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Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines.With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed. [ABSTRACT FROM AUTHOR]

We previously reported that the cell and colony motion of oral keratinocytes are correlated with proliferative capacity, and speculated that this may be a specific index for monitoring cell quality. However, how cell motility and proliferation are regulated by signaling pathways remains unelucidated. Here, we found that the regulation of cell motility and proliferative capacity of oral keratinocytes can be attributed to the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis. The EGFR downstream cascade involving the Src/PI3K/Akt/mTOR signaling pathway showed a major effect on cell motility and proliferative capacity in oral keratinocytes. Furthermore, both EGFR and Src attenuated E‐cadherin expression. Taken together, these findings provide a potential basis for future quality control of cells for therapeutic use. [ABSTRACT FROM AUTHOR]

Cells interact with their surrounding environment through a combination of static and dynamic mechanical signals that vary over stimulus types, intensity, space, and time. Compared to static mechanical signals such as stiffness, porosity, and topography, the current understanding on the effects of dynamic mechanical stimulations on cells remains limited, attributing to a lack of access to devices, the complexity of experimental set‐up, and data interpretation. Yet, in the pursuit of emerging translational applications (e.g., cell manufacturing for clinical treatment), it is crucial to understand how cells respond to a variety of dynamic forces that are omnipresent in vivo so that they can be exploited to enhance manufacturing and therapeutic outcomes. With a rising appreciation of the extracellular matrix (ECM) as a key regulator of biofunctions, researchers have bioengineered a suite of ECM‐mimicking hydrogels, which can be fine‐tuned with spatiotemporal mechanical cues to model complex static and dynamic mechanical profiles. This review first discusses how mechanical stimuli may impact different cellular components and the various mechanobiology pathways involved. Then, how hydrogels can be designed to incorporate static and dynamic mechanical parameters to influence cell behaviors are described. The Scopus database is also used to analyze the relative strength in evidence, ranging from strong to weak, based on number of published literatures, associated citations, and treatment significance. Additionally, the impacts of static and dynamic mechanical stimulations on clinically relevant cell types including mesenchymal stem cells, fibroblasts, and immune cells, are evaluated. The aim is to draw attention to the paucity of studies on the effects of dynamic mechanical stimuli on cells, as well as to highlight the potential of using a cocktail of various types and intensities of mechanical stimulations to influence cell fates (similar to the concept of biochemical cocktail to direct cell fate). It is envisioned that this progress report will inspire more exciting translational development of mechanoresponsive hydrogels for biomedical applications. [ABSTRACT FROM AUTHOR]

Recently, the randomized phase‐II Triton study demonstrated that mesenchymal stromal cell (MSC) therapy facilitated early tacrolimus withdrawal in living donor kidney transplant recipients. The current sub‐study analyzed formation of de novo donor‐specific HLA antibodies (dnDSA) in the context of the degree of HLA eplet mismatches. At the time of protocol biopsy at 6 months, 7/29 patients (24%) in the MSC group and 1/27 patient (3.7%) in the control group had developed dnDSA. In the MSC group, all dnDSA were anti‐HLA‐DQ; two patients had anti‐DQ alone and five patients combined with anti‐class I, HLA‐DR or ‐DP. Despite excess dnDSA formation in the MSC‐arm of the study, the evolution of eGFR (CKD‐EPI) and proteinuria were comparable 2 years posttransplant. All dnDSA were complement‐binding and three patients had antibody‐mediated rejection in the protocol biopsy, but overall rejection episodes were not increased. Everolimus had to be discontinued in nine patients because of toxicity, and tacrolimus was reintroduced in six patients because of dnDSA formation. The HLA‐DQ eplet mismatch load independently associated with dnDSA (adjusted hazard ratio = 1.07 per eplet mismatch, p = 0.008). A threshold of ≥11 HLA‐DQ eplet mismatches predicted subsequent dnDSA in all 11 patients in the MSC group, but specificity was low (44%). Further research is warranted to explore HLA molecular mismatch load as a biomarker to guide personalized maintenance immunosuppression in kidney transplantation. [ABSTRACT FROM AUTHOR]

Nonadherence is common in individuals with sickle cell disease (SCD) on hydroxyurea therapy and can be observed with waning improvements in hematologic parameters or biomarkers like mean cell volume and fetal hemoglobin level over time. We modeled the impact of hydroxyurea nonadherence on longitudinal biomarker profiles. We estimated the potential nonadherent days in individuals exhibiting a drop in biomarker levels by modifying the dosing profile using a probabilistic approach. Incorporating additional nonadherence using our approach besides existing ones in the dosing profile improves the model fits. We also studied how different patterns in adherence give rise to various physiological profiles of biomarkers. The key finding is consecutive days of nonadherence are less favorable than when nonadherence is interspersed. These findings improve our understanding of nonadherence and how appropriate intervention strategies can be applied for individuals with SCD susceptible to the severe impacts of nonadherence. [ABSTRACT FROM AUTHOR]

In an attempt to identify potent antitumor agents for the fight against non‐small cell lung cancer, new thiazolyl hydrazones (2a–n) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of the MTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2‐[2‐((Isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(4‐methylsulfonylphenyl)thiazole (2k) (IC50 = 1.43 ± 0.12 µM) and 2‐[2‐((isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(1,3‐benzodioxol‐5‐yl)thiazole (2l) (IC50 = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC50 = 3.90 ± 0.10 µM) on A549 cell lines; 2‐[2‐((isoquinolin‐5‐yl)methylene)hydrazinyl]−4‐(4‐methoxyphenyl)thiazole (2j) (IC50 = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC50 = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC50 = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC50 concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced‐fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell lines via Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways. [ABSTRACT FROM AUTHOR]

Summary: Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high‐throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD‐box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non‐malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene‐CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT). [ABSTRACT FROM AUTHOR]

Immunotherapy with anti‐PD1/PD‐L1 is effective in only a subgroup of patients with malignant pleural mesothelioma (MPM). We investigated the efficacy of a combination of anti‐PD1/PD‐L1 and dendritic cell (DC) therapy to optimally induce effective anti‐tumor immunity in MPM in both humans and mice. Data of nine MPM patients treated with DC therapy and sequential anti‐PD1 treatment were collected and analyzed for progression‐free survival (PFS) and overall survival (OS). Survival and T‐cell responses were monitored in AC29 mesothelioma‐bearing mice treated concurrently with the combination therapy; additionally, the role of the tumor‐draining lymph node (TDLN) was investigated. The combination therapy resulted in a median OS and PFS of 17.7 and 8.0 months, respectively. Grade 3 to 4 treatment‐related adverse events had not been reported. Survival of the mesothelioma‐bearing mice treated with the combination therapy was longer than that of untreated mice, and coincided with improved T‐cell activation in peripheral blood and less T‐cell exhaustion in end stage tumors. Comparable results were obtained when solely the TDLN was targeted. We concluded that this combination therapy is safe and shows promising OS and PFS. The murine data support that PD‐L1 treatment may reinvigorate the T‐cell responses induced by DC therapy, which may primarily be the result of TDLN targeting. [ABSTRACT FROM AUTHOR]

Background and Objectives: Serum eye drops (SEDs) are used to treat ocular surface disease (OSD) and to promote ocular surface renewal. However, their use and production are not standardized, and several new forms of human eye drops have been developed. Materials and Methods: The International Society for Blood Transfusion Working Party (ISBT WP) for Cellular Therapies held a workshop to review the current types of eye drops of human origin (EDHO) status and provide guidance. Results: The ISBT WP for Cellular Therapies introduced the new terminology 'EDHO' to emphasize that these products are analogous to 'medical products of human origin'. This concept encompasses their source (serum, platelet lysate, and cord blood) and the increasingly diverse spectrum of clinical usage in ophthalmology and the need for traceability. The workshop identified the wide variability in EDHO manufacturing, lack of harmonized quality and production standards, distribution issues, reimbursement schemes and regulations. EDHO use and efficacy is established for the treatment of OSD, especially for those refractory to conventional treatments. Conclusion: Production and distribution of single‐donor donations are cumbersome and complex. The workshop participants agreed that allogeneic EDHO have advantages over autologous EDHO although more data on clinical efficacy and safety are needed. Allogeneic EDHOs enable more efficient production and, when pooled, can provide enhanced standardization for clinical consistency, provided optimal margin of virus safety is ensured. Newer products, including platelet‐lysate‐ and cord‐blood‐derived EDHO, show promise and benefits over SED, but their safety and efficacy are yet to be fully established. This workshop highlighted the need for harmonization of EDHO standards and guidelines. [ABSTRACT FROM AUTHOR]

ABSTRACT Rotator cuff tendon tears are one of the most common shoulder pathologies, especially in the aging population. Due to a poor healing response and degenerative changes associated with aging, rotator cuff repair failure remains common. Although cell-based therapies to augment rotator cuff repair appear promising, it is unknown whether the success of such a therapy is age-dependent. We hypothesized that autologous cell therapy would improve tendon-to-bone healing across age groups, with autologous juvenile cells realizing the greatest benefit. In this study, juvenile, adult, and aged rats underwent bilateral supraspinatus tendon repair with augmentation of one shoulder with autologous tendon-derived cell-seeded polycaprolactone scaffolds. At 8 weeks, shoulders treated with cells in both juvenile and aged animals exhibited increased cellularity, increased collagen organization, and improved mechanical properties. No changes between treated and control limbs were seen in adult rats. These findings suggest that cell delivery during supraspinatus repair initiates earlier matrix remodeling in juvenile and aged animals. This may be due to the relative 'equilibrium' of adult tendon tissue with regards to catabolic and anabolic processes, contrasted with actively growing juvenile tendons and degenerative aged tendons. This study demonstrates the potential for autologous cell-seeded scaffolds to improve repairs in both the juvenile and aged population. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1250-1257, 2017. [ABSTRACT FROM AUTHOR]

Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest‐derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short‐chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome‐wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA‐mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short‐chain fatty acid metabolism‐induced MEK1/2 signaling. Synopsis: Fecal microbiota transplantation synergy with enteric neural crest‐derived cell transplantation is tested in a rat model of hypoganglianosis to provide a non‐surgical treatment option of neurocristopathies including Hirschsprung disease. The intestinal microenvironment in a rat model of hypoganglionosis negatively influences enteric neural crest‐derived cell (ENCC) proliferation and migrationFecal microbiota transplantation (FMT) relieves hypoganglionosis symptoms and promotes ENCC transplantation in vitro and vivo.Some genera, particularly Bacteroides and Clostridium, increased after FMT, which coincided with short‐chain fatty acid (SCFA) production.SCFA exposure stimulated ENCC proliferation, migration, and supported ENCC transplantation in the treatment of hypoganglionosis via the MEK1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Mobile delivery of apheresis services is an increasingly important component of health care equity, as patients should not have to transfer care providers or travel far distances to receive critical therapeutic apheresis procedures or cell therapy‐based treatments. Therefore, the availability of such services should be expanded. Study design and methods: In this "How Do I" article, we provide a detailed overview of the elements necessary to initiate and maintain a successful mobile apheresis service, including challenges and potential solutions. Results: Safe and efficient operation of a mobile apheresis service must consider acquisition of physical assets, such as apheresis sites, personnel, equipment and supplies, communication devices, and transportation vehicles, and optimize organizational aspects, such as staff responsibilities, service partnerships, logistics management, case scheduling and triage, and billing. In the era of cellular therapy, additional critical considerations include regulatory compliance and facility accreditation. Discussion: To our knowledge, no previous publication provides the extensive details described herein to set up and maintain a successful mobile apheresis service, and thus will be very helpful to those facilities wishing to initiate or expand mobile apheresis services. [ABSTRACT FROM AUTHOR]

Background: The shortage of donor organs for transplantation remains a worldwide problem. The utilization of suboptimal deceased donors enlarges the pool of potential organs, yet consequently, clinicians face the difficult decision of whether these sub‐optimal organs are of sufficient quality for transplantation. Novel technologies could play a pivotal role in making pre‐transplant organ assessment more objective and reliable. Methods: Ex vivo normothermic machine perfusion (NMP) at temperatures around 35–37°C allows organ quality assessment in a near‐physiological environment. Advanced magnetic resonance imaging (MRI) techniques convey unique information about an organ's structural and functional integrity. The concept of applying magnetic resonance imaging during renal normothermic machine perfusion is novel in both renal and radiological research and we have developed the first MRI‐compatible NMP setup for human‐sized kidneys. Results: We were able to obtain a detailed and real‐time view of ongoing processes inside renal grafts during ex vivo perfusion. This new technique can visualize structural abnormalities, quantify regional flow distribution, renal metabolism, and local oxygen availability, and track the distribution of ex vivo administered cellular therapy. Conclusion: This platform allows for advanced pre‐transplant organ assessment, provides a new realistic tool for studies into renal physiology and metabolism, and may facilitate therapeutic tracing of pharmacological and cellular interventions to an isolated kidney. [ABSTRACT FROM AUTHOR]

Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). B This article refers to 'Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction - the SCIENCE trial' by A.A. Qayyum I et al i ., published in this issue on pages 576-587. b The global pandemic of heart failure (HF) affected more than 64 million people worldwide in 2017,[1] severely reducing quality of life (QoL), causing multiple hospital readmissions and premature deaths, and resulting in overwhelming costs for healthcare systems. [Extracted from the article]

Immunoprotection and oxygen supply are vital in implementing a cell therapy for type 1 diabetes (T1D). Without these features, the transplanted islet cell clusters will be rejected by the host immune system, and necrosis will occur due to hypoxia. The use of anti‐rejection drugs can help protect the transplanted cells from the immune system; yet, they also may have severe side effects. Cell delivery systems (CDS) have been developed for islet transplantation to avoid using immunosuppressants. CDS provide physical barriers to reduce the immune response and chemical coatings to reduce host fibrotic reaction. In some CDS, there is architecture to support vascularization, which enhances oxygen exchange. In this review, we discuss the current clinical and preclinical studies using CDS without immunosuppression as a cell therapy for T1D. We find that though CDS have been demonstrated for their ability to support immunoisolation of the grafted cells, their functionality has not been fully optimized. Current advanced methods in clinical trials demonstrate the systems are partly functional, physically complicated to implement or inefficient. However, modifications are being made to overcome these issues. [ABSTRACT FROM AUTHOR]

Purpose: Despite substantial animal evidence, cell therapy in humans remains in its infancy. The purpose of this study was to examine the potential therapeutic effects and safety of cell therapy in the treatment of tendon disorders. Methods: According to the PRISMA guideline, a systematic review was performed on clinical studies concerning cell therapy in tendon disorders. A comprehensive search including the 5 databases of MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library until December 2021 was carried out and associated with hand searching. The quality of the eligible studies was assessed using the tools suggested by Cochrane recommendations. Qualitative synthesis was performed in 2 tables and discussed separately for rotator cuff, elbow, patella, Achilles, and gluteal tendons. Results: Through 6017 records, 22 studies were included in the qualitative synthesis, including 658 patients. All the studies administered autologous cells, except one that used allogenic adipose-derived mesenchymal stem cells (Allogenic AD-MSC). Almost all studies demonstrated the safety of cell injection in their follow-up period with no serious side effects or immunologic reactions, with only a few related minor adverse events in some cases. The included studies showed the effectiveness of cell injection in tendinopathies of different sites, rotator cuff, elbow, patella, Achilles, and gluteal tendons. Among the rotator cuff studies, 4 comparative studies claimed that cell therapy is a more efficient treatment with a lower retear rate and pain level compared to the control group. However, one study found no differences between the groups. No controlled study has been performed on elbow tendinopathies, but 5 case series demonstrated the effectiveness of cell injection in elbow tendon disorders. For Achilles tendinopathies, only one randomized controlled trial (RCT) found that both cell therapy and control groups showed significant pain reduction and functional improvement with no statistical differences at the 6 months follow-up, but the cell therapy group had improved faster at earlier follow-ups. Patellar tendinopathy was studied in 2 RCTs, one did not show a significant difference and the other showed superior improvement compared to controls. Conclusion: Cell therapy showed promising results and the available evidence suggests that it is safe at several sites of tendon disease. Based on available evidence, cell therapy should be suggested in specific conditions at each site. To approve cell therapy for tendon diseases, randomized clinical trials are required with a large sample size and long-term follow-ups. Level of evidence: IV [ABSTRACT FROM AUTHOR]

CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks. [ABSTRACT FROM AUTHOR]

The unlimited proliferative capacity of human pluripotent stem cells (hPSCs) fortifies it as one of the most attractive sources for cell therapy application in diabetes. In the past two decades, vast research efforts have been invested in developing strategies to differentiate hPSCs into clinically suitable insulin‐producing endocrine cells or functional beta cells (β cells). With the end goal being clinical translation, it is critical for hPSCs and insulin‐producing β cells to be derived, handled, stored, maintained and expanded with clinical compliance. This review focuses on the key processes and guidelines for clinical translation of human induced pluripotent stem cell (hiPSC)‐derived β cells for diabetes cell therapy. Here, we discuss the (1) key considerations of manufacturing clinical‐grade hiPSCs, (2) scale‐up and differentiation of clinical‐grade hiPSCs into β cells in clinically compliant conditions and (3) mandatory quality control and product release criteria necessitated by various regulatory bodies to approve the use of the cell‐based products. [ABSTRACT FROM AUTHOR]

Purpose: Advanced non‐small cell lung cancer (NSCLC) is still a challenging indication for conventional photon radiotherapy. Proton therapy has the potential to improve outcomes, but proton treatment slots remain a limited resource despite an increasing number of proton therapy facilities. This work investigates the potential benefits of optimally combined proton–photon therapy delivered using a fixed horizontal proton beam line in combination with a photon Linac, which could increase accessibility to proton therapy for such a patient cohort. Materials and methods: A treatment planning study has been conducted on a patient cohort of seven advanced NSCLC patients. Each patient had a planning computed tomography scan (CT) and multiple repeated CTs from three different days and for different breath‐holds on each day. Treatment plans for combined proton–photon therapy (CPPT) were calculated for individual patients by optimizing the combined cumulative dose on the initial planning CT only (non‐adapted) as well as on each daily CT respectively (adapted). The impact of inter‐fractional changes and/or breath‐hold variability was then assessed on the repeat breath‐hold CTs. Results were compared to plans for IMRT or IMPT alone, as well as against combined treatments assuming a proton gantry. Plan quality was assessed in terms of dosimetric, robustness and NTCP metrics. Results: Combined treatment plans improved plan quality compared to IMRT treatments, especially in regard to reductions of low and medium doses to organs at risk (OARs), which translated into lower NTCP estimates for three side effects. For most patients, combined treatments achieved results close to IMPT‐only plans. Inter‐fractional changes impact mainly the target coverage of combined and IMPT treatments, while OARs doses were less affected by these changes. With plan adaptation however, target coverage of combined treatments remained high even when taking variability between breath‐holds into account. Conclusions: Optimally combined proton‐photon plans improve treatment plan quality compared to IMRT only, potentially reducing the risk of toxicity while also allowing to potentially increase accessibility to proton therapy for NSCLC patients. [ABSTRACT FROM AUTHOR]

The timely management of skin wounds has been an unmet clinical need for centuries. While there have been several attempts to accelerate wound healing and reduce the cost of hospitalisation and the healthcare burden, there remains a lack of efficient and effective wound healing approaches. In this regard, stem cell‐based therapies have garnered an outstanding position for the treatment of both acute and chronic skin wounds. Stem cells of different origins (e.g., embryo‐derived stem cells) have been utilised for managing cutaneous lesions; specifically, mesenchymal stem cells (MSCs) isolated from foetal (umbilical cord) and adult (bone marrow) tissues paved the way to more satisfactory outcomes. Since angiogenesis plays a critical role in all four stages of normal wound healing, recent therapeutic approaches have focused on utilising stem cells for inducing neovascularisation. In fact, stem cells can promote angiogenesis via either differentiation into endothelial lineages or secreting pro‐angiogenic exosomes. Furthermore, particular conditions (e.g., hypoxic environments) can be applied in order to boost the pro‐angiogenic capability of stem cells before transplantation. For tissue engineering and regenerative medicine applications, stem cells can be combined with specific types of pro‐angiogenic biocompatible materials (e.g., bioactive glasses) to enhance the neovascularisation process and subsequently accelerate wound healing. As such, this review article summarises such efforts emphasising the bright future that is conceivable when using pro‐angiogenic stem cells for treating acute and chronic skin wounds. [ABSTRACT FROM AUTHOR]

We are going through the greatest global health crisis of the last decades, the coronavirus disease 2019 (COVID‐19) pandemic. It may cause morbidity and mortality in some cases, and there is no therapeutic approach with reproducible and favorable outcomes. As clinical manifestations differ from patient to patient, any report regarding clinical symptoms has been beneficial for early detection and treatment. Due to the immunomodulatory effect of mesenchymal stem cells (MSCs), MSCs‐based therapy has been approved to be one of the therapeutic strategies for COVID‐19 management. For the first time in the literature, we reported generalized lymphadenopathy with fever and no sign of respiratory distress in a 16‐year‐old patient with confirmed COVID‐19 infection as the main clinical signs. We also introduce decidual stromal cells as a potential immunomodulatory treatment for COVID‐19–infected patients. [ABSTRACT FROM AUTHOR]

Metabolic disorder is one of the hallmarks of cancers, and reprogramming of metabolism is becoming a novel strategy for cancer treatment. Citrate is a key metabolite and critical metabolic regulator linking glycolysis and lipid metabolism in cellular energy homeostasis. Here it is reported that citrate treatment (both sodium citrate and citric acid) significantly suppresses tumor cell proliferation and growth in various tumor types. Mechanistically, citrate promotes excessive lipid biosynthesis and induces disruption of lipid metabolism in tumor cells, resulting in tumor cell senescence and growth inhibition. Furthermore, ATM‐associated DNA damage response cooperates with MAPK and mTOR signaling pathways to control citrate‐induced tumor cell growth arrest and senescence. In vivo studies further demonstrate that citrate administration dramatically inhibits tumor growth and progression in a colon cancer xenograft model. Importantly, citrate administration combined with the conventional chemotherapy drugs exhibits synergistic antitumor effects in vivo in the colon cancer models. These results clearly indicate that citrate can reprogram lipid metabolism and cell fate in cancer cells, and targeting citrate can be a promising therapeutic strategy for tumor treatment. [ABSTRACT FROM AUTHOR]

Increased transplant activity calls for improved stem cell collection, especially when peripheral blood is the preferred source of haematopoietic progenitor cells (HPCs). Plerixafor is a bicyclam molecule that mobilizes CD34+ cells by reversibly disrupting CXCR4‐CXCL12‐supported HPC retention. Plerixafor is given with granulocyte colony‐stimulating factor (G‐CSF) to help harvest autologous CD34+ cells for transplantation when mobilization with G‐CSF fails. Mobilization protocols with the same doses of plerixafor and G‐CSF have been used off‐label in healthy allogeneic donors, with equal success and scarce side effects, both in adult and paediatric patients. Plerixafor has also been used as a sole mobilization agent. Plerixafor alone or coupled with G‐CSF might lead to harvesting distinct cellular populations conferring improved engraftment properties and increased survival. Those characteristics might make plerixafor an especially attractive mobilization agent, particularly for non‐related donations. However, available data are limited, and long‐term follow‐up is needed to clarify the best scenario for using plerixafor with or without G‐CSF in healthy donors. In this review, we will summarize the evidence supporting this practice, highlighting the practical aspects and providing clues for an expanded use of plerixafor. [ABSTRACT FROM AUTHOR]

The author discusses the importance of transfusion medicine in the development of innovative cellular therapeutics. He points on the decision of the editorial board to have a new section in the journal which will focus on cellular therapy. He adds that the scientists in transfusion medicine play an important role in the various projects on cellular therapy. The author mentions the main topics of the new section which include cell-based therapies, stem cell sources and gene therapy.

Background information. The identification of a source of stem cells able to regenerate skeletal muscle was the goal of numerous studies with the aim to develop new therapeutic approaches for genetic muscle diseases or muscle injuries. A series of studies have demonstrated that stem cells derived from various tissues may have a role in the regeneration of damaged muscles, but this contribution is always very weak. Thus we established a project aiming to reprogramme non-muscle cells into the skeletal striated differentiation pathway. Results. We transduced several human primary adult stem or progenitor cells using a recombinant lentivirus containing the coding sequence of the Myf5 gene considered as a master gene for the determination of skeletal striated muscle. These original results are the first demonstration of a myogenic conversion of human mesenchymal and endothelial cells by Myf5. Conclusions. The procedure described in the present paper could be used to develop new research protocols with the prospect of using these cells as therapeutic agents. [ABSTRACT FROM AUTHOR]

There is emerging interest in the use of standardized virally inactivated human platelet lysate preparations rich in GFs (growth factors) for cell cultures, cell therapy and clinical applications. In the present paper, we report a simple process to prepare a virally inactivated platelet lysate preparation rich in TGF-β1 (transforming growth factor-β1), EGF (epidermal growth factor) and IGF (insulin-like growth factor) and depleted of PDGF (platelet-derived growth factor) and VEGF (vascular endothelial growth factor). Apheresis platelet concentrates were treated by the S/D (solvent/detergent) viral inactivation procedure, then subjected to an oil extraction followed by adsorption with activated charcoal and finally sterile-filtered. The resulting preparation contained a mean of 368.4, 2.4 and 54.7 ng/ml of TGF-β1, EGF and IGF respectively. PDGF-AB and VEGF were essentially completely removed by the charcoal treatment. The mean albumin, IgG, IgM and IgA and fibrinogen contents were approx. 40.0, 8.5, 0.87, 1.66 and 2.65 mg/ml respectively, cholesterol and triglycerides were at 15 and 20.7 mg/ml respectively and TnBP (tri-n-butyl phosphate) and Triton X-45 were at 8.7 and 8.8 p.p.m. respectively. Supplementing MEM (minimum essential medium) with 1–10% of this S/D-treated platelet lysate promoted the proliferation of MG63 and SIRC cell lines as well as, or better than, 10% (v/v) FBS (fetal bovine serum), as based on the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. The process used to prepare such S/D-treated platelet lysates is easily scalable for industrial production. Our results open up the possibility to evaluate the potential of this new preparation for stem cell expansion and/or bone tissue engineering and regeneration. [ABSTRACT FROM AUTHOR]

The article presents the abstracts of papers on various topics including viral risks of plasma-derived medicinal products, developing a blood donor program, pathogen reduction and inactivation, bacterial contamination of blood products, auto-transfusion, national blood inventory management, and cellular therapies.

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10–14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III–IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report. [ABSTRACT FROM AUTHOR]

Leukocyte apheresis is necessary in various cellular therapies. However, maintenance of a stable flow rate during leukocyte apheresis is often difficult, even in patients or donors without major problems. Despite this, predictive methods and evidence regarding the reality of the situation are limited. We conducted a retrospective analysis involving adult patients who required leukocyte apheresis for the treatment of neoplasms using WT1-pulsed dendritic cell vaccine. Monocytes were separated from apheresis products to obtain dendritic cells. All the patients were pre-evaluated based on laboratory and chest X-ray findings and subjected to an identical apheresis procedure. The occurrence of poor blood collecting flow during leukocyte apheresis was monitored, and the frequency, clinical information, and associated risk factors were analyzed. Among 160 cases, poor blood collecting flow was observed in 53 cases (33.1%) in a median time of 54 min (range, 2-127 min) post-initiation of leukocyte apheresis. Owing to difficulty in obtaining higher collecting flow, a longer procedure time was required, and in some cases, the scheduled apheresis cycles could not be completed. Consequently, the number of harvested monocytes was low. Multivariable analysis indicated that female patients have an increased risk of poor inlet flow rate. Furthermore, prolonged QT dispersion (QTD) calculated using Bazett's formula was found to be a risk factor. Although the patients did not present any major problems during leukocyte apheresis, poor blood collecting flow was observed in some cases. Sex and pre-evaluated QTD might be useful predictors for these cases; however, further prospective evaluation is necessary. [ABSTRACT FROM AUTHOR]

Peripheral nerve and spinal cord injuries affect millions of people worldwide often leading to lifelong disability and pain. Cell therapy using autologous Schwann cells are currently being investigated for the treatment of these injuries and are showing great potential. In particular, skin‐derived Schwann cells offer a non‐invasive option for highly therapeutic cells that have been shown to regenerate tissue and restore function. However, it is estimated that for an effective therapy, hundreds of millions of Schwann cells are needed, and current static and spinner flask methods cannot generate these clinical numbers. Therefore, this study utilizes control systems facilitated by stirred suspension bioreactors to monitor and maintain the pH and dissolved oxygen at levels that promote cell proliferation and survival. By adapting the current culture practices to scalable bioreactor platforms, we were able to control the dissolved oxygen creating new expansion protocols that enabled the bioreactor process to grow to clinical scale, producing 667 × 106 cells in a single 500 mL bioreactor in 7 days. Since individual injury is different in terms of complexity and severity, and therefore cell needs, by changing the available surface area in the bioreactor, this developed process is highly adjustable to meet the cell quantity needs for each individual treatment. Following the bioprocess, cells that were harvested from the microcarriers continue to express typical Schwann cell markers suggesting that they retain phenotypic stability. By increasing the production potential of skin‐derived Schwann cells, this therapy is one step closer to the clinic with the hope for ultimately restoring function and improving quality of life to patients with neural injuries. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a ubiquitous herpes virus that develops lifelong latency following primary infection and can be reactivated following immune suppression. CMV encephalopathy has been described in few reports after hematopoietic stem cell transplantation and in patients with acquired immunodeficiency syndrome. To the best of our knowledge, CMV encephalopathy following CAR‐T cells infusion had not been previously reported. Initial CMV viral load and monitoring are crucial in patients with CAR‐T cells to allow early intervention with aggressive antiviral treatment without delay if needed. [ABSTRACT FROM AUTHOR]

Cell and gene therapies have shown enormous promise across a range of diseases in recent years. Numerous adoptive cell therapy modalities as well as systemic and direct‐to‐target tissue gene transfer administrations are currently in clinical development. The clinical trial design, development, reporting, and analysis of novel cell and gene therapies can differ significantly from established practices for small molecule drugs and biologics. Here, we discuss important quantitative considerations and key competencies for drug developers in preclinical requirements, trial design, and lifecycle planning for gene therapies. We argue that the unique development path of gene therapies requires practicing quantitative drug developers—statisticians, pharmacometricians, pharmacokineticists, epidemiologists, and medical and translational science leads—to exercise active collaboration and cross‐functional learning across development stages. [ABSTRACT FROM AUTHOR]

The field of cell and gene therapy (CGT) is maturing at a rapid rate. Manufacturing remains a major challenge and manufacturing failures and limitations are a notable source of CGT products not meeting specification or being held back from regulatory approvals. To ensure that products remain compliant and competitive throughout their lifecycle, CGT process development requires both ongoing advancement of fit‐for‐purpose technologies to allow for and support well‐designed development studies, and a methodology that enables these studies to occur effectively during focused product development campaigns. We describe a framework for ongoing innovation in CGT process development, manufacturing, and clinical testing, based on the quality by design (QbD) approach. We propose use of the concepts of process discovery, process characterization, and process development in an iterative way to refine the design space as a product matures. This strategy is enabled by the early implementation of broad and robust analytics, and a modular approach to accelerate optimization. With these strategies, CGT developers can prospectively plan for comparability studies and develop in a stage‐appropriate manner, to allow for ongoing innovation and improvements from discovery through to commercialization. [ABSTRACT FROM AUTHOR]

Abstracts of papers published within the issue are presented, including one on therapeutic applications of genome editing, another on targeting multiple sclerosis through monoclonal antibodies and a paper on academic development of cell-based therapy.

The fields of dermatology and transplantation biology have recently come together in clinical trials of bone marrow transplantation for severe inherited blistering skin diseases. But the original link between these two disciplines goes back to an extraordinary publication in 1953 in Nature by Peter Medawar and colleagues that explored the immunological basis of successful skin transplantation between different strains of mice and how 'foreign' antigens could be perceived as 'self'. This work led to the emergence of blood and bone marrow transplantation and thus transformed the practice of modern medicine. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) is a burgeoning therapeutic modality within human immuno‐oncology. Novel approaches towards ACT are being developed in the pre‐clinical setting faster than they can be evaluated in human clinical trials. Many of the therapeutic approaches used in human medicine have already been evaluated to some degree in canine patients. While this form of immunotherapy in veterinary medicine is still in its infancy, as these approaches develop, canine ACT will become a tool for both the veterinary oncologist and the translational researcher. This review details canine ACT trials to date, with attention given to the precedents provided by human oncology. [ABSTRACT FROM AUTHOR]

Objectives: The derivation of neural crest stem cells (NCSCs) from human pluripotent stem cells (hPSCs) has been commonly induced by WNT activation in combination with dual‐SMAD inhibition. In this study, by fine‐tuning BMP signalling in the conventional dual‐SMAD inhibition, we sought to generate large numbers of NCSCs without WNT activation. Materials and methods: In the absence of WNT activation, we modulated the level of BMP signalling in the dual‐SMAD inhibition system to identify conditions that efficiently drove the differentiation of hPSCs into NCSCs. We isolated two NCSC populations separately and characterized them in terms of global gene expression profiles and differentiation ability. Results: Our modified dual‐SMAD inhibition containing a lower dose of BMP inhibitor than that of the conventional dual‐SMAD inhibition drove hPSCs into mainly NCSCs, which consisted of HNK+p75high and HNK+p75low cell populations. We showed that the p75high population formed spherical cell clumps, while the p75low cell population generated a 2D monolayer. We detected substantial differences in gene expression profiles between the two cell groups and showed that both p75high and p75low cells differentiated into mesenchymal stem cells (MSCs), while only p75high cells had the ability to become peripheral neurons. Conclusions: This study will provide a framework for the generation and isolation of NCSC populations for effective cell therapy for peripheral neuropathies and MSC‐based cell therapy. The derivation of NCSCs from hPSCs by a modified dual‐SMAD inhibition without WNT activation. We showed that the p75high population formed spherical cell clumps, while the p75low cell population generated a 2D monolayer. When the two groups were isolated and differentiated, both p75high and p75low cells were differentiated into MSCs, but peripheral neurons differentiated only from p75high cells. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are involved in the regeneration of the different missing or compromised periodontal tissues. MSC‐derived small extracellular vesicles (sEV) have recently been explored as a favorable substitution for stem cell therapy, as they are capable of producing therapeutic effects comparable to those of their parent cells, with advantages over cell therapy. The aim of this review is to evaluate the use of mesenchymal stem cells (MSC)‐derived sEV as cell‐free therapy in periodontal regeneration. A review of the scientific literature on sEV and their use in periodontal regeneration was performed. The main characteristics of sEV are described, and their mechanisms of action and potential biological effects in periodontal regeneration are studied. A summary of existing preclinical studies conducted in animals is performed. The results indicate that sEV derived from MSC are emerging as a promising new therapeutic tool in the field of periodontal regeneration and may become an ideal therapeutic option. In this review, we have summarized recent advances in this regard in order to better understand this newly emerging treatment. First results in vivo are promising and show a favorable potential for cell‐free therapy in periodontal regeneration. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a serious complication of preterm delivery and low birthweight infants. The incidence of BPD has not decreased, and there is no effective treatment for the disease. Since the survival rate of premature infants has increased, it has become difficult to obtain pathological tissue samples from BPD death cases. There is also no in vitro experimental system for complex three‐dimensional structures, such as alveolarization and pulmonary angiogenesis; thus, the use of animal models is necessary to elucidate the pathology of BPD and develop new treatments. To date, BPD animal models were being developed by exposing immature animal lungs to various stimuli. In the present review, I summarize BPD animal models that use (i) highly concentrated oxygen, (ii) mechanical ventilation, and (iii) infection/inflammation. In addition, with mesenchymal stromal cell (MSC) therapy for BPD as an example, I will discuss the expectations for new treatments that would be applied from animal models to humans. [ABSTRACT FROM AUTHOR]

Background: We investigated the effect of dual‐frequency sonication on the viability of B16F10 melanoma cells in the presence of methylene blue (MB) encapsulated in nanoliposomes. Methods: Treatment protocols were studied: sonication groups (40 kHz, 1 MHz and dual‐frequency), the same sonication groups with nanoliposomes containing MB, MB free and nanoliposomes containing MB groups, and so sham and control groups. The nanoliposomes were prepared by the lipid film hydration method. The cell viability of the different treatment groups was evaluated by the MTT assay. Results: The dual‐frequency protocols caused higher viability losses compared to the kHz and MHz sonications (P <.05). In presence of the nanoliposomes containing MB, dual frequency led to 6% and 3% viability for 600 and 1200 seconds, respectively, while the corresponding values were 10% and 4% for the 40 kHz protocols and 22% and 9% for the 1 MHz, as compared to the control group (100%). The result of KI dosimetry showed that the cavitation activity of the dual‐frequency protocol was about 1.23, as compared to sonication at 40 kHz and 1 MHz. Conclusion: Enhancement of inertial cavitation induction by dual‐frequency sonication may be the primary effective mechanism, which causes increased sonochemical processes and drug release from nanocarriers. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are the subject of intense research as they are a potential therapeutic tool for several clinical applications. The new MSCs action models are focused on the use of MSC‐derived secretome which contains several growth factors, cytokines, microRNAs, and extracellular vesicles such as exosomes. Exosomes have recently emerged as a component with great potential involved as mediators in cellular communication. The isolation and identification of exosomes has made it possible for them to be used in cell‐free therapies. The purposes of this study are: (i) to detect exosomes released into adipose‐derived MSC conditioned cell culture medium, (ii) to identify exosome morphology, and (iii) to carry out a complete characterization of said exosomes. Moreover, it is aimed at determining which method for exosome isolation would be best to use. Precipitation has been identified as a highly useful method of exosome isolation since it provides higher efficiency and purity values than other methods. A broad characterization of the exosomes present in the MSC‐conditioned medium was also carried out. This work fills a gap in the existing literature on bioactive molecules which have attracted a great deal of interest due to their potential use in cellular therapies. [ABSTRACT FROM AUTHOR]

Restoration of form and function requires apposition of tissues in the form of flaps to reconstitute local perfusion. Successful reconstruction relies on flap survival and its integration with the recipient bed. The flap's precariously perfused hypoxic areas undergo adaptive microvascular changes both internally and in connection with the recipient bed. A cell‐mediated, coordinated response to hypoxia drives these adaptive processes, restoring a tissue's normoxic homeostasis via de novo vasculogenesis, sprouting angiogenesis, and stabilizing arterialization. As cells exert prolonged and coordinated effects on site, their use as biological agents merit translational consideration of sourcing angio‐competent cells and delivering them to territories enduring microcirculatory acclimatization. Angio‐competent cells abound in adipose tissue: a reliable, accessible, and expendable source of adipose‐derived cells (ADC). When subject to enzymatic digestion and centrifugation, adipose tissue separates its various ADC: A subset of buoyant oil‐dense adipocytes (the tissue's parenchymal component) accumulates on a supra‐natant layer, whereas the mesenchymal component remains in the infra‐natant sediment, containing the tissue's stromal vascular fraction (SVF), where angio‐component cells abound. The SVF can be further manipulated, selected, or culture expanded into more specific stromal subsets (herein defined as adipose stromal cells, ASC). While promising clinical applications for ADC await clinical proof and regulatory authorization, basic science investigation is needed to elucidate the specific ADC mechanisms that influence microvascular growth, remodeling, and function following flap surgery. The objective of this article is to share the clinical perspectives of reconstructive plastic surgeons regarding the use of ADC‐based therapies to help with flap tissue integration, revascularization, and wound healing. Specifically, the focus will be on considering the potential for ADC as therapeutic agents and how their clinical application motivates basic science opportunities. [ABSTRACT FROM AUTHOR]

Summary: Immunotherapies have emerged as highly promising approaches to treat cancer patients. Allogeneic haematopoietic cell transplantation (HCT) is the most validated tumour immunotherapy available to date but its clinical efficacy is limited by toxicities, such as graft‐versus‐host disease (GVHD) and treatment resistance leading to relapse. The problems with new cellular therapies and checkpoint inhibitors are similar. However, development of biomarkers post‐HCT, particularly for toxicities, has taken off in the last decade and has expanded greatly. Thanks to the advances in genomics, transcriptomics, proteomics and cytomics technologies, blood biomarkers have been identified and validated in promising diagnostic tests, prognostic tests stratifying for future occurrence of GVHD, and predictive tests for responsiveness to GVHD therapy and non‐relapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. This review outlines a path from biomarker discovery to first clinical correlation, focusing on soluble STimulation‐2 (sST2) ‒ the interleukin (IL)‐33‐decoy receptor ‒ which is the most validated biomarker. [ABSTRACT FROM AUTHOR]

Summary: Recent advances in high‐throughput genomics have enabled the direct tracking of outputs from many cell types, greatly accelerating the study of developmental processes and tissue regeneration. The capacity for long‐term self‐renewal with multilineage differentiation potential characterises the cellular dynamics of a special set of developmental states that are critical for maintaining homeostasis. In haematopoiesis, the archetypal model for development, lineage‐tracing experiments have elucidated the roles of haematopoietic stem cells to ongoing blood production and the importance of long‐lived immune cells to immunological memory. An understanding of the biology and clonal dynamics of these cellular fates and states can provide clues to the response of haematopoiesis to ageing, the process of malignant transformation, and are key to designing more efficacious and durable clinical gene and cellular therapies. [ABSTRACT FROM AUTHOR]

The field of organoid engineering promises to revolutionize medicine with wide‐ranging applications of scientific, engineering, and clinical interest, including precision and personalized medicine, gene editing, drug development, disease modelling, cellular therapy, and human development. Organoids are a three‐dimensional (3D) miniature representation of a target organ, are initiated with stem/progenitor cells, and are extremely promising tools with which to model organ function. The biological basis for organoids is that they foster stem cell self‐renewal, differentiation, and self‐organization, recapitulating 3D tissue structure or function better than two‐dimensional (2D) systems. In this review, we first discuss the importance of epithelial organs and the general properties of epithelial cells to provide a context and rationale for organoids of the liver, pancreas, and gall bladder. Next, we develop a general framework to understand self‐organization, tissue hierarchy, and organoid cultivation. For each of these areas, we provide a historical context, and review a wide range of both biological and mathematical perspectives that enhance understanding of organoids. Next, we review existing techniques and progress in hepatobiliary and pancreatic organoid engineering. To do this, we review organoids from primary tissues, cell lines, and stem cells, and introduce engineering studies when applicable. We discuss non‐invasive assessment of organoids, which can reveal the underlying biological mechanisms and enable improved assays for growth, metabolism, and function. Applications of organoids in cell therapy are also discussed. Taken together, we establish a broad scientific foundation for organoids and provide an in‐depth review of hepatic, biliary and pancreatic organoids. [ABSTRACT FROM AUTHOR]

Background: Numerous conditions are responsive to therapeutic apheresis (TA) and cellular therapy (CT) treatments. Both TA and CT are two broad and diverse knowledge fields within transfusion medicine (TM). We therefore sought to survey all the TM fellowship program directors (PDs) in the United States to examine the current fellow state education in TA and CT. Methods: A 37‐question survey was sent to all PDs to collect details of TA and CT training for TM fellows. Results: Responses from 29/51 (56.9%) surveyed programs were received. Most PDs considered TA and CT training for their fellows more than adequate. Two PDs from programs that did not directly oversee TA and CT services at their training sites stated that their program's training in these two areas were only "slightly adequate" or "moderately inadequate." Detailed analysis of training in TA, cell collection, and CT suggests that trainees from programs with direct oversight of these services had longer training and more learning experiences compared to those in which outside rotations were required. Conclusions: Transfusion medicine fellowship training in TA and CT varies. Most respondents, and particularly those from programs directly overseeing TA services, reported their fellows were adequately prepared in TA. Cellular therapy collections and laboratory operations, however, are less consistent areas of training despite the rapid expansion of these fields. Our survey suggests that a greater emphasis in CT training is needed. [ABSTRACT FROM AUTHOR]

Adverse event (AE) and adverse reaction (AR) reporting are key components of patient safety and surveillance systems. Review and analysis of this data yields opportunities for process improvement, product information and interventions, and can lead to improved patient outcomes and donor safety overall. AE and AR reporting for cellular therapy products is fragmented and not well characterized in a central reference. This review article, authored by experts from various organizations, serves to summarize the current state of reporting and offers opportunities for streamlining and coordination, as well as key reference for professionals in this field. [ABSTRACT FROM AUTHOR]

In recent decades, mesenchymal stromal cells (MSCs) biomedical utilizing has attracted worldwide growing attention. After the first report of the human MSCs obtaining from the bone marrow (BM) tissue, these cells were isolated from wide types of the other tissues, ranging from adipose tissue to dental pulp. Their specific characteristics, comprising self‐renewality, multipotency, and availability accompanied by their immunomodulatory properties and little ethical concern denote their importance in the context of regenerative medicine. Considering preclinical studies, MSCs can modify immune reactions during tissue repair and restoration, providing suitable milieu for tissue recovery; on the other hand, they can be differentiated into comprehensive types of the body cells, such as osteoblast, chondrocyte, hepatocyte, cardiomyocyte, fibroblast, and neural cells. Though a large number of studies have investigated MSCs capacities in regenerative medicine in varied animal models, the oncogenic capability of unregulated MSCs differentiation must be more assessed to enable their application in the clinic. In the current review, we provide a brief overview of MSCs sources, isolation, and expansion as well as immunomodulatory activities. More important, we try to collect and discuss recent preclinical and clinical research and evaluate current challenges in the context of the MSC‐based cell therapy for regenerative medicine. [ABSTRACT FROM AUTHOR]

End‐stage liver diseases are an increasing health burden, and liver transplantations are currently the only curative treatment option. Due to a lack of donor livers, alternative treatments are urgently needed. Human liver organoids are very promising for regenerative medicine; however, organoids are currently cultured in Matrigel, which is extracted from the extracellular matrix of the Engelbreth‐Holm‐Swarm mouse sarcoma. Matrigel is poorly defined, suffers from high batch‐to‐batch variability and is of xenogeneic origin, which limits the clinical application of organoids. Here, a novel hydrogel based on polyisocyanopeptides (PIC) and laminin‐111 is described for human liver organoid cultures. PIC is a synthetic polymer that can form a hydrogel with thermosensitive properties, making it easy to handle and very attractive for clinical applications. Organoids in an optimized PIC hydrogel proliferate at rates comparable to those observed with Matrigel; proliferation rates are stiffness‐dependent, with lower stiffnesses being optimal for organoid proliferation. Moreover, organoids can be efficiently differentiated toward a hepatocyte‐like phenotype with key liver functions. This proliferation and differentiation potential maintain over at least 14 passages. The results indicate that PIC is very promising for human liver organoid culture and has the potential to be used in a variety of clinical applications including cell therapy and tissue engineering. [ABSTRACT FROM AUTHOR]

Background: Stem cell therapy is a novel treatment option for people living with osteoarthritis. Research investigating stem cell therapy for this debilitating condition has predominantly involved the pathogenesis of the cells and efficacy of the treatment. There is little understanding of patients' expectations and experiences of stem cell therapy treatment. Objective: To explore the expectations and experiences of people undergoing stem cell therapy for the treatment of knee osteoarthritis. Design: An exploratory, descriptive, qualitative study using semi‐structured interviews was conducted. Setting and participants: Participants were recruited into two groups: (a) Expectations Group (n = 15); the expectations of stem cell treatment were explored with participants that were yet to commence stem cell therapy. (b) Experiences Group (n = 15); the experiences of stem cell therapy were explored with participants 12 months after their initial stem cell treatment. Transcripts were analysed using thematic analysis to identify themes in both groups. Results: Themes for the Expectations Group were active involvement in the treatment; treatment will improve symptoms; and benefits of treatment outweigh the risks. Themes for the Experiences Group were symptoms of treatment; satisfaction with treatment; and anticipation of further improvement. Discussion and conclusions: The findings are the first qualitative study to represent patients' perspective on expectations and experiences of stem cell therapy for knee osteoarthritis. They provide insight into the potential areas for improvement within this field to aid patients' preparation and approach to the treatment, promoting patient‐centred care. [ABSTRACT FROM AUTHOR]