A type of blood cell cancer called angioimmunoblastic T-cell lymphoma (AITL) can develop as mutations accumulate with age in the stem cells from which the T cells in the blood develop.

However, the underlying mechanism by which AITL develops was unknown. Now, a team from the University of Tsukuba in Japan have shown that B cells, another type of blood cells, accumulate mutations in genes that control how the genetic material in the cell is packaged. These aberrant B cells then interact with T cells and lead to the development of AITL.

The paper, Clonal germinal center B cells function as a niche for T-cell lymphoma, was published in the journal Blood.

Blood cells such as B cells and T cells, involved in immunity, develop from stem cells in the bone marrow. Sometimes, mutations occur in individual stem cells that lead to the mutant stem cell giving an increased output of blood cells, all of which carry identical mutations.

The likelihood of this increases with age, known as age-related clonal hematopoiesis, or ACH. ACH is known to be linked to various cancers. AITL, a cancer of the T cells, is linked to ACH with mutations in a gene called TET2. The team used mouse models and human samples to show that theTET2 mutation needed to be present in all blood cells, not just the T cells, for a mouse model to develop AITL.

Using single-cell RNA sequencing, a technique that can show which genes are active within just one cell, they were able to profile the immune cells present in the samples. This revealed a significant increase in the number of aberrant germinal center B cells, a type of B cells with activating and proliferative capacities. These B cells showed recurrent mutations to genes for histone proteins, which organize the genetic material in the cell into higher structures. They also showed alterations to the pattern of a DNA modification called methylation, which affects the genes expressed in the cell.

B cells and T cells can interact through molecules on the cell surface known as CD40 and CD40 ligand.

Analysis of the single-cell sequencing data identified this interaction between CD40 and CD40 ligand as potentially essential for mediating crosstalk between the aberrant B cells and the tumor cells, said lead author Manabu Fujisawa.

Most importantly, the survival of the mice with AITL could be prolonged by treatment with an antibody designed to inhibit CD40 ligand, said main author Mamiko Sakata-Yanagimoto.

The genes expressed in the aberrant mouse GCB cells are also expressed in cells from human AITL withTET2 mutations.

This means that antibodies against CD40 ligand could potentially be a new therapeutic approach to human AITL.

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University of Tsukuba researchers understand the mechanism of AITL - Labiotech.eu

Bone Marrow Stem Cells Comments Off on University of Tsukuba researchers understand the mechanism of AITL – Labiotech.eu | August 26th, 2022

Certain patients with Wilm's tumor-expressing solid tumors are eligible to be treated with an investigational agent in a phase 1 clinical trial.

The first patient was dosed in a phase 1 dose escalation study (NCT05360680) which is evaluating CUE-102, of the interleukin 2 (IL-2) series, as monotherapy for the treatment of patients with Wilms Tumor 1 (WT1)-positive recurrent/metastatic cancers. The study will focus on colorectal, gastric, pancreatic, and ovarian cancers, according to a press release from Cue Biopharma.1

CUE-102 has the potential to activate the patients immune system against numerous WT1-expressing cancers, including solid tumors and hematologic malignancies, and has demonstrated selective and significant activation of WT1-specific T cells in preclinical studies. We believe that CUE-102 can play an important role in changing the treatment landscape for patients with WT1-positive cancers, by potentially delivering higher efficacy and lower toxicities than current available treatments, said Ken Pienta, MD, acting chief medical officer of Cue Biopharma, in a press release.

In a preclinical study of CUE-102 tested humans with peripheral blood mononuclear cells (PBMC) for cellular activity and specificity, while in vivo CUE-102 is testing in mice who are human leukocyte antigen HLA-A2 transgenic. Investigators found that CUE-102 both activates and expands WT1-specific CD8-positive T cells from PBMC of healthy donors. Similar to results seen with CUE-101, CUE-102 showed significant functional reduction of the IL-2 components.The in vivo study found CUE-102 expands polyfunctional WT1-specific CD8-positive T cells from mice who were nave and previously immunized, but the treatment did not alter the frequencies of other immune lineages.The in vivo study also found the WT1-specific CD8-positive T cells had a polyfunctional response to peptide-loaded target cells and selectively killed WT1-presenting target cells.These results, along with a tolerable safety profile, support the initiation of the phase 1 trial of CUE-102.2

This phase 1 study aims to find the dose-limiting toxicity and maximum-tolerated dose of CUE-102. The secondary end points include safety and tolerability, antitumor response rate, antitumor duration of response, antitumor clinical benefit rate, progression-free survival, and overall survival. The dose escalation portion of the trial will administer CUE-102 in intravenous doses of 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, and an experimental recommended phase 2 dose every 3 weeks for up to 2 years.3

Eligible patients in this phase 1 study will include patients who have colorectal, gastric, pancreatic, or ovarian cancer who have an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, have a human leukocyte antigen (HLA)-A*0201 genotype as determined by genomic testing, and tumors who are WT1-positive. Patients will be deemed ineligible if patients with central nervous system metastases have been treated and be asymptomatic, have a history of prior allogeneic bone marrow, stem cell, or solid organ transplant, treatment with radiation therapy within 14 days before the first dose of CUE-102, and a history of clinically significant cardiovascular disease.3

Initiating this phase 1 clinical study of CUE-102 at a starting dose of 1mg/kg, a clinically active dose in our Phase 1 CUE-101 clinical trial for HPV+ head and neck cancer, is an important step forward in demonstrating the modularity of our Immuno-STAT platform and the broader clinical potential of our CUE-100 series of biologics, said Dan Passeri, chief executive officer of Cue Biopharma, in the press release. We believe, given the preservation of the core molecular framework between CUE-102 and CUE-101 with the primary exception of the tumor-specific epitope, initiating the dose escalation trial at 1 mg/kg will result in reduced time and cost to evaluate tolerability at therapeutically active doses.

References

1. Cue biopharma doses first patient in phase 1 study of CUE-102 for Wilms Tumor 1 (WT1) - expressing cancers. Press release. Cue Biopharma; August 22, 2022. Accessed August 23, 2022. https://www.cuebiopharma.com/investors-media/news/

2. Zhang C, Girgis N, Merazga Z, et al. 720CUE-102 selectively activates and expands WT1-specific T cells for the treatment of patients with WT1+ malignancies. Journal for ImmunoTherapy of Cancer. 2021;9:doi: 10.1136/jitc-2021-SITC2021.720

3. A phase 1 in patients with HLA-A*0201+ and WT1+ recurrent/metastatic cancers. ClinicalTrials.gov. Updated July 7, 2022. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05360680?term=NCT05360680&draw=2&rank=1&view=recor

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Phase 1 Trial of CUE-102 in WT1+ Solid Tumors is Now in Motion - Targeted Oncology

Bone Marrow Stem Cells Comments Off on Phase 1 Trial of CUE-102 in WT1+ Solid Tumors is Now in Motion – Targeted Oncology | August 26th, 2022

MIAMI, Aug. 25, 2022 (GLOBE NEWSWIRE) -- LongeveronInc. (NASDAQ: LGVN),a clinical stage biotechnology company developing cellular therapies for chronic, aging-related and life-threatening conditions, today announced that the European Patent Office (EPO) has issued a notice of its intent to grant the Company a patent (EP Application No. 15861319.0) related to methods to treat endothelial dysfunction and monitor the efficacy of allogeneic mesenchymal cell therapies, also known as medicinal signaling cells (MSCs). The cells are administered to patients with cardiovascular disease through the monitoring of a protein, Vascular Endothelial Growth Factor (VEGF), which is a signal protein produced by many cells that stimulates the formation of blood vessels.

We are extremely pleased to receive this notice from the European patent office, said Chris Min, M.D., Ph.D., Interim Chief Executive Officer and Chief Medical Officer at Longeveron. This patent will bolster our robust intellectual property portfolio and support our goal of delivering effective cell therapies for a range of aging-related and life-threatening conditions.

The patent is titled Methods for Monitoring Efficacy of Allogeneic Mesenchymal Stem Cell Therapy in a Subject. Longeverons lead investigational product is Lomecel-B, a cell therapy product derived from MSCs. Many of Longeverons clinical studies point to Lomecel-B exerting effects through pro-vascular functions and/or reducing endothelial dysfunction, a condition where the lining of blood vessels is abnormal leading to diminished health of blood vessels and blood flow regulation.

The Company is evaluating the use of MSCs to treat several indications, including Hypoplastic Left Heart Syndrome (HLHS), a rare and life-threatening congenital heart defect that affects approximately 1,000 babies per year. Longeveron received both a Rare Pediatric Disease Designation and Orphan Drug Designation from the United States Food and Drug Administration in 2021 for Lomecel-B for the treatment of infants with HLHS. Longeveron is currently evaluating Lomecel-B for HLHS in a Phase 2a trial.

Longeveron is also conducting a trial of Lomecel-B in patients with Alzheimers Disease in the US and for aging frailty in Japan.

Now that the European Patent Office has issued an Intention to Grant, Longeveron will await grant of the patent and then begin the process of registering the patent in a number of nation members of the European Patent Organization. In those jurisdictions where the patent is registered, the patent is expected to expire in November of 2035.

About Longeveron Inc.

Longeveron is a clinical stage biotechnology company developing cellular therapies for specific aging-related and life-threatening conditions. The Companys lead investigational product is the Lomecel-B cell-based therapy product, which is derived from culture-expanded medicinal signaling cells (MSCs) that are sourced from bone marrow of young, healthy adult donors. Longeveron believes that by using the same cells that promote tissue repair, organ maintenance, and immune system function, it can develop safe and effective therapies for some of the most difficult disorders associated with the aging process and other medical disorders. Longeveron is currently sponsoring Phase 1 and 2 clinical trials in the following indications: Alzheimers disease, hypoplastic left heart syndrome (HLHS), Aging Frailty, and Acute Respiratory Distress Syndrome (ARDS). Additional information about the Company is available at http://www.longeveron.com.

Cautionary Note Regarding Forward-Looking Statements

Certain statements in this press release that are not historical facts are forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, which reflect management's current expectations, assumptions, and estimates of future performance and economic conditions, and involve risks and uncertainties that could cause actual results to differ materially from those anticipated by the statements made herein. Forward-looking statements are generally identifiable by the use of forward-looking terminology such as "believe," "expects," "may," "looks to," "will," "should," "plan," "intend," "on condition," "target," "see," "potential," "estimates," "preliminary," or "anticipates" or the negative thereof or comparable terminology, or by discussion of strategy or goals or other future events, circumstances, or effects. Factors that could cause actual results to differ materially from those expressed or implied in any forward-looking statements in this release include, but are not limited to, statements about the ability of Longeverons clinical trials to demonstrate safety and efficacy of the Companys product candidates, and other positive results; the timing and focus of the Companys ongoing and future preclinical studies and clinical trials and the reporting of data from those studies and trials; the size of the market opportunity for the Companys product candidates, including its estimates of the number of patients who suffer from the diseases being targeted; the success of competing therapies that are or may become available; the beneficial characteristics, safety, efficacy and therapeutic effects of the Companys product candidates; the Companys ability to obtain and maintain regulatory approval of its product candidates; the Companys plans relating to the further development of its product candidates, including additional disease states or indications it may pursue; existing regulations and regulatory developments in the U.S., Japan and other jurisdictions; the Companys plans and ability to obtain or protect intellectual property rights, including extensions of existing patent terms where available and its ability to avoid infringing the intellectual property rights of others; the need to hire additional personnel and the Companys ability to attract and retain such personnel; the Companys estimates regarding expenses, future revenue, capital requirements and needs for additional financing; the Companys need to raise additional capital, and the difficulties it may face in obtaining access to capital, and the dilutive impact it may have on its investors; the Companys financial performance, and the period over which it estimates its existing cash and cash equivalents will be sufficient to fund its future operating expenses and capital expenditures requirements. Further information relating to factors that may impact the Company's results and forward-looking statements are disclosed in the Company's filings with the Securities and Exchange Commission, including Longeverons Annual Report on Form 10-K for the year ended December 31, 2021, filed with the SEC on March 11, 2022, and the Companys Quarterly Reports on Form 10-Q for the periods ended March 31, 2022, and June 30, 2022. The forward-looking statements contained in this press release are made as of the date of this press release, and the Company disclaims any intention or obligation, other than imposed by law, to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Investor Contact:

Elsie YauStern IR, Inc.212-698-8700elsie.yau@sternir.com

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Longeveron Receives Intent to Grant Notice from the European Patent Office for Methods to Monitor Efficacy of Lomecel-B - BioSpace

Bone Marrow Stem Cells Comments Off on Longeveron Receives Intent to Grant Notice from the European Patent Office for Methods to Monitor Efficacy of Lomecel-B – BioSpace | August 26th, 2022

MONDAY, Aug. 22, 2022 (HealthDay News) -- The COVID-19 pandemic was associated with a decrease in transplantation in 2020, according to a study published in the July 1 issue of the American Journal of Surgery.

Alejandro Suarez-Pierre, M.D., from the University of Colorado School of Medicine in Aurora, and colleagues examined adult transplantation data as time series data in a population-based cohort study. Models of transplantation rates were developed using data from 1990 to 2019 to project the expected 2020 rates in a theoretical scenario in which the pandemic did not occur. Observed-to-expected (O/E) ratios were calculated for transplants.

The researchers found that 32,594 transplants were expected in 2020, but 30,566 occurred (O/E, 0.94; 95 percent confidence interval, 0.88 to 0.99). A total of 50,241 waitlist registrations occurred compared with 58,152 expected (O/E, 0.86; 95 percent confidence interval, 0.80 to 0.94). For kidney, liver, heart, and lung, the O/E ratios (95 percent confidence intervals) of transplants were 0.92 (0.86 to 0.98), 0.96 (0.89 to 1.04), 1.05 (0.91 to 1.23), and 0.92 (0.82 to 1.04), respectively. The corresponding O/E ratios (95 percent confidence intervals) of waitlist registrations were 0.84 (0.77 to 0.93), 0.95 (0.86 to 1.06), 0.99 (0.85 to 1.18), and 0.80 (0.70 to 0.94).

"The COVID-19 pandemic was associated with a significant deficit in solid organ transplantation, donation, and waitlist registrations in the United States in 2020. The impact was strongest in kidney transplantation and waitlist registration," the authors write. "While the pandemic persisted through 2020, the transplant system adapted remarkably well with a record number of transplantations performed."

Abstract/Full Text

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Drop Seen in Transplantation in 2020 With COVID-19 Pandemic - Consumer Health News | HealthDay - HealthDay News

Bone Marrow Stem Cells Comments Off on Drop Seen in Transplantation in 2020 With COVID-19 Pandemic – Consumer Health News | HealthDay – HealthDay News | August 26th, 2022

New York, Aug. 23, 2022 (GLOBE NEWSWIRE) -- Kenneth Research has published a detailed market report on Global Cell Banking Outsourcing Market for the forecast period, i.e., 2022 2031, which includes the following factors:

Global Cell Banking Outsourcing Market Size:

The global cell banking outsourcing market generated the revenue of approximately USD 7200.1 million in the year 2021 and is expected to garner a significant revenue by the end of 2031, growing at a CAGR of ~18% over the forecast period, i.e., 2022 2031. The growth of the market can primarily be attributed to the development of advanced preservation techniques for cells, and increasing adoption of regenerative cell therapies for the treatment of chronic diseases such as cancer. Additionally, factors such as growing demand for gene therapy, and increasing worldwide prevalence of cancer are expected to drive the market growth. According to the World Health Organization, nearly 10 million people died of cancer across the globe in 2020. The most recurrent cases of deaths because of cancer were lung cancer which caused 1.80 million deaths, colon, and rectum cancer which caused 916 000 deaths, liver cancer which caused 830 000 deaths, stomach cancer which caused 769 000 deaths, and breast cancer which caused 685 000 deaths. Furthermore, it was noticed that about 30% of cancer cases in low and lower-middle income nations are caused by cancer-causing diseases such the human papillomavirus (HPV) and hepatitis.

Get a Sample PDF of This Report @ https://www.kennethresearch.com/sample-request-10070777

Global Cell Banking Outsourcing Market: Key Takeaways

Increasing Geriatric Population across the Globe to Boost Market Growth

Increasing demand for stem cell therapy, and increasing biopharmaceutical production are estimated to fuel the growth of the global cell banking outsourcing market. Among the geriatric population around the world, the demand of stem cell therapy is at quite a high rate. Hence, growing geriatric population across the globe is also expected be an important factor to influence the market growth. According to the data by World Health Organisation (WHO), the number and proportion of geriatric population, meaning the people aged 60 years and older in the population is rising. The number of people aged 60 years and older was 1 billion in 2019. This number is estimated to increase to 1.4 billion by 2030 and 2.1 billion by 2050.

In addition to this, increasing prevalence of chronic diseases, supportive initiatives by governments around the world, and growing awareness about stem cell banking are predicted to be major factors to propel the growth of the market. The growth of the global cell banking outsourcing market, over the forecast period, can be further ascribed to the rising investments in the R&D activities to continuously bring up more feasible solutions for medical procedures. According to research reports, since 2000, global research and development expenditure has more than tripled in real terms, rising from approximately USD 680 billion to over USD 2.5 trillion in 2019.

Browse to access In-depth research report on Global Cell Banking Outsourcing Market with detailed charts and figures: https://www.kennethresearch.com/report-details/cell-banking-outsourcing-market/10070777

Global Cell Banking Outsourcing Market: Regional Overview

The global cell banking outsourcing market is segmented into five major regions including North America, Europe, Asia Pacific, Latin America, and the Middle East and Africa region.

Advanced Healthcare Facilities Drove Market in the North America Region

The market in the North America region held the largest market share in terms of revenue in the year 2021. The growth of the market in this region is majorly associated with the increasing number of pharmaceutical companies & manufacturers in the region, and increasing awareness for the use of stem cells as therapeutics. Increasing number of bone marrow and cord blood transplants throughout the region is also estimated to positively influence the market growth. It was noted that, 4,864 unrelated and 4,160 related bone marrow and cord blood transplants were performed in the United States in 2020.

Increasing Prevalence of Chronic Diseases to Influence Market Growth in the Asia Pacific Region

On the other hand, market in the Asia Pacific region is estimated to grow with the highest CAGR during the forecast period. The market in this region is driven by the increasing investment in biotechnology sector by government and private companies specifically in countries such as China, India, and Japan. Moreover, the increasing pool of patient with chronic diseases, such as cancer, and the ongoing research & development activities for cancer treatment is expected to propel the growth of the market. Further, increasing percentage of regional health expenditure contributing to the GDP is also estimated to be a significant factor to influence the growth of the cell banking outsourcing market in the Asia Pacific region. As per The World Bank, in the year 2019, share of global health expenditure in East Asia & Pacific region accounted to 6.67% of GDP.

Get a Sample PDF of the Global Cell Banking Outsourcing Market @ https://www.kennethresearch.com/sample-request-10070777

The study further incorporates Y-O-Y growth, demand & supply and forecast future opportunity in:

Middle East and Africa (Israel, GCC [Saudi Arabia, UAE, Bahrain, Kuwait, Qatar, Oman], North Africa, South Africa, Rest of Middle East and Africa).

Global Cell Banking Outsourcing Market, Segmentation by Bank Phase

The bank storage segment held the largest market share in the year 2021 and is expected to maintain its share by growing with a notable CAGR during the forecast period. The market growth is anticipated to be driven by the development of effective preservation technologies such as cryopreservation technique. Cryopreservation is a technique in which low temperature is used to preserve the living cells and tissue for a longer time. With the growing healthcare expenditure per capita across the world, demand for bank storage increasing notably. As sourced from The World Bank, in 2019, worldwide health expenditure per capita was USD 1121.97.

Access full Report Description, TOC, Table of Figure, Chart, etc. @ https://www.kennethresearch.com/sample-request-10070777

Global Cell Banking Outsourcing Market, Segmentation by Product

The adult cell banking segment is estimated to hold a substantial market share in the global cell banking outsourcing market during the forecast period. The growth of this segment can be attributed to the significant prevalence of chronic diseases among the adults around the globe. For instance, according to the National Library of Medicine 71.8% of adult population suffered from cardiovascular diseases, 56% had diabetes, and 14.7% adults had arthritis as of 2020.

Global Cell Banking Outsourcing Market, Segmentation by Cell Type

Global Cell Banking Outsourcing Market, Segmentation by Bank Type

Few of the well-known market leaders in the global cell banking outsourcing market that are profiled by Kenneth Research are SGS SA, WuXi AppTec, LifeCell International Pvt. Ltd., BSL Bioservice, LUMITOS AG, Cryo-Cell International, Inc., REPROCELL Inc, CORDLIFE GROUP LIMITED, Reliance Life Sciences, and Clean Biologics and others.Enquiry before Buying This Report @ https://www.kennethresearch.com/sample-request-10070777

Recent Developments in the Global Cell Banking Outsourcing Market

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Kenneth Research is a leading service provider for strategic market research and consulting. We aim to provide unbiased, unparalleled market insights and industry analysis to help industries, conglomerates and executives to take wise decisions for their future marketing strategy, expansion and investment, etc. We believe every business can expand to its new horizon, provided a right guidance at a right time is available through strategic minds. Our out of box thinking helps our clients to take wise decision so as to avoid future uncertainties.

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Global Cell Banking Outsourcing Market to Grow at a CAGR of ~18% during 2022-2031; Market to Expand Owing to the Development of Advanced Cell...

Bone Marrow Stem Cells Comments Off on Global Cell Banking Outsourcing Market to Grow at a CAGR of ~18% during 2022-2031; Market to Expand Owing to the Development of Advanced Cell… | August 26th, 2022

An American Heart Association fellowship will allow a Binghamton graduate student to further her research in developing 3D heart models. Natalie Weiss is interested in the pharmaceutical implications for treating cardiac fibrosis, an abnormal thickening and scarring of heart tissue that is common with many types of heart diseases and conditions.

The AHA is such a big and well-respected organization, so it is a nice validation to see that they value my research and ideas, said Weiss, a biomedical engineering doctoral student from the Thomas J. Watson College of Engineering and Applied Science who received a competitive two-year pre-doctoral fellowship.

Weiss conducts her work in the lab of Tracy Hookway, assistant professor of biomedical engineering. The team uses cell culture, 3D modeling of stem cells and live imaging of tissue for regenerative medicine therapy.

Natalie has been a huge asset to my lab, Hookway said. Shes incredibly intelligent and very ambitious, and shes not afraid to ask questions.

Weiss research involves creating working models of human hearts and then testing various drugs and therapies with the goal of resolving or improving cardiac fibrosis. She uses stem cells derived from human skin to make heart muscle cells and then combines them with proteins, sugars and a gel polymer, which is then piped into a 3mm donut ring mold (of sorts). The process takes about a week and a half, but once the cells are added to the mold, the ring forms overnight into a simplified, beating human heart model.

By testing on these models, it saves time, money and testing on animals, Weiss said, adding that she often has 40 rings going at a time. What Im hoping to do, once the models are a little more advanced, is replicate the stiffness of cardiac fibrosis in the model and then test a couple of drugs and see if it responds in a positive way.

As a high school student in East Meadow, Long Island, Weiss knew she was interested in the medical field. She volunteered in an emergency room and got her EMT certification.

Ive also always loved problem solving taking things apart and figuring out how they worked, she said. I wasnt aware I could put those two interests together until a biomedical engineering major kept popping up again and again as I was researching college programs.

She received her undergraduate degree in biomedical engineering at Stony Brook University in 2019, and then started her graduate career at Binghamton that fall. She selected the program because she was impressed with Hookway, who would become her advisor.

I wanted someone who I can connect with, Weiss said. Dr. Hookway really seemed like someone who would advocate for her students, so I knew she was going to care about my progress and help me out.

Once Weiss completes her doctorate, she hopes to complete a post-doctoral fellowship and then become a professor and run her own research lab.

This article was originally published in Discover-e.

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Heart Association fellowship to support research - Binghamton

Cardiac Stem Cells Comments Off on Heart Association fellowship to support research – Binghamton | August 26th, 2022

Abstract:Background: One of the best and most effective applied and tolerable approaches for cardioprotecion is the regular exercise. In situation of exercise activity and even cardiac ischemic injury, the activity of the myocardial stem cells and their recruiting factors are changed so that contribute the adaptation and repairment of the myocardium. The aim of this study was to investigate the effect of myocardial preconditioning with high intensive interval training on SDF-1a myocardial levels, CXCR4 receptors and c-kit after acute myocardial infarction in male rats. Methods: 20 male Wistar rats (8 week old ,weight 234.8 5.7 g) were randomly divided into 4 groups of control (C), training (T), myocardial infraction (MI) and training+ myocardial infraction (T+MI). The training groups performed two weeks of high-intensity interval training in four sections. Each section included two or three days of practice sessions and two sessions each per a day. The number or intensity of the intervals increased in each section. SDF-1, CXCR4 and C-Kit proteins were measured by the Western blot method in the myocardial tissue and myocardial injury enzymes (CK, LDH, troponin T) were measured in serum.Results: The results of this study showed that that SDF-1, CXCR4 and C-Kit had a significant increase after two weeks of high intensity interval training and myocardial infraction. Also, serum enzyme measurements showed a positive effect of exercise, so that in the myocardium injury enzymes significantly increased in the myocardial infarction group compared with the other three groups, training and training- myocardial infarction (P<0.001). As well as, there was a significant difference between the groups of training -myocardial infarction in all of the enzymes of the myocardium injury compared to the control and training groups. Conclusions: Even short terms of high intensity interval training can increase the levels of proteins SDF1-a, CXCR4 and C-Kit in order to cardioprotection against myocardial injury through recruitment stem cells.

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High intensity interval training protects the heart against acute myocardial infarction through SDF-1a, CXCR4 receptors and c-kit levels - Newswise

Cardiac Stem Cells Comments Off on High intensity interval training protects the heart against acute myocardial infarction through SDF-1a, CXCR4 receptors and c-kit levels – Newswise | August 26th, 2022

The therapeutic efficacy of intravenous hiPSC-MSCs infusion without intramuscular cellular transplantation

First, we determined whether hiPSC-MSCs could migrate into the ischemic limb after a single intravenous cellular infusion. Our results showed that most of the hiPSC-MSCs engrafted into the liver 12h after infusion (Supplementary Fig.1). The engrafted hiPSC-MSCs gradually migrated into the ischemic limb at day 3 and disappeared at day 14 (Supplementary Fig.1). A few cells engrafted in the ischemic limb, the engraftment rate was extremely low, evidenced by the DiR signal that was 9.8106 at day 7 after a single intravenous administration of 5105 hiPSC-MSCs versus 1.4109 7 days after a single intramuscular injection.

To compare intravenous cellular administration and intramuscular cellular delivery, three groups of mice that received intravenous hiPSC-MSC infusion once, every week or every 3 days without intramuscular administration of hiPSC-MSCs respectively and one group that received intramuscular hiPSC-MSC delivery only were employed (Fig.1a). Intravenous administration of hiPSC-MSCs once, every week or every 3 days without intramuscular administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups significantly improved blood perfusion from day 7 onwards compared with the ischemia group (Fig.1b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/week and Saline-MSC/3 days groups further increased blood perfusion at day 35 compared with the Saline-MSC/once group (Fig.1b, all p<0.05), although there was no difference between the first two groups (Fig.1b, p>0.05). Nevertheless intramuscular administration of hiPSC-MSCs in the MSC-Saline group achieved a better beneficial effect than intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups from day 21 onwards (Fig.1b, all p<0.05).

To evaluate blood perfusion in the groups that received intravenous hiPSC-MSCs infusion without intramuscular hiPSC-MSCs transplantation, Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation (a). A single or repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week or Saline-MSC/3 days groups significantly increased blood perfusion from day 7 onwards compared with the ischemia group. Moreover, repeated intravenous hiPSC-MSCs infusion further improved blood perfusion at day 35. Nonetheless intramuscular hiPSC-MSC transplantation in the MSC-Saline group showed a superior beneficial effect over repeated intravenous hiPSC-MSC infusion in the Saline-MSC/week and Saline-MSC/3 days groups (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs without intramuscular administration of hiPSC-MSCs improved blood perfusion. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days without intramuscular administration of hiPSC-MSCs further increased blood perfusion compared with a single intravenous injection, although there was no significant difference between intravenous administration repeated every week versus every 3 days. Nonetheless intramuscular administration of hiPSC-MSCs achieved a better beneficial effect than intravenous administration of hiPSC-MSCs once, every week or every 3 days.

Five groups of ICR mice were employed in the main experiment (Fig.2): (1) ischemia group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of culture medium at day 7; (2) MSC-Saline group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (3) MSC-MSC/once group receiving intravenous administration of 5105 hiPSC-MSCs immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (4) MSC-MSC/week group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every week following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7; (5) MSC-MSC/3 days group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every 3 days following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7.

There are five groups of ICR mice in main experiment: ischemia group, MSC-Saline group, MSC-MSC/once group, MSC-MSC/week group, MSC-MSC/3 days group.

Serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Fig.3a). After induction of ischemia, blood perfusion of the ligated limb significantly decreased to an extremely low level relative to the non-ligated limb in the ischemia group (2.980.56), MSC-Saline group (2.960.30), MSC-MSC/once group (2.950.48), MSC-MSC/week group (3.010.29) and MSC-MSC/3 days group (2.970.30). There was no significant difference between the five groups (Fig.3b, all p>0.05). These results confirmed that acute hind-limb ischemia was induced in all groups. Intramuscular administration of hiPSC-MSCs with intravenous administration of saline or with intravenous administration of hiPSC-MSCs once or every week or every 3 days in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups resulted in a significant and progressive improvement in the blood perfusion of the ligated limb from day 14 onwards compared with the ischemia group (Fig.3b, all p<0.05). Intravenous administration of hiPSC-MSCs significantly increased blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.3b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased blood perfusion from day 28 onwards compared with the MSC-MSC/once group (Fig.3b, all p<0.05). Nevertheless there was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week versus MSC-MSC/3 days groups throughout the study period. On day 35, blood perfusion of the ligated hind limb in the ischemia, MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups were 30.570.81, 40.560.84, 44.990.75, 50.410.68 and 51.120.86 respectively.

Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation to evaluate blood perfusion in the ischemic hind limbs (a). After intramuscular transplantation of hiPSC-MSCs, blood perfusion was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group from day 14 onwards (all p<0.05). A single and repeated intravenous hiPSC-MSC infusion further improved blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with MSC-Saline group (all p<0.05). Moreover, the blood perfusion was significantly higher in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (all p<0.05). There was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs improved blood perfusion in a mouse model of hind-limb ischemia relative to intramuscular hiPSC-MSC transplantation without systemic hiPSC-MSC delivery. In addition, repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved the therapeutic effects of hiPSC-MSC-based therapy compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To evaluate neovascularization in the ischemic limb, immunohistochemical staining with anti-mouse alpha-smooth muscle antigen (-SMA) and anti-mouse von Willebrand factor (vWF) antibodies were performed to assess arteriogenesis and angiogenesis following cellular transplantation respectively (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not increase arteriogenesis and capillary formation (Fig.4b,c, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved arteriogenesis and capillary formation compared with the ischemia group (Fig.4b,c, all p<0.05). On day 35, compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased neovascularization (Fig.4b,c, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups further improved neovascularization compared with the MSC-Saline group on day 35 (Fig.4b,c, p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further promoted neovascularization compared with the MSC-MSC/once group (Fig.4b,c, all p<0.05). There was no difference in neovascularization between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4b,c, all p>0.05).

Immunohistochemical staining with anti-mouse vWF (green) and anti-mouse -SMA (red) antibodies was performed to assess angiogenesis and arteriogenesis in ischemic tissues. Massons trichrome staining was performed to evaluate the degree of fibrosis (a). On day 14, neovascularization was markedly increased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, neovascularization was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on neovascularization compared with the MSC-Saline group (all p<0.05). Moreover, neovascularization was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (b, c). On day 14, fibrosis was remarkably decreased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, fibrosis was significantly reduced in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on reduction of fibrosis compared with the MSC-Saline group (all p<0.05). Moreover, the anti-fibrotic effect was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (d).

To assess the degree of fibrosis in the ischemic limb, Massons Trichrome staining were performed to determine the percentage of fibrotic tissue in the ischemic limb (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not decrease fibrosis (Fig.4d, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the ischemia group (Fig.4d, all p<0.05). Compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly ameliorated fibrosis on day 35 (Fig.4d, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the MSC-Saline group (Fig.4d, all p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further decreased fibrosis compared with the MSC-MSC/once group (Fig.4d, all p<0.05). There were no differences in fibrosis between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4d, all p>0.05).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs promoted neovascularization and reduced fibrosis in a mouse model of hind-limb ischemia. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further increased the neovascularization and decreased the fibrosis following cellular transplantation compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Fluorescent imaging of ischemic hind limbs was performed immediately and every week after induction of ischemia to access the cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs (Fig.5a). To avoid any confusion on the fluorescent signal, intravenous administered hiPSC-MSCs were not labeled with DiR. There was no significant difference in fluorescent signal intensity over the ischemic hind limb after intramuscular cellular transplantation (Fig.5b, all p>0.05). Systemic intravenous administration of hiPSC-MSCs significantly increased cellular engraftment and survival in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.5b, all p<0.05). Moreover, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further improved cellular engraftment and survival from day 21 onwards compared with the MSC-MSC/once group (Fig.5b, all p<0.05). There was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC/week and MSC-MSC/3 days groups throughout the study period. On day 35, the estimated survival rates in MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups decreased to 2.590.31%, 8.330.54%, 13.560.49% and 14.230.42%, respectively (Supplementary Fig.2 and Supplementary Data1).

A series of fluorescent images of ischemic hind limbs was performed immediately and every week following intramuscular transplantation of hiPSC-MSCs to detect the fate of intramuscularly transplanted hiPSC-MSCs (a). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly prolonged the survival of intramuscular transplanted hiPSC-MSCs from day 14 onwards compared with the MSC-Saline group (all p<0.05). Moreover, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the survival of intramuscularly transplanted hiPSC-MSCs from day 21 onwards compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs were further confirmed by immunohistochemical double staining with anti-human GAPDH and anti-human mitochondria antibodies (Fig.6a). Systemic intravenous administration of hiPSC-MSCs significantly increased human GAPDH and human mitochondria positive cells over the ischemic hind limb in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.6b, all p<0.05). Moreover, on day 35, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased the human GAPDH and human mitochondria positive cells compared with the MSC-MSC/once group (Fig.6b, all p<0.05). No difference between the MSC-MSC/week and MSC-MSC/3 days groups was noted (Fig.6b, all p>0.05).

The engraftment of intramuscularly transplanted hiPSC-MSCs was further confirmed by double immunohistochemical staining with anti-human GAPDH (green) and anti-human mitochondria antibodies (red) at day 14 and 35 (a). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the engraftment of intramuscularly transplanted hiPSC-MSCs from day 14 onwards (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the engraftment of intramuscular transplanted hiPSC-MSCs at day 35 compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs enhanced engraftment and survival of intramuscularly transplanted hiPSC-MSCs. In addition, repeated intravenous administration every week or every 3 days further increased the cellular engraftment and survival compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week versus every 3 days.

Immunohistochemical staining with anti-mouse CD68 antibody was performed to calculate the number of macrophages after cellular transplantation and evaluate the infiltration of macrophages (Fig.7a). M2 macrophages were further characterized by immunohistochemical staining with anti-mouse Arginase-1 antibody (Fig.7a). Although there was no significant difference between any of the five groups at day 7 and 14 after induction of ischemia (Fig.7b, all p>0.05), intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased M2 macrophage polarization in the ligated limb from day 14 onwards relative to the ischemia group (Fig.7c, all p<0.05). Moreover, intravenous administration of hiPSC-MSCs remarkedly promoted M2 macrophage polarization in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.7c, all p<0.05). On day 35, intramuscular administration of hiPSC-MSCs in MSC-Saline group had significantly decreased the infiltration of macrophages although the M2 macrophage percentage was similar to that in the ischemia group (Fig.7b,c, all p<0.05). Systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased macrophage infiltration and increased M2 macrophage polarization relative to the MSC-Saline group (Fig.7b,c, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further reduced the infiltration of macrophages and increased the polarization of M2 macrophages compared with the MSC-MSC/once group (Fig.7b,c, all p<0.05). There was no noticeable difference in either the infiltration of macrophages or polarization of M2 macrophages between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.7b,c, all p>0.05).

Muscular infiltration of macrophages was determined by immunohistochemical staining with anti-mouse CD68 antibody (green) at day 7, 14, and 35. Number of M2 macrophages was detected by immunohistochemical staining with anti-mouse Arginase-1 antibodies (red) (a). At day 35, after intramuscular transplantation of hiPSC-MSCs, total macrophages were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased the muscular infiltration of macrophages compared with the MSC-Saline group (all p<0.05). In addition, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased the muscular infiltration of macrophages compared with the MSC-MSC/once group (all p<0.05). Nevertheless no significant difference was observed between groups at day 7 and 14 (all p>0.05) (b). Intramuscular transplantation of hiPSC-MSCs without intravenous hiPSC-MSC infusion significantly increased the polarization of M2 macrophages at day 14 compared with the ischemia group (p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the polarization of M2 macrophages from day 7 onwards (all p<0.05). Repeated hiPSC-MSCs infusion further promoted the polarization of M2 macrophages compared with a single intravenous hiPSC-MSCs infusion in the MSC-MSC/once group at day 35 (all p<0.05) (c).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs decreased the infiltration of macrophages and increased the polarization of M2 macrophages. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased the infiltration of macrophages and increased the polarization of M2 macrophages compared with a single intravenous injection, whereas no significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

The limb tissue level of a specific subset-related cytokines was measured using a commercial mouse inflammatory factor array. For anti-inflammatory cytokines, on day 14, there was no significant difference on interleukin (IL)10 and vascular endothelial growth factor (VEGF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3a,b, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly increased IL-10 and VEGF compared with the ischemia group (Supplementary Fig.3a,b, all p<0.05). Moreover, an increase of IL-10 was observed in the MSC-MSC/week and MSC-MSC/3 days groups relative to the MSC-Saline group (Supplementary Fig.3a,b, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not significantly improved IL-10 relative to ischemia group. Nevertheless, systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved IL-10 compared with the ischemia group (Supplementary Fig.3a, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased IL-10 compared with the MSC-MSC/once group (Supplementary Fig.3a, all p<0.05). No significant difference on VEGF was observed among all five groups on day 35 (Supplementary Fig.3b, all p<0.05).

For inflammatory cytokines, on day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-1A and IL-17A compared with the ischemia group (Supplementary Fig.3c,d, all p<0.05). Nonetheless, there was no significant difference among the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups (Supplementary Fig.3c,d, all p>0.05). There was no significant difference on IL-2 and macrophage colony-stimulating factor (MCSF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3e,f, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-2 and MCSF compared with the ischemia group (Supplementary Fig.3e,f, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced IL-17A relative to ischemia group (Supplementary Fig.3d, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased IL-17A compared with the MSC-Saline and MSC-MSC/once groups respectively (Supplementary Fig.3d, all p<0.05). No significant difference on IL-1A, IL-2 and MCSF was observed among all five groups on day 35 (Supplementary Fig.3c,e,f, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could improve anti-inflammatory cytokines and decreased inflammatory cytokines. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved anti-inflammatory cytokines and decreased inflammatory cytokines compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Flow cytometry analysis of fresh splenocytes was performed to assess splenic Tregs and natural killer (NK) cells populations and so determine the in vivo immunomodulatory effect of systemic administration of hiPSC-MSCs (Fig.8a). Splenic NK cells were defined as both a CD49b-FITC and NK1.1-APC positive cell population. Our result showed that splenic NK cells progressively decreased following intramuscular hiPSC-MSC transplantation or intravenous hiPSC-MSC infusion in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, whereas no significant difference was noted between different time points in the ischemia group (Supplementary Fig.4a). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 14 onwards (Fig.8b, all p<0.05). Systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced splenic NK cells from day 7 onwards relative to the ischemia and MSC-Saline groups (Fig.8b, all p<0.05). Repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further reduced splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (Fig.8b, all p<0.05). Nonetheless no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8b, all p>0.05).

Splenic Tregs and NK cells were determined by flow cytometry analysis at day 7, 14 and 35 (a). After intramuscular transplantation of hiPSC-MSCs, splenic NK cells were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 7 onwards compared with the ischemia and MSC-Saline groups (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (b). After intramuscular transplantation of hiPSC-MSCs, splenic Tregs were significantly increased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups at day 35 compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs compared with the ischemia and MSC-Saline groups (all p<0.05). Moreover, repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (c).

Splenic Tregs were determined as Foxp3 positive cells in a proportion of pre-gated CD4 positive cells. Our result showed that splenic Tregs reached a peak on day 7 in the MSC-MSC/once group, whereas these immunomodulatory cells continued to increase in the MSC-MSC/week and MSC-MSC/3 days groups. No significant difference was observed between different time points in the ischemia and MSC-Saline groups (Supplementary Fig.4b). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs on day 35 (Fig.8c, all p<0.05). Intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved splenic Tregs from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.8c, all p<0.05). Repeated systemic intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (Fig.8c, all p<0.05), but there was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8c, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could modulate systemic immune cell activation by decreasing splenic NK cells as well as increasing splenic Tregs. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased splenic NKs and increased splenic Tregs compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To compare the survival and engraftment of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, fluorescent imaging of ischemic hind limb was performed immediately and every week in the MSC-Saline-Cyc, MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups (Supplementary Fig.5a). There was no significant difference in cellular engraftment between the MSC-MSC/once and MSC-Saline-Cyc groups through this study (Supplementary Fig.5b, p>0.05). Although repeated intravenous infusion of hiPSC-MSCs without subcutaneous administration of cyclosporine A remarkedly increased cell engraftment in the MSC-MSC/week group relative to the MSC-MSC/once group (Supplementary Fig.5b, p<0.05), no significant difference was observed after subcutaneous administration of cyclosporine A between the MSC-MSC/week-Cyc and MSC-MSC/once-Cyc groups (Supplementary Fig.5b, p>0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the cell engraftment in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.5b, p>0.05).

To compare the therapeutic efficacy of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Supplementary Fig.6a). When comparison between the MSC-MSC/once and MSC-Saline-Cyc groups was performed, intravenous infusion of hiPSC-MSCs significantly improved blood perfusion in the MSC-MSC/once group relative to MSC-Saline-Cyc group during the first 2 weeks (Supplementary Fig.6b, p<0.05). Following intramuscular hiPSC-MSC transplantation at day 7, blood perfusion progressly increased in the MSC-MSC/once and MSC-Saline-Cyc groups. Nevertheless, no significant difference was observed between the MSC-MSC/once and MSC-Saline-Cyc groups from day 21 onwards (Supplementary Fig.6b, p>0.05). Repeated intravenous infusion of hiPSC-MSCs with or without subcutaneous administration of cyclosporine A significantly improved blood perfusion at day 35 in the MSC-MSC/week and MSC-MSC/week-Cyc groups compared with the MSC-MSC/once and MSC-MSC/once-Cyc groups respectively (Supplementary Fig.6b, p<0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the blood perfusion in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.6b, p>0.05).

Cumulatively, our results demonstrated that no significant difference was observed in cell engraftment between a single or repeated intravenous hiPSC-MSC infusion and subcutaneous administration of cyclosporine A. Although there was no significant difference in blood perfusion between the cyclosporine A and single hiPSC-MSC infusion, a significantly improved blood perfusion was observed in the repeated hiPSC-MSC infusion groups relative to the cyclosporine A group. Furthermore, subcutaneous administration of cyclosporine A did not further increased cell engraftment or therapeutic efficacy in either single or repeated hiPSC-MSC infusion groups.

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Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -...

Cardiac Stem Cells Comments Off on Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -… | August 26th, 2022

SOMERVILLE, Mass.--(BUSINESS WIRE)--Cellarity, a life sciences company founded by Flagship Pioneering to transform the way medicines are created, announced today the release of a unique single-cell dataset to accelerate innovation in mapping multimodal genetic information across cell states and over time. This dataset will be used to power a competition hosted by Open Problems in Single-Cell Analysis.

Cells are among the most complex and dynamic systems and are regulated by the interplay of DNA, RNA, and proteins. Recent technological advances have made it possible to measure these cellular features and such data provide, for the first time, a direct and comprehensive view spanning the layers of gene regulation that drive biological systems and give rise to disease.

Advancements in single-cell technologies now make it possible to decode genetic regulation, and we are excited to generate another first-of-its-kind dataset to support Open Problems in Single Cell Analysis, said Fabrice Chouraqui, PharmD, CEO of Cellarity and a CEO-Partner at Flagship Pioneering. Developing new machine learning algorithms that can predict how a single-cell genome can drive a diversity of cellular states will provide new insights into how cells and tissues move from health to disease and support informed design of new medicines.

To drive innovation for such data, Cellarity generated a time course profiling in vitro differentiation of blood progenitors, a dataset designed in collaboration with scientists at Yale University, Chan Zuckerberg Biohub, and Helmholtz Munich. This time course will be used to power a competition to develop algorithms that learn the underlying relationships between DNA, RNA, and protein modalities across time. Solving this open problem will help elucidate complex regulatory processes that are the foundation for cell differentiation in health and disease.

While multimodal single-cell data is increasingly available, methods to analyze these data are still scarce and often treat cells as static snapshots without modeling the underlying dynamics of cell state, said Daniel Burkhardt, Ph.D., cofounder of Open Problems in Single-Cell Analysis and Machine Learning Scientist at Cellarity. New machine learning algorithms are needed to learn the rules that govern complex cell regulatory processes so we can predict how cell state changes over time. We hope these new algorithms can augment the value of existing or future single-modality datasets, which can be cost effectively generated at higher quality to streamline and accelerate research.

In 2021, Cellarity partnered with Open Problems collaborators to develop the first benchmark competition for multimodal single-cell data integration using a first-of-its-kind multi-omics benchmarking dataset (NeurIPS 2021). This dataset was the largest atlas of the human bone marrow measured across DNA, RNA, and proteins and was used to predict one modality from another and learn representations of multiple modalities measured in the same cells. The 2021 competition saw winning submissions from both computational biologists with deep single-cell expertise and machine learning practitioners for whom this competition marked their first foray into biology. This translation of knowledge across disciplines is expected to drive more powerful algorithms to learn fundamental rules of biology.

For 2022, Cellarity and Open Problems are extending the challenge to drive innovation in modeling temporal single-cell data measured in multiple modalities at multiple time points. For this years competition, Cellarity generated a 300,000-cell time course dataset of CD34+ hematopoietic stem and progenitor cells (HSPC) from four human donors at five time points. HSPCs are stem cells that give rise to all other cells in the blood throughout adult life, and a 10-day time course captures important biology in CD34+ HSPCs. Being able to solve the prediction problems over time is expected to yield new insights into how gene regulation influences differentiation.

Entries to the competition will be accepted until November 15, 2022. For more information, visit the competition page on Kaggle.

About Open Problems in Single Cell Analysis

Open Problems in Single-Cell Analysis was founded in 2020 bringing together academic, non-profit, and for-profit institutions to accelerate innovation in single-cell algorithm development. An explosion in single-cell analysis algorithms has resulted in more than 1,200 methods published in the last five years. However, few standard benchmarks exist for single-cell biology, both making it difficult to identify top performing algorithms and hindering collaboration with the machine learning community to accelerate single-cell science. Open Problems is a first-of-its-kind international consortium developing a centralized, open-source, and continuously updated framework for benchmarking single-cell algorithms to drive innovation and alignment in the field. For more information, visit https://openproblems.bio/.

About Cellarity

Cellaritys mission is to fundamentally transform the way medicines are created. Founded by Flagship Pioneering in 2017, Cellarity has developed unique capabilities combining high-resolution data, single cell technologies, and machine learning to encode biology, predict interventions, and purposefully design breakthrough medicines. By focusing on the cellular changes that underlie disease instead of a single target, Cellaritys approach uncovers new biology and treatments and is applicable to a vast array of disease areas. The company currently has programs underway in metabolic disease, hematology, immuno-oncology, and respiratory disease. For more info, visit http://www.cellarity.com.

About Flagship Pioneering

Flagship Pioneering conceives, creates, resources, and develops first-in-category bioplatform companies to transform human health and sustainability. Since its launch in 2000, the firm has, through its Flagship Labs unit, applied its unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in more than $100 billion in aggregate value. To date, Flagship has deployed over $2.9 billion in capital toward the founding and growth of its pioneering companies alongside more than $19 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 41 transformative companies, including Denali Therapeutics (NASDAQ: DNLI), Evelo Biosciences (NASDAQ: EVLO), Foghorn Therapeutics (NASDAQ: FHTX), Moderna (NASDAQ: MRNA), Omega Therapeutics (NASDAQ: OMGA), Rubius Therapeutics (NASDAQ: RUBY), Sana Biotechnology (NASDAQ: SANA), and Seres Therapeutics (NASDAQ: MCRB).

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Cellarity Releases Novel, Open-Source, Single-Cell Dataset and Invites the Machine Learning and Computational Biology Communities to Develop New...

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My gold standard would be the use of an orthobiologic joint treatment, such as autologous protein solution, as it would be the least invasive joint treatment for a pregnant mare as only one injection is recommended, while other regenerative products often recommend a series of treatments for best effects, she adds.

Orthobiologic treatments are processed using the horses own blood, often stallside, to isolate properties beneficial to the joint. These treatments can provide targeted pain relief without the potential negative physiological and metabolic side effects (e.g., spontaneous abortion, harm to the fetus) of steroid use. The downside is these treatments are significantly more expensive than steroids.

In most cases I would feel comfortable injecting a fetlock joint in a pregnant mare with a low dose of a steroid such as triamcinolone if I felt it was indicated for the quality of life of the mare and orthobiologic treatments were not an option financially, Crosby says. Treatment with polyacrylamide (hydro)gel (PAAG) could also be considered, although (manufacturers of) these formulations often recommend pretreatment with a steroid for best effects. Polyacrylamide gel works by reducing friction in a joint, which can be a very effective option for advanced arthritis.

Fitz is a 14-year-old Morgan gelding with early onset pituitary pars intermedia dysfunction (PPID, formerly equine Cushings disease). His condition is well-controlled on 1 milligram of pergolide (Prascend) daily, and his owner shows him regularly in saddle seat shows. Earlier this year Fitz was diagnosed with coffin joint osteoarthritis. He improved on a polysulfated glycosaminoglycan (Adequan) series but is still experiencing performance issues.

Bonny Henderson, DVM, IVCA, CVA, CREP, owner of Henderson Equine Clinic, in Avon, New York, is a huge proponent of adjunct therapies. Prior to injections she recommends her clients try a variety of nutraceuticals to provide building blocks for the healing process and to decrease systemic inflammation. She says shes had incredible results with this approach.

I like to combine Eastern and Western medicine for my patients, Henderson says. I try to get people to treat the whole horse, identify what is causing the lameness and why exactly the cause occurredin other words, the functional limitations predisposing the horse to the injury itself. Then I treat both the lameness and the underlying cause.

This case requires careful attention because of the horses endocrine disease. PPID horses can be more sensitive to steroids, and this can result in laminitis, says Henderson. Even if hes well-maintained, you have to take into account his body condition score and hoof capsule. If the hoof capsule contains external growth rings wider in the heel than the toe, youve likely had some prior clinical or subclinical (not showing obvious signs) laminitic episodes. There is a lot of concussion going through these horses feet; ground force reactions are much more pronounced due to the shoeing package and actions of the horse and have a greater impact on the hoof. You have to watch out for a subclinical condition of what we used to term road founder that would compound the metabolic issue of PPID.

In these complex cases Henderson says she reaches for an orthobiologic. I would first ultrasound this joint to visualize the health of the cartilage, she says. If there is cartilage present, I would start with an autologous protein solution. If the lameness is from an injury or if there is a lot of (inflammation in the joint fluid), I would recommend injecting -2 macroglobulin, followed by the autologous protein solution once the inflammation is resolved.

The -2 macroglobulin injections are relatively novel treatments in equine practice. This orthobiologic isolates the horses natural -2 macroglobulin, a potent anti-inflammatory with molecules typically too large to cross into the joint. The veterinarian can then inject the -2 macroglobulin into the joint to reduce the synovitis (joint inflammation) without the negative effects of corticosteroids.

Clover is a 22-year-old Thoroughbred mare. She is a retired racehorse-turned-jumper-turned-dressage horse. Her multitude of careers has left her with relatively severe carpal arthritis of her right forelimb, with osteochondral fragments and excessive bony changes. She has a very caring owner who has tried just about anything to keep the mare comfortable, including rounds of polysulfated glycosaminoglycan, intravenous hyaluronic acid, and systemic anti-inflammatories. Clover is still lame and resistant to flexion of the carpus. This joint is end-stage.

When osteophytes (bone spurs) are present in a joint, they are not usually the direct cause of a horses pain. In my experience, the greater pain comes from synovitis and the lack of cartilage. I would talk to the owner about -2 macroglobulin, because these cases often require a multiple-layered treatment plan, says Henderson. I would also recommend following the -2 macroglobulin with a 2.5% polyacrylamide hydrogel once the severe inflammation is controlled.

Researchers have shown that the 2.5% PAAG provides the synovial lining with structure and stability and facilitates increased production of joint fluid. The integration of the product into the membrane, thickening the structure, also provides shock absorption. It essentially increases joint lubrication and provides a cushion in these end-stage joints.

Often, horses with end-stage OA stop responding to medical management, at which point surgical fusion of the joint can offer long-term comfort.

Cole is an 8-year-old Warmblood stallion who competes in the hunter/jumper ring. His attending veterinarian has diagnosed him via radiographs and computed tomography with osteoarthritic changes in his distal cervical vertebrae, causing a left forelimb lameness.

Cervical pain and dysfunction in the horse has become increasingly recognized as a cause of poor performance and can be more involved than just pain originating from the joint proper, says Michael Caruso III, VMD, Dipl. ACVS-LA, owner of Reedsdale Equine Specialists, in Nashville, Tennessee, who specializes in equine lameness diagnosis and treatment.

While OA can affect any joint, the cervical vertebrae can be an insidious location. Osteoarthritis of the cervical articular process joints (is) obviously a disease of the cartilage surface and bone, but other structures are involved and intimately associated with the joint, including the joint capsule, synovium, subchondral bone (beneath the cartilage), and paraspinal muscles, Caruso explains.

Because cervical OA is so complex, vets must combine multiple methods to treat it. I believe that many horses with cervical facet joint pain/osteoarthritis require a multimodal approach to treatment depending upon the age of the horse and severity of the dysfunction, he says. We know that horses with neck arthritis can present with a wide range of issues, from poor performance and intermittent forelimb lameness to ataxia (incoordination).

Cervical joint OA can disrupt the adjacent spinal cord nerve roots, causing this neurologic manifestation.

Injection must be performed using ultrasound guidance, Caruso says. I would inject the articular process joints with a corticosteroid (betamethasone or triamcinolone), plus or minus hyaluronic acid, plus or minus (the antimicrobial) amikacin and, depending on the horses range of motion and muscle tension, might prescribe a muscle relaxant (methocarbamol) and/or perform mesotherapy and shock wave for any muscular/fascial pain adjacent to the affected joints.

Caruso says he would take any metabolic issues into account before injecting corticosteroids. In horses that have some sort of metabolic dysfunction, I will routinely utilize orthobiologics in the affected joints, he says, adding that his personal preferences are platelet-rich plasma (PRP) and autologous conditioned serum.

All horses treated for cervical pain are prescribed therapeutic rehabilitation, Caruso says. Dynamic exercises of not only the cervical region but also the whole body appear to positively affect muscle activation and strengthening. The exercise program aims to improve joint stability and range of motion by focusing on the deep paravertebral muscles.

Remington is a 6-year-old Warmblood gelding who competes in the jumpers. He becomes lame in the right hind, and his veterinarian isolates the lameness to the stifle. On imaging, the medial (toward the midline) meniscus looks enlarged and mottled. He is referred for an arthroscopy of his medial femorotibial joint. The surgeon suggests injecting it six weeks following the procedure.

With this case, Caruso says hed first recommend injecting mesenchymal stem cells (MSCs) into the medial femorotibial joint. While we have lots to learn about stem cells, in the stifleespecially postoperatively with meniscal damagestem cells have been shown to improve the long-term outcome for return to work in the horse, he says.

He cites one study (Ferris et al., 2014) on the outcome of horses undergoing stifle surgery plus bone-marrow-derived mesenchymal stem cell injections. The researchers found that of the horses treated for stifle injury with surgery and stem cells, 75% returned to some level of work postoperatively, which compares to previous reports of 60-63% with surgery alone.

The stifle is one joint that I will recommend injection with bone-marrow-derived MSCs following arthroscopic surgery as a first-line treatment, Caruso says. This is one joint that I believe stem cells have an advantage if finances allow.

Veterinarians typically harvest stem cells from the horse at the time of surgery, usually from the sternum, pelvis, or tibia. While they have potent healing factors, they are generally more expensive than the other orthobiologics mentioned. If an owner cant afford that price tag following stifle surgery, Caruso recommends PRP.

Clinically, I see a great response (from PRP) both in soft tissues and in joints, he says. I feel that MSC injection in stifle cases with proper rehabilitation following meniscal injury are more successful with less convalescent time.

While joint injection techniques are well-documented, the tricky part is what goes into the syringe. Gone are the days of simple corticosteroid injections as our only optionthough theyre still used and have a place in equine medicine. The insights from these veterinarians show we have several ways to approach a lameness, especially a complicated joint case.

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Equine Joint Injections: Case by Case The Horse - TheHorse.com

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Creative Biolabs stem cell platform offers expertise in the generation, bioprocess scale-up, and differentiation of iPSCs.

New York, USA August 3, 2022 Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from somatic cells. iPSC technology has evolved rapidly since its inception in 2006 and has been widely used for disease modeling.

The global iPSC market is expected to grow from $2431.2 million in 2021 to $2640.80 million in 2022 at a compound annual growth rate (CAGR) of 8.6%. Meanwhile, the market is expected to reach $3571.48 million in 2026 at a CAGR of 7.8%, according to the Report Linker.

Creative Biolabs has constructed an advanced platform that offers various iPSC services, including:

iPSC reprogramming service

iPSC culture service

Pluripotency characterization service

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With years of exploration in the iPSC development, Creative Biolabs is dedicated to providing helpful iPSC culture services, including maintenance of iPSC, 3D culture of iPSC, as well as scale-up of iPSC culture.

Researchers at Creative Biolabs have built two unique systems for iPSCs culture, which are the feeder-dependent culture system and the feeder-free culture system. In order to break the bottleneck for mass production of high-quality iPSCs, Creative Biolabs has built a 3D culture system for iPSC expansion and differentiation based on a thermoreversible hydrogel. The 3D culture system enables a long-term and serial expansion of multiple human iPSC lines via a mild process. With these wonderful advantages, the 3D culture system may be useful at various scales, from basic biological research to clinical trials.

Moreover, the use of bioreactor systems has greatly improved the development of dynamic suspension culture. Bioreactor systems can promote the control of iPSC aggregation, avoid the formation of gradients, and improve the mass transfer, thus leading to higher cell density.

With the advanced iPSC development platform, Creative Biolabs offers high-quality iPSC genome editing services. Nowadays, the application of custom-engineered sequence-specific nucleases enables genetic changes in human cells to be easily accessed with much greater efficiency and precision, such as CRISPR/Cas9 and TALEN. iPSC genome editing services at Creative Biolabs can help achieve the following goals:

Knock out a gene of interest

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Tag a gene of interest with required reporters

Reversion to wildtype in disease-derived iPSC line

Explore more top-notch services for stem cell therapy development at https://www.creative-biolabs.com/stem-cell-therapy.

About Creative Biolabs

With professional scientists and years of experience, Creative Biolabs provides high-quality products and services in the field of stem cell therapy development for customers all over the world.

Media ContactCompany Name: Creative BiolabsContact Person: Candy SwiftEmail: Send EmailPhone: 1-631-830-6441Country: United StatesWebsite: https://www.creative-biolabs.com/stem-cell-therapy

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IPS Cell Therapy Comments Off on Creative Biolabs Leads the Forefront of iPSC Technology – Digital Journal | August 10th, 2022

When coronary arteries are blocked, starving the heart of blood, there are good medications and treatments to deploy, from statins to stents. Not so for heart failure, the leading factor involved in heart disease, the top cause of death worldwide.

Its whats on death certificates, said cardiologist Christine Seidman.

Seidman has long been interested in heart muscle disorders and their genetic drivers. She studies heart failure and other conditions that affect the myocardium the muscular tissue of the heart not the blood vessels where atherosclerosis and heart attacks come from, although their consequences are also felt in the myocardium, including heart failure.

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With her colleagues at Brigham and Womens Hospital and Harvard Medical School, she and a long list of international collaborators have been exploring the genetic underpinnings of heart failure. Based on experiments deploying a new technique called single-nucleus RNA sequencing on samples from heart patients, on Thursday they reported in Science their discovery of how genotypes change the way the heart functions.

Their work raises the possibility that some of the molecular pathways that lead to heart failure could be precisely targeted, in contrast to treating heart failure as a disease with only one final outcome.

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Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting, she said. To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

Seidman talked with STAT about the research, including how snRNAseq solves the smoothie problem, and what it might mean for patients. The conversation has been edited for clarity and brevity.

What happens in heart failure?

The heart becomes misshapen in one of two ways. It either becomes hypertrophied, where the walls of heart muscle become thickened and the volume within the heart is diminished, in what we call hypertrophic cardiomyopathy. Or it becomes dilated, when the volume in the heart is expanded and the walls become stretched. I think of it as an overinflated balloon, and that is called dilated cardiomyopathy.

Hypertrophy and dilatation are known to cause the heart over time to have profoundly diminished functional capacity. And clinically, we call that heart failure, much more commonly arising from dilated cardiomyopathy.

What does it feel like to patients?

When we see patients clinically, theyre short of breath, they have fluid retention. When we look at their hearts, we see that the pump function is diminished. That has led to a hypothesis of heart failure as sort of the end stage of many different disorders, but eventually the heart walks down a final common pathway. Then you need a transplant or a left ventricular assist device, or youre going to die prematurely.

What can be done?

Heart failure is a truly devastating condition, and it can arise early in life, in middle age, and in older people. There is no treatment for it, no cure for it, except cardiac transplantation, of course, which provides a whole host of other problems.

How did you approach this problem?

One of the questions we wanted to answer is, are there signals that we can discern that say there are different pathways and there are molecules that are functioning in those pathways that ultimately converge for failure, but through different strategies of your heart?

We treat every patient with heart failure with diuretics. We give them a series of different medications to reduce the pressure against which the heart has to contract. Im clinically a cardiologist, but molecularly Im a geneticist, so it doesnt make sense. If your house is falling down because the bricks are sticking together or if its falling down because the roof leaks and the water is pooling, you do things differently.

Tell me how you used single-cell RNA sequencing to learn more.

Looking at RNA molecules gives us a snapshot of how much a gene is active or inactive at a particular time point. Until recently, we couldnt do that in the heart because the approach had been to take heart tissue, grind it all up, and look at the RNAs that are up or down. But that gives you what we call a smoothie: Its all the different component cells those strawberries, blueberries, bananas mixed together.

But theres a technology now called single-cell RNA sequencing. And that says, what are the RNAs that are up or down in the cardiomyocytes as compared to the smooth muscle cells, as compared to the fibroblasts, all of which are in the cells? You get a much more precise look at whats changing in a different cell type. And thats the approach that we use, because cardiomyocytes [the cells in the heart that make it contract] are very large. Theyre at least three times bigger than other cells. We cant capture the single cell it literally does not fit through the microfluidic device. And so we sequenced the nuclei, which is where the RNA emanates from.

What did you find?

There were some similarities, but what was remarkable was the degree of differences that we saw in cardiomyocytes, in endothelial cells, in fibroblasts. Theres a signature thats telling us I walked down this pathway as compared to a different one that caused the heart to fail, but through activation or lack of activation of different signals along the way.

And that to me is the excitement, because if we can say that, we can then go back and say, OK, what happens if we were to have tweaked the pathway in this genotype and a different pathway in a different genotype? Thats really what precision therapy could be about, and thats where we aim to get to.

Whats the next step?

It may be that several genotypes will have more similarities as compared to other genotypes. But understanding that, I think, will allow us to test in experimental models, largely in mice, but increasingly in cellular models of disease, in iPS [induced pluripotent stem] cells that we can now begin to use molecular technologies to silence a pathway and see what that does to the cardiomyocytes, or silence the fibroblast molecule and see what that does in that particular genotype.

To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

What might this mean for patients?

If we knew that an intervention would make a difference thats where the experiments are we would intervene when we saw manifestations of disease. So the reason I can tell you with confidence that certain genes cause dilated cardiomyopathy is theres a long time between the onset of that expansion of the ventricle until you develop heart failure. So theres years for us to be able to stop it in its tracks or potentially revert the pathology, if we can do that.

What else can you say?

I would be foolish not to mention the genetic cause of dilated cardiomyopathy. Ultimately, if you know the genetic cause of dilated cardiomyopathy, this is where gene therapy may be the ultimate cure. Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting.

My colleagues have estimated that approximately 1 in 250 to 1 in 500 people may have an important genetic driver of heart muscle disease, cardiomyopathy. Thats a huge number, but not all of them will progress to heart failure, thank goodness. Around the world, there are 23 million people with heart failure. Its what ends up on most peoples death certificate. It is the most common cause of death.

Its a huge, huge burden. And there really is no cure for it except transplantation. We dont have a reparative capacity, so were going to have to know a cause and be able to intervene precisely for that cause.

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New research digs into the genetic drivers of heart failure, with an eye to precision treatments - STAT

IPS Cell Therapy Comments Off on New research digs into the genetic drivers of heart failure, with an eye to precision treatments – STAT | August 10th, 2022

The concept of synthesizing small-scale human organs in lab dishes has matured from pure science fiction to legitimate bioscientific reality in recent years. However, the usefulness of organoids as a research tool for studying the digestive system quickly ran into a roadblock, due to the fact that these in-demand tissues remain difficult to create.

Organoids are stem cell-derived three-dimensional tissue cultures that are designed to exhibit detailed characteristics of organs or act as model organs to produce a specific cell type in laboratory conditions. However, when growing organoids, the yield from each batch of starting material can vary massively and can even fail to produce any viable organoids at all. This of course results in severe delays in their production and utilization in pre-clinical experiments that test the efficacy and safety of drugs.

In a recently published paper from Stem Cell Reports, researchers from Cincinnati childrens (OH, USA) have developed a new practice that overcomes the organoid production hurdle. This novel procedure is already being utilized within the medical facility to boost organoid studies. However, because the materials utilized can be frozen and thawed while still producing high-quality organoids, this discovery allows for the shipment of starter materials to other labs anywhere in the world, foreseeably leading to a dramatic increase in the utilization of human gastrointestinal organoids in medical research.

This method can make organoids a more accessible tool, explains the first author Amy Pitstick, manager of the Pluripotent Stem Cell Facility at Cincinnati Childrens. We show that the aggregation approach consistently produces high yields and we have proven that precursor cells can be thawed from cryogenic storage to produce organoids of the small intestine.

Using this approach will make it possible for many research labs to use organoids in their experiments without the time and expense of learning how to grow induced pluripotent stem cells (iPSCs), states corresponding author Chris Mayhew, director of the Pluripotent Stem Cell Facility. The ability to freeze the precursor cells also will allow labs to easily make organoids without having to start each new experiment with complicated and highly variable iPSC differentiation.

Generally, organoid creation begins with the collection of skin or blood cells, which are then transformed in the lab to become induced pluripotent stem cells. To create intestinal organoids, highly skilled lab professionals produce a flat layer of organ precursor cells known as the mid-hindgut endoderm.

Under the correct conditions, early-stage organoids, termed spheroids, autonomously develop into a three-dimensional ball of cells. These are then collected and placed into a growth medium, which supplies the required signals for the cells to develop into the specialized cell types of a human organ.

However, the quantity of spheroids produced in this manner has been unpredictable. The Cincinnati Childrens researchers discovered that they could harvest the unused precursor cell layer and employ a centrifuge to transport cells into hundreds of tiny wells housed on small plastic plates. This causes the creation of 3D cell aggregates, which may then be collected and utilized to produce organoids.

The experiment described in the research paper demonstrates that the spheroids created in this manner had no discernible differences from those that formed naturally. The scientists then stored samples of the progenitor cells in freezers. These cells generated viable spheroids after being frozen and aggregated.

The paper goes on to verify that these spheroids can be consistently grown into mature organoids, which can simulate organ function. In the case of this research, the mature organoids went on to mimic the function of the small intestine, large intestine and the antrum, the portion of the stomach that links to the intestine.

Although this development is a welcome and promising advance in organoid fabrication, years of research will be required to create organoids large enough and complex enough to be utilized as replacement tissue in transplant surgery. However, having access to a large number of readily manufactured organoids offers up numerous possibilities for medical study.

More labs will be able to create patient-specific organoids in order to evaluate drugcombination therapiesfor precision treatment of complex or rare disease states that necessitate personalized care. Scientists also conducting basic research to understand more about the genetic factors and molecular pathways at play in digestive tract diseases will be able to incorporate organoids in their experiments by procuring frozen spheroid precursors.

In his current effort to generate transplantable intestinal tissues, Michael Helmrath, Director of Clinical Translation for the Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Childrens, has already begun employing materials made from this new method.

This is a great step forward for the field on many fronts, Helmrath says. To be able to reduce the complexity of the process and provide higher yields is beneficial to our work. And to be able to translate the methods to other labs will help move regenerative medicine forward.

Source: https://linkinghub.elsevier.com/retrieve/pii/S2213671122003599

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New milestone organoid synthesis will boost disease and drug development research - RegMedNet

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Professor Augustinus Baders skincare products contain the patented TFC8 technology, backed by 30 years of science and research - and results have shown an increase by 110% of more elasticity in the skin as well!

Image: Augustinus Bader)

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Augustinus Bader, whos earned a cult-beauty status thanks to his rejuvenating skin care products, is the man whom Jennifer Aniston, Kim Kardashian and Victoria Beckham all love too. And its not just celebrities who hail his namesake products as the secret weapon behind nourished and renewed skin, but beauty editors and dermatologists too. Not to mention contain the patented TFC8 technology, which is backed by 30 years of science and research.

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Have you used any of the Augustinus Bader skincare products before? Or are you keen to give them a try and see what they could do for you? Let us know your thoughts in the comments section below.

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Victoria Beckham and Kim Kardashian are fans of Augustinus Baders skincare range - and you can get 20% off - The Mirror

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that targets motor neurons, gradually bereaving patients of their ability to control muscle movements. Scientists discovered more than 50 potential disease-causing genes and linked several cellular pathways to ALS, but the syndromes diverse clinical and genetic nature make it difficult to predict and interfere with disease progression.1

Researchers discovered a T cell population in mice that mirrors ALS-4 disease progression.

In a recent study published in Nature, Laura Campisi, Ivan Marazzi, and colleagues at Icahn School of Medicine at Mount Sinai discovered an immune cell signature in patients with early onset ALS (ALS-4) that mirrors disease progression and may contribute to neuronal death.2 These findings could have significant implications for ALS diagnostics, prognostics, and therapeutics.

Laura Campisi joined Marazzis laboratory wanting to better understand how the body mounts immune responses. She set out to molecularly profile activated immune cells and discovered several immunity regulators, including SENATAXIN (SETX). Because SETX mutations cause ALS-4, Campisi wondered if ALS might join the suite of other neurodegenerative diseases such as narcolepsy, Alzheimers disease, and Parkinsons disease that scientists recently connected to the immune system.3,4,5,6

To test whether the immune system plays a role in ALS-4 disease progression, Campisi turned to a mouse model that carries the most common human SETX mutation.7 She replaced their mutated hematopoietic stem cells (HSCs)progenitors that form immune cellswith wildtype ones and found that they protected against disease. In contrast, replacing healthy HSCs with SETXmutant ones in wildtype mice did not cause disease. This set of experiments showed that mutant HSCs and their progeny contribute to disease, but do not cause disease on their own. This is extremely strong preclinical evidence that forms a basis for pharmaceutically targeting these cells, said David Gate, an assistant professor of neurology at Northwestern University, who was not involved in this study.

Campisi and her colleagues next characterized the immune system in pre-symptomatic mice and discovered an ALS-specific immune cell signature: ALS-4 mice contained more CD8+ T cells in their blood and cerebrospinal fluid (CSF) prior to symptom onset, and this cell population continued to expand as the disease progressed. While Campisis team faced pandemic-related difficulties in recruiting enough ALS-4 patients to confirm these findings, they are now teaming up with clinicians to expand their preclinical trials. We want to follow this [T cell] population in patients to see if they express specific markers that can predict if and when the disease progresses, Campisi said.

My hypothesis is that the T cells are autoreactive, so they are reacting against a cellular antigen.Laura Campisi, Icahn School of Medicine at Mount Sinai

To find what these T cells responded to, Campisi sequenced them and found that nearly all cells expressed the same T cell receptor, suggesting they bind the same antigen. The problem is that it is very difficult to find the antigen. I dont think it is an infection because [the] mice live in a pathogen-free facility. My hypothesis is that the T cells we found are autoreactive, so they are reacting against a cellular antigen, Campisi said.

Given that ALS targets motor neurons, Campisi wondered if the ALS-4 T cells promoted disease progression because they react to and are activated by a protein in the brain. To test this hypothesis, Campisi injected ALS-4mice with brain cancer cells that express neuronal antigens to see if the T cell population would react and confer protection against the cancer type. It was pretty striking: the tumors became so big in wildtype mice that I had to stop the experiment, but the [mutant] mice that were in the same cage were completely fine, their tumor was not growing, Campisi said. In contrast, there was no protection against skin-related cancer cells that she injected as a control. The T cells that infiltrated the ALS-4 mices brain tumors expressed the same T cell receptor as cells found in their CSF. While Gate cautions that cancer cells typically express many newly created neoantigens, Campisis data suggests that the T cell population likely recognizes a brain cell-related antigen.

Campisis challenge now lies in identifying the actual antigen and therapeutically targeting these T cells to slow and restrict the disease course. In ALS, you probably have a defect that starts with neurons, triggering a cascade of events. So, even if you restore what is wrong in neurons, we have to [also] target the other players, Campisi said.

References

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Mutant T Cells That Drive Amyotrophic Lateral Sclerosis (ALS) Progression May React To a Brain Antigen - The Scientist

Skin Stem Cells Comments Off on Mutant T Cells That Drive Amyotrophic Lateral Sclerosis (ALS) Progression May React To a Brain Antigen – The Scientist | August 10th, 2022

The procedure recommended by most doctors might not always be a good option, as it could turn a potentially benign situation into a malignant one.

Thomas Seyfried, Ph.D., professor in the biology department at Boston College, is a leading expert and researcher in the field of cancer metabolism and nutritional ketosis. His book, Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer is a foundational textbook on this topic, and in August 2016, he received the Mercola.com Game Changer Award for his work.

Here, we discuss the mechanisms of cancer and the influence of mitochondrial function, which plays a crucial role in the development and treatment of this disease. Hislandmark cancer theory is available as a free PDF.

Many of his views are now encapsulated in his most paper,1Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis, published online December 27, 2018. Hes also published a number of other papers2,3,4on the metabolic underpinnings of cancer.

The paper is a review and hypothesis paper identifying the missing link in Otto Warburgs central theory,Seyfried explains. [Warburg] defined the origin of cancer very accurately back in the 1920s, 30s, 40s and 50s in his work in Germany. Basically, he argued and provided data showing that all cancer cells, regardless of tissue origin, were fermenters. They fermented lactic acid from glucose as a substrate.

Even in the presence of oxygen, these cells were fermenting. This is clearly a defect in oxidative phosphorylation. The problem is that for decades, people said Warburg was wrong mainly because we see a lot of cancer cells take up oxygen and make adenosine triphosphate (ATP) from within the mitochondria People began to question, If cancer cells have normal respiration, why would they want to use glucose as a fermentable fuel?

The whole concept became distorted The cancer cells simply choose to ferment rather than respire. Now, of course, if you look under the electron microscope at majority of cancers, youll see that the mitochondria are defective in a number of different ways. Their structures are abnormal. The numbers are abnormal. There are many abnormalities of mitochondria seen directly under electron microscopy. Clearly, Warburg was not wrong.

Before we delve into the meat of how cancer actually occurs it would be good to review a diagnostic strategy that nearly all of us are offered when confronted with a cancer diagnosis. It is vital to understand that this may not be your best strategy and that for many it would be wise to avoid the biopsy.

Seyfried warns against doing biopsies, as this procedure may actually cause the cancer to spread. A tumor is basically a group of proliferating cells in a particular part of your body. For purposes of diagnosis, a small biopsy sample will often be taken to ascertain whether the tumor is benign or malignant.

The problem is that when you stab into the cancer microenvironment to remove a part of the tissue, it creates a wound in that microenvironment that in turn elicits the invasion by macrophages and other immune cells.

If you already have an acidic microenvironment, you run the risk of causing a fusion hybridization event in that microenvironment between your macrophages and cancer stem cells (as discussed below). This could turn a potentially benign situation into a malignant one, and if the tumor is malignant, stabbing into it could make a bad situation worse.

The question is, what is the value of doing a biopsy in the first place? We take biopsies of breast tissue to get a genomic readout of the different kinds of mutations that might be in the cells. Now, if cancer is not a genetic disease and the mutations are largely irrelevant, then it makes no sense to do that in the first place. If the tumor is benign, why would you want to stab it? If the tumor is malignant, why would you ever want to stab it?

I came to this view by reading so many articles in the literature based on brain cancer, breast cancer, colon cancer, liver cancer showing how needle biopsies have led to the dissemination of these tumor cells, putting these people at risk for metastatic cancer and death,Seyfried says.

In metabolic therapy you would not touch the tumor; you would not disturb the microenvironment. By leaving it alone, you allow the tumor to shrink and go away.

When you start to look at this as a biological problem, many of the things that we do in cancer make no sense. We have, in brain cancer, people say, You have a very low-grade tumor. Lets go in and get it out. What happens is you go in and get it out, and then the following year it turns into a glioblastoma.

How did that happen? Well, you disturbed the microenvironment. You allowed these cells that are marginally aggressive to become highly aggressive. Then you lead to the demise of the patient,Seyfried says.

That happens significantly because its called secondary glioblastoma arising from therapeutic attempt to manage a low-grade tumor. The same thing can happen with all these different organs. You stab breast tumors, you stab colon tumors, you run the risk of spreading the cells

My argument is the following: If the patient has a lump, whether its in the breast, in the colon, lung or wherever or a lesion of some sort, that should be the cue to do metabolic therapy.

Do metabolic therapy first. In all likelihood, it will shrink down and become less aggressive. Then the option becomes, Should we debulk completely rather than doing some sort of a biopsy? We want to reduce the risk, because if we can catch the whole tumor completely, then we dont run the risk of spreading it

In our procedure, you bring the body back into a very high state of metabolic balance, and then you strategically go and degrade the tumors slowly without harming the rest of the body.

Radiation, chemo and the strategies that were using today dont do this. Theyre based on the gene theory of cancer that genetic mutations are causing the cell cycle to grow out of control. Well, this is not the case. Again, a lot of these toxic procedures need to be rethought, reanalyzed in my mind.

In biology, structure determines function. This is an evolutionarily conserved concept. So, how can mitochondria be structurally abnormal in tissue, yet have normal respiration? As Seyfried notes, this doesnt make sense. Confusion has arisen in part because many study cancer in culture, and make profound statements and comments regarding what happens in culture, Seyfried says.

If you look at cancer cells in culture, many of them do take in oxygen and make ATP, but at the same time, theyre fermenting. This was the conundrum. They called it the Warburg Effect. Theyre fermenting, but many people at the same time thought their respiration was normal.

This was the main problem with Warburgs theory. But Warburg clearly said in his papers [that] its not the fact that they take in oxygen; its how much ATP they can generate from oxidative phosphorylation, which is the normal respiratory capacity of the mitochondria.

As explained by Seyfried, if you measure ATP and look at oxygen consumption in tumor cells, it appears theyre making ATP and taking in oxygen, therefore, their respiration is assumed to be normal. However, when you look at the tissues in cancer patients, the mitochondria are abnormal.

What I and Dr. Christos Chinopoulos from Semmelweis University in Budapest, Hungary, who is the world-leading expert on mitochondrial physiology and biochemistry realized [was] that the mitochondria of tumor cells are actually fermenting amino acids, glutamine in particular. Theyre not respiring. Theyre fermenting an alternative fuel, which is glutamine,Seyfried says.

With this understanding, Warburgs theory can be proven correct cancer arises from damage to the mitochondrias ability to produce energy through respiration in their electron transport chain.

The compensatory fermentation involves not only lactic acid fermentation, but also succinic acid fermentation using glutamine as a fermentable fuel. Its been known for decades that glutamine is a main fuel for many different kinds of cancers, but most people thought it was being respired, not fermented.

Seyfried and Chinopoulos discovery confirms that cancer cells in fact have damaged respiration, and to survive, the cancer cells must use fermentation. The two most available fermentable fuels in the cancer microenvironment are glucose and glutamine. Hence, targeting glucose and glutamine is a crucial component of cancer treatment.

Without glucose and glutamine, the cancer cells will starve, as they cannot use ketones. The simplest approach to cancer then is to bring patients into therapeutic ketosis, and then strategically target the availability of glucose and glutamine.

Basically, what were saying [is] that mitochondrial substrate-level phosphorylation is a non-oxidative metabolism mechanism inside the mitochondria that would generate significant amounts of energy without oxidative phosphorylation,Seyfried says.

According to Seyfried, mitochondrial dysfunction is at the heart of nearly every type of cancer. Unfortunately, few oncologists have this understanding and many still believe cancer is the result of genetic defects. However, nuclear transfer experiments clearly show cancer cannot be a genetic disease.

Theres been no rational scientific argument that I have seen, to discredit the multitude of evidence showing that the [genetic] mutations are not the drivers but the effects [of mitochondrial dysfunction],Seyfried says.

As a matter of fact, theres new information now where people are finding so-called genetic drivers of cancer expressed and present in normal cells, normal skin and also esophagus This is another [issue] how you get these so-called driver mutations in normal tissues. Were also finding some cancers that have no mutations, yet, theyre fermenting and growing out of control.

There are a number of new observations coming out that challenge the concept that cancer is a genetic disease. And once you realize that its not a genetic disease, then you have to seriously question the majority of therapies being used to manage the disease. This [helps] explain [why] we have 1,600 people a day dying from cancer in the United States.

Why do we have such an epidemic of suffering and death when we have been studying this disease for decades? Well, if you look at the massive amounts of scientific papers being written on cancer, youll often find that theyre structured around gene defects.

What Im saying is that if cancer is not a genetic disease and the mutations are downstream epiphenomena, why would the field continue to focus on things that are mostly irrelevant to the nature of the disease? What Im saying is very devastating, because Im telling the majority of the people in the field that theyre basically wasting their time

I think we can drop the death rate of this disease by about 50% in 10 years if cancer is treated as a mitochondrial metabolic disease, targeting fermentable fuels rather than using toxic therapies that are focused on downstream effects.

Radiation is designed to stop DNA replication. DNA replication requires energy. If you pull the plug on their fermentable fuels, theyre not going to be able to replicate anyway All of the things that were doing to treat cancer is basically approaching the disease from a misunderstanding of the biology

We know viruses can cause cancer. We know radiation causes cancer. We know carcinogens cause cancer. We know intermittent hypoxia causes cancer. We know systemic inflammation causes cancer. We know just getting older puts you at risk for more cancer.

We know there are inherited mutations in the genome that can cause cancer. But how are all these things linked through a common pathophysiological mechanism? The common pathophysiological mechanism is damaged through the structure and function of the mitochondria.

Every one of the issues including inherited mutations, damage the respiration of a particular population of cells in a tissue. You look at the breast cancer gene (BRCA 1), for example. People will say, Cancer must be a genetic disease because you inherit a mutation that causes the disease.

You only get the disease if that mutation disrupts the function of the mitochondria. Fifty percent of women who carry the mutation never get cancer or breast cancer because the mutation, for some reason, did not damage the mitochondria in that person.

So, to summarize, the true origin of cancer is damage to the respiratory function of the mitochondria, triggering compensatory fermentation, which is run by oncogenes. Oncogenes play a role by facilitating the entry of glucose and glutamine into the cell to replace oxidative phosphorylation.

Seyfried also has a very different view on the biology of metastasis (the spread of cancer). He explains:

Weve looked at cancer stem cells in a number of our preclinical models These guys grow like crazy in place. The tumor just keeps expanding, but it doesnt spread. It doesnt spread into the bloodstream or metastasize to various organs.

We discovered a very unusual cancer 20 years ago. It took us 10 to 15 years to figure out what it was. You can put a few of these cells anywhere in the mouses body and within three to four weeks, this mouse is full of metastatic cancer. It made the cover of the International Journal of Cancer, when we published this back in 2008, but we had worked on the problem for years.

We couldnt figure out what it was that made these cells so incredibly metastatic. We found out that once we identified the biology of the cell, it turned out [it has] many characteristics in common with the macrophage, which is one of the most powerful immune cells in our body.

We said, Wow. Is this unique only to this kind of cell or do metastatic cancers in humans also express characteristics of macrophages? We looked and we found that almost every major cancer that metastasizes has characteristics of macrophages. Then we said, Well, how could this possibly happen? Is it coming from the macrophage?

A number of scientists have all clearly shown that there is some fusion hybridization character going on. In other words, macrophages, our wound-healing cells, they come into a microenvironment where you might find many proliferating neoplastic stem cells, but they dont have the capacity to metastasize.

Its only when the macrophages fuse with these stem cells that you have a dysregulated energy metabolism coming in this hybrid cell. This hybrid cell now has characteristics of both stem cells and macrophages.

The stem cell is not genetically equipped to enter and exit tissue. The macrophage, as a normal cell of your body, is genetically equipped to enter and exit tissue and live in the bloodstream. Theyre very strongly immunosuppressive. These are all characteristics of metastatic cancer.

According to Seyfried, metastatic cancer cells are essentially a hybrid, a mix of an immune system cell and a dysregulated stem cell, the latter of which could originate from a disorganized epithelial cell or something similar. In short, its a hybrid cell with macrophage characteristics.

Macrophages are essential for wound healing and part of our primary defense system against bacterial infections. They live both in the bloodstream and in tissues, and can go anywhere in the body. When an injury or infection occurs, they immediately move in to protect the tissue.

The metastatic cancer cell has many of those same properties,Seyfried explains,But the energy and the function of the cell is completely dysregulated, so it proliferates like crazy but has the capacity to move and spread through the body, so its a corrupted macrophage. We call it a rogue macrophage.

Like macrophages, metastatic cancer cells can also survive in hypoxic environments, which is why most angiogenic therapies are ineffective against metastatic cancer.

So, what do these metastatic hybrid cells need to survive? Both macrophages and immune cells are major glutamine consumers, and according to Seyfried, you can effectively kill metastatic cells by targeting glutamine.

However, it must be done in such a way so as to not harm the normal macrophages and the normal immune cells. In other words, it must be strategic. For this reason, Seyfried developed a press-pulse therapy for cancer, which allows the patient to maintain normal immune system function, while at the same time targeting the corrupted immune cells the macrophage fusion hybrid metastatic cells as well as inflammation.

The therapies we are using to attempt to kill these [metastatic] cells put us at risk for having the cells survive and kill us. You can control these cells for a short period of time, but they can hunker down and enter into some sort of a slightly dormant state, but they reappear.

People say, Oh, these tumor cells are so nifty and smart they can come back at you. The problem is youve never really challenged them on their very existence, which is they depend on fermentation to survive. If you dont target their fermentation, theyre going to continue to survive and come back at you.

Many of the therapies that we use radiation, chemo and some of these other procedures are not really going after the heart of the problem. That oftentimes puts you at risk for the recurrence of the disease. Your body is already seriously weakened by the toxic treatments. And in the battle, you lose. If you are fortunate enough to survive your body is still beat up.

You have now put your [body] at risk for other kinds of maladies Why are we using such toxic therapies to kill a cell when we know what its weaknesses are? These are the paradigm changes that will have to occur as we move into the new era of managing cancer in a logical way.

To properly address cancer, then, you need to clean up the microenvironment, because the microenvironment will strategically kill cells that are dependent on fermentation while enhancing cells that arent. At the same time, the microenvironment will also reduce inflammation.

You also have to be very careful not to kill your normal and healthy immune cells, because they need glutamine too,Seyfried says. What we find is that when we strategically attack the tumor this way, it turns out that our immune cells are paralyzed.

The cancer cells are killed, but the normal immune cells are paralyzed. Theyre not dying, theyre just not doing their job. What we do is we back off the therapy a little; allow the normal immune cells to regain their biological capacity, pick up dead corpses, heal the microenvironment, and then we go after the cancer cells again.

Its a graded response, knowing the biology of the normal cells and the abnormal biology of the tumor cells. This is a beautiful strategy. Once people know how you can play one group of cells off another, and how you can strategically kill one group of cells without harming the other cells, it really becomes a precision mechanism for eliminating tumor cells without harming the rest of the body.

You dont need to be poisoned and irradiated. You just have to know how to use these procedures to strategically kill the cells. Protecting normal macrophages is part of the strategic process. Killing the corrupted ones is part of the strategic process. Again, you have to put all of these together in a very logical path. Otherwise, youre not going to get the level of success that we should be getting.

This strategy is what Seyfried calls press-pulse treatment, and essentially involves restricting the fermentable fuels glucose and glutamine in a cyclical fashion to avoid causing damage to normal cells and tissues. Glucose is effectively restricted through a ketogenic diet. Restricting glutamine is slightly trickier.

The press-pulse strategy was developed from the concept of press-pulse in the field of the paleobiology. A press was some chronic stress on populations, killing off large numbers, but not everything, because some organisms can adapt to stress. The pulse refers to some catastrophic event.

The simultaneous occurrence of these two unlikely events led to the mass extinction of almost all organisms that existed on the planet. This was a cyclic event over many hundreds of millions of years. The geological records show evidence for this press-pulse extinction phenomenon.

What we simply did was take that concept and say, Lets chronically stress the tumor cells. They need glucose. You can probably kill a significant number of tumor cells by just stressing their glucose. Thats the press. The press is different ways to lower blood sugar. You put that chronic stress on top of the population either by restricted ketogenic diets [or] therapeutic fasting. There are a lot of ways that you can do this.

Also, emotional stress reduction. People are freaked out because they have cancer, therefore their corticoid steroids are elevated, which elevates blood sugar. Using various forms of stress management, moderate exercise all of these will lower blood sugar and contribute to a chronic press and stress on the cancer cells.

However, youre not going to kill all cancer cells if you just take away glucose. Because the other fuel thats keeping the beast alive is the glutamine. We have to pulse, because we cant use a press for glutamine targeting, because then youre going to kill your normal immune cells or impair them, and they are needed for the eventual resolution of the disease.

What were going to do is were going to pulse various drugs. We dont have a diet system that will target glutamine. Glutamine is everywhere. Its the most abundant amino acid in your body But you have to use [the drugs] very strategically; otherwise they can harm our normal immune system and then be counterproductive

I think that once we understand how we can target effectively glutamine without harming our normal immune cells this is the strategy that will make most of these other therapies obsolete Its cost-effective and non-toxic and it will work very well.

But were still at the very beginning of this. We need to continue to develop the doses, timing and scheduling of those drugs that are most effective in targeting glutamine that can be done without harming the rest of the cells in our body.

If you would like to support Dr. Seyfrieds research, please consider making a donation to the Foundation For Metabolic Cancer Therapies. The donation tag is on the top row of the of the foundationsite. This Foundation is dedicated to supporting Dr. Seyfrieds studies using metabolic therapy for cancer management with 100% of the donated funds going directly to research on metabolic therapy for cancer.

Originally published July 31, 2022 on Mercola.com

Views expressed in this article are the opinions of the author and do not necessarily reflect the views of The Epoch Times. Epoch Health welcomes professional discussion and friendly debate. To submit an opinion piece, please follow these guidelines and submit through our form here.

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Why Glucose Restrictions Are Essential in Treating Cancer - The Epoch Times

Skin Stem Cells Comments Off on Why Glucose Restrictions Are Essential in Treating Cancer – The Epoch Times | August 10th, 2022

Raising the dead sounds like science fiction, but a team of medical scientists at Yale University have managed to achieve just thatat least on a cellular level. They successfully revived cells from pigs that were dead for an hour, as a Nature study published August 3 reports. While the study authors emphasize the technology is ages away from being used on people, the work could eventually help keep human tissues alive longer, increasing the supply of viable organs for transplants.

These cells are functioning hours after they should not be, said Nenad Sestan, a professor of neuroscience and comparative medicine at Yale and lead author of the study, in a news briefing per CNN. And what this tells us is that the demise of cells can be halted. And their functionality restored in multiple vital organs. Even one hour after death.

Sestan and his colleagues received 100 pigs from a local breeder. They placed the pigs on ventilators and shocked the animals hearts to induce cardiac arrest. An hour after confirmed death, the Yale scientists used two systems to pump blood back into the bodiesan ECMO machine removed carbon dioxide and added oxygenated blood to one group, while another device, called OrganEx, pumped artificial blood back into the other. That fluid entered the blood vessels of the dead pigs, where synthetic forms of hemoglobin and other molecules protected cells from degradation and stopped blood clots.

After six hours, the researchers recorded signs of oxygen recirculating into the pigs tissues. A heart scan confirmed signs of electrical activity in the heart of pigs on the OrganEx machine, though those organs did not fully restart. Elsewhere, there were signs of business as usual, too: The livers of the deceased pigs resumed production of a protein called albumin. Additionally, the cells of other vital organs were responsive to glucose, suggesting the pigs metabolic processes were working again.

The experiment is not the first time scientists have tried to redefine life and death. In the early 20th century, there were attempts to reboot the brains of deceased monkeys. And in 2019, neuroscientists reanimated the brains of decapitated pigs four hours after they died in a slaughterhouse.

Studies such as these raise questions about what it means to be dead. We presume death is a thing, it is a state of being, Nita Farahany, a Duke law professor who studies ethical, legal and social implications of emerging technologies, told The New York Times. Are there forms of death that are reversible? Or not?

The findings also call into question who is considered legally dead, especially as medicine adapts to make cardiac death one day reversible. People tend to focus on brain death, but theres not much consensus on when cardiac death occurs, Arthur Caplan, a bioethicist at New York University told Nature News. This paper brings that home in an important way.

Ethical challenges abound if technology such as this were applied to people. In 2016 Indias medical research council, citing ethical concerns, blocked a planned clinical trial that aimed to revive brain-dead people to a minimally conscious state using a mix of stem cells and other techniques.

While the current study showed no signs of brain activity in the pigs, the researchers observed the heads, necks, and torsos moved. If brain activity was restored, there is no telling how functional or conscious the pigs would be, making it one of a slew of ethical questions scientists will need to answer as they breach this murky area of science.

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Pigs died after heart attacks. Scientists brought their cells back to life. - Popular Science

Cardiac Stem Cells Comments Off on Pigs died after heart attacks. Scientists brought their cells back to life. – Popular Science | August 10th, 2022

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Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -...

Cardiac Stem Cells Comments Off on Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -… | August 10th, 2022

Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, from the Qyang and Campbell laboratories at Yale, provides a mechanism to identify abnormalities linked with a hereditary cardiac condition, hypertrophic cardiomyopathy (HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.

Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited cardiac disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate cardiac muscle contraction, compromising the hearts ability to pump blood. However, the mechanisms behind the disease are poorly understood.

For this multi-model study, the researchers used stem cell approaches to understand the mechanisms that drive inherited HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate insights into the genetic causes of disease and the development of new treatments using the patients own cells.

This is a humbling experience that a patients disease phenotypes teach researchers fundamental basic knowledge that sets the stage for innovative new therapies. Furthermore, our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues, said Yibing Qyang, PhD, associate professor of medicine (cardiology) and of pathology.

We wanted to understand the disease mechanism and find a new therapeutic strategy, Park said.

Probing the heart disorders mechanismThe concept originated with an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care for this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of the patients blood and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying cardiac knowledge, they coaxed iPSCs into patients own cardiomyocytes (heart cells) for cardiac disease studies. We discovered a general mechanism which explains the disease progression, said Park.

Next, they engineered heart tissues that resembled the early-onset disease scenario of the young patient. The disease was a severe presentation at the age of 18 months, which suggested that the disease started at the fetal/neonatal stage.

The next phase of the study was to recreate a 3-D model that was used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised if the mutation is present. This was performed in collaboration with Stuart Campbell, PhD, and Sewanan from Yales Department of Biomedical Engineering. Coupled with computational modeling for muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of the tissue at three-dimensional levels.

Finally, using advanced gene editing technologies, the research team modified these mutations. They discovered that after the mutations were corrected, the disease was reversed. These insights about sarcomeric protein mutations could lead to novel therapeutics for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.

Our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues.

Yibing Qyang, PhDWe can apply these findings to cardiac conditions associated with hypertension, diabetes, or aging, said Riaz.

Applying the findings to heart diseaseOne of the fundamental challenges was that we needed to generate iPSCs from the patients family, Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process which takes over a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.

We are hopeful that our findings will be replicated in the scientific community, said Riaz. This is an example of bed to bench research, where scientists extract materials from clinics and conduct the experiment in the laboratory and then discover new methods to treat patients.

The authors also noted that RNA sequencing could be used as a guide to characterize the disease at a molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. We can now screen multiple drugs to see whether any of those drugs are able to rescue the phenotype, they said.

Riaz, now an associate research scientist in the Qyang lab, began as a cancer researcher. He earned a PhD from the Erasmus University Medical Center, based in Rotterdam, Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.

Park, also from the Qyang lab, graduated from Seoul National University, South Korea in 2013. He completed postdoctoral research at the University of Missouri where he focused on vascular biology and emerging areas in stem cell technology.

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Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education - India Education Diary

Cardiac Stem Cells Comments Off on Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education – India Education Diary | August 10th, 2022

Immediate cord clamping (ICC), within a few seconds after birth, became routine in the latter half of the 20th century, as part of a tranche of medical birth-related interventions that collectively, undoubtedly improved maternal and neonatal survival and outcomes [1]. The trend to ICC (within 15-20 seconds after birth) was partly driven by some early studies suggesting that the most benefit in terms of blood volume is achieved within this time frame [2], and that deferred cord clamping (DCC) increased rates of polycythemia and jaundice [1]. It may also have been partly driven by increased rates of operative deliveries and consequent pressure to minimize surgical times, as well as the increased availability and effectiveness of neonatal resuscitation. Furthermore, ICC was proposed as a means to reduce the risk of maternal exposure to fetal blood group antigens at a time (before RhD immunoprophylaxis) when hemolytic disease of the fetus and newborn was far more common than it is now.

Formal evidence that ICC was beneficial was never sought, and recent research summarized in systematic reviews [3-6] has suggested that it may be harmful when compared with DCC for various intervals from 30 seconds until when the cord stops pulsating (defined in some studies as physiological cord clamping). ICC before the onset of breathing exposes the newborn baby to a period of significantly restricted cardiac function, whereas DCC until after the onset of breathing (which often does not occur until late in the first minute after birth) may mean that the expanding pulmonary circulation is able to fill with blood from the placenta, rather than by reverse flow across the ductus arteriosus [7]. This may improve left ventricular preload and stabilize pressures and flows in major vessels [7].

In addition, when cord clamping is deferred, babies may receive a transfusion of blood from the umbilical cord and placenta. A recent systematic review demonstrated that DCC in preterm babies improves peak hematocrit in the first week by 2.7% (95% confidence intervals (CI) 1.88-3.52) and reduced the proportion of babies receiving any subsequent blood transfusion (RD: -0.07, 95%CI -0.11 to -0.04) [6]. Some studies have found a weight increase in the first two minutes after birth when the cord is not clamped, supporting the hypothesis of placental transfusion [8]. Yet, recent evidence shows that placental transfusion may not always occur (Conference abstract: Vijayaselvi R, Abraham A, Kumar M, Kuruvilla A, Mathews J, Duley L. Measuring Umbilical Flow and Placental Transfusion for Preterm Births: Weighing Babies at 33-36 Weeks Gestation with Cord Intact. 1st Congress of Joint European Neonatal Societies; 2015).

The relative roles of cardiovascular stabilization at birth versus placental transfusion in improving outcomes have not been established. Understanding the contributions of these two mechanisms has significant implications for research and practice: for example, if the size of placental transfusion is more important, then prescribing a top-up transfusion soon after birth for babies with lower than average hemoglobin (who are known to be at higher risk of various adverse outcomes) [9] may be justified, especially for the babies for whom DCC has been precluded by maternal or fetal conditions. These include significant maternal bleeding, and monochorionic twins, where deferred cord clamping in the first twin could lead to one twin losing blood to the other. However, if it is the effects on improving cardiovascular stability in the first minutes (with consequential benefits for cardiorespiratory function and reducing severity of illness during the subsequent neonatal intensive care unit (NICU) stay), regardless of the magnitude of transfusion, then early top-up transfusion is unlikely to be helpful.

Observational studies suggest that exposure to blood transfusion itself is harmful to preterm babies, increasing the risk of adverse outcomes [10]. However, this suggestion has not been supported by the small number (to date) of randomized controlled trials of blood (red cell) transfusion thresholds [11-14]. It is unlikely to be the means by which DCC reduced deaths in the largest trial to date of deferred cord clamping in preterm babies, the Australian Placental Transfusion Study (APTS), and in the most recent systematic review on this, because neither showed a difference in rates of other adverse outcomes [6,15].

Another possibility is that it is the umbilical cord blood stem cells received by the baby are the main reason for the observed benefits to both survival and reduced requirement for later blood transfusion [16]. Umbilical cord blood has been demonstrated to be such a good contributor to hematopoiesis that it is a recognized stem cell resource for pediatric and adult hematopoietic stem cell transplant [17]. In addition, umbilical cord blood is a potential regenerative and immunomodulatory agent for a variety of clinical conditions [18], so in this case, the extent of placental transfusion would be critical to the improvement of outcomes, and transfusion with adult red cells would not suffice. There are no established methods to quantify the contribution of umbilical cord stem cells to placental transfusion. However, a larger volume of placental transfusion results in the baby receiving more nucleated cells [19], including more umbilical cord stem cells.

Discerning whether these effects (initial enhanced cardiovascular stability leading to early and sustained reduction in severity of illness or volume of placental transfusion) appear to be the main driver of improved outcomes is likely to contribute to practice change, as well as to informing the design of future research studies into methods to improve outcomes of high-risk newborn babies and reduce their transfusion dependence.

The causal mechanisms of reduced transfusion requirements found in DCC relative to ICC are yet to be resolved. The aim of the study is to address the question; In preterm infants (P) does DCC (I) compared to ICC (C) reduce dependence on red cell transfusion via enhanced cardiovascular stability (mediator 1, M1) or via an increased volume of placental transfusion (M2).

The study is a nested retrospective study, called the Transfusions in the APTS Newborns Study (TITANS) (study registration: ACTRN12620000195954), of the cohort of babies who were enrolled and randomly assigned to ICC or DCC in the Australian and New Zealand (NZ) sites for APTS (study registration: ACTRN12610000633088). This design has been developed to take advantage of the comprehensive dataset already collected for APTS, and because there is currently no suitable prospective study that could address the same research questions in such a large group of participants.

Babies had been considered eligible for APTS if obstetricians or maternal-fetal medicine specialists anticipated that delivery would occur before 30 weeks of gestation. Exclusion criteria included fetal hemolytic disease, hydrops fetalis, twin-twin transfusion, genetic syndromes, and potentially lethal malformations. Further details are available in the original APTS publication [15]. In the present TITANS analysis, we will also exclude any baby with a diagnosis of hemolytic anemia or aplastic/hypoplastic anemia.

There were 1401 babies enrolled for APTS from the 13 Australian and 5 NZ hospital sites [15]. APTS data was provided to the TITANS team on 31 July, 2020. It is planned to collect additional data from Australian and NZ APTS sites using a customised, secure web-based database application (REDCap) [20], which is maintained by the University of Sydney, Sydney, Australia. Data will be obtained from source documents (patient hospital records and laboratory reports) using the electronic data collection application from each study site. The individual participant data collected will correspond to the minimum data required to answer the research questions. Baby identification (ID) and other babies details from APTS will be used to re-identify participants and link them to hospital records. Identified data will be collected, in order to allow linkage between the data newly collected from patient records and hospital laboratories and the existing APTS dataset. The data will be checked with respect to range, internal consistency, consistency with published reports and missing items. After data cleaning and analysis, data will be stored in re-identifiable form, with each participants data being identified with the same study numbering system as used for the APTS study.

We will combine the data already extracted, stored and cleaned from APTS with the additional data obtained from study sites for each participating baby, to determine which factors are most influential in reducing transfusion requirements. The specific objectives are, after adjustment for prior risk factors (listed below), to determine:

1.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by placental transfusion (measured by hematocrit (Hct)) as seen in Figure 1 (a, c) following the causal path X M1 Y, where X is the intervention, ICC or DCC, Y is the outcome, mediator M1 is placental transfusion, and M2 is initial severity of illness stability

2.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by initial severity of illness (respiratory support, sampling line yes/no and total duration number, blood pressure, cumulative blood sample volume) as seen in Figure 1 (b, c) following the causal path X M2 Y

3.Whether the effect of cord clamping intervention on the outcome (blood transfusions) is driven by multiple mediators (placental transfusion and initial severity of illness) as seen in Figure 1 (c)

4.Whether cording clamping intervention (ICC or DCC) has a direct effect on the outcome after accounting for the mediators as seen in all panels of Figure 1: X Y.

The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee in November 2019 (Version 3.0, Reference 2019/ETH12819), the Mater Misericordiae Ltd Human Research Ethics Committee (Version 1.0, Reference HREC/MML/56247), the Mercy Health Human Research Ethics Committee (Version 2.0, Reference 2020-078), and the Southern Health and Disability Ethics Committee (Version 1.0, Reference 19/STH/195). The ethics committees have granted a waiver of consent. The study is conducted in accordance with the National Health and Medical Research Council Statement on Ethical Conduct in Research Involving Humans.

Intervention

The intervention consisted of either immediate or delayed cord clamping (as assigned in APTS). Immediate clamping was defined as clamping the cord within 10 seconds of delivery. Delayed clamping was defined as clamping the cord at least 60 seconds after delivery, with the infant held as low as possible, below the introitus or placenta, and with no palpation of the cord. Variations in the protocol were allowed if they would aid the mother, baby, or both. If the baby was non-vigorous (heart rate <100 beats per minute, low muscle tone, or lack of breathing, or crying), clinicians were allowed to break protocol using their discretion. Cord milking was not part of the protocol for either intervention. Further details may be sourced from the original APTS publication [15].

Outcomes

The primary outcome is the proportion of babies receiving red cell transfusion (for restoration of hemoglobin or blood volume). The secondary outcomes are number of transfusions per baby, cumulative transfusion volume (mL/kg) per baby, and primary reasons for each transfusion.

Putative Mediators

M1: Indicators of placental transfusion to be assessed will be hematocrit (on admission, highest on the first day, highest in the first week collected before any postnatal transfusion).

M2: Indicators of initial severity of illness to be assessed will be cumulative blood sample volume collected throughout hospital stay (number of blood tests multiplied by hospitals usual sample volume for each type of test), sampling line (umbilical arterial line or peripheral arterial line) - yes/no and total duration, mechanical ventilation or inspired O2, and blood pressure.

Sensitivity Analyses (For the Primary Outcome Analysis Only)

Sensitivity analyses will adjust for the following variables: gender, birth <27 weeks vs. 27 weeks, method of delivery (vaginal versus cesarean), intraventricular hemorrhage (IVH) (yes/no and grade III/IV yes/no), surgery for patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and sodium in the first 24 hours of life. We will also test model assumptions relating to sequential ignorability and post-randomization confounding (discussed further in the data analysis plan).

Potential Confounders (Covariates)

The following covariates may be used for adjustment in the analysis: gestational age at randomization before birth and any oral iron supplement pre-transfusion.

Timing of Assessments

Putative mediating variables will only be analyzed if they have been measured before the outcome and will be excluded if there is not adequate time and date information available. If the multiple mediator model is applied, careful consideration of timing information will be evaluated. If there is insufficient empirical information to conclude the causal ordering of mediators (M1 causes M2), we will adjust our analytic approach (as discussed in the analysis plan) and discuss any limitations.

Data Analysis Plan

The analysis will include all babies who were initially randomized in the APTS trial for whom we were able to obtain the relevant data and be based on intention-to-treat. All statistical analyses will be conducted in R version 4.1.3 (2022-03-10; R Foundation for Statistical Computing, Vienna, Austria). Descriptive characteristics for continuous data will be presented as means or medians, as appropriate, and categorical data will be presented as frequencies and percentages.

A model-based inference approach will be applied to estimate the average causal mediation effect (ACME), average direct effect (ADE), and the average total effect as recommended [23-25]. This approach will be applied with the R mediation package [26]. We will initially fit two models, one model with mediation as the dependent variable and intervention as the independent variable (mediator model), and a second model with the outcome as the dependent variable, and both mediation and intervention as independent variables (outcome model). To account for the clustering of multiples, estimates will be calculated with generalized estimating equations with a compound symmetric correlation structure to account for within subject correlations. Depending on the outcome (binary, count, skew) these will be modelled with the appropriate family and link functions.

A counterfactual framework will be applied to the mediator and outcome models to simulate the values of the mediator and outcome to estimate the potential values of the mediator. This process is used to estimate the ACME, ADE, and average total effects; 95%CI will be estimated with 1000 bootstrap simulations.

We will apply single mediator models on both placental transfusion variables and initial severity of illness variables if mediators are statistically independent, as seen in Table 1. Independence will be tested using linear regression and any appropriate link functions. If both mediators are not statistically independent, we will investigate the possibility of multiple mediator models, which require an expanded framework for analysis [21]. Here we assume that initial severity of illness is causally related to placental transfusion. For this process, we will use the method developed by Imai and Yamamoto [21] to estimate the ACME and ADE. Following this, 95%CI will be estimated with 1000 bootstrap simulations. If theoretical and empirical timing data and sensitivity analyses suggest that M1 and M2 have non-causal correlation and may be affected by an unmeasured latent mediator, we will adjust our approach to estimate interventional direct and path-specific indirect effects [27,28].

Sensitivity analyses have been limited to a set of biologically plausible and clinically meaningful groups that will be explored by including them for adjustment with covariates, and with the introduction of interaction terms if appropriate. Missing data will be described, reasons for missing data will be explored, and the impact of missing data on conclusions about the treatment effect on the primary outcome will also be explored where possible (e.g., using sensitivity analyses and multiple imputation techniques).

Methodological Assumptions

The causal mediation approach assumes sequential ignorability: that the treatment effect on the outcome is not confounding and that the mediator effect on the outcome is not confounded. As treatment was randomly allocated to neonates, we will assume that the treatment-mediator relationship is not confounded. However, the mediator itself has not been randomized. Thus, unknown confounders may be driving a spurious effect in the mediator-outcome relationship. We will employ additional sensitivity analyses to estimate whether any mediation effects are sensitive to the violation of the assumption of sequential ignorability. To test the possibility of unmeasured confounders we will examine the correlation between residuals in the mediator model and the outcome model. If there is no correlation this would suggest there is no unmeasured confounding, if there is correlation between the residuals, an unmeasured mediator may be affecting both the measured mediator and the outcome. We will apply the method developed by Imai et al. andTingley et al. [23,26] that uses sensitivity analyses to evaluate if the ACME estimate is sensitive to unmeasured confounding.

Post-randomization confounders are dependent on the treatment allocated, affect both mediator and outcome, and can corrupt the mediation estimate. In the context of the present trial, it is possible that non-adherence to the intervention is a post-randomization confounder. We are analyzing our data based on intention to treat principles; however, a sensitivity analysis based on the actual time of cord clamping to assess the influence of non-adherence with the treatment protocol on our estimates may be performed.

Blood transfusions of neonates have been associated with a number of serious adverse outcomes [29]. Nevertheless, there are few evidence-based methods to reduce transfusion exposure [30]. The APTS study found that DCC was associated with a statistically significant reduced need for red cell transfusions by about 10% compared to ICC [15]. However, the mechanism remains unclear.

The study will, at a minimum, provide further information that should increase clinicians understanding of the pathways by which DCC (or other methods to accomplish placental transfusion) results in beneficial patient outcomes. Since one of the main barriers to implementation is lack of understanding about the mechanisms by which such a simple practice change should have such dramatic effects, this should improve adherence to recommendations to defer cord clamping for most babies, thereby reducing mortality and transfusion incidence.

By elaborating on the mechanisms, it may also provide good evidence for how other routine neonatal intensive care practices and interventions affect likelihood of needing to transfuse. Better understanding of these effects may lead to other testable hypotheses or improvements in other aspects of practice, further reducing transfusion exposure and improving other outcomes.

Potential limitations of the study include the dependence on some routinely collected clinical data, which were not collected at the time by the original study according to predefined research definitions. However, we have no reason to think that potential problems of data quality would have been influenced by study group allocation and so do not anticipate that this will be a source of bias.

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Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus

Cardiac Stem Cells Comments Off on Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort – Cureus | August 10th, 2022