Bioengineering breakthroughs:The impact of stem cell models on advanced therapy medicinal product development

The burgeoning field of bioengineering has witnessed significant strides due to the advent of stem cell models,particularly in their application in advanced therapy medicinal products(ATMPs).In this review,we examine the multifaceted impact of these developments,emphasizing the potential of stem cell models to enhance the sophistication of ATMPs and to offer alternatives to animal testing.Stem cell-derived tissues are particularly promising because they can reshape the preclinical landscape by providing more physiologically relevant and ethically sound platforms for drug screening and disease modelling.We also discuss the critical challenges of reproducibility and accuracy in measurements to ensure the integrity and utility of stem cell models in research and application.Moreover,this review highlights the imperative of stem cell models to align with regulatory standards,ensuring using stem cells in ATMPs translates into safe and effective clinical therapies.With regulatory approval serving as a gateway to clinical adoption,the collaborative efforts between scientists and regulators are vital for the progression of stem cell applications from bench to bedside.We advocate for a balanced approach that nurtures innovation within the framework of rigorous validation and regulatory compliance,ensuring that stem cell-base solutions are maximized to promote public trust and patient health in ATMPs.

Advance in bone marrow derived cell therapy:CD31-expressing cells as next generation cardiovascular cell therapy

In the recent past,bone marrow(BM)-derived cells have been used to regenerate damaged cardiovascular tissues post myocardial infarction (MI).Recent clinical trials have shown controversial results in recovering damaged cardiac tissue. New progress has shown that the underlying mechanisms of cell-based therapy relies more heavily on humoral and paracrine effects rather than on new tissue generation.However,studies have also reported the potential of new endothelial cell generation from BM cells.Thus,efforts have been made to identify cells having higher humoral or therapeutic effects as well as their surface markers.Specifically, BM-derived CD31^+ cells were isolated by a surface marker and demonstrated high angio-vasculogenic effects. I will present recent advances in the therapeutic use of BM-derived cells and the usefulness of CD31^+ cells as a next generation cell therapy.

Identification of genes associated with gall bladder cell carcinogenesis:Implications in targeted therapy of gall bladder cancer

Gall bladder cancer(GBC)is becoming a very devastating form of hepatobiliary cancer in India.Every year new cases of GBC are quite high in India.Despite recent advanced multimodality treatment options,the survival of GBC patients is very low.If the disease is diagnosed at the advanced stage(with local nodal metastasis or distant metastasis)or surgical resection is inoperable,the prognosis of those patients is very poor.So,perspectives of targeted therapy are being taken.Targeted therapy includes hormone therapy,proteasome inhibitors,signal transduction and apoptosis inhibitors,angiogenesis inhibitors,and immunotherapeutic agents.One such signal transduction inhibitor is the specific short interfering RNA(siRNA)or short hairpin RNA(shRNA).For developing siRNAmediated therapy shRNA,although several preclinical studies to evaluate the efficacy of these key molecules have been performed using gall bladder cells,many more clinical trials are required.To date,many such genes have been identified.This review will discuss the recently identified genes associated with GBC and those that have implications in its treatment by siRNA or shRNA.

Effect of etoposide plus thalidomide as maintenance therapy on progression-free survival of elderly patients with advanced non-small cell lung cancer

Objective The aim of the study was to evaluate the efficacy and safety of etoposide plus thalidomide as maintenance therapy for elderly patients with advanced non-small cell lung cancer（NSCLC） without disease progression after first-line chemotherapy.Methods After four to six cycles of platinum-based first-line therapy, 64 elderly patients with advanced NSCLC without disease progression who were treated in the General Hospital of Shenyang Military Region（China） from 2014 to 2016 were enrolled in this study. According to the different maintenance treatment methods, patients were divided as having received etoposide plus thalidomide therapy（treatment group, n = 32） and best supportive care（control group, n = 32）. Disease control and progression-free survival（PFS） were compared between the two groups. Results The recent curative effect objective response rates of the treatment group and the control group were 31.3% and 3.1%, respectively, and the disease control rates were 71.9% and 31.3%, respectively. The Kaplan-Meier survival curves of the two groups were significantly different（χ2 = 26.532, P = 0.001）. The median PFS for the treatment group and control group was 6.0 months [95% confidence interval（CI） = 4.3–7.9 months] and 3.2 months（95% CI = 2.6–3.8 months）, respectively. The side effects in the treatment group included hematologic abnormalities, gastrointestinal toxicity, and impaired liver function, which were relieved after symptomatic support therapy and drug withdrawal.Conclusion Etoposide plus thalidomide as maintenance therapy is associated with a significantly longer PFS with tolerable toxicity for elderly patients with advanced NSCLC.AcknowledgementThe authors would like to thank Liu Zhongzheng for his technical assistance.

New era of personalized medicine:Advanced therapy medicinal products in Europe

Advanced therapy medicinal products are human medical therapies based on genes,cells,or tissues,and due to their characteristics,they offer new innovative opportunities for the treatment of diseases and injuries,especially for diseases beyond the reach of traditional approaches.These therapies are at the forefront of innovation and have historically been very controversial,although in the last decade they have gained prominence while the number of new advanced therapies has increased every year.In this regard,despite the controversy they may generate,they are expected to dominate the market in the coming decades.Technologies based on advanced therapies are the present and future of medicine and bring us closer to the long-awaited precision medicine.Here we review the field as it stands today,with a focus on the molecular mechanisms that guided the different advanced therapies approved by the European Medicines Agency,their current status,and their legal approval.

Design strategies,advances and future perspectives of colon-targeted delivery systems for the treatment of inflammatory bowel disease

Inflammatory bowel diseases(IBD)significantly contribute to high mortality globally and negatively affect patients’qualifications of life.The gastrointestinal tract has unique anatomical characteristics and physiological environment limitations.Moreover,certain natural or synthetic anti-inflammatory drugs are associated with poor targeting,low drug accumulation at the lesion site,and other side effects,hindering them from exerting their therapeutic effects.Colon-targeted drug delivery systems represent attractive alternatives as novel carriers for IBD treatment.This review mainly discusses the treatment status of IBD,obstacles to drug delivery,design strategies of colon-targeted delivery systems,and perspectives on the existing complementary therapies.Moreover,based on recent reports,we summarized the therapeutic mechanism of colon-targeted drug delivery.Finally,we addressed the challenges and future directions to facilitate the exploitation of advanced nanomedicine for IBD therapy.

Strategies and challenges in the treatment of chronic venous leg ulcers

Evaluating patients with chronic venous leg ulcers(CVLUs)is essential to find the underlying etiology.The basic tenets in managing CVLUs are to remove the etiological causes,to address systemic and metabolic conditions,to examine the ulcers and artery pulses,and to control wound infection with debridement and eliminating excessive pressure on the wound.The first-line treatments of CVLUs remain wound care,debridement,bed rest with leg elevation,and compression.Evidence to support the efficacy of silver-based dressings in healing CVLUs is unavailable.Hydrogen peroxide is harmful to the growth of granulation tissue in the wound.Surgery options include a high ligation with or without stripping or ablation of the GSVs depending on venous reflux or insufficiency.Yet,not all CVLUs are candidates for surgical treatment because of comorbidities.When standard care of wound for 4 wk failed to heal CVLUs effectively,use of advanced wound care should be considered based on the available evidence.Negative pressure wound therapy facilitates granulation tissue development,thereby helping closure of CVLUs.Autologous split-thickness skin grafting is still the gold standard approach to close huge CVLUs.Hair punch graft appears to have a better result than traditional hairless punch graft for CVLUs.Application of adipose tissue or placenta-derived mesenchymal stem cells is a promising therapy for wound healing.Autologous platelet-rich plasma provides an alternative strategy for surgery for safe and natural healing of the ulcer.The confirmative efficacy of current advanced ulcer therapies needs more robust evidence.

CLINICAL STUDY IN ACCELERATED HYPERFRACTIONATED IRRADIATION IN THE TREATMENT OF LOCAL ADVANCED NON-SMALL CELL LUNG CANCER

Objective To evaluate the effect of accelerated hyperfractionated irradiation (AHFJ) and conventional fractionated irradiation (CFI) for local advanced non- small cell lung cancer (NSCLC). Methods The patients of AI-IFJ group were irradiated to large-field target volume by a daily fraction of 2Gy, and small-field target volume by a daily fraction of 1Gy with more than 6h interval. The total dose of large-field target volume was SOGy/25Fx/SW and of small-field target volume was 7SGy/SOFx/5W. The patients in CFI group were irradiated by a daily fraction of 2Gy to the total dose of 66Gy/33Fx/6. 6W. After 3 months of radiotherapy, the tumor response rates of complete recovery (CR), partial recovery (PR), and no change (NC) and 1- and 2- year survival rate in the two groups were observed. Results The tumor response rates of CR,PR,NC in AHFI group and CFI group were 22.9%(8/35), 60.0%(21/35), 17.1%(6/35) and 11.4% (4/35), 51.4% (18/35), 37.2% (13/35) respectively (P>0. 05). All patients were followed up 2 years or more. The 1- and 2- year survival rates in AHFI group and CFI group were 62.9% (22/35), 31 .4% (11/35) and 42.9% (15/35) , 17.1% (6/35) respectively (P< 0.05). The incidences of esophagitis and pneumonitis in AHFI group and CFI group were 34.3% (12/35), 22. 9% (8/35) and 40.0% (14/35), 17.1% (6/35)(P>0. 05). Conclusion In comparison with CFI, AHFI may increase 1- and 2- year sur-vival rate after treatment of local advanced non-small cell lung cancer, while the radio-reactions, either early or late, did not increase significantly.

Research on the Regulatory Framework of Advanced Therapies in the European Union and the United States

Objective To study the regulatory framework of advanced therapies in the European Union and the United States,and to provide reference for the regulation of cell-and gene-based therapeutic products in China.Methods The legal and regulatory documents,annual reports,work information and related literature published on the websites of the FDA and European Medicines Agency(EMA)were reviewed to analyze the regulatory models of advanced therapies in the European Union and the United States.Results and Conclusion the United States and the European Union have carried out a lot of work in the classification standards of advanced therapies,policy formulation and accelerated listing procedures.Therefore,they have established a relatively mature regulatory system.China can learn from their experience and continuously improve the regulatory system to help the sustainable development of gene and cell therapy industry.

Special Nanoskin-ACT-Biological Membranes from Deep Wounds

Bacterial cellulose (BC) is established as a newest biomaterial, and it can be used for medical and odontology applications. In addition, it has called attention for uses such as membrane for wound care and tissue engineering. In this work, the bacterial cellulose fermentation process is modified by the addition of natural materials before the bacteria are inoculated. In vivo behavior using natural ECM for regenerative medicine is presented and completed wound healing process is 3 months.

To Explore the Chinese Medicine Syndrome Types and Integrative Therapy from Clinical Relative Factors of Patients with Advanced Prostate Cancer

Current Situation and Problems of the Treatment in Advanced Prostate Cancer In recent years,the incidence of prostate cancer shows a rising trend in China with an increase of 70%and has been the first place in the growth rate of malignant tumor in the male reproductive system. Prostate cancer has become a serious threat to male senior’s health.Because of the application of

Lymphocyte-to-monocyte ratio is a short-term predictive marker of ulcerative colitis after induction of advanced therapy

Advanced therapies for patients with mild-to-severe ulcerative colitis(UC)may result in treatment failure.We examined whether the lymphocyte-to-monocyte ratio(L/M ratio)could predict the failure of advanced therapies.This retrospective,observational,cohort study included 73 patients who were treated with advanced therapies at the Hamamatsu University School of Medicine(Shizuoka,Japan)between February 2011 and November 2020.The patients were divided into the nonfailure and failure groups,and their leukocyte counts and ratios before induction were examined.Univariate and multivariate analyses were performed to identify the prognostic factors.Advanced therapies failed within 3 months in 15(20.5%)patients.Only the L/M ratio was significantly lower in the failure group than in the non-failure group(P=0.004).Receiveroperating characteristic(ROC)curve analysis revealed that an L/M ratio of ≤3.417 was predictive of treatment failure;the area under the curve(AUC)was 0.747(95%CI,0.620–0.874).Kaplan–Meier analysis revealed that the failure-free rate was significantly lower in the group with an L/M ratio of≤3.417 than in the group with an L/M ratio of>3.417(log-rank test P=0.002).Cox proportional hazard regression analysis identified an L/M ratio of≤3.417 as an independent risk factor for failure within 3 months after the induction of advanced therapies.Furthermore,ROC analysis of patients who did not receive immunomodulators also revealed that the cut-off L/M ratio was 3.417 and the AUC was 0.796(95%CI,0.666–0.925).In patients receiving advanced therapies for active UC,the L/M ratio can predict treatment failure within 3 months.L/M ratios could facilitate the transition from advanced therapies to subsequent treatments.