scholarly journals Mesenchymal stem cell therapies for liver cirrhosis: MSCs as “conducting cells” for improvement of liver fibrosis and regeneration

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Atsunori Tsuchiya ◽  
Suguru Takeuchi ◽  
Takayuki Watanabe ◽  
Tomoaki Yoshida ◽  
Shunsuke Nojiri ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Liver Disease ◽  
Alternative Therapy ◽  
Culture Conditions ◽  
General Information ◽  
Study Data ◽  
Cell Therapies ◽  
Allogeneic Mscs ◽  
Umbilical Cord Tissue ◽  
Route Cost

Abstract Mesenchymal stem cells (MSCs) can be cultured relatively easily and can be obtained not only from the bone marrow, but also from medical waste such as adipose tissue and umbilical cord tissue. Because of its low antigenicity, allogeneic MSC injection is safe. MSCs have been evaluated in more than 900 clinical trials in a variety of fields, with more than 50 clinical trials related to liver diseases. Experiments have suggested that MSCs function as “conducting cells” to affect various “effective cells” such as T cells, B cells, and macrophages. Recent clinical trials have focused on allogeneic MSCs. Thus, studies are needed to determine the most effective cell source, culture conditions, cell numbers, administration frequency, administration route, cost, safety, and liver disease treatments. Recently, the functions of exosomes have gained attention, and cell-free therapy may become possible as an alternative therapy for liver disease. In this review, we introduce general information, mechanism, representative clinical study data, recently started or planned clinical trials, and possibility of cell-free therapy of MSCs.

scholarly journals Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001595
Author(s):  
Gerd R Burmester ◽  
Peter Nash ◽  
Bruce E Sands ◽  
Kim Papp ◽  
Lori Stockert ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ulcerative Colitis ◽  
Clinical Trials ◽  
Psoriatic Arthritis ◽  
Adverse Events ◽  
Special Interest ◽  
Phase 1 ◽  
Incidence Rates ◽  
Study Data ◽  
System Organ Class

ObjectivesTo analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.MethodsThe analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.Results13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.ConclusionsThe tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

Regulating Innovation in the Early Development of Cell Therapies

2020 ◽  
Author(s):  
Andrew R Exley ◽  
James McBlane
Keyword(s):  
Clinical Trials ◽  
Nk Cell ◽  
Genetic Manipulation ◽  
Clinical Trial Data ◽  
Cell Receptor ◽  
Mitigation Measures ◽  
Safety Testing ◽  
Cell Therapies ◽  
Commercial Use ◽  
Allogeneic Cell

Abstract Clinical need for paradigm shifts in efficacy and safety is driving the rapid and wide-ranging innovation in cell therapies for cancer beyond existing regulatory frameworks. Critical issues emerging during clinical trials frequently reflect unresolved elements of the regulation of innovation conundrum from earlier stages of development. We address this challenge using a global regulators’ perspective on the pre-clinical development of cell therapies, as a navigational aid to intended commercial use which maximises the clinical relevance of developmental data. We examine the implications of tumour targeting based on B cell, NK cell, conventional and unconventional T cell receptor domains; multiplex approaches; genetic manipulation strategies; and autologous versus allogeneic cell sources. We propose that detailed characterisation of both the cell source and final product is critical to optimising manufacture of individualised autologous or off the shelf allogeneic cell therapies, enabling product consistency to underpin extrapolation of clinical trial data to the expected commercial use. We highlight preclinical approaches to characterising target antigens including the Human Cell Atlas initiative, multi-dimensional cell culture, and safety testing against activated, proliferating or stressed control cells. Practical solutions are provided for preclinical toxicity studies when cell therapies target uniquely human tumour antigens, including illustrative mitigation measures for potential toxicity likely to support timely approval of first in human clinical trials. We recommend addressing the regulation of innovation conundrum through serial engagement between innovators and regulators early in the development of cell therapies for cancer, accelerating patient access whilst safeguarding against unacceptable toxicities.

scholarly journals Self-organization and culture of Mesenchymal Stem Cell spheroids in acoustic levitation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathan Jeger-Madiot ◽  
Lousineh Arakelian ◽  
Niclas Setterblad ◽  
Patrick Bruneval ◽  
Mauricio Hoyos ◽  
...  
Keyword(s):  
Cell Culture ◽  
3D Cell Culture ◽  
Culture Conditions ◽  
Acoustic Levitation ◽  
Cell Sheets ◽  
Cell Therapies ◽  
Cellular Models ◽  
Cell Spheroids

AbstractIn recent years, 3D cell culture models such as spheroid or organoid technologies have known important developments. Many studies have shown that 3D cultures exhibit better biomimetic properties compared to 2D cultures. These properties are important for in-vitro modeling systems, as well as for in-vivo cell therapies and tissue engineering approaches. A reliable use of 3D cellular models still requires standardized protocols with well-controlled and reproducible parameters. To address this challenge, a robust and scaffold-free approach is proposed, which relies on multi-trap acoustic levitation. This technology is successfully applied to Mesenchymal Stem Cells (MSCs) maintained in acoustic levitation over a 24-h period. During the culture, MSCs spontaneously self-organized from cell sheets to cell spheroids with a characteristic time of about 10 h. Each acoustofluidic chip could contain up to 30 spheroids in acoustic levitation and four chips could be ran in parallel, leading to the production of 120 spheroids per experiment. Various biological characterizations showed that the cells inside the spheroids were viable, maintained the expression of their cell surface markers and had a higher differentiation capacity compared to standard 2D culture conditions. These results open the path to long-time cell culture in acoustic levitation of cell sheets or spheroids for any type of cells.

scholarly journals Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1442
Author(s):  
Pau Vancells Lujan ◽  
Esther Viñas Esmel ◽  
Emilio Sacanella Meseguer
Keyword(s):  
Clinical Trials ◽  
Liver Disease ◽  
Critical Role ◽  
Dietary Treatment ◽  
Dietary Interventions ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Effective Form ◽  
Unhealthy Diet

NAFLD is the world’s most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.

What are the reciprocal influences of randomized clinical trials and the patient–psychiatrist relationship?

1999 ◽  
Vol 14 (2) ◽  
pp. 93-100
Author(s):  
J. Catteau ◽  
C. Cyran ◽  
R. Bordet ◽  
C.E. Thomas ◽  
B.A. Dupuis
Keyword(s):  
Clinical Trials ◽  
Depressive Disorders ◽  
Randomized Clinical Trials ◽  
Antidepressant Drugs ◽  
Antidepressant Medication ◽  
Study Data ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Clinical Trials ◽  
Reciprocal Influences

SummaryThe goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

scholarly journals Progenitor Cell Therapy for the Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Peter A. Walker ◽  
Matthew T. Harting ◽  
Shinil K. Shah ◽  
Mary-Clare Day ◽  
Ramy El Khoury ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Progenitor Cell ◽  
Neurological Injury ◽  
Cell Therapies ◽  
Potential Efficacy ◽  
Cord Injury

Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials.

scholarly journals Applicability of a Web-Based, Individualized Exercise Intervention in Patients With Liver Disease, Cystic Fibrosis, Esophageal Cancer, and Psychiatric Disorders: Process Evaluation of 4 Ongoing Clinical Trials (Preprint)

2017 ◽  
Author(s):  
Daniel Pfirrmann ◽  
Nils Haller ◽  
Yvonne Huber ◽  
Patrick Jung ◽  
Klaus Lieb ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cystic Fibrosis ◽  
Clinical Trials ◽  
Liver Disease ◽  
Activity Level ◽  
Daily Routine ◽  
Intervention Period ◽  
Web Based ◽  
Significant Change ◽  
Disease Specific

BACKGROUND In the primary and secondary prevention of civilization diseases, regular physical activity is recommended in international guidelines to improve disease-related symptoms, delay the progression of the disease, or to enhance postoperative outcomes. In the preoperative context, there has been a paradigm shift in favor of using preconditioning concepts before surgery. Web-based interventions seem an innovative and effective tool for delivering general information, individualized exercise recommendations, and peer support. OBJECTIVE Our first objective was to assess feasibility of our Web-based interventional concept and analyze similarities and differences in a sustained exercise implementation in different diseases. The second objective was to investigate the overall participants’ satisfaction with our Web-based concept. METHODS A total of 4 clinical trials are still being carried out, including patients with esophageal carcinoma scheduled for oncologic esophagectomy (internet-based perioperative exercise program, iPEP, study), nonalcoholic fatty liver disease (hepatic inflammation and physical performance in patients with nonalcoholic steatohepatitis, HELP, study), depression (exercise for depression, EXDEP, study), and cystic fibrosis (cystic fibrosis online mentoring for microbiome, exercise, and diet, COMMED, study). During the intervention period, the study population had access to the website with disease-specific content and a disease-specific discussion forum. All participants received weekly, individual tailored exercise recommendations from the sports therapist. The main outcome was the using behavior, which was obtained by investigating the log-in rate and duration. RESULTS A total of 20 participants (5 from each trial) were analyzed. During the intervention period, a regular contact and a consequent implementation of exercise prescription were easily achieved in all substudies. Across the 4 substudies, there was a significant decrease in log-in rates (P<.001) and log-in durations (P<.001) over time. A detailed view of the different studies shows a significant decrease in log-in rates and log-in durations in the HELP study (P=.004; P=.002) and iPEP study (P=.02; P=.001), whereas the EXDEP study (P=.58; P=.38) and COMMED study (P=.87; P=.56) showed no significant change over the 8-week intervention period. There was no significant change in physical activity within all studies (P=.31). Only in the HELP study, the physical activity level increased steadily over the period analyzed (P=.045). Overall, 17 participants (85%, 17/20) felt secure and were not scared of injury, with no major differences in the subtrials. CONCLUSIONS The universal use of the Web-based intervention appears to be applicable across the heterogonous collectives of our study patients with regard to age and disease. Although the development of physical activity shows only moderate improvements, flexible communication and tailored support could be easily integrated into patients’ daily routine. CLINICALTRIAL iPEP study: ClinicalTrials.gov NCT02478996; https://clinicaltrials.gov/ct2/show/NCT02478996 (Archived by WebCite at http://www.webcitation.org/6zL1UmHaW); HELP study: ClinicalTrials.gov NCT02526732; http://www.webcitation.org/6zJjX7d6K (Archived by WebCite at http://www.webcitation.org/6Nch4ldcL); EXDEP study: ClinicalTrials.gov NCT02874833; https://clinicaltrials.gov/ct2/show/NCT02874833 (Archived by WebCite at http://www.webcitation.org/6zJjj7FuA)

scholarly journals Somatostatin receptor radionuclide therapy in neuroendocrine tumors

2021 ◽  
Vol 28 (3) ◽  
pp. R81-R93
Author(s):  
Mintallah Haider ◽  
Satya Das ◽  
Taymeyah Al-Toubah ◽  
Eleonora Pelle ◽  
Ghassan El-Haddad ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Radionuclide Therapy ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Peptide Receptor Radionuclide Therapy ◽  
Study Data ◽  
Combination Therapies ◽  
Peptide Receptor ◽  
Therapeutic Landscape ◽  
Receptor Agonists And Antagonists

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

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