Harnessing benefits of stem cells for heart regeneration – Full Circle

Mehdi Nikkhah, an associate professor of biomedical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, and his collaborators at Mayo Clinic in Arizona have been awarded a $2.7 million grant by the National Institutes of Health to research how stem cell engineering and tissue regeneration can aid in heart attack recovery.

The research will be conducted in collaboration with Wuqiang Zhu, a cardiovascular researcher and professor of biomedical engineering at Mayo Clinic.

Nikkhah and Zhu are exploring stem cell transplantation to repair and possibly regenerate damaged myocardium, or heart tissue. Their work is focused on the development of a new class of engineered heart tissues with the use of human induced pluripotent stem cells, or hiPSCs, and has resulted in two published papers in ACS Biomaterials.

A heart attack, medically termed as a myocardial infarction, occurs when a coronary artery that sends blood and oxygen to the heart becomes obstructed. This blockage is often the result of an accumulation of fatty cholesterol-containing deposits, known as plaques, within the hearts arteries.

When these plaques rupture, a cascade of events is initiated, leading to the formation of a blood clot. These blood clots can obstruct the artery, impeding blood flow to the heart muscle, thus triggering a heart attack.

When someone has a heart attack, a portion of muscle tissue on the left ventricle, which pumps the blood throughout the whole body, is damaged, Nikkhah says. Over time, the other parts of the heart have to take on more workload, consequently leading to catastrophic heart failure.

A team of biomedical engineers in the School of Biological and Health Systems Engineering, part of the Fulton Schools, and medical researchers at Mayo Clinic in Arizona are taking a novel step forward in using stem cell technology and regenerative medicine to aid in heart attack recovery.

Nikkhah is developing engineered heart tissues, or EHTs, with electrical properties to simulate the contraction function typically found within the native hearts tissue.

He is integrating the EHTs with gold nanorods to enhance electrical conductivity among stem cells. Gold is a suitable material because it is conductive and non-toxic to human cells, making the nanorods safe for medical research and translational studies.

In the lab, Nikkhahs team mixes the gold nanorods with a biocompatible hydrogel to form a tissue construct a patch of stem cells to rejuvenate damaged cardiac muscle tissue, offering a promising outcome for heart regeneration.

After we generate the patch, we get the engineered hiPSCs from Dr. Zhus lab at Mayo Clinic, Nikkhah says. They seed the cells on the patch and look at their biological characterization, including cell proliferation, cell viability and gene expression analysis, to see how the cells respond to the conductive hydrogel.

We have successfully used hiPSC-derived cardiomyocytes and cardiac fibroblasts to create beating heart tissues, Nikkhah says. After the tissue maturation, we transfer the patch to Dr. Zhus lab to be implanted into an animal model.

The successful integration and proliferation of these cells can lead to the formation of new, healthy heart tissue, potentially reversing the damage caused by the heart attack and enhancing the recovery process.

Reprogrammed human stem cells have nearly limitless potential because they can be differentiated into various cell types. That means hiPSCs can also be used to construct capillaries and blood vessels, which are essential for restoring adequate blood flow and oxygen supply to the damaged areas of the heart.

This process involves the differentiation of hiPSCs into endothelial cells, which form the lining of blood vessels, thereby facilitating the reconstruction of the hearts vascular network.

Michelle Jang, a graduate student in Nikkhahs lab, is currently studying EHTs to improve cell maturation and observe its electrical properties.

My engagement in this project showed a deep interest in how biomedical engineering technology and biology intersect to create new therapeutic possibilities in the field of regenerative medicine, Jang says. Im excited to see how my current research will further evolve and potentially contribute valuable insights to biomedical research.

Using these techniques, Nikkhah and Zhu can observe the capacity of programmed cells to regenerate damaged heart tissue. With continued advancement in regenerative medicine, there is potential for significant positive impact on outcomes for patients suffering from heart attacks.

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Embryonic Brain Overgrowth Dictates Autism Severity, New Research Suggests – University of California San Diego

In remarkable parallel, the more overgrowth a BCO demonstrated, the more overgrowth was found in social regions of the profound autism childs brain and the lower the childs attention to social stimuli. These differences were clear when compared against norms of hundreds and thousands of toddlers studied by the UC San Diego Autism Center of Excellence. Whats more, BCOs from toddlers with profound autism grew too fast as well as too big.

The bigger the brain, the better isnt necessarily true, agreed Alysson Muotri, Ph.D., director of the Sanford Stem Cell Institutes Integrated Space Stem Cell Orbital Research Center at the university. Muotri and Courchesne collaborated on the study, with Muotri contributing his proprietary BCO-development protocol that he recently shared via publication in Nature Protocols, as well as his expertise in BCO measurement.

Because the most important symptoms of profound autism and mild autism are experienced in the social affective and communication domains, but to different degrees of severity, the differences in the embryonic origins of these two subtypes of autism urgently need to be understood, Courchesne said. That understanding can only come from studies like ours, which reveals the underlying neurobiological causes of their social challenges and when they begin.

One potential cause of BCO overgrowth was identified by study collaborator Mirian A.F. Hayashi, Ph.D., professor of pharmacology at the Federal University of So Paulo in Brazil, and her Ph.D. student Joo Nani. They discovered that the protein/enzyme NDEL1, which regulates growth of the embryonic brain, was reduced in BCOs of those with autism. The lower the expression, the more enlarged the BCOs grew.

Determining that NDEL1 was not functioning properly was a key discovery, Muotri said.

Courchesne, Muotri and Hayashi now hope to pinpoint additional molecular causes of brain overgrowth in autism discoveries that could lead to the development of therapies that ease social and intellectual functioning for those with the condition.

Co-authors of the study include Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo and Janaina S. de Souza.

Funding: This work was supported by grants from the National Institute of Deafness and Communication Disorders, the National Institutes of Health, the California Institute for Regenerative Medicine and the Hartwell Foundation. We thank the parents of the toddlers in San Diego whose stem cells were reprogrammed to BCOs.

Disclosures: Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis, focusing on therapeutic applications customized for autism spectrum disorders and other neurological disorders origin genetics. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. Eichler is a scientific advisory board member of Variant Bio, Inc. The other authors have no conflicts of interest to declare.

The UCSD Autism Center of Excellence is a world leader in autism research. It has made pioneering discoveries that enable early detection and treatment of autism in infants and toddlers through innovative behavior and eye tracking tests. The Centers groundbreaking discoveries on the developmental neurobiology of autism have led to fundamental knowledge of the molecular, cellular, and brain growth and function causes of autism.

The Sanford Stem Cell Institute (SSCI) is a global leader in regenerative medicine and a hub for stem cell science and innovation in space. SSCI aims to catalyze critical basic research discoveries, translational advances and clinical progress terrestrially and in space to develop and deliver novel therapeutics to patients. The SSCI is directed by Catriona Jamieson, M.D., Ph.D., a leading physician-scientist in cancer stem cell biology whose research explores the fundamental question of how space alters cancer progression.

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Embryonic Brain Overgrowth Dictates Autism Severity, New Research Suggests - University of California San Diego

Stem Cells Market Driven by Tech Integration and Innovation – openPR

The global stem cells market is witnessing unprecedented growth, driven by advancements in medical research and increasing acceptance of stem cell therapies. This report delves into the key highlights of the market, analyzing trends, investments, and future prospects that are shaping this dynamic sector.

Market Revenue and Growth Projections

The global stem cells market is on a robust growth trajectory. By 2032, the market is projected to increase by an impressive USD 37.8 billion. This substantial growth is underpinned by a compound annual growth rate (CAGR) of 11.3% from 2023 to 2032. Such a significant CAGR indicates strong market confidence and the potential for continued expansion as more breakthroughs in stem cell research and applications emerge.

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Regional Market Leaders

In 2022, North America dominated the global stem cells market, commanding over 43% of the market share. This leadership position is largely attributed to the extensive research infrastructure, significant funding, and early adoption of advanced medical technologies in the region. The presence of leading research institutions and biotechnology companies in North America further consolidates its market dominance.

Investment in Stem Cell Research

A critical driver of the stem cells market is the substantial investment in research and development. In 2019, the US National Institutes of Health (NIH) invested over $1.5 billion in stem cell research, making it the largest funder globally. This level of investment underscores the importance of stem cells in medical research and the commitment of the US government to advancing this field. The NIH's funding supports a wide range of projects, from basic science to clinical trials, thereby fostering innovation and accelerating the translation of research findings into clinical applications.

Increase in Clinical Trials

The number of clinical trials utilizing stem cells has been steadily increasing over the past decade. By 2020, there were over 5,000 active stem cell trials worldwide. This surge in clinical trials is indicative of the growing confidence in stem cell therapies and their potential to revolutionize medical treatments. Clinical trials are essential for evaluating the safety and efficacy of new therapies, and the high number of ongoing trials suggests a vibrant and active research community working towards bringing new stem cell-based treatments to market.

Therapeutic Potential of Stem Cells

Stem cells hold immense potential for treating a variety of diseases and injuries. According to the NIH, stem cells could be instrumental in treating conditions such as cancer, diabetes, heart disease, and Parkinson's disease. This wide-ranging therapeutic potential is one of the key factors driving investment and research in the field. Stem cells' ability to differentiate into various cell types makes them versatile tools in regenerative medicine, offering hope for treatments that can repair or replace damaged tissues and organs.

Rising Awareness and Acceptance

Another significant factor contributing to the growth of the stem cells market is the rising awareness and acceptance of stem cell therapies. As more research validates the efficacy and safety of these treatments, public and professional acceptance is increasing. This growing acceptance is crucial for market expansion, as it encourages more patients to seek stem cell therapies and more healthcare providers to offer these innovative treatments.

Stem Cells Market Segmentation

Stem Cells Market By Product Adult Stem Cells o Dental Stem Cells o Neuronal Stem Cells o Adipose-derived Stem Cells o Mesenchymal Stem Cells o Dedifferentiated fat (DFAT) Cells o HematopoieticStem Cells o Umbilical Cord Stem Cells o Other ASC's Human Embryonic Stem Cells Very Small Embryonic Like Stem Cells Induced Pluripotent Stem Cells

Stem Cells Market By Application Regenerative Medicine o Oncology o Hematology o Neurology o Injuries o Liver Disorder o Incontinence o Diabetes o Orthopedics o Others Drug Discovery and development

Stem Cells Market By Technology Cryopreservation Cell Acquisition o Bone Marrow Harvest o Apheresis o Umbilical Blood Cord Cell production o Isolation o Therapeutic Cloning o In-Vitro fertilization o Cell Culture Expansion and Sub-Culture

Stem Cells Market By Therapy Autologous Stem Cell Therapy Allogenic Stem Cell Therapy

Future Prospects and Challenges

Looking ahead, the future of the stem cells market appears promising, with continued growth anticipated. However, the market also faces several challenges. Regulatory hurdles, ethical concerns, and the high cost of stem cell therapies are significant barriers that need to be addressed. The regulatory landscape for stem cell treatments is complex and varies significantly across different countries, which can slow down the approval and commercialization of new therapies. Ethical issues related to the use of embryonic stem cells also pose challenges, although the development of induced pluripotent stem cells (iPSCs) has mitigated some of these concerns.

Moreover, the high cost of developing and administering stem cell therapies can limit their accessibility. Ensuring that these therapies are affordable and accessible to a broad patient population will be crucial for the long-term success of the market.

Stem Cells Market Table of Content:

CHAPTER 1. Industry Overview of Stem Cells Market CHAPTER 2. Research Approach CHAPTER 3. Market Dynamics And Competition Analysis CHAPTER 4. Manufacturing Plant Analysis CHAPTER 5. Stem Cells Market By Product CHAPTER 6. Stem Cells Market By Application CHAPTER 7. Stem Cells Market By Technology CHAPTER 8. Stem Cells Market By Therapy CHAPTER 9. North America Stem Cells Market By Country CHAPTER 10. Europe Stem Cells Market By Country CHAPTER 11. Asia Pacific Stem Cells Market By Country CHAPTER 12. Latin America Stem Cells Market By Country CHAPTER 13. Middle East & Africa Stem Cells Market By Country CHAPTER 14. Player Analysis Of Stem Cells Market CHAPTER 15. Company Profile

Conclusion

In conclusion, the global stem cells market is set for significant growth, driven by substantial investments, increasing clinical trials, and the expanding therapeutic potential of stem cells. North America remains at the forefront of this market, supported by strong research funding and infrastructure. While the market faces challenges, particularly in regulatory and ethical domains, the overall outlook is positive. Continued advancements in research and increasing acceptance of stem cell therapies promise to unlock new possibilities in medical treatment, potentially transforming the landscape of healthcare in the coming decades.

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Stem Cells Market Driven by Tech Integration and Innovation - openPR

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a … – Nature.com

Patients

Patients eligible for the study were aged 12 years, weighed 30kg and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 if aged 18 years34 and Karnofsky or Lansky PS60% if aged 16 years or 12 to <16 years35, respectively (see Supplementary Tables 5 and 6 for details of PS scoring systems). All patients were to receive either peripheral blood or bone marrow allo-HSCT for hematologic malignancy from unrelated donors who were 8 of 8 or 7 of 8 human leukocyte antigen (HLA)-matched (a single allele mismatch at HLA-A, HLA-B and HLA-C, and HLA-DRB1 was permitted). A total of 441 patients were screened for eligibility. After screening, 343 patients were randomly assigned 1:1 to receive vedolizumab (174 patients) or placebo (169 patients) treatment. Randomization was stratified by age (patients aged 18 years or aged 12 to <18 years); HLA match (8 of 8 versus 7 of 8); conditioning regimen intensity (myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC)); and anti-thymocyte globulin (ATG) use (with versus without ATG). Patients received either vedolizumab 300mg or placebo intravenously on day 1 and days +13, +41, +69, +97, +125 and +153 after allo-HSCT in addition to standard GVHD prophylaxis (CNI plus methotrexate or mycophenolate mofetil). Nine patients did not receive study treatment, five were randomized to vedolizumab and four were randomized to placebo treatment.

Of 334 patients who received 1 dose of study treatment (analyzed for safety study end points), 333 also received allo-HSCT (analyzed for efficacy study end points), 168 in the vedolizumab group and 165 in the placebo group. For patients discontinuing the study, reasons for discontinuation included death (26 out of 57 patients in the vedolizumab group and 34 out of 71 in the placebo group), withdrawal by the patient (16 versus 18) and adverse events (AEs; 6 versus 5) (Fig. 1). Median (range) exposure to treatment was 40.0 (18.142.1) weeks for vedolizumab and 39.7 (18.142.3) weeks for placebo. In the vedolizumab group, patients received a mean (s.d.) of 5.4 (2.1) and median (range) 7.0 (17) treatment doses; 52.7% of patients in the vedolizumab group received all seven doses. A mean (s.d.) of 5.1 (2.3) and median (range) 7.0 (17) doses were received in the placebo group; 50.9% of patients in this group received all seven doses. Patient numbers were reduced to 60% of the planned sample size of 558 because of early enrollment termination owing to the impact of COVID-19 on recruitment. Consequently, more patients (n=137, 41.1%) received ATG at baseline than the 25% planned.

Discontinuation of the study refers to all patients who discontinued before the end of the long-term follow-up safety survey period of the study, 6 months after the last dose of study treatment. Withdrawn by physician is noted as reason other. Patients included in the analysis for efficacy end points per protocol were those who received 1 dose of study treatment and also received allo-HSCT. One patient was randomized to receive vedolizumab but did not receive allo-HSCT; per protocol, this patient was not included in the analysis of efficacy end points but was included in the analysis of safety end points.

Patient and transplant characteristics were balanced between treatment groups (Table 1 and Extended Data Table 1). The median age was 55.0 years (range, 1674 years; 1 aged <18 years) and 62.8% were male. The most frequent underlying malignancies were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoid leukemia (ALL). The conditioning regimen intensity was either MAC (52.4% in the vedolizumab group versus 53.9% in the placebo group) or RIC. GVHD prophylaxis (with or without ATG) was tacrolimus (TAC)+methotrexate (MTX; 42.3% versus 50.3%) or TAC+mycophenolate mofetil (MMF; 3.0% versus 3.0%); cyclosporine (CYS)+MTX (30.4% versus 23.0%) or CYS+MMF (14.3% versus 12.1%). The proportion of patients who received ATG prophylaxis was balanced between treatment groups: 42.3% (n=71) in the vedolizumab group versus 40.0% (n=66) in the placebo group; 57.7% versus 60.0% did not receive ATG.

Neutrophil engraftment occurred in 165 patients in the vedolizumab treatment group and 160 patients in the placebo group. The median (range) time to neutrophil engraftment was 16.0 (835) days in the vedolizumab group and 15.0 (831) days in the placebo group. Platelet engraftment occurred in 159 patients in the vedolizumab group and 148 patients in the placebo group. The median (range) time to platelet engraftment was 18.0 (1136) days in the vedolizumab group and 17.0 (0233) days in the placebo group.

The primary study end point was lower-GI aGVHD-free survival by day +180 after allo-HSCT. There were 24 (14.3%) patients in the vedolizumab group with an event of lower-GI aGVHD or death by day +180 after allo-HSCT compared to 47 (28.5%) patients in the placebo group (Fig. 2a). The frequency of lower-GI aGVHD by maximum clinical stage (see Supplementary Table 1 for a description of clinical staging of aGVHD9) is shown in Fig. 2b for each treatment group, with four cases of stage 24 lower-GI aGVHD in the vedolizumab group compared to 14 cases observed in those who received placebo. The KaplanMeier (KM) estimate for lower-GI aGVHD-free survival by day +180 was 85.5% (95% confidence interval (CI) 79.290.1) for the vedolizumab group and 70.9% (63.277.2) for the placebo group (Fig. 2c). The risk of a lower-GI aGVHD event or death by day +180 after allo-HSCT was 55% less in the vedolizumab group compared to the placebo group (hazard ratio (HR) 0.45, 95% CI 0.270.73; P<0.001). Results were consistent for sensitivity analyses of the primary end point (Table 2), including events occurring within a 7-day time frame at day +187 after allo-HSCT, stratified log-rank tests by randomization stratification factors, analysis with corrected stratification information, competing risk analysis and an analysis excluding aGVHD events graded stage 0 or unknown. By day +180 after allo-HSCT, 23 patients (13.7%) in the vedolizumab group versus 43 (26.1%) in the placebo group had an event of death or lower-GI aGVHD (when aGVHD events graded stage 0 or unknown were excluded) (HR 0.47, 95% CI 0.280.78; P=0.0029). In subgroup analyses of the primary end point (Fig. 2d and Extended Data Fig. 1), HRs consistently favored vedolizumab over placebo regardless of HLA match, conditioning regimen intensity, use of ATG or stem-cell source (bone marrow or peripheral blood). The overall incidence of upper-GI aGVHD, skin aGVHD and aGVHD in the liver by day +180 after allo-HSCT was similar between treatment groups (Supplementary Table 7).

Analysis included all randomized patients who received 1 dose of study treatment and received allo-HSCT. All statistical tests were two-sided. a, Graph shows number and proportion of patients with a lower-GI aGVHD event or death; censored for patients who had not had the lower-GI aGVHD event or died or had the event after a prespecified time, for example, last contact or day +180 after allo-HSCT, whichever occurred first. If a patient had a lower-GI aGVHD event and died due to any cause, including lower-GI aGVHD, the time to event was derived as the time to the first qualifying event (lower-GI aGVHD event). b, Frequency of lower-GI aGVHD by maximum clinical stages 04 by day +180 after allo-HSCT for patients in vedolizumab and placebo treatment groups and also the corresponding frequency of skin aGVHD and liver aGVHD in these treatment groups by maximum clinical stages 04 by day +180 after allo-HSCT. CI was based on the ClopperPearson method. c, KM estimate for the primary study end point lower-GI aGVHD-free survival from first study treatment (day 1) to lower-GI aGVHD event or death due to any cause. Red line shows the vedolizumab group; blue line shows the placebo group; open circles indicate censored patients. HR obtained via a Cox proportional hazards model with treatment group, stratified by randomization stratification factors: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC), ATG (with or without) and P value from a log-rank test (P=0.0009). d, Forest plot of prespecified subgroup analyses for the primary study end point of lower-GI aGVHD-free survival by day +180 after allo-HSCT: conditioning regimen MAC or RIC, with or without ATG, CNI TAC or CYS, HLA match, and stem cell source peripheral blood or bone marrow. HRs plotted with 95% CIs were obtained via a Cox proportional hazards model with treatment group stratified by randomization strata. Results for the remaining prespecified subgroup analyses are shown in Extended Data Fig. 1.

The KM estimates for the five key secondary end points analyzed at day +180 after allo-HSCT are shown in Fig. 3.

ae, KM estimates for the secondary efficacy end points. Analyses included all randomized patients who received 1 dose of study treatment and allo-HSCT. In the fixed-sequence hierarchical testing procedure, once 1 efficacy end point was not significant (P0.05), testing of subsequent end points was not performed. P values were obtained using a log-rank test unless otherwise stated. All statistical tests were two-sided. *P value is significant for vedolizumab versus placebo. HR and 95% CI values were obtained from a Cox proportional hazards model with treatment group stratified by randomization strata: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC) and ATG (with or without). Time to first documented lower-GI aGVHD, relapse of underlying malignancy or death from any cause. Sensitivity analysis, excluding lower-GI aGVHD events classified as clinical grade 0 or unknown. NRM was a competing risk in this competing risk sensitivity analysis; P value for comparison of vedolizumab with placebo was obtained by a Grays test. Time to first documented IBMTR grade CD aGVHD (any organ) or death from any cause. **Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade CD aGVHD (any organ) or death. P value was obtained by a Grays test. Death from first dose of study treatment without occurrence of a relapse. Relapse was a competing risk in this sensitivity analysis; NRM was the time from first study treatment to death without occurrence of a relapse; P value was obtained by a Grays test. Overall survival by day +180 was the analysis of the time from the first dose of study treatment to death from any cause. All deaths were defined as events in this analysis. Time to first documented IBMTR grade BD aGVHD (any organ) or death from any cause. Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade BD aGVHD (any organ) or death. P value was obtained by a Grays test.

There was a statistically significant difference favoring vedolizumab over placebo for lower-GI aGVHD-free and relapse of the underlying malignancy-free survival by day +180 after transplant. The KM estimated survival for this end point was 78.9% for the vedolizumab treatment group versus 65.4% for the placebo group. Events of lower-GI aGVHD, relapse or death for this end point occurred in 11, 18 and 6 patients, respectively from the vedolizumab group (total of 35, 20.8%) and 31, 13 and 12 (total of 56, 33.9%) in the placebo group (HR 0.56, 95% CI 0.370.86; P=0.0043). A statistically significant treatment difference favoring vedolizumab for this end point was also maintained after a sensitivity analysis excluding stage 0 and unknown lower-GI aGVHD events (HR 0.59, 95% CI 0.380.91; P=0.0130) (Fig. 3). The secondary end point of IBMTR grade CD aGVHD of any organ-free survival by day +180 (see Supplementary Table 3 for description of aGVHD severity grading using the IBMTR severity index), also demonstrated a statistical difference between vedolizumab and placebo treatment groups. The KM estimated survival for this end point was 78.9% for vedolizumab the treatment group versus 67.7% in the placebo group. Events of grade CD aGVHD of any organ or death counted for this end point occurred in 35 patients (20.8%) receiving vedolizumab versus 52 (31.5%) receiving placebo (HR 0.59, 95% CI 0.390.91; P=0.0204). In a competing risk analysis (death and relapse as competing risks), cumulative incidence of IBMTR grade CD aGVHD by day +180 was lower for the vedolizumab group (13.2%, 95% CI 8.618.8) than the placebo group (21.6%, 95% CI 15.628.2; P=0.0446) (Fig. 3). Secondary end point sensitivity analyses (Supplementary Table 8) and subgroup analyses (Extended Data Fig. 2) showed consistent results with decreased risk in the vedolizumab group compared to the placebo treatment group. The secondary end point of non-relapse mortality (NRM) by day +180 did not meet statistical significance, with 10 patients (6.0%) in the vedolizumab group and 19 (11.5%) in the placebo group (HR 0.48, 95% CI 0.221.04; P=0.0668) dying of non-relapse causes. Following the hierarchical statistical testing procedure, the subsequent fourth and fifth secondary end points were not tested for statistical significance. The KM estimate for the fourth secondary end point of overall survival was 89.7% for the vedolizumab treatment group and 84.4% in the placebo group. All-cause deaths by day +180 counted for this analysis occurred in 17 patients (10.1%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.63, 95% CI 0.341.17; P=0.1458). For the fifth secondary end point of IBMTR grade BD aGVHD of any organ-free survival by day +180, KM estimated survival was 66.4% for the vedolizumab treatment group and 52.3% in the placebo group. Grade BD aGVHD events in any organ counted for this end point occurred in 47 patients (28.0%) in the vedolizumab group and 64 (38.8%) in the placebo group with deaths also counted in 9 and 13 patients in the vedolizumab and placebo groups, respectively (HR 0.64, 95% CI 0.460.91; P=0.0105).

Results for the main exploratory end points at day +180 and day +365 after transplant are summarized (Extended Data Tables 3 and 4). The cumulative incidence of all chronic GVHD events by day +180 was 20.7% (95% CI 14.827.2) in the vedolizumab group versus 21.9% (95% CI 15.828.6) in the placebo group (death and relapse as competing risks; nominal P=0.7555). Chronic GVHD requiring systemic immunosuppression by day +180 occurred in three (1.8%) patients in the vedolizumab group (severity was moderate in two patients and severe in one) and four (2.4%) in the placebo group (one mild, two moderate and one patient had severe chronic GVHD) (Extended Data Table 3). KM estimates for GVHD (any organ)-free and relapse (of the underlying malignancy)-free survival by day +180 were 80.1% in the vedolizumab group and 69.7% in the placebo group; events for this end point occurred in 33 (19.6%) of patients in the vedolizumab group and 49 (29.7%) in the placebo group (HR 0.61, 95% CI 0.390.96; nominal P=0.0243). Events of clinical stage 24 lower-GI aGVHD or death by day +180 occurred in fewer patients in the vedolizumab group (19, 11.3%) than in the placebo group (33, 20.0%) (HR 0.52, 95% CI 0.290.91; nominal P=0.0222). KM estimates for clinical stage 24 lower-GI aGVHD-free survival were 88.5% and 79.5%, respectively. By day +180 grade 24 aGVHD-free survival (per MAGIC criteria10, see Supplementary Table 4) also seemed to favor vedolizumab over placebo; KM estimates were 74.1% for vedolizumab and 63.3% for placebo, with events occurring in 43 (25.6%) and 59 (35.8%) patients, respectively (HR 0.67, 95% CI 0.450.99; nominal P=0.0421). Frequency of lower-GI aGVHD by maximum MAGIC grade were also reported for each treatment group, with corresponding values for maximum MAGIC grade of skin and liver aGVHD (Extended Data Table 2).

Progression-free survival in vedolizumab and placebo treatment groups by day +180 were 83.1% (95% CI 76.588.0) versus 77.6% (95% CI 70.483.3), respectively. Cumulative incidence of all relapse and death events for time to relapse (of the underlying malignancy) by day +180 were similar across treatment groups 10.9% (95% CI 6.716.2) for vedolizumab versus 10.6% (95% CI 6.416.0) for placebo (death as a competing risk; nominal P=0.9090). By day +180, there was no significant difference in relapse of the underlying malignancy between treatment groups, occurring in 18 (10.7%) patients from the vedolizumab group and 17 (10.3%) from the placebo group (HR 1.32, 95% CI 0.513.40; nominal P=0.9821; Extended Data Table 3).

Consistent results were obtained for primary and secondary efficacy end points when these were assessed as exploratory study end points 1 year after allo-HSCT (Extended Data Table 4). By day +365 after allo-HSCT, 21.4% of patients in the vedolizumab group and 33.9% in the placebo group had an event of lower-GI aGVHD or death (HR 0.53, 95% CI 0.350.81; nominal P=0.0041). KM estimates for lower-GI aGVHD-free survival 1 year after transplant were 78.1% for vedolizumab and 65.1% for placebo. Events of IBMTR grade CD aGVHD of any organ or death by day +365 occurred in 47 (28.0%) of patients in the vedolizumab group and 59 (35.8%) of patients in the placebo group (HR 0.68, 95% CI 0.461.00; nominal P=0.0709). Death without relapse occurred in 15 patients (8.9%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.49, 95% CI 0.250.95; nominal P=0.0670). All-cause deaths by day +365 occurred in 28 patients (16.7%) in the vedolizumab group and 36 (21.8%) in the placebo group (HR 0.67, 95% CI 0.411.11; nominal P=0.1741). IBMTR grade BD aGVHD in any organ or death events occurred in 69 patients (41.1%) in the vedolizumab group and 82 (49.7%) in the placebo group (HR 0.71, 95% CI 0.520.99; nominal P=0.0534). Incidence of relapse of the underlying malignancy at day +365 was also comparable between treatment groups occurring in 19.6% of patients in the vedolizumab group versus 13.3% for placebo (HR 2.13, 95% CI 0.974.65; nominal P=0.2097; Extended Data Table 4).

The safety analyses included 334 patients (169 patients in the vedolizumab group and 165 in the placebo group) who received 1 dose of study treatment and were assessed up to 18 weeks after the last dose of study treatment. Median (range) treatment exposure was 280.0 (127295) days for the vedolizumab group (mean (s.d.) of 5.4 (2.05) doses) and 278.0 (127296) days for the placebo group (mean 5.1 (2.25) doses). AEs of grade 3 or higher occurred in 92.3% of patients who received vedolizumab and 89.1% who received placebo (Table 3); the most frequent AEs of grade 3 or higher were anemia (29.6% versus 31.5%); neutropenia (31.4% versus 29.7%); febrile neutropenia (43.8% versus 42.4%); stomatitis (27.2% versus 26.7%); and decreased platelet count (21.9% versus 24.8%). Serious AEs occurred in 120 patients (71.0%) who received vedolizumab and 114 (69.1%) who received placebo (Extended Data Table 5). AEs led to treatment discontinuation in 44 (26.0%) versus 51 patients (30.9%) (Extended Data Table 6).

Table 3 lists serious infections among other AEs (serious and non-serious) prespecified as being of special interest (AESIs) in the study. Occurrence of post-transplant lymphoproliferative disease and Clostridioides infections are also reported in Table 3. AESIs included cytomegalovirus (CMV) colitis, which was reported in one patient from each treatment group (0.6% of patients in vedolizumab group 0.6% in the placebo group). Overall, CMV reactivation was reported in 23.7% of patients in the vedolizumab group and 18.2% in the placebo group. Most of the CMV reactivation events were grade 1 to grade 2 and none was above grade 3. The proportions of patients with grade 3 CMV reactivation were similar in both treatment groups. CMV infections were analyzed in subgroups of patients who received ATG prophylaxis or not (Supplementary Table 9). For those receiving ATG, grade 3 CMV infections occurred in seven patients (4.1%) in the vedolizumab group and six patients (3.6%) in the placebo group and serious CMV infections in seven (4.1%) versus three patients (1.8%), respectively. For patients treated without ATG, the frequency of grade 3 CMV infections was numerically lower in vedolizumab-treated versus placebo-treated patients (1 (0.6%) versus 3 (1.8%), respectively), one patient in the vedolizumab treatment group had a serious CMV infection. Other serious infections (excluding CMV colitis) occurred in 125 (74.0%) of patients receiving vedolizumab versus 111 (67.3%) receiving placebo. These are listed by infection type (Extended Data Table 7). The most common serious infections were CMV reactivation (23.7% versus 18.2%); pneumonia (7.7% versus 8.5%); sepsis (5.3% versus 7.3%); and bacteremia (4.7% versus 5.5%) (Table 3). Serious abdominal and GI infections occurred in eight patients receiving vedolizumab (4.7%) and three receiving placebo (1.8%). Clostridioides infections occurred in 14 (8.3%) patients in the vedolizumab treatment group and six (3.6%) patients in placebo treatment group; of these 2.4% of patients in each treatment group had Clostridioides colitis (C.difficile colitis or Clostridioides colitis). For safety end points, statistical analyses were not adequately powered for comparisons between treatment groups. There were five patients with an AE of human polyomavirus infection; none of these was diagnosed as progressive multifocal leukoencephalopathy (PML). One patient with AML relapse and subsequent additional therapy developed PML, with a fatal outcome ~6 months after the last dose of vedolizumab. An independent adjudication committee deemed the most probable cause of this event to be the immunosuppressive treatment for AML. Secondary malignancies occurred in seven patients (4.1%) in the vedolizumab group and 16 (9.7%) in the placebo group. Post-transplant lymphoproliferative disease occurred in three patients (1.8%) in the placebo group only (Table 3).

Overall, 48 patients died during the period from first dose of study treatment to 18 weeks after last dose: 21 (12.4%) in the vedolizumab group and 27 (16.4%) in the placebo group. Leading causes of death were multiple organ dysfunction syndrome (3.0% versus 1.8%); AML recurrence (0.6% versus 2.4%); respiratory failure (1.8% versus 1.2%); pneumonia (1.2% versus 1.2%); and sepsis (0.0% versus 1.8%). Intestinal aGVHD was listed as cause of death in 0.0% versus 1.2% patients, aGVHD in liver (0.6% versus 0.6%) and aGVHD (0.6% versus 0.0%). An additional 17 patients died during the period from 18 weeks post-treatment to 12 months after HSCT: eight in the vedolizumab group and nine in the placebo group (Extended Data Table 8).

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Pilot Study in JNCCN Explores New Approach for Reducing Anxiety and Improving Quality of Life after Stem Cell … – PR Newswire

Researchers at Brigham and Women's Hospital and Dana-Farber Cancer Institute found significant uptake and scalability in phone-based "PATH" intervention to improve psychological well-being in blood cancer patients.

PLYMOUTH MEETING, Pa., June 11, 2024 /PRNewswire/ -- New research in the June 2024 issue of JNCCNJournal of the National Comprehensive Cancer Networkhighlights a promising approach for alleviating distress, enhancing quality of life, improving physical function, and reducing fatigue in patients with blood cancers who undergo hematopoietic stem cell transplantation (HSCT). The study used a randomized clinical trial to evaluate the feasibility of a nine-week, phone-delivered, positive psychology program called Positive Affect for the Transplantation of Hematopoietic stem cells intervention (PATH), that was specifically tailored to the needs of this population. The findings indicate that the PATH intervention is both feasible and well-received by this patient population, as most of the patients (91%) who received the PATH intervention completed all of the intervention sessions and found them easy and helpful.

"The active identification and treatment of psychological distress, like anxiety, in patients with cancer are crucial."

"Having 9 out of 10 people complete all the sessions is great," explained lead researcherHermioni L. Amonoo, MD, MPP, MPH, Brigham and Women's Hospital/Dana-Farber Cancer Institute. "We designed PATH with the needs of HSCT survivors in mind. First, PATH is accessible to patients, as they can learn the skills and engage with the intervention over phone from wherever they areeliminating the need to travel to the cancer center. Second, the weekly exercises can be completed by patients at their convenience using the PATH manual, which guides patients on how to use the exercises and skills. This means that the actual phone sessions only last 15-20 minutes, in contrast to other well-established psychotherapies like cognitive behavioral therapy, which typically last 60-90 minutes per session. Third, we carefully curated the intervention sessions based on which activities patients can safely engage in while their immune system recovers following the transplant. For instance, unlike in other medical populations, we did not include exercises that focus on community service, which might unnecessarily expose patients to risks."

The pilot study was conducted at the Brigham and Women's Hospital/Dana-Farber Cancer Institute from August 2021 to August 2022. A total of 70 adult patients with blood cancers who have received HSCT, were randomized into two groups, with the intervention beginning about 100 days after HSCT. Those randomized into the PATH arm participated in a variety of weekly positive psychology exercises focused on gratitude, personal strengths, and meaning. Not only was participation high94% completed at least six of the nine sessions and 91% completed all ninethe intervention had promising effects on patient-reported outcomes immediately after completion of the program and again at week 18.

Dr. Amonoo added: "Cancer care providers should consider the potential benefits of psychosocial resources and interventions like PATH that focus on enriching positive emotions to bolster their patients' well-being. While the active identification and treatment of psychological distress, like anxiety, in patients with cancer are crucial, encouraging patients to engage in simple, structured, and systematic exercises aimed at fostering positive thoughts and emotions, such as gratitude, has the potential to enhance well-being as well."

"This positive psychology intervention highlights the importance of not only screening for distress but the promise of creating mechanisms that enhance well-being and reduce distress in our patients," commented Jessica Vanderlan, PhD, Manager, Siteman Psychology Service, Licensed Clinical Psychologist, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Vice Chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Panel for Distress Managementwho was not involved in this research. "Development of clinical interventions that are brief (15-20 minutes) and delivered by phone could greatly improve patient access to care. This type of accessibility is important in an oncology population, especially in acute recovery periods with many competing demands and physical symptoms."

To read the entire study, visit JNCCN.org. Complimentary access to "A Positive Psychology Intervention in Allogeneic Hematopoietic Stem Cell Transplantation Survivors (PATH): A Pilot Randomized Clinical Trial" is available until September 10, 2024.

AboutJNCCNJournal of the National Comprehensive Cancer Network More than 25,000 oncologists and other cancer care professionals across the United States readJNCCNJournal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about innovation in translational medicine, and scientific studies related to oncology health services research, including quality care and value, bioethics, comparative and cost effectiveness, public policy, and interventional research on supportive care and survivorship.JNCCNfeatures updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care.JNCCNis published by Harborside/BroadcastMed. VisitJNCCN.org. To inquire if you are eligible for aFREEsubscription toJNCCN, visitNCCN.org/jnccn/subscribe. Follow JNCCN at x.com/JNCCN.

About the National Comprehensive Cancer NetworkThe National Comprehensive Cancer Network (NCCN) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, equitable, and accessible cancer care so all patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation. NCCN also advances continuing education, global initiatives, policy, and research collaboration and publication in oncology. Visit NCCN.org for more information.

Media Contact:Rachel Darwin267-622-6624[emailprotected]

SOURCE National Comprehensive Cancer Network

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Maturation of human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) on polycaprolactone and … – Nature.com

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Original post:
Maturation of human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) on polycaprolactone and ... - Nature.com

iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric … – Nature.com

Reprogramming of PBMCs into iPSCs

iPSC lines were generated as previously described [34, 35]. Briefly, peripheral blood mononuclear cells (PBMCs) were isolated from the blood of 3 healthy individuals as well as from 3 AD patients after obtaining informed consent under the oversight of the Johns Hopkins Institutional Review Board. All samples except for AD_2 and AD_3 were obtained through the Johns Hopkins Alzheimers Disease Research Center (ADRC). PBMCs from patients AD_2 and AD_3 are from the ongoing Escitalopram for agitation in Alzheimers disease (S-CitAD) clinical trial (NCT03108846) [33]. PBMCs were expanded in culture, enriched for erythroblasts, and subsequently electroporated for the delivery of episomal vectors MOS, MMK and GBX (Addgene) using a 4DNucleofector (Lonza) according to the manufacturers instructions. After transfection, cells were transferred onto tissue culture plates coated with vitronectin (VTN) in DMEM with 10% FBS (v/v) and supplemented with 5ng/mL of bone morphogenetic protein4 (BMP4). The following day and thereafter, the medium was replaced with xeno-free and feeder-free Essential 8TM medium (E8, ThermoScientific). Between day 13 and 15 of reprogramming, cells presenting the TRA160 pluripotency marker were isolated from the newly generated iPSC colonies using the MACSTM MicroBeads magnetic beads (Miltenyi Biotec). Generated iPSC lines were kept in culture in E8 medium on VTN-coated plates for more than 12 passages before being characterized and used for experiments. For characterization, immunocytochemistry (ICC, see 2.7 below) was performed to check for the presence of multiple pluripotency markers (OCT4, NANOG and TRA-1-60). The iPSC lines underwent flow cytometric analysis to further validate the presence of TRA-1-60 (see 2.4 below).

Human iPSC lines were differentiated into serotonergic (5-HT) neurons by activating WNT and SHH signaling in a 3D in vitro platform [32, 36, 37]. Briefly, to better mimic brain development, the iPSCs were first used to form embryoid bodies (EBs). Induced PSCs were first centrifuged (200 x g, 1min) to form aggregates in ultra-low attachment, round-bottom 96-wells-plates (5000 cells/well, 50L/well) in mTeSRTM medium supplemented with the selective ROCK inhibitor y-27632 (Tocris) on day 0. Starting on the following day, the EBs were cultured to differentiate into neural precursors cells (NPCs) specific to the hindbrain over the course of 3 weeks using serotonergic NPC medium (SNm, see TableS1 in the supplementary information for the full composition). On day 1, 50L of SNm with double the amount of trophic factors were carefully added to start diluting out the mTeSR. On days 2 and 3, 50L of SNm was added to the differentiating EBs. Having reached 200L, 50% (100L) of SNm medium was exchanged daily until day 21. After the 3 initial weeks, growing NPC organoids were transferred to 6-wells-plates (8 NPC-organoids/well, 2mL/well), and they were grown in neural differentiation medium (NDm, see TableS1). NDm was exchanged every 3 days. While in the 6-wells-plates, the organoids were kept on an orbital shaker (ThermoFisher, orbital diameter: 22cm, 50rpm). Hindbrain organoids containing serotonergic neurons (5-HT-organoids) were ready for characterization and experiments after 6 weeks.

In order to evaluate morphological changes of the organoids over time, brightfield images (BF) were taken using an EVOS M5000 microscope (Invitrogen) daily for the first 21 days, then every 3 days until day 42, concurrent with medium changes time points. For the quantification of the area and circularity of the organoids, we developed an in-house algorithm using Python (the full code is available as an open resource on github [38]). Briefly, the images are treated by the code as gray-scale images ranging from 0255 of intensity values. The organoids are segmented using Felzenswalb algorithm [39] with a previous Gaussian smoothing of the images with a 6 pixels size standard deviation kernel. We enforced a minimum size of 3 pixels for the segmentation. In the next step, to improve the results of the segmentation, we manually set a threshold to differentiate background from organoids to 90 (intensity values). Once the segmentation was performed, the code selects the largest region, excluding background, as a binary mask delimiting the organoid. Finally, the area (A) is then computed integrating the pixels inside the mask. To determine the perimeter (P) of the organoid, we computed the integral of the magnitude of the gradient of the binary mask delimiting the organoid [40]. The circularity (C) or roundness of the organoid can be defined from the area and the perimeter as:

$$C=frac{4pi A}{{P}^{2}}$$

(1)

The more round-like the shape, the closest it can approach the maximum of C=1, whereas C values smaller than 1 are indicative of non-circular shapes. The values of the area and perimeter are converted from pixel units to mm using a scale bar given by the microscope, the circularity is adimensional. Representative images of segmentation results are found in FigureS1 (supplementary information).

To evaluate the successful reprogramming of PBMCs into iPSCs, cells were dissociated into singlecell suspensions with TrypLETM (Life Technologies). They were then washed and resuspended in PBS with 1% BSA (wt/v). They were labeled with the primary antibody antihuman TRA160 (Millipore). For the subsequent detection, iPSCs were labeled with secondary antimouse IgMAlexaFluor555 (Thermo Scientific) antibody.

To compare iPSCs and the 5-HT-organoids they were differentiated into, iPSCs and 5-HT-organoids were dissociated with TrypLETM and Gentle cell dissociation reagent (STEM cells technologies) respectively. Cells were washed and resuspended in PBS with 1% BSA (wt/v), following which they were fixed and permeabilized with Cytofix/Cytoperm solution (BD Biosciencence) according to manufacturers instructions. Samples were subsequently labeled using AlexaFluor488 conjugated anti-human TUJ1 and AlexaFluor647 conjugated anti-human TPH2 antibodies (ThermoScientific). The former is a general neuronal marker, whereas the latter is specific for serotonergic neurons.

All samples were analyzed on a BD LRS Fortessa (BD Biosciences) or on a SH800S cell sorter (SONY Biotechnology). The data was processed using FlowJoTM v10.8.1 software. A full list of the antibodies used for flow cytometry and ICC is available in TableS2 in the SI.

To evaluate the differentiation of iPSCs into 5-HT-organoids, quantitative reverse transcription PCR (qRT-PCR) analysis was performed. Messenger RNA (mRNA) was extracted from cellular pellets of iPSCs and 5-HT-organoids using RNA extraction kit (Zymo research), and it was transcribed into complementary DNA (cDNA) by reverse transcriptase using the Superscript III kit (Invitrogen) following manufacturers instructions. The generated cDNAs were used as the template for the qPCR reaction with iTaq Universal SYBR Green (Biorad), which was performed with a CFX Connect thermal cycler (Biorad). The primers used were obtained from Integrated DNA technologies and they were for TRA-1-60 (iPSC marker), NKX2.2 (serotonergic NPC), LMXbI and TUJ1 (neurons), TPH2 and FEV (serotonergic neurons). All forward and reverse primer sequences (purchased from Integrated DNA Technologies) are listed in TableS3 (SI).

Hindbrain organoids were washed three times with D-PBS (pH 7.4) and placed in a 1.5mL centrifugation tube with 1.2mL of freshly prepared 4% (v/v) paraformaldehyde and left incubating for 18h at 4C. They were then washed for 10min with D-PBS with 0.1% (v/v) Tween20 (Sigma) 3 times. For cryoprotection, the organoids were placed in 30% (wt/v) sucrose in D-PBS and left to equilibrate at 4C until they did not float in it anymore (ca. 4h, but it can vary depending on organoid size and density). The organoids were then transferred to an embedding mold which was carefully filled with O.C.T. compound embedding matrix (ThermoFisher). Snap freezing was done by submerging the molds with the embedded organoids in a slurry of dry ice added to 96% ethanol. The frozen organoids were then stored at 80C before being sectioned in 10m slices at the Johns Hopkins University SOM Microscopy facility.

Evaluation of pluripotency markers by ICC on adherent human iPSCs was performed as previously described [35]. Briefly, adherent iPSCs in 12-well plates were washed in PBS and fixed with 4% (v/v) paraformaldehyde in PBS (pH 7.4) for 15min, and permeabilized with Triton X-100 (0.1%, v/v in PBS). To limit non-specific binding, cells were blocked in 10% goat serum (v/v in PBS) for 1h at 4C. They were then stained with either one of the primary antibodies for pluripotency markers, i.e., anti-human TRA-1-60, NANOG andOCT4 at 4Covernight. Cells were subsequently washed with PBS, and they were then incubated with the appropriate secondary antibody for 1h at 4C. In the final step, cells were washed with PBS three times, and then stained with DAPI to visualize the nuclei.

Cryo-preserved and sectioned 5-HT-organoids were similarly stained for ICC to confirm the presence of neuronal marker TUJ1, serotonin (5-HT), and neural progenitor cells (NPCs) markers Nestin and NKX2.2 (necessary to determine serotonergic fate) [41]. Confocal fluorescence imaging was performed with a Leica SP8 inverted microscope (DMi8CEL), and the images were analyzed with a Leica LAS X software.

A full list of the antibodies used for flow cytometry and ICC is available in TableS3 in the SI.

Levels of 5-HT present in the extracellular supernatant were measured by enzyme-linked immunosorbent assay (ELISA) using the Serotonin ELISA kit (Enzo Life Sciences) according to the manufacturers instructions. To test the effect of the SSRI escitalopram oxalate, 10 and 100M of the drug were added to NDm and incubated with the eight 5-HT organoids for 1h prior to repeat measurement of supernatant 5-HT. The concentration range was initially chosen based on prior literature [36]; a metabolic activity assay was performed to ensure that the used concentrations were not toxic in our systems (see FigureS3 in the supplementary information).

All experiments were performed in at least 3 biologically independent replicates (n), and at least 36 technical repeats (N) unless stated otherwise. The results are presented as meanstandard deviation (SD). One-way ANOVA test, followed by Tukeys Honest Significant Difference test, was performed to pairwise evaluate if there were statistically significant mean differences between groups for Fig.6bd. The results were displayed using GraphPad Prism version 9.0.0 (121) for Windows, GraphPad Software, San Diego, California USA, http://www.graphpad.com. Statistically significant results are indicated with their respective p-values and asterisks as follows: p0.05 (*), p0.01 (**) or p0.001 (***).

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iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric ... - Nature.com

A cell therapy to heal a broken heart – Drug Discovery News

For many people, surviving a heart attack is just the beginning. Within minutes after one or more areas of the heart stop receiving oxygen, cardiac muscle cells begin to die. Given the limited regeneration potential of the heart, its response to this destruction is to replace the lost cells with scar tissue.

Matthieu de Kalbermatten, CEO of CellProthera, said that their product, ProtheraCytes, mimics one of the natural responses of the body after heart attack by mobilizing progenitor blood CD34+ stem cells towards the cardiac tissue.

Credit: Studio Chlorophylle

This scar is just there to save the patient, said Matthieu de Kalbermatten, chief executive officer of the biotechnological company CellProthera. The heart wont pump blood as efficiently as before, and if the damage is severe, it can result in chronic heart failure. The [organ] becomes weaker and weaker, [leading to] a high mortality after three to five years, plus bad quality of life, he explained.

Drugs and therapies prescribed after a heart attack may improve patient survival rates, but they do not repair the injured cardiac tissue, said de Kalbermatten. His team at CellProthera aims to prevent this long-term damage by injecting patients with their own, lab-expanded, stem cells.

The promise of this cell therapy, called ProtheraCytes, is to intervene early within a month after the heart attack and inject these cells in the hope that they will help regenerate the tissue, reducing the scar area and regaining partial heart function.

The researchers at CellProthera focus their efforts on the regenerative potential of CD34+ stem cells, which give rise to all types of blood cells in the body as well as the endothelial cells that line the insides of blood vessels. Since the early 2000s, studies have shown that CD34+ cells mobilize from the bone marrow into peripheral blood circulation shortly after a heart attack (1,2). These observations suggest that the human body naturally calls for these cells to come and help after such an event, but de Kalbermatten hypothesized that the migration might not be sufficient to heal after a severe heart attack. With Protheracytes, he said, We are trying to mimic [this] natural phenomenon, but just making it bigger and stronger.

To achieve this goal, the team first obtains CD34+ cells from the patient a few weeks to a month after the heart attack. After administering a growth factor to the patient to stimulate the bone marrows production of these cells, doctors take a blood draw from the patient and isolate the CD34+ cells. The team use their own cell expansion protocol and technology for in vitro proliferation to increase the number of these cells. Finally, nine days after the blood draw, there is a CD34+ suspension ready to be injected back into the patient, de Kalbermatten said. The cells are maintained fresh during that period. He noted, We dont freeze them. Keeping the cells fresh allows for higher cell viability and potency, he explained.

A doctor then injects the stem cell suspension via a catheter directly into the left ventricle muscle wall of the patient. CellProthera partnered with the biotech company BioCardia, which designed a specialized catheter known as the Helix Transendocardial Biotherapeutic Delivery System. The goal was to deliver therapeutic agents cells, genes, or proteins directly into the heart muscle to offer better results than injecting them into the coronary arteries, while also avoiding cardiac surgery, explained Peter Altman, chief executive officer of BioCardia.

Injecting them into the myocardium as opposed to just sending them down the capillaries [might be] better, concurred Robb MacLellan, a practicing cardiologist and physician scientist studying regenerative therapies at the University of Washington who is not associated with CellProthera or BioCardia. With gene therapy, doing that leads to better delivery amounts.

Using a patients own cells for transplant comes with advantages and disadvantages. The alternative option, an allogeneic transplant, might be more efficient since the production of cells does not rely on the patient, and cell quantities may be less limited. Yet, using foreign cells poses rejection risks.

We are trying to mimic [this] natural phenomenon, but just making it bigger and stronger. - Matthieu de Kalbermatten, CellProthera

Autologous transplantation, on the other hand, is very safe, de Kalbermatten said. Since cells are from the patient, rejection is unlikely, and there is no need for immunosuppressive drugs. However, using the patients own cells has other requirements, such as a well-designed logistic bench-to-bedside process. We have developed a technology that is totally automated, he said. You take a kit; you take the blood; you put it in the machine; you get a product. That standardization also reduces costs, he added.

The benefits from the therapy do not rely on the stem cells differentiating into cardiomyocytes, but the secretion of factors makes the difference. The release of these factors may modulate endogenous repair processes (3). Its the beauty about the cell as a drug, because the cell is a small factory that is able to react to the environment, de Kalbermatten said.

This idea that cells can impact scar formation and scar resolution has been around for decades ... in cardiology, said MacLellan. Yet, he noted that while researchers have tried to use cell therapies to modulate the healing process post injury in the heart and other organs, none of them have translated into standard of care.

Translating preclinical studies of stem cell therapies to successful clinical trials to treat acute myocardial infarction has proved challenging. One reason for this is the lack of rigor and standardized protocols in many preclinical studies (4).

The various drugs beta blockers, angiotensin-converting enzyme (ACE) inhibitors, aspirin administered to patients after a heart attack may also account for this difference, said MacLellan. If you get on that cocktail of medicines, your prognosis is then very good, he said. That has really frustrated these cell therapy trials, he added. [Most] preclinical trials never use the same medication background that we use in patients. Researchers need to prove that cell therapies add to these existing therapies, and thats a high bar, he added.

Differences in the delivery methods between animal and human cell therapy protocols may also explain the inconsistencies between preclinical and clinical outcomes for acute myocardial infarction. Researchers often deliver the cells surgically into the heart muscle in small animal models, while for humans, they mostly use catheters that go into the coronary arteries. Using the BioCardia Helix catheter may help bring cell therapies in humans closer to achieving the positive results reported in preclinical studies, according to Altman.

Once the stem cell suspension is ready, scientists at CellProthera ship it from the manufacturing site to the clinical site where doctors prepare the patient for the cell injection.

Credit: CellProthera

In addition to the delivery system, MacLellan acknowledged that ProtheraCytes has two more primary differences that stand out from what researchers have previously done, namely, the process for obtaining and expanding the CD34+ cells and the timing of the infusion.

CellProthera is currently conducting a clinical trial to reveal whether these variations in their protocol result in more successful clinical translation than previous attempts. Already in the 2000s, the founder of CellProthera, Philippe Henon, led a pilot study on seven patients who had suffered a severe heart attack. That first trial was nonrandomized, and the surgeons injected the cells directly into the cardiac tissue by open heart surgery, explained de Kalbermatten. The outcome for six of the patients was promising. Thats why we decided to start this adventure.

Now, the teams Phase 1/2b randomized clinical trial evaluates the safety and efficacy of their therapy in 33 patients. For assessing the efficacy, they use primarily magnetic resonance imaging (MRI). This is the most precise imaging system that you can have these days, said de Kalbermatten. They compare, for instance, visible damage after the heart attack versus six months after injection of ProtheraCytes. The aim is to determine whether the therapy reduces the area in the heart that became nonviable after the heart attack. The interim data based on this parameter is already very compelling, said de Kalbermatten. The team also measures other markers that are predictive of the future outcome of the disease, he added.

Completing this assessment will provide enough information to potentially advance to the next stage and design a Phase 3 trial. In this study, they plan to assess survival rate and hospitalization for worsening heart failure.

There is a lot of history to overcome in this field, MacLellan said, but he is optimistic about the future. The scientific community may be emerging from the period of disappointment regarding cell therapies, he suggested, and well-designed randomized controlled trials will add important information about their value.

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A cell therapy to heal a broken heart - Drug Discovery News

Results From Phase II Trial Suggest Stem Cell Treatment May Improve Certain Symptoms of Multiple Sclerosis – Managed Healthcare Executive

Researchers led by Saud A. Sadiq, M.D., director and chief research scientist of the Tisch Multiple Sclerosis Research Center of New York, completed a phase 2 clinical trial investigating the use of autologous stem cell-derived neural progenitors as a treatment option in patients with progressive forms of multiple sclerosis (MS).

The study results were published last month in Stem Cell Research & Therapy.

The National Multiple Sclerosis Society provided $1 million in partial funding for the trial.

The study included 54 patients with secondary-progressive or primary-progressive MS and an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5. EDSS scores range from 0 to 10, with larger numbers indicating a greater level of disability.

Participants were randomized to receive autologous bone marrow mesenchymal stem cell (MSC)-derived neural progenitors (MSC-NP) or saline by intrathecal injection. MSC-NPs are a type of MSCs that have an enhanced expression of neural and cell signaling genes.

Half of the participants received MSC-NP injections every two months for one year, and the other half received saline injections. The two groups were switched during the second year, so each participant received the study treatment for one year.

The primary study outcome was improvement in the EDSS Plus score. This is a composite score of the EDSS scale, timed 25-foot walk, and nine-hole peg test, which measures upper limb function.

The study did not meet the primary endpoint.

However, the researchers noted that some secondary outcomes were achieved. These included improvements in bladder function and the six-minute walk test.

The participants in the MSC-NP groups also had reduced brain gray matter atrophy and changes in biomarkers that indicated a potential for reduced inflammation and tissue repair.

No serious adverse effects were reported.

The researchers concluded, Although the primary outcome of EDSS-based improvement was not met, the significant improvement in secondary walking outcomes addresses an unmet need in MS patients with progressive disability.

They added, [Intrathecal] MSC-NP injection was associated with improved bladder function which is a relevant quality of life issue in people with MS. In addition, we found indirect evidence of a neuroprotective effect as seen by brain MRI cortical gray matter volume changes.

Sadiq and his colleagues recommend further studies with endpoints measuring ambulatory abilities and optimal dosing of MSC-NPs.

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Results From Phase II Trial Suggest Stem Cell Treatment May Improve Certain Symptoms of Multiple Sclerosis - Managed Healthcare Executive

Purity, potency, and safety affordably in stem cell therapy – pharmaphorum

In a new episode of the pharmaphorum podcast, web editor Nicole Raleigh discusses stem cell therapy, and accessibility to and affordability of such treatment, with Rafael E Carazo Salas, founder and CEO of CellVoyant, an AI-first biotechnology company spun out from the University of Bristol.

From totipotent stem cells at conception, to pluripotent, multipotent, oligopotent, and unipotent stem cells by adulthood every disease essentially boils down to a dysfunction in the cells and tissues in organs, and cells should be the ideal therapy. Blood transfusions are a historic example, but in the modern concept, by harnessing stem cells, functional specialised cells can be used to alleviate, substitute, substitute, and repair the body.

Cell therapy will help heal the world, says Salas if only we will allow it to. From CAR-T for blood cancers to emerging research in stem cell therapy for diabetes, even for neurodegenerative diseases, stem cells are thought to offer potential hope for currently untreatable conditions, but there is a responsibility to do things right.

The UK is an academic powerhouse, globally recognised for its high level training and innovation and invention. Indeed, the UK is uniquely placed to spin out companies. Unlike the US, however, the attitude towards equity is only now changing in academic institutions in Britain, permitting a more inspiring innovation ecosystem that attracts talent.

Again, as Salas says, cell therapy could help heal the world but only if the costs permit accessibility. And thats where CellVoyant aims to come in, utilising predictive AI to select better cells, optimise targets, increase yield, accelerate processes, and lead to more affordable treatments that reach patients.

You can listen to episode 136a of thepharmaphorum podcastin the player below, download the episode to your computer, or find it - and subscribe to the rest of the series - iniTunes,Spotify,Google Podcasts,Amazon Music, andPodbean.

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Purity, potency, and safety affordably in stem cell therapy - pharmaphorum