells before the drug was administered. Researchers plan to conduct clinical trials with larger groups while adjusting the dosage and other conditions in the future.

There are about 9,000 people in Japan who suffer from ALS. The disease causes motor neurons to progressively die, resulting in paralysis, with many patients requiring a ventilator to stay alive. Its exact cause is unknown, and no fundamental treatments have been established.

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Drug that stops ALS progression found using iPS cells from patients - The Japan Times

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October 5th, 2021

The Appalling Moral Failure of Francis Collins – Discovery Institute

By daniellenierenberg

Photo: Francis Collins, by NIH Image Gallery, via Flickr.

Francis Collins, Director of the National Institutes of Health (NIH),has just announcedhis intention to step down at the end of 2021 after more than 12 years heading the agency. The accolades are already rolling in. Noted evangelical political commentator David French, for example, rushed to praise Collins as a national treasure.

But Collinss real legacy is anything but praiseworthy, and the tendency of figures in the faith community to ignore his real record is far from admirable.

This year of all years should have made the truth about Francis Collins clear. Last month, documents were released suggesting that top National Institutes of Health (NIH) officials may haveliedwhen they denied that the NIH had funded gain of function research in Wuhan, China, that could have resulted in a pathogen that could infect humans.

After reviewing the documents, Rutgers University biologist Richard Ebright had a blistering response: The documents make it clear that assertions by the NIH Director, Francis Collins, and the NIAID Director, Anthony Fauci, that the NIH did not support gain-of-function research or potential pandemic pathogen enhancement are untruthful.

It was another blow to the reputation of Collins in a year when his agency has faced multiple scandals and controversies.

Among evangelical Christians and other people of faith in America, Collins has long been the equivalent of a rock star. But Collinss days of glory as a non-partisan role model, especially for the faith community, may be numbered and its not just because of the latest scandal over the origins of COVID-19.

In recent months, Collinss agency has become embroiled in controversies over its funding of stomach-churning medical experiments involving body parts harvested from aborted babies. The disclosures about the experiments followed Collinssrepealearlier this year of restrictions on the use of aborted fetal tissue in NIH-funded research.

Collins has also stirred controversy with his increasingly shrill attacks on unvaccinated Americans and his support for harsh mandatory vaccination policies that will require the firing of employees who choose not to be vaccinated with a COVID-19 vaccine.

The former head of the Human Genome Project, Collins catapulted to fame (and the cover ofTimeMagazine) in 2000 with the announcement of a working draft of the sequence of the human genome.He then became a hero to many Christians with the publication in 2006 of his bookThe Language of God, which recounted his journey from atheism to Christianity.

In an increasingly polarized national environment, Collins is one of the rare heads of a major federal agency to serve under both Republican and Democratic Presidents. Appointed by President Obama to head the NIH in 2009, Collins continued in that role under President Trump and now President Biden. He has regularly drawn praise from lawmakers on both sides of the aisle. At gatherings of evangelical Christians, he has been known to strum the guitar and sing worship songs and receive the adoration of attendees. At one 2019 eventit was reportedthat conference participants lined up for selfies with him.

In 2020, Collins wasawarded the prestigious Templeton Prize, worth more than $1.3 million, for his work integrating science and faith. Previous recipients of the prize have included Mother Teresa, John Polkinghorne, Charles Colson, and Aleksandr Solzhenitsyn.

Among secular as well as religious journalists, Collins often receives what verges on fawning treatment. A writer forThe New Yorkergushedthat Collins is a model of geek cool. He likes big, noisy motorcycles, and, despite a mild manner, he is famously unself-conscious. At the unlikeliest moments, he will strap on a guitar and accompany himself in song, often a tune he has composed for the occasion.

This year, however, Collinss reputation has taken continued beatings, not just because of evasive answers about the role of the NIH in gain-of-function research in China, but also because of publicity around NIH-funded experiments that many Americans, especially people of faith, would find horrific.

In May, reports surfaced aboutmacabre NIH-funded experimentsthat utilized body parts collected fromaborted human fetuses to createhumanized mouse and rodent models with full-thickness human skin.For the experiments, researchersat the University of Pittsburghcut into tiny pieces human fetal spleen, thymus, and liver organs and then transplanted the tissues and hematopoietic stem cells into irradiated mice. Researchers also sliced off skin from the scalp of the aborted babies and then grafted the fetal skin onto the mice. In the words of the scientists: Full-thickness human fetal skin was processed via removal of excess fat tissues attached to the subcutaneous layer of the skin, then engrafted over the rib cage, where the mouse skin was previously excised.

The body parts used for these experiments were harvested from aborted human fetuses with a gestational age of 18-20 weeks. By that age, an unborn baby hasbrain wavesand abeating heart. He canhear sounds and move his limbs and eyes, and his digestion system has started to work.In other words, the human fetuses whose organs were harvested for this NIH-funded research were well-developed tiny humans, not blobs of undifferentiated cells.

In August, an additional project funded by the NIH came to light thanks to documents obtained in a Freedom of Information Act lawsuit by Judicial Watch and the Center for Medical Progress. The lawsuit was filed after Collinss NIH dragged its feet in responding.According to Judicial Watch, the documents show that theNIH has provided nearly $3 million in tax dollars to support a fetal organ harvesting operation by the University of Pittsburgh in its quest to become a Tissue Hub for human fetal tissue ranging from 6 to 42 [!] weeks gestation.

David Daleiden, president of the Center for Medical Progress,commented: The NIH grant application for just one of Pitts numerous experiments with aborted infants reads like an episode ofAmerican Horror Story. Infants in the womb, some old enough to be viable, are being aborted alive and killed for organ harvesting, in order to bring in millions of dollars in taxpayer funding.

Daleiden furtherallegedthat NIH funding was used to underwrite labor induction abortions, where the baby is pushed out of the mother whole and then killed to obtain the desired tissues. In other words, the NIH was facilitating a process where babies, some of the age of viability, [are] to be delivered alive, and then killing them by cutting their kidneys out.

Francis Collins self-identifies as an evangelical Christian, and most evangelicals as well as faithful Catholics regard abortion as the destruction of innocent human life.

So how has Collins responded to these revelations? With horror? With a pledge to investigate? With a promise to stop taxpayer funding of such research?

Since early August, Ive repeatedly tried to get Collins to answer questions about these NIH funded experiments using aborted fetal organs and tissues.Does Collins support this research funded by his agency? Does he have any ethical objections to it? How does he personally justify the research given his religious convictions? I repeatedly emailed these and other questions to the media contacts for the NIH Office of the Director.

The response? His office has refused to answer.

But its not just NIH research involving humans that has been raising controversy this year. In recent months, Collinss NIH has come under fire for fundingabusive medical experiments on dogsthat critics say were unnecessary as well as barbaric. The experiments were funded by the NIH division headed by Anthony Fauci, but that division is under the ultimate oversight of Collins. In late August, 15 members of Congresssent a letterraising questions about the research.

Again, I tried to get a response from Collins about this latest controversy. Again, he refused to respond to questions.

Ironically, while Collins is AWOL when it comes to answering basic questions about the research his agency is funding, he is more than willing to speak out on other topics, especially COVID-19, where he is now becoming a polarizing figure to many because ofincreasingly shrill advocacy of compulsory vaccination as well as his demonization of those who choose not to take a COVID-19 vaccine.

At the end of April,Collins claimedthat he would not require NIH employees to get vaccinated, and he seemed to argue for a positive approach of selling the benefits of vaccines rather than demonizing the unvaccinated or engaging in finger-wagging. Yet by early August his public posture had changed. He was nowcheerleading for compulsory vaccine requirementsimposed by private businesses as well as enthusiastically overseeing compulsory vaccinations for the very workers at the NIH that he earlier said would not face compulsory vaccination.

After President Bidens speech in September declaringwar on the unvaccinated, Collins ramped up his own rhetoric.In an appearance on MSNBC after Bidens speech, Collins firstsuggestedunvaccinated people were selfish, declaring that this is really an occasion to think about loving your neighbor, not just yourself.

Collins then branded both unvaccinated people and politicians who dont favor vaccine mandates as killers on the wrong side of history. Dismissing their views as merely a philosophical political argument that is part of the culture war, Collins complained that this philosophical political argument is killing people, including, Im sad to say, some children. We have to get past this if we really have a future as a nation.

I would like to say particularly to those leaders who are on the wrong side of this, what Lincoln said one time, Collins declared. Citizens, we will not escape history. Do you want to be looked at in the lens of that backward look ten years from now and defend what you did when in fact, we are losing tens of thousands of lives that didnt have to die?

A question for Collins: Is attacking your fellow citizens (including many fellow Christians) as heartless killers because they disagree with you on either vaccinations or vaccine mandates an example of loving your neighbor?

Whatever one thinks about COVID-19 vaccinations, Collinss over-the-top rhetoric demonizing those he disagrees with as killers is beyond the pale, especially for someone who wears his Christianity on his sleeve. As I have writtenelsewhere, his rhetoric is also based on several falsehoods.

So just how far is Collins willing to go to push coercive medicine? Thats an interesting question.

In my home state of Washington, the governor has issuedan emergency orderthat will compel private religious schools and day care centers as well as other private businesses to fire employees later this month if they wont get vaccinated. While there technically is a route for religious exemptions, it is so narrow and onerous that many religious people may not qualify.

Its now being suggested in some states that discharged employeeswont be able to get unemployment benefits. Perhaps the idea is that if the unvaccinated dont die of COVID they can die of starvation instead.

As if that werent bad enough, the unvaccinated face the denial of medical care. Also in my home state, the University of Washington medical system is now apparently denyingorgan transplantsto patients who are unvaccinated, even if those patients have a credible medical reason for not having the vaccinations.

This is pure, unadulterated social Darwinism: Brand a whole class of people as biologically unfit (in this case, the unvaccinated) and then make sure they cant receive medical care, hold jobs, or basically survive. Heap scorn on them, demonize them as killers, and stir up hatred against them so other people begin to abuse them. If Collins is truly concerned about the judgment of history, he should read a little more widely about the sorry results of demonizing entire classes of people as the enemies of society.

Let me be clear: I am not arguing here about whether people ought to get COVID-19 vaccinations, or whether those vaccinations are helpful. For the record, depending on ones risk profile, I think vaccinations are in a persons best interest. The issue is whether in the name of vaccination people should be stripped of their livelihoods, denied medical care, and demonized as enemies of society. In any morally sane universe, the policies being proposed are as immoral as they are unprecedented.

So does Francis Collins endorse depriving unvaccinated people of their right to work and to support their families? Does he endorse denying them unemployment insurance? Does he go even further and endorse denying medical care to the unvaccinated?

I again asked Collins media relations staff for answers. Again, crickets.

Although Collins likes to tout his personal faith, he appears to have very little concern for any sort of conscience rights of fellows religious believers who disagree with him.After all, he dutifully served in a previous administration that repeatedly weakenedconscience protectionsfor medical workers opposed to abortion and thatviolated federal lawby turning a blind eye when California mandated abortion coverage in all private insurance plans.

It might also be noted that as late as December 2020, Collins was still urging thatmost churches should not meet in person, even implying that they shouldnt do sountil the summer or fall of 2021.

And his current promotion of compulsory vaccinations seemingly has no qualifiers. At least, he isnt talking about any.

Collins hasconcededthat various COVID-19 vaccines used cell lines originally derived from an aborted fetus in either their production or testing, which is one reason some people have moral qualms about the vaccines. Yet you wont find Collins advocating for the conscience rights of these people. In fact, Collins has been silent in the face of attacks on religious exemptions for vaccines.

Reasonable people can disagree about whether the use of abortion-derived cell lines is a moral deal-killer for the vaccines. But thats the point: Reasonable people candisagreeabout what violates their conscience. The test of support for religious liberty is not whether you only support the right of people who agree with you.

Not being willing to stand up for the conscience rights of others to determine their own medical treatment is not morally neutral. It is a moral failure. In the words of theCatholic Bishops of Colorado, A person is morally required to obey his or her conscience, and others should respect the right of others to follow their conscience.

Alas, for those who have followed Francis Collins closely over the years, his current failures of moral leadership come as no surprise. As I will discuss in an upcoming article, Collinss career has been one long testament to moral cowardice and confusion.

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The Appalling Moral Failure of Francis Collins - Discovery Institute

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October 5th, 2021

Therapy and Prevention Strategies for Myocardial Infarction | IJN – Dove Medical Press

By daniellenierenberg

Introduction

The growing burden of ischemic heart disease (IHD) is a major public health issue. The most harmful type of IHD is acute myocardial infarction (MI), which leads to loss of tissue and impaired cardiac performance, accounting for two in five deaths in China.1 Timely revascularization after MI, including percutaneous coronary intervention, thrombolytic treatment and bypass surgery, is key to improving cardiac function and preventing post-infarction pathophysiological remodeling.2 However, these effective but invasive approaches cannot be used in all patients owing to their applicability, which is limited based on specific clinical characteristics, and the possibility of severe complications such as bleeding and reperfusion injury.2,3 Attempts to limit infarct size and improve prognosis using pharmacotherapy (including antiplatelet and antiarrhythmic drugs and angiotensin-converting enzyme inhibitors) without reperfusion has been proven generally inefficient, due to non-targeted drug distribution and side effects, and short half-life of some drugs.1,3,4 Consequently, many patients in which this approach is used still progress to cardiac hypertrophy and heart failure.1 Growth and rupture of atherosclerotic plaques and the ensuing thrombosis are the major causes of acute MI.4 Currently available interventions for atherosclerosis (AS) including statins can reduce acute MI, but the effects vary between individuals, and leave significant residual risks.58 Some chemotherapies, such as docetaxel9 and methotrexate,10,11 also seem to have beneficial effects in AS; however, systemic administration of these drugs is limited because of their adverse effects.12 The demand for safer and more efficient therapies and prevention strategies for MI is therefore increasing.

Several optimized strategies have so far been explored, one of which is the application of nanoparticles (NPs). These nanoscale particles have been widely used in the treatment of tumors and neural diseases.13,14 NPs enable delivery of therapeutic compounds to target sites with high spatial and temporal resolution, enhancement of tissue engineering processes and regulation of the behaviour of transplants such as stem cells. The application of NPs improves the therapeutic effects and minimizes the adverse effects of traditional or novel therapies, increasing the likelihood that they can be successfully translated to clinical settings.1518 However, research on NPs in this field is still in its infancy.5,1921 This review summarizes the latest NP-based strategies for managing acute MI, mostly published within the past 7 years, with a particular focus on effects and mechanisms rather than particle types, which have been extensively covered in other reviews (Figure 1). In addition, we offer an initial viewpoint on the value of function-based systems over those based on materials, and discuss future prospects in this field.

Figure 1 Overview of nanoparticle-based strategies for the treatment and prevention of myocardial infarction. Nanoparticles are capable of delivering therapeutic agents and nucleic acids in a stable and targeted manner, improving the properties of tissue engineering scaffolds, labeling transplanted cells and regulating cell behaviors, thus promoting the cardioprotective effects of traditional or novel therapies.

A multitude of NP types are currently under investigation, including lipid-based NPs, polymeric NPs, micelles, inorganic NPs, and exosomes. Virus can also be considered as NPs; however they will not be discussed in this review.22 NPs made from different materials show similar in vivo metabolic kinetic characteristics and protective effects on infarcted heart.19,20 Function-based NP types, oriented towards a specific purpose, may be preferable compared with traditional types, on account of their practicality in basic research and clinical translation. In this review, we discuss NPs used in the treatment and prevention of MI that fall into the following four categories: 1) circulation-stable nanocarriers (polymeric, lipid or inorganic particles); 2) targeted delivery vectors (magnetic or particles modified to improve target specificity); 3) enhancers of tissue engineering; and 4) regulators of cell behavior (Figure 1). We propose that the choice of each NP for any given application should be primarily based on the roles or mechanisms they perform.

Many NPs, whether composed of either naturally occurring or synthetic materials, act as nanocarriers to improve the circulating stability of therapeutic agents.15,16 Polymeric NPs comprise one of the most widely employed types, with excellent biocompatibility, tunable mechanical properties, and the ability be easily modified with therapeutic agents using a broad range of chemical techniques.23,24 The most commonly used polymer for these NPs is polylactide-co-glycolide (PLGA), which has Food and Drug Administration approval.25,26 Recently, there has been a therapeutic emphasis on polydopamine (PDA), from which several related nanomaterials have been created, including PDA NPs and PDA NP-knotted hydrogels.27,28 NPs made from polylactic acid (PLA),29,30 poly--caprolactone (PCL),31 polyoxalates,32 polyacrylonitrile,33 chitosan29,34 and hollow mesoporous organosilica35 have also been constructed and administered in vitro in cells and in vivo in animal models.

Lipid NPs or liposomes are also considered promising candidates for the delivery of therapeutic agents, due to their morphology, which is similar to that of cellular membranes and ability to carry both lipophilic and hydrophilic drugs. These non-toxic, non-immunogenic and biodegradable amphipathic nanocarriers can be designed to reduce capture by reticuloendothelial cells, increase circulation time, and achieve satisfactory targeting.36,37 Solid lipid NPs (SLNs) combine the advantages of polymeric NPs, fat emulsions, and liposomes, remaining in a solid state at room temperature. Active key components of SLNs are mainly physiological lipids, dispersed in aqueous solution containing a stabilizer (surfactant).38 Micelles are made by colloidal aggregation in a solution through self-assembly of amphiphilic polymers, or a simple lipidic layer of transfer vehicles;39 these have been used in cellular and molecular imaging40 and treatment41 for a long time.

Inorganic NPs used in basic IHD research are classified as metal, metal compounds, carbon,42 or silicon NPs;43 these are relatively inert, stable, and biocompatible. Gold (Au),44 silver (Ag)45 and copper (Cu)46 are commonly used materials in their production. These NPs can be delivered orally,47 or injected intravenously48 or intraperitoneally.56 However, they are more widely used to construct electrically conductive myocardial scaffolds in tissue engineering.49,50 Myocardial patches and scaffolds are promising therapeutic approaches to repairing heart tissue after IHD; incorporating conductive NPs can further improve functionality, introducing beneficial physical properties and electroconductivity. Some organic particles, such as liposomes anchored with poly(N-isopropylacrylamide)-based copolymer groups, are also suitable for the production of effective nanogels or patches for this purpose.37

Several metal compounds have been used for treatment of IHD.5154 The application of magnetic particles made from iron oxide has been of particular interest in recent research. These NPs are more prone to manipulation with an external magnetic field, and thus serve as powerful tools for targeted delivery of therapeutics. In addition, modification with targeted peptides or antibodies is another approach to the construction of targeted delivery systems.

Another strategy to protect cardiac performance after MI is the transplantation of cells; however, the beneficial effects of this are currently limited.58 Many NPs can improve the behavior of cells; in this context, they may stimulate cardioprotective potential. In particular, exosomes a major subgroup of extracellular vesicles (EVs) with a diameter of 30150nm, which are secreted via exocytosis55 represent novel, heterogeneous, biological NPs with an endogenous origin. They are able to carry a variety of proteins, lipids, nucleic acids, and other bioactive substances.5557 Mechanistic studies have confirmed that exosomes offer a cell-free strategy to rescue ischemic cardiomyocytes (CMs).59,60

The physical properties of NPs, including size, shape, and surface charge, impact on how biological processes behave, and consequently, responses in the body.61 The recommended definition of NPs in pharmaceutical technology and biomedicine includes a limitation that more than 50% of particles should be in a size distribution range of 10100 nm.39 However, this is not strictly distinguished in studies, so for the purposes of this review, we have relaxed this definition. Small NPs have a faster uptake and processing speed and longer blood circulation half-lives than larger ones; a decreased surface area results in increased reactivity to the microenvironment and greater speed of release of the compounds they carry.6163 However, an exception to this principle is that, among particles of less than 50 nm diameter, larger NPs have longer circulatory half-lives.64,65 NPs can be spherical, discoidal, tubular or dendritic.61,63 The impact of NP shape on uptake and clearance has also been revealed;66,67 for instance, spheres endocytose more easily,20 while micelles and filomicelles target aortic macrophages, B cells, and natural killer (NK) cells in the immune system more effectively than polymersomes.68 In terms of charge, cationic NPs are more likely to interact with cells than negatively charged or neutral particles because the mammalian cell membrane is negatively charged.62 As a result, positively charged particles are reported to be more likely to destabilize blood cell membranes and cause cell lysis.61 Additionally, the rate of drug release is largely determined by the diameter of the pore. Motivated by the idea, Palma-Chavez et al developed a multistage delivery system by encapsulating PLGA NPs in micron-sized PLGA outer shells.69

Some types of NPs, such as micelles, possess coreshell morphological structures: a core composed of hydrophobic block segments is surrounded by hydrophilic polymer blocks in a shell that stabilizes the entire micelle. The core provides enough space to accommodate compounds, while the shell protects drug molecules from hydrolysis and enzymatic degradation.36 Surface chemical composition largely governs the chemical interactions between NPs and molecules in the body. Appropriate surface coatings can create a defensive layer, protect encapsulated cargo, and affect biological behaviors. Coating with inert polymers like polyethylene glycol (PEG) is the most commonly used method, which hinders interactions with proteins, alters the composition of the protein corona, attenuate NP recognition by opsonins which tag particles for phagocytosis, and extend the half-life of particles.36,70 Additionally, PEG coating helps the therapeutic agents reach ischemic sites, because PEGylated macromolecules tend to diffuse in the interstitial space of the heart.71 Functionalization of gangliosides can further attenuate the immunogenicity of PEGylated liposomes without damaging therapeutic efficacy.72 Removal of detachable PEG conjugates in the microenvironment of the target sites improves capture by cells. Wang and colleagues synthesized PDA-coated tanshinone IIA NPs by spontaneous hydrophobic self-assembly.73 Polyethyleneimine (PEI) is capable of condensing nucleic acid and overcoming hamper of cell membrane. Therefore, modification with PEI is mainly used for the transport of DNA and RNA.74 Of note, despite their inertness, novel NPs composed of metals can also be modified with compounds such as PEG, thiols, and disulfides.48,75 Hydrogels mixed with peptide-coated Au NPs attain greater viscosity than hydrogels mixed with Au NPs.24

Targeted delivery is a primary goal in the development of nanocarriers. Passive targeting is based on enhanced permeability in ischemic heart tissue, which does not meet the needs of clinical application.76 This fact has prompted work on targeting agent modification and magnetic guidance. Conjugation with specific monoclonal antibodies is a feasible method for delivering drug payloads targeted to ischemic lesions. Copper sulfide (CuS) NPs coupled to antibodies targeting transient receptor potential vanilloid subfamily 1 (TRPV1), permit specific binding to vascular smooth muscle cells (SMCs), and can also act as a switch for photothermal activation of TRPV1 signaling.52 In another study conducted by Liu and colleagues, two types of antibodies, binding CD63 (expressed on the surface of exosomes) or myosin light chain (MLC, expressed on injured CMs) are utilized to allow NPs to capture exosomes and accumulate in ischemic heart tissue. These NPs have a unique structure comprising an ferroferric oxide core and PEG-decorated silica shell, which simultaneously enables magnetic manipulation and molecule conjugation via hydrazone bonds.21 Targeted peptides such as atrial natriuretic peptide (ANP),43 S2P peptide (plague-targeting peptide),77 and stearyl mannose (type 2 macrophage-targeting ligand)16 allow NPs to precisely target atherosclerotic tissue and ischemic heart lesions. Modification with EMMPRIN-binding peptide (AP9) has been shown to enable more rapid uptake of micelles by H9C2 myoblasts and primary CMs and to deliver drug payloads targeted to lesions in vivo.78,79 Another strategy for targeted nanocarriers is to produce cell mimetic carriers. Using the inflammatory response as a marker after MI,76 Boada and colleagues synthesized biomimetic NPs (leukosomes) by integrating membrane proteins purified from activated J774 macrophages into the phospholipid bilayer of NPs. Local chronic inflammatory lesions demonstrated overexpression of adhesion molecules, which bound leukosomes efficiently.80

The biocompatibility of NPs is difficult to predict because any interaction with molecules or cells can cause toxic effects. Generally, NPs remain in blood, but can also extravasate from vasculature with enhanced permeability, or accumulate in the mononuclear phagocyte system.81 Important causes of NP-associated toxicity include: oxidative stress injury and cell apoptosis secondary to the production of free radicals, lack of anti-oxidants, phagocytic cell responses, and the composition of some types of particles.61 Hepatotoxicity, nephrotoxicity and any other potential off-target organ damage caused by accumulation of particles, especially those with poor degradability and slow clearance, are also essential to explore in toxicity tests.82 Additionally, the evaluation of evoked immune responses according to the expression of inflammatory factors and stimulation of leukocytes in cell lines and animal models is also important.83

A few studies have reported NP-associated acute and chronic hazards in pharmacological applications, although some of these observations may be contentious. Specifically, aggregation of non-functionalized carbon nanotubes (CNTs) has been observed owing to inherent hydrophobicity of these particles.61 Aside from inflammation and T lymphocyte apoptosis, multi-walled CNTs can rupture cell membranes, resulting in macrophage cytotoxic effects.84,85 Silica NPs induce vascular endothelial dysfunction and promoted the release of proinflammatory and procoagulant factors, mediated by miR-451a negative regulation of the interleukin 6 receptor/signal transducer and activator of transcription/transcription factor (IL6R/STAT/TF) signaling pathway.8688 Metal NPs, such as Au and Ag, can also penetrate the cell membrane, increase oxidative stress and decrease cell viability.89,90 Consequently, exposure to Au may cause nephrotoxicity91 and reversible cardiac hypertrophy.92 El-Hussainy and colleagues observed myocardial dysfunction in rats given alumina NPs.93,94 Nemmar and colleagues investigated the toxicity of ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs) administered intravenously, which resulted in cardiac oxidative stress and DNA damage as well as thrombosis.95 Cell-derived exosomes and a majority of natural polymers are considered relatively safe;83 however, Babiker and colleagues demonstrated that dendritic polyamidoamine NPs compromise recovery from ischemia/reperfusion (I/R) injury in isolated rat hearts.96 The effects of degradation byproducts are also of concern.83 An advantage of the nanoscale size of NPs is that their injection is unlikely to block the microvascular system; however, it remains controversial whether NPs give rise to arrhythmias.97 These factors highlight that examining the biocompatibility of NPs both in vitro and in vivo is a vital component of preclinical or clinical research.

NP toxicity depends on many parameters, including material composition, coating, size, shape, surface charges and concentration.39 For instance, larger particles seem to be more favorable from a toxicology standpoint.83 However, single-walled CNTs are considered more harmful than multi-walled CNTs, due to their smaller size resulting in less aggregation and increased uptake by macrophages.61 Cationic AuNPs are more toxic compared with anionic AuNPs, which appear to be nontoxic.98 Generally speaking, NP-associated toxicity can be lowered by functionalization with nontoxic surface molecules, stabilization and localization in the region of interest by using scaffolds.24,99 The toxicity of CNTs mediated by oxidative stress and inflammation was reduced using these strategies in several studies.24,100 Local application and targeted delivery also enabled dose reduction and concurrently decreased the incidence of adverse effects. Administration of therapeutic agents directly into the infarcted or peri-infarcted myocardium is a conventional approach with a low risk of inducing embolization.

NP is a suitable method for the administration of therapeutic agents in terms of the minimization of side effects, enhanced stability of cargo, and possibility of controlled delivery and release.76 Detailed information on the experimental design and results of the latest studies on the use of NPs as therapeutic vectors are provided in Table 1. Recently, several drugs approved for clinical use as immunosuppressants have been suggested as potentially effective cardioprotective agents. For example, NPs containing cyclosporine A inhibited apoptosis and inflammation in ischemic myocardium by improving mitochondrial function.25,101 Commercial methotrexate also showed minor cardioprotective effects; additionally, when loaded into lipid core NPs, adenosine bioavailability and echocardiographic and morphometric results were all improved a rats model of MI.102 Margulis and colleagues developed a method to fabricate NPs via a supercritical fluids setup, which loaded and transferred celecoxib, a lipophilic nonsteroidal anti-inflammatory drug, into the NPs. These celecoxib-containing NPs alleviated ejection function damage and ventricular dilation by inducing significant levels of neovascularization.103 Furthermore, a series of investigations indicated that drugs used for hypoglycemia (eg pioglitazone, exenatide and liraglutide)104106 and lipid lowering (statins)107 attenuate the progression of post-MI heart failure, and are therefore also potential therapeutic cargoes for NPs in the treatment of MI.

NP systems also offer an alternative method for delivering plant-derived therapeutic agents, most of which belong to traditional Chinese medicine. Its of vital importance because of the criticization on adverse reactions caused by direct injection of such complexes. Cheng and colleagues designed a dual-shell polymeric NP as a multistage, continuous, targeted vehicle of resveratrol, a reactive oxygen species (ROS) scavenger. Due to the severe oxide stress in areas of infarction, the proposed antioxidant-delivery NPs represent a new method to effectively treat MI. These NPs are modified with two peptides, targeting ischemic myocardium and mitochondria, respectively; cardioprotective effects have been confirmed in both hypoxia/reoxygenated (H/R) H9C2 cells and I/R rats.108 In addition, Dong and colleagues also demonstrated that puerarin-SLNs produced smaller areas of infarction in a MI rat model, evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. These particles were modified with cyclic arginyl-glycyl-aspartic acid peptide, a specific targeting moiety to v3 integrin receptors, which are highly expressed on endothelial cells (ECs) during angiogenesis.109 In a recent study, quercetin was loaded into mesoporous silica NPs, which enhanced the inhibition of cell apoptosis and oxidative stress, improving ventricular remodeling and promoting the recovery of cardiac function by activating the janus kinase 2 (JAK2)/STAT3 pathway.110 Similarly, curcuminpolymer NPs, administered by gavage, improved serum inflammatory cytokine levels compared with direct administration of curcumin.111

Translation of novel bioactive agents into clinical practice has been limited, owing to lack of sufficient bioavailability and systemic toxicity.76 Encapsulating small molecules such as 3i-1000 (an inhibitor of the GATA4NKX2-5 interaction),43 TAK-242 (inhibitor of toll-like receptor 4, TLR4)112 and C143 (inhibitor of ERK1/2)113 in NPs promotes myocardial repair after MI without the risk of uncontrolled and off-target adverse effects. Administration of vascular endothelial growth factor (VEGF) causes elevated vascular permeability and tissue edema. The cardioprotective effects of VEGF-loaded polymeric NPs injected either intravenously114 or intramyocardially115 eliminated vascular leakage due to promotion of lymphangiogenesis. Further studies have confirmed these results and add to the evidence that combined delivery of VEGF with other growth factors is recommended, since VEGF primarily drives the formation of new capillaries.116 Furthermore, in line with previous research, similar therapeutic effects have been demonstrated in studies using polymeric NPs loaded with stromal cell derived factor 1 (SDF-1) and insulin-like growth factor 1 (IGF-1).117,118

We also notice that some novel payloads in NPs-based therapy for MI have been studied. For example, deoxyribozyme-AuNP can silence tumor necrosis factor- (TNF-).119 A target that is implicated in irreversible heart damage after MI; its effects are mediated by free radical production, downregulation of contractile proteins, and initiation of pro-inflammatory cytokine cascades. Mesoporous iron oxide NPs containing the hydrogen sulfide donor compound diallyl trisulfide act as a platform for the controlled and sustained release of this therapeutic gas molecule. The application of these NPs at appropriate concentrations, resulted in the preservation of cardiac systolic performance without any observable detrimental effects on homeostasis in vivo.15

With increasing insight into the molecular mechanisms of MI, a particular emphasis on gene therapy has emerged. Gene expression can be modulated by DNA fragments, messenger RNA (mRNA), microRNA (miRNA) and small interfering RNA (siRNA), which thus represent new approaches for treating ischemia. Currently available nucleic acid delivery systems are mainly divided into viral and non-viral systems. However, virus-based approaches are limited by their potential for uncontrollable mutagenesis.36 From a clinical point of view, NP represents a suitable choice as novel non-viral nucleic acid vector, which could feasibly transfect in a stable, targeted, and sustained manner (as shown in Table 2).

Table 2 NPs-Based Nucleic Acid Delivery Systems for Treatment for MI Reported in the Last 7 Years

As a common gene vehicle, plasmids face the risk of being destroyed by DNase and immunoreactivity in the serum, and transduction in non-target organs.120 A recent study by Kim and colleagues aligns with current research trends focused on virus-free therapies, in which carboxymethylcellulose NPs were designed to transfer 5-azacytidine to halt proliferation, and deliver plasmid DNA containing GATA4, myocyte enhancer factor 2C (MEF2C), and TBX5 to induce reprogramming and cardiogenesis of mature normal human dermal fibroblasts.121 In a methodological study, lipidoid NPs were used to successfully deliver pseudouridine-modified mRNA, encoding enhanced green fluorescent protein.122

MiRNAs act as essential regulators of cellular processes through post-transcriptional suppression; increasing evidence reveals miRNAs play critical roles in cardiovascular diseases. An miRNA-transferring platform with self-accelerating nucleic acid release, containing a heparin core and an ethanolamine-modified poly(glycidyl methacrylate) shell, has been constructed and used as an efficient vector of miR-499, which inhibits cardiomyocyte apoptosis.123 Intravenous administration of anionic hyaluronan-sulfate NPs (mean diameter 130 nm) enable the stable delivery of miR-21 mimics, thus modulating the expression of TNF, transforming growth factor (TGF), and suppressor of cytokine signaling 1 (SOCS1). Consequently, these NPs switch the phenotype of macrophages from pro-inflammatory to reparative, promote neovascularization and reduced collagen deposition.124 Interestingly, silencing miR-21 using antagomiR-21a-5p in a nanoparticle formulation has also been shown to reduce expression of pro-inflammatory cytokines in vitro, and attenuate inflammation and fibrosis in mice with autoimmune myocarditis.125 A number of other potentially therapeutic miRNAs have also been successfully transferred to CMs in recent works, including miR-146a, miR-146b-5p, miR-181b, miR-199-3p, miR-214-3p, miR-194-5p and miR-122-5p.126128 Evaluation of angiogenesis, cardiac function, and scar size in these studies indicated that injectable miRNANPs can deliver miRNA to restore injured myocardium efficiently and safely. Yang and colleagues developed an in vivo miRNA delivery system incorporating a shear-thinning hydrogel and NPs characterized by surface presence of miRNA and cell-penetrating peptide (CPP).126 Additionally, angiotensin II type 1 receptor-targeting peptide-modified NPs serve as targeted carriers for anti-miR-1 antisense oligonucleotide, significantly reducing apoptosis and infarct size.129

SiRNAs inhibit gene expression by mediating mRNA cleavage in a sequence-specific manner, highlighting NP-based RNA interference as another viable approach to modulate cellular phenotype and attenuate cardiac failure. Dosta and colleagues demonstrated that poly(-amino ester) particles modified by adding lysine-/histidine-oligopeptides could represent a system for the transfer of siRNA.130 Studies have now revealed that chemokine CC motif ligand 2 (CCL2) and its cognate receptor CC chemokine receptor 2 (CCR2) promoted excessive Ly6Chigh inflammatory monocyte infiltration in infarcted area and aggravate myocardial injury.131 Photoluminescent mesoporous silicon nanoparticles (MSNPs) carrying siCCR2 have been reported to improve the effectiveness of transplanted mesenchymal stem cells (MSCs) in reducing myocardial remodeling after acute MI.131 Targeted transportation and enhanced uptake with minimum leakage improved the efficiency of delivery via NPs, significantly outperforming the control group. Taken together, these studies demonstrate that NPs act as promising drug delivery systems in the treatment of MI.

Myocardial patches and scaffolds, consisting of either bioactive hydrogels or nanofibers, are minimally invasive, relatively localized, and targeted approaches to repair the heart after IHD. Those biomaterials must have an anisotropic structure, mechanical elasticity, electrical conductivity, and the ability to promote ischemic heart repair.132 A variety of NPs have been applied in this field, among which inorganic NPs have been the focus of most research efforts.42 These investigations of inorganic NPs can be divided into four categories based on their effects and the mechanisms involved, which are described in this section.

NPs enhance physical properties and electroconductivity, which is essential for the biomaterials to properly accommodate cardiac cells and subsequently resulted in cell retention, cell-cell coupling and robust synchronized beating behavior. CNTs are able to increase the required physical properties of scaffolds, such as maximum load, elastic modulus, and toughness.133,134 Gelatin methacrylate (GelMA) also has decreased impedance, hydrogel swelling ratio, and pore diameter, as well as increased Youngs modulus when combined with gold nanorods (AuNRs).135 Given this insight, highly electroconductive NPs have been increasingly investigated.34,99 Specifically, Ahadian and colleagues revealed that a higher integrated CNT concentration in gels resulted in greater conductivity.136 Zhou and colleagues verified the therapeutic effects of patches incorporating single-walled CNT for myocardial ischemia, which halted progressive cardiac dysfunction and regenerated the infarcted myocardium.137 Spherical AuNPs have also been shown to increase the conductivity of chitosan hydrogels in a concentration-dependent manner.138 Interestingly, silicon NPs mimic the effects of AuNRs without affecting conductivity or stiffness, as reported by Navaei and colleagues.139

Several studies demonstrate the effects of CNT on CM functions. When CMs are cultured on multi-walled CNT substrates or treated with CNT-integrated patches, these cells show spontaneous electrical activity.34,99,140 Brisa and colleagues functionalized reverse thermal gels with AuNPs, investigating the phenotype of CMs in vitro; the growth of cells with a CM phenotype was observed, along with gap junction formation.141 CMs exposed to AuNR-containing GelMa show higher affinity, leading to packed and uniform tissue structure.135 These conductive scaffolds also facilitate the robustness and synchrony of spontaneous beating in CMs without damaging their viability and metabolic activity.

Combined incorporation of inorganic NPs and cells represents a feasible strategy to promote therapeutic effects. Despite some reports on the cytotoxicity of Au,89,90 no significant loss of viability, metabolism, migration, or proliferation of MSCs in scaffolds containing AuNP is reported. A CNT-embedded, electrospun chitosan/polyvinyl alcohol mesh is reported to promote the differentiation of MSCs to CMs.142 In another approach, Baei and colleagues added AuNPs to chitosan thermosensitive hydrogels seeded with MSCs.138 There was a significant increase in expression of early and mature cardiac markers, indicating enhanced cardiomyogenic differentiation of MSCs compared to the matrix alone, while no difference in growth was observed. Gao et al created a fibrin scaffold, in which cells and AuNPs were suspended simultaneously; these bioactive patches were shown to promote left ventricular function and decrease infarct size and apoptosis in the periscar boarder zone myocardium in swine models of acute MI.97 These studies of AuNP-containing scaffolds demonstrated reduced infarct and fibrotic size, as well as facilitated angiogenesis and cardiac function, which can be attributed at least in part to the enhanced expression of connexin 43 and atrial natriuretic peptide, and activation of the integrin-linked kinase(ILK)/serine-threonine kinase (p-AKT)/GATA4 pathway.49,143,144 Scaffolds containing Ag NPs evoke M2 polarization of macrophages in vitro;145 which may also play a role in cardioprotective action because M2 macrophages are capable of promoting cardiac recovery via the secretion of anti-inflammatory cytokines, collagen deposition, and neovascularization.146

Similarly, CNT also act synergically with poly(N-isopropylacrylamide) scaffolds containing adipose-derived stem cells;147 significant improvement of cardiac function and increased implantation and proliferation of stem cells has been observed with these scaffolds, compared with scaffolds without CNT.147 Selenium NPs148 and titania NPs53 have been shown to improve the mechanical and conductive properties of chitosan patches, promoting their ability to support proliferation and the synchronous activity of cells growing on these patches.

Mounting evidence demonstrates the unique benefits of using cardiac scaffolds with magnetic NPs such as SPIONs; these benefits include, but are not limited to, significant improvements in cell proliferation149 and assembly of electrochemical junctions.150 Given that magnetic manipulation enhances the therapeutic efficacy of iron oxide NPs in cardiac scaffolds, Chouhan and colleagues designed a magnetic actuator device by incorporating magnetic iron oxide NPs (MIONs) in silk nanofibers; this resulted in more controlled drug release properties, as well as the promotion of proliferation and maturation in CMs.151 Magnetic NPs can be used to label induced pluripotent stem cell (iPSC)-derived CMs via conjugation with antibodies against signal-regulatory protein . Zwi-Dantsis and colleagues reported the construction of tailored cardiac tissue microstructures, achieved by orienting MION-labelled cells along the applied field to impart different shapes without any mechanical support.152 However, the interactions between and effects of NPs and cells in scaffolds, and the cardioprotective efficacy of patches in which NP-labelled cells are suspended, require further elucidation.

Polymeric nanomaterials have also been investigated in the context of cardiac bioengineering materials; for instance, water-swollen polymer NPs have been used to prepare nanogels. With a 3D structure containing cross-linked biopolymer networks, nanogels can encapsulate, protect, and deliver various agents.83,153 PDA-coated tanshinone IIA NPs suspended in a ROS-sensitive, injectable hydrogel via PDA-thiol bonds significantly improved cardiac performance, accompanied by inhibition of the expression of inflammation factors in rat model.73 After implanting cryogel patches consisting of GelMa and linked conductive polypyrrole NPs154 or scaffolds of electrospun GelMA/polycaprolactone with GelMA-polypyrrole NPs,155 left ventricular (LV) ejection fraction (EF) has been shown to increase, with a concurrent decrease in infarct size, in MI animal models.

Progenitor or stem cell-based therapy in the form of injections and engineered cardiac patches, discussed in the previous section, has been recognized as a promising strategy to improve the cardiac niche and ameliorate adverse remodeling processes and fibrosis after acute MI.56,156,157 However, poor survival and low engraftment rates for transplanted cells are still major challenges in this field.157 Among possible optimization strategies, combining NPs with stem cell therapy is of great interest (Table 3).

Table 3 Studies Combining NPs and Cell Therapy Reported in the Last 7 Years

Accumulating evidence has shown two main mechanisms for NP-loaded cell therapy in the context of MI treatment. Firstly, various NP types could efficiently improve survival and cell proliferation, modulating differentiation of implanted cells in the ischemic microenvironment.62,158 Specifically, electrically driven nanomanipulators could guide cardiomyogenic differentiation of MSCs: in a previous study, electroactuated gold NPs were administrated with pulsed electric field stimulation, and tube-like morphological alterations were observed, along with upregulation of cardiac specific markers.143 Adipose-derived stem cells that load PLGA-simvastatin NPs promoted differentiation of these cells into SMCs and ECs, and had cardioprotective effects in a mouse model of MI induced by left anterior descending ligation.17 Secondly, engraftment rate is another important factor affecting treatment efficacy in this context.159 Zhang and colleagues designed silica-coated, MION-labelled endothelial progenitor cells; intravenous administration of these cells in a rat model of MI significantly improved cardiac performance, as indicated by echocardiogram, morphological, and histological evidence, and neovascularization. This indicates magnetic guidance may potentially address the problem of low levels of stem cell retention, which has typically been observed.51 In particular, NPs can link the therapeutic cells to injured CMs, thereby promoting cell anchorage and engraftment. To this end, Cheng and colleagues established a magnetic, bifunctional cell connector by conjugating NPs with two antibodies: one against cell determinant (CD)45, which is expressed on bone marrow-derived stem cells, and one against MLC. The magnetic core of this NP also enabled physical enrichment in ischemic heart tissue using external magnets.160 More than one mechanism may be involved in a study. Chen and colleagues fabricated a sustained release carrier of insulin-like growth factor (IGF), a pro-survival agent, via in situ growth of Fe3O4 NPs on MSNPs. In this study, the NPs promoted both the survival and retention of MSCs, and intramyocardial injection of the NP-labeled MSCs was able to ameliorate functional and histological damage without any obvious toxicity in vivo.161 However, SPION labeling does not seem to improve therapeutic efficiency, as demonstrated by Wang and colleagues in a study using hypoxia-preconditioned SPION-labeled adipose-derived stem cells (ASCs).162

Primary criticisms of cell-based therapies include their potential immunogenicity, arrhythmogenicity and tumorigenicity. It is widely accepted that the beneficial effects of cell-based therapy are mainly attributable to paracrine effects rather than directly replenishing lost CMs;56 researchers are therefore investigating of cell-free approaches. Exosomes have attractive properties including stable transport, homing to target tissues or cells, and penetration of biological barriers, as well as being more biocompatible with lower immunogenicity than cell-based approaches. Interestingly, post-MI circulating exosomes serve as important cardioprotective messengers.163,164 Manipulating their biodistribution has proven to be a viable strategy to reduce infarct size, promoting angiogenesis and ejection functions.21 However, from a therapeutic standpoint, the lack of control over endogenous exosome production and cargo encapsulation limits the use of this naturally-present mechanism for therapeutic enhancement. The low purity and weak targeting of natural exosomes are two further obstacles to overcome before clinical application. Strategies to address these include finding robust sources; optimized isolation methods for higher yields, efficiency and purity; and improving therapeutic payloads. These have been systematically summarized in other reviews.165167

AS is considered a low-grade, chronic inflammatory disease, characterized by accumulation and deposition of cholesterol in arteries, as well as remodeling of the extracellular matrix in the intima and inner media.12,168 Inflammation of ECs, proliferation of SMCs, and recruitment of monocytes and macrophages play a critical role in the development of AS. NPs allow for the packaging of large amounts of therapeutic compounds in a compact nanostructure, specifically targeting pathological mechanisms and attenuating atherogenesis. Optimization of the loaded drug and NP target together lead to enhanced efficacy while minimizing side effects.169 In this section, we summarize recent breakthroughs in the order of pathological progression, as shown in Table 4.

Primary prevention refers to control of the risk factors of AS, one of which is hypertension.170 PLA NPs have been shown to improve the efficacy of aliskiren, the first oral direct renin inhibitor and the first in a new class of antihypertensive agents.29 Encapsulation in nanocarriers also renders the application of anandamide viable, which was once limited; recent research revealed that this new therapy could lower blood pressure and LV mass index in rats.171 Similar results were observed in a study in which angiotensinogen was silenced using small hairpin RNA.172 NPs may also help to make more anti-hypertensive drugs available, reduce side effects such as asthma, and lessen the effective dosage by providing sustained drug release over time. The link between AS and diabetes mellitus, which describes a group of metabolic disorders, has also been investigated in numerous studies.173 Possible mechanisms include oxidative stress, altered protein kinase signaling, and epigenetic modifications. Cetin and colleagues successfully constructed NP-based drug delivery systems for the administration of metformin, an oral antihyperglycemic agent with low oral bioavailability and short biological half-life.174 NPs are also promising tools for improving the oral bioavailability of insulin, which is of great interest because oral insulin will significantly increase patients compliance.175,176

The inflammatory hypothesis of AS is now widely established, making selective targeting and accumulation of NPs in inflammatory lesions attractive therapeutic strategies. Targeting macrophages in apoE-/- mice has been shown to result in decreased phagocytosis and suppression of inflammatory genes in lesional macrophages, thus lessening burden of atherosclerotic plaques.177 Tom and colleagues used NPs consisting of high-density lipoprotein (HDL), a known atheroprotective bionanomaterial, as carriers for TNF receptor-associated factor in mice, and observed reductions in both leukocyte recruitment and macrophage activation.178 Both single-walled CNT and HDL-NPs have a favorable safety profile. In a pathological context, activated endothelial tissue expresses more adhesion molecules, such as selectins, than usual. These molecules are thus potential targets for cardiovascular nanomedicine. Glycoprotein Ib (GPIb)179 and biotinylated Sialyl Lewis A (sLeA)69 specifically bind to selectins, leading to the accumulation of conjugated NPs in injured vessels; an in vitro study demonstrated that GPIb-conjugated NPs could bind to target surfaces, where they were taken up by activated ECs under shear stress conditions. In another study, Sager and colleagues simultaneously inhibited five adhesion molecules associated with leukocyte recruitment in post-MI apoE-/- mice. Inflammation in plaque and ischemic heart, rendering acute coronary events and post-MI complications less likely to occur.180 However, targeting inflammatory process may have heterogeneous effects in humans because the targeting moieties and target receptors may be overexpressed in several different pathologic conditions in addition to AS. Oxidation is another factor involved in the development of AS. Upregulation of endothelial nitric oxide synthase (eNOS) leads to vascular construction and other AS-promoting effects. Pechanova and colleagues observed that the application of PLA NPs resulted in larger decreases in NOS than direct administration.29

Aside from these processes, avoiding plaque rupture and thrombosis could be another therapeutic aim. Nakashiro and colleagues showed that delivering pioglitazone via NPs inhibited plaque rupture in apoE-/- mice.181 The integrin 3 is upregulated in angiogenic vasculature, which is ubiquitous in plaque ruptures, which may lead to MI.182 3 integrin-targeted NPs provide a site-specific drug delivery platform that has been shown to successfully stabilize plaques in rabbits.182 Ji and colleagues used NPs composed of albumin with an average diameter of 225.6 nm to deliver a plasmid containing the tissue-type plasminogen activator gene (t-PA); this system plays a role in preventing thrombosis in addition to attenuating intimal thickness and proliferation of vascular SMCs.183 NPs consisting of engineered amphipathic cationic peptide and serine/threonine protein kinase JNK2 siRNA also reduces thrombotic risk, plaque necrotic area, and vascular barrier disorder in mice given the equivalent of a 14-week western diet.184

Innovation and development of therapies based on NPs in recent years has led to significant advances towards complete repair of the injured myocardium following acute MI. Nevertheless, developing clinically relevant solutions remains difficult for several reasons. Firstly, as shown in tables, there is little consistency among studies regarding the characteristics of NPs, their payloads, and their methods of administration, as well as methods used for evaluating cardiac repair. It can be difficult to control characteristics such as the size of the synthesized particles in a narrow range, even within single studies. Such significant heterogeneity can lead to differences in observed results in repeated experiments, or under different conditions. Secondly, although many studies have focused on the health effects of unintentional exposure to NPs by inhalation or ingestion,185,186 most of the studies on medical applications of NPs have not reported on toxicity of NP systems until recently.73 Remarkably, there has not been a consensus on NP-associated adverse effects in existing reports, making assessments of biocompatibility a priority for NP characterization.

NPs have emerged as a powerful tool for controlling cell signaling pathways in regenerative strategies using novel therapeutics and drugs that are unsuitable for direct administration. One advantage of the application of NP systems is the ability to release the drug payload or regulate gene expression in a stable and controlled manner. Therefore, many otherwise serious side effects, such as sudden arrhythmic deaths resulting from persistent and uncontrolled expression of miRNA by viral vectors, may be completely avoided.187 More research is required to develop stable and efficient methods of NP production, improve encapsulation efficiency of drugs, and achieve satisfactory targeting. In particular, a greater focus on investigating NP-based switches, including optical, electrical and magnetic methods, has enabled the regulation of cell signaling, exemplified by the development of a CuS NP-based photothermal switch.52 Optimizing tissue engineering scaffolds containing conductive NPs is a promising strategy for the protection of the myocardium after ischemia by mimicking the myocardial extracellular matrix. Improvements in understanding of cardiac repair mechanisms, and how these biomaterials may interfere with them, is therefore urgently needed. Furthermore, heart repair is complex and involves many processes, including apoptosis, angiogenesis, inflammatory infiltration, and fibrosis. Therefore, novel treatments should be designed using NP-based integrative strategies based on these multiple different mechanisms. However, its important to highlight that synergistic effects of different drug payloads, NPs, and NPcell combined strategies should be addressed, as not all may be compatible with one another. Future research should focus on these aspects to translate NP-based therapeutic strategies for MI into practical and effective clinical use.

The authors report no conflicts of interest in this work.

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October 5th, 2021

Mantarray: Scalable Human-relevant 3D Engineered Cardiac and Skeletal Muscle Tissues for Therapeutics Discovery Upcoming Webinar Hosted by Xtalks -…

By daniellenierenberg

Learn how these advanced 3D tissue models generated on the Mantarray platform can improve the physiological relevance of preclinical cardiac and skeletal muscle models, accelerating the discovery of new medicines.

TORONTO (PRWEB) October 05, 2021

3D cellular models and organs-on-chips are poised to add tremendous value by providing human data earlier in the drug discovery pipeline. There is intense interest in adopting these 3D models in preclinical and translational research, but their complex implementation has remained a roadblock for many labs.

In this webinar, Curi Bio will present its Mantarray platform, which represents an easy-to-use, flexible, and scalable system for generating 3D EMTs at high-throughput with the ability to measure contractility in parallel. The platform features a novel method of casting 3D tissues that can be easily performed by nearly any cell biology researcher and can be readily adapted to a variety of cell lines and extracellular matrices. In addition, Mantarrays novel magnetic sensing modality permits contractility measurement of 24 tissues in parallel and in real time, while the cloud data analysis portal takes the guesswork out of analyzing and comparing results across experiments.

Register for this webinar to hear an overview of the technology, along with application examples across various use cases, including:

Join Dr. Nicholas Geisse, Chief Science Officer at Curi Bio, for the live webinar on Friday, October 22, 2021 at 1pm EDT.

For more information, or to register for this event, visit Mantarray: Scalable Human-Relevant 3D-Engineered Cardiac and Skeletal Muscle Tissues for Safety and Efficacy Studies.

ABOUT XTALKS

Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global life science, food and medical device community. Every year, thousands of industry practitioners (from life science, food and medical device companies, private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers.

To learn more about Xtalks visit http://xtalks.comFor information about hosting a webinar visit http://xtalks.com/why-host-a-webinar/

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October 5th, 2021

Five Heart Stories For International Heart Day – Cosmos

By daniellenierenberg

Today is International Heart Day, and Cosmos is looking back on the stories that make our hearts flutter.

Scientists have taken another step in the quest to create a Google map of the human body by putting together a detailed cellular and molecular map of the healthy heart.

An international team analysed almost half a million individual cells and cell nuclei from six different regions of the heart, obtained from 14 organ donors whose hearts were healthy but unsuitable for transplantation.

The result is theHeart Cell Atlas, which, shows the huge diversity of cells and reveals heart muscle cell types, cardiac protective immune cells and an intricate network of blood vessels. It also predicts how the cells communicate to keep the heart working.

Sometimes, the heart just stops for no perceivable reason. Sudden cardiac arrest (SCA) is a prevalent hidden killer, even for younger people: 40% of those who die from SCA are under 50 years old.

SCA is not as rare as we would like it to be, says cardiologist Elizabeth Paratz, whos undertaking her PhD at the Baker Heart and Diabetes Institute, Melbourne. In the last year in Victoria, 750 young people under 50 have suffered an SCA. This is almost exactly five times the road toll over the same time in this age group, yet we hear a lot more publicity about road fatalities in young people.

Paratz is researching the prevalence and causes of SCA, as well as looking at ways to diagnose it better. There are multiple causes of SCA, and theyre hard to pinpoint in young people.

The controversial use of stem cells to help patients recover from a heart attack may work, but not because it grows new heart muscle.

Research in mice has found that injecting stem cells into the heart triggers an immune response that makes the scar stronger and the heart beat more forcefully.

Thestudy, published in the journalNature, suggests the current practice of injecting stem cells into a patients blood may not be optimal: direct injection into the heart could be more effective.

In a preclinical trial on a beating human heart, researchers have found that a drug candidate developed from the venom of the worlds deadliest spider, the funnel web, may hold promise for heart attack treatment and transplants.

The researchers, led by Meredith Redd of the University of Queensland (UQ), and Sarah Scheuer of Victor Chang Cardiac Research Institute, tested a protein called Hi1a, found in the Fraser Island (Kgari) funnel web venom, on a beating heart that had been exposed to heart attack stresses.

After a heart attack, blood flow to the heart is reduced, resulting in a lack of oxygen to heart muscle, says Nathan Palpant of UQ, corresponding author of the paper.

The lack of oxygen causes the cell environment to become acidic, which combine to send a message for heart cells to die.

The Hi1a protein from spider venom blocks acid-sensing ion channels in the heart, so the death message is blocked, cell death is reduced, and we see improved heart cell survival.

The Chinese Finger Trap a tubular braided novelty beloved by kids and pranksters around the world provided the inspiration for a nifty bit of biotech that looks set to save sick kids a whole lot of heartache. Literally.

Pedro del Nido from Boston Childrens Hospital in the US heads a team that has designed a proof-of-concept device that promises to dramatically cut down on surgery for children with certain types of heart defects.

At present, kids with defective mitral and tricuspid heart valves must undergo surgery in which a corrective implant is installed. The problem, however, is that children grow: the heart increases in size, and requires at least one, and often several, further surgical interventions so that a correspondingly larger implant can be installed.

Needless to say, these repeated bouts of open-heart surgery are extremely traumatic and disruptive.

Now, however, Nido and Karp may have come up with an elegant and clever solution: an implant that grows with the organ.

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Five Heart Stories For International Heart Day - Cosmos

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October 5th, 2021

Stem cells may be the key to saving white rhinos from extinction – Sciworthy

By daniellenierenberg

It is too late for conservation efforts to save the northern white rhinoceros, but with recent scientific advancements there may still be hope to bring back this beloved species. In a recently published paper, scientist Marisa Korody and her colleagues at San Diego Zoo Global (USA) and at the Department of Molecular Medicine at Scripps Research (USA) describe their exciting progress on using stem cells to revive the northern white rhino.

The northern white rhino is functionally extinct, meaning there are not enough of these rhinos left to save the species. In fact there are only two northern white rhinos left: a mother and a daughter. But for decades, scientists have preserved cell samples from 15 northern white rhinos containing enough genetic material to potentially bring this species back from the brink. These preserved samples hold fibroblast cells the type of skin cells that secrete collagen from white rhinos. With these scientists newly developed methods, fibroblast cells can be converted into something much more valuable: induced pluripotent stem cells. These stem cells can differentiate into any cell type in the body including heart cells, muscle cells, and reproductive cells.

In theory, by converting fibroblast cells into reproductive cells, scientists could create genetically unique rhino embryos. Alongside other assisted reproduction technologies, scientists could implant a new embryo into a closely-related southern white rhino, where the baby northern white rhino could develop as an otherwise normal pregnancy. By completing this process multiple times, scientists may be able to establish a stable population of northern white rhinos.

In 2011, this research team generated induced pluripotent stem cells from the samples of another endangered species, but unfortunately since this process was found to harm the recipient genomes, this method was largely unsuccessful. Despite this setback, in 2015 the authors met with colleagues worldwide to consider ways to save the northern white rhino, and they concluded that methods involving induced pluripotent stem cells may still be the most promising solution. Over the following years, the scientists worked to improve their methods, and these improvements are documented in their recent paper. These experiments represent the first step in a long-term plan to bring the northern white rhino back through assisted reproduction techniques.

Right from the start, the scientists faced a whole host of challenges. Through trial and error they modified the growth medium for the cells, optimizing it for rhinoceros cells. With their improved growth medium, scientists successfully generated induced pluripotent stem cell lines from 11 rhinoceros individuals. This has never been done before and represents a huge stride forward in the path to recovering this species.

Before trying to make their first rhino, the scientists needed to stress these induced pluripotent stem cells and sequence their genomes to determine if the cell quality is good enough to potentially produce new, viable rhinos. They maintained colonies of these cells in long-term cultures and exposed these colonies to different conditions to give insight into how resilient these cells could be. These tests demonstrated that long-term culture did not affect the potential for these cells to differentiate into cardiac lineage cells, confirming that these cells are stable long-term. The researchers also confirmed that these pluripotent cells could potentially produce gametes, the egg and sperm cells that are used for sexual reproduction. These advancements indicate that with these newly developed protocols, induced pluripotent stem cells are a promising tool that could someday help recover the northern white rhino.

Although this study includes some exciting results, there is still much work to do. For example, scientists must now sequence the genomes of the northern and southern white rhino so other researchers can analyze the stem cells ability to stay the same over time. Despite the work that still needs to be done, these promising advancements could someday help the northern white rhino population recover. This method may also work for saving other endangered or extinct species, as long as the genetic material needed is available. Long-term, these scientists plan to continue a series of experiments that could ultimately bring this beloved rhino, and potentially other endangered species, back from the brink of extinction.

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October 5th, 2021

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