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For decades, clinicians have witnessed no therapeutic advances for small cell lung cancer, including no US Food and Drug Administration‐approved targeted therapies; recently, immune‐checkpoint blockade has emerged as a promising new option for the treatment of patients with relapsed small cell lung cancer (including recent US Food and Drug Administration approval of nivolumab in the third‐line setting) and soon may represent the frontline standard of care in combination with chemotherapy. However, there is a need to uncover biomarkers to guide patient selection and develop novel approaches to enhance response to immunotherapies. [ABSTRACT FROM AUTHOR]

A response by Michael K. McGuire to a letter to the editor about their article "A Pilot Study to Evaluate a Tissue-Engineered Bilayered Cell Therapy as an Alternative to Tissue From the Palate" which appeared in a previous issue is presented.

Background Information Atherosclerosis is an inflammatory disease, in which risk factors such as hyperlipidemia and hypertension affect the arterial endothelium, resulting in dysfunction, cell damage or both. The number of circulating endothelial progenitor cells and microparticles provides invaluable outcome prediction for atherosclerosis disease. However, evidence for the therapeutic potential of endothelial progenitor cells and microparticles in atherosclerosis development is limited. Our study was designed to investigate the possible protective role of a cell therapy-based approach, using endothelial progenitor cells and the dual behaviour of circulating platelet microparticles, on atherosclerosis development in hypertensive-hypercholesterolemic hamster model. Consequently, control hamsters received four intravenous inoculations of: (1) 1×105 endothelial progenitor cells of healthy origins in one dose per month, during four months of diet-induced atherosclerosis, and after hypertensive-hypercholesterolemic diet for further four months; (2) in a second set of experiments, 1×105 endothelial progenitor cells of healthy origins or/and 1×105 platelet microparticles of atherosclerotic origins were inoculated every other month during hypertensive-hypercholesterolemic diet. Results Endothelial progenitor cell treatment had the following effects: (1) re-established plasmatic parameters: cholesterol and triglyceride concentrations, blood pressure, heart rate, cytokine and chemokine profiles, platelet microparticle pro-thrombotic activity and endothelial progenitor cell paracrine activity reflected by cytokine/chemokine detection; (2) reduced lipid, macrophage and microparticle accumulation in liver; (3) reduced atherosclerosis development, revealed by decreased lipid, macrophage and microparticle content of arterial wall; (4) induced the recruitment and incorporation of endothelial progenitor cells into liver and arterial wall; (5) improved arterial dysfunction by increasing contraction and relaxation; (6) reduced the protein expression of specific pro-inflammatory molecules in liver and arterial wall. Platelet microparticle transplantation aggravated the above-mentioned biomarkers and atherosclerosis process, which were partially reverted with co-inoculation of platelet microparticles and endothelial progenitor cells. Conclusions With this study, we demonstrate in a hypertensive-hypercholesterolemic hamster model, that the endothelial progenitor cell-based therapy suppresses the development of atherosclerosis and reduces hepatic lipid and macrophage accumulation with the consequent alleviation of dyslipidaemia and hypertension. Significance Our results support the notion that increasing the number of circulating endothelial progenitor cells by different ways could be a promising therapeutic tool for atherosclerosis. [ABSTRACT FROM AUTHOR]

Adoptive cell immunotherapy for human diseases, including the use of T cells modified to express an anti-tumour T-cell receptor ( TCR) or chimeric antigen receptor, is showing promise as an effective treatment modality. Further advances would be accelerated by the availability of a mouse model that would permit human T-cell engineering protocols and proposed genetic modifications to be evaluated in vivo. NOD- scid IL2rγ null ( NSG) mice accept the engraftment of mature human T cells; however, long-term evaluation of transferred cells has been hampered by the xenogeneic graft-versus-host disease ( GVHD) that occurs soon after cell transfer. We modified human primary CD4+ T cells by lentiviral transduction to express a human TCR that recognizes a pancreatic beta cell-derived peptide in the context of HLA- DR4. The TCR-transduced cells were transferred to NSG mice engineered to express HLA- DR4 and to be deficient for murine class II MHC molecules. CD4+ T-cell-depleted peripheral blood mononuclear cells were also transferred to facilitate engraftment. The transduced cells exhibited long-term survival (up to 3 months post-transfer) and lethal GVHD was not observed. This favourable outcome was dependent upon the pre-transfer T-cell transduction and culture conditions, which influenced both the kinetics of engraftment and the development of GVHD. This approach should now permit human T-cell transduction protocols and genetic modifications to be evaluated in vivo, and it should also facilitate the development of human disease models that incorporate human T cells. [ABSTRACT FROM AUTHOR]

Cell microencapsulation and subsequent transplantation of the microencapsulated cells require multidisciplinary approaches. Physical, chemical, biological, engineering, and medical expertise has to be combined. Several natural and synthetic polymeric materials and different technologies have been reported for the preparation of hydrogels, which are suitable to protect cells by microencapsulation. However, owing to the frequent lack of adequate characterization of the hydrogels and their components as well as incomplete description of the technology, many results of in vitro and in vivo studies appear contradictory or cannot reliably be reproduced. This review addresses the state of the art in cell microencapsulation with special focus on microencapsulated cells intended for xenotransplantation cell therapies. The choice of materials, the design and fabrication of the microspheres, as well as the conditions to be met during the cell microencapsulation process, are summarized and discussed prior to presenting research results of in vitro and in vivo studies. Overall, this review will serve to sensitize medically educated specialists for materials and technological aspects of cell microencapsulation. [ABSTRACT FROM AUTHOR]

The field of adoptive cell transfer includes chimeric antigen receptor (CAR) engineered T cells, constructs that emerged from basic research into principles of immunology and have transformed into clinically effective therapies for haematological malignancies. T cells engineered to express these artificial receptors hold great promise, but also carry significant risk. While permanent genetic modification of mature T cells appears safe, modulating their in vivo function is difficult, partly because the robust response can trigger other arms of the immune system. Suicide systems and toxicity management with cytokine blockade or signal transduction modulators have emerged as a new frontier in this field, a far cry from early problems getting CAR T cells to work at all. Currently, clinical trials in patients with relapsed or refractory B cell malignancies treated with CD19-specific CAR T cells have induced durable remissions in adults and children. Results from these trials indicate that more work needs to be done to understand biomarkers of efficacy, the role of T cell persistence and how to integrate this care into standard practice. Cell therapy will not be a 'one size fits all' class of medicine, and here we will discuss the development of this therapy and important questions for its future. [ABSTRACT FROM AUTHOR]

Current cell therapies, despite all of the progress in this field, still faces major ethical, technical and regulatory hurdles. Because these issues possibly stem from the current, restricted, stereotypical view of cell ultrastructure and function, we must think radically about the nature of the cell. In this regard, the author's theory of the cell memory disc offers 'memory-based therapy', which, with the help of immune system rejuvenation, nervous system control and microparticle-based biodrugs, may have substantial therapeutic potential. In addition to its potential value in the study and prevention of premature cell aging, age-related diseases and cell death, memory therapy may improve the treatment of diseases that are currently limited by genetic disorders, risk of tumour formation and the availability and immunocompatibility of tissue transplants. [ABSTRACT FROM AUTHOR]

Background and Objectives Biological raw materials, the basis for cellular therapies such as stem cells, have a significantly greater degree of complexity than their traditional pharmaceutical counterparts. This can be attributed to the inherent variation of its source - human beings. Currently, cell therapies are made in small, ad hoc batches, but larger scale production is a prerequisite to meeting future demand and will require a quality-by-design approach to manufacturing that will be designed around, or be robust to this variation. Quantification of variation will require understanding of the current baseline and stratification of its sources. Materials and Methods Haematopoietic stem cell therapy was chosen as a case study to explore this variation, and a PRISMA-guided (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) systematic meta-analysis was carried out for a number of predetermined cell measurements. Results From this data set, it appears that the extent of variation in therapeutic dose (in terms of transplanted total nucleated cells and CD34+ cells per kilogram) for HSCT is between one and four orders of magnitude of the median. Conclusions This is tolerated under the practice of medicine but would be unmanageable from a biomanufacturing perspective and raises concerns about comparable levels of efficacy and treatment. A number of sources that will contribute towards this variation are also reported, as is the direction of travel for 4 greater clarity of the scale of this challenge. [ABSTRACT FROM AUTHOR]

Background: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). Autologous cell therapy products (CTP) are obtained from patients with advanced peripheral arterial disease to be injected at the site of ischemia. Thrombogenicity of CTPs has not yet been assessed. The objectives were: 1) to assess thrombotic risk in candidates for cell therapy, 2) to evaluate two different CTPs in terms of thrombogenic potential, and 3) to evaluate clinical thrombotic events.Study Design and Methods: In this ancillary study of a Phase I and II clinical trial, bone marrow (BM)-CTPs (n = 20) and CTPs obtained by cytapheresis (peripheral blood [PB]-CTPs; n = 20) were compared. Inflammatory and coagulation markers were measured at baseline and 24 hours after CTP implantation. CTP cell content and tissue factor (TF) expression (mRNA and protein) were analyzed. Thrombin generation assessed CTP-related thrombogenicity.Results: All patients presented cardiovascular risk factors. At baseline, the patients' biologic profile was characterized by high levels of fibrinogen, C-reactive protein (CRP), D-dimer, interleukin (IL)-6, and plasmatic TF, whereas IL-10 was low. Although different in terms of cell composition, both BM- and PB-CTPs support low thrombin generation. Twenty-four hours after implantation, biologic markers remained stable in the PB-CTP group, except for IL-6. In the BM-CTP group, a significant increase of IL-6 but also of CRP and D-dimer was observed. Clinically, one single patient developed deep vein thrombosis 24 hours after the implantation of autologous PB-CTP.Conclusion: CTPs supported low thrombin generation and were well tolerated after calf implantation. [ABSTRACT FROM AUTHOR]

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The emergence of stem cell technologies and their potential applications in regenerative medicine have generated immense interest by both the lay public and clinicians. Unproven and unregulated cell-based therapies are commercially available both in Australia and internationally, and reports of patient uptake (stem cell tourism) and associated morbidity are increasingly frequent. Clinicians in all fields will require an enhanced understanding of the basic science principles and current state of play in regenerative medicine in order to effectively counsel patients regarding these therapies in the setting of both commercial ventures and clinical trials. This review aims to concisely highlight the key clinically pertinent features of these trials and briefly discuss the specific therapeutic potential, mechanism of action and risks associated with these variables. [ABSTRACT FROM AUTHOR]

The history of the ISBT since its foundation in 1937 may be divided into four phases: (i) Formation and development (1935-1985), (ii) Years of crisis (1985-2000), (iii) Reformation (2000-2010), (iv) A professional organization (2010-present). While the ISBT was initially founded to organize congresses, today it stands forth as a global, diversified and respected scientific organization in the field of transfusion, also having an educational branch and governing international reference functions. During the last 25 years, women have taken a more prominent role in the organization. The challenge for the future is for ISBT to be the Society of first choice for professionals in the field of transfusion medicine and cellular therapies. [ABSTRACT FROM AUTHOR]

Background Porcine Sertoli cells ( pSCs) have been employed for cell therapy in pre-clinical studies for several chronic/immune diseases as they deliver molecules associated with trophic and anti-inflammatory effects. To be employed for human xenografts, pSCs products need to comply with safety and stability. To fulfill such requirements, we employed a microencapsulation technology to increase pre-transplant storage stability of specific pathogen-free pSCs ( SPF- pSCs) and evaluated the in vivo long-term viability and safety of grafts. Methods Specific pathogen free neonatal pigs underwent testis excision under sterility. pSCs were isolated, characterized by immunofluorescence ( IF) and cytofluorimetric analysis ( CA) and examined in terms of viability and function [namely, production of anti-müllerian hormone ( AMH), inhibin B, and transforming growth factor beta-1 ( TFGβ-1)]. After microencapsulation in barium alginate microcapsules (Ba- MC), long-term SPF- pSCs (Ba- MCp SCs) viability and barium concentrations were evaluated at 1, 24 throughout 40 h to establish pre-transplant storage conditions. Results The purity of isolated pSCs was about 95% with negligible contaminating cells. Cultured pSCs monolayers, both prior to and after microencapsulation, maintained high function and full viability up to 24 h of storage. At 40 h post-encapsulation, pSCs viability decreased to 80%. Barium concentration in Ba- MCp SCs lagged below the normal maximum daily allowance and was stable for 4 months in mice with no evident side effects. Conclusions Such results suggest that this protocol for the isolation and microencapsulation of pSCs is compatible with long-haul transportation and that Ba- MCp SCs could be potentially employable for xenotransplantation. [ABSTRACT FROM AUTHOR]

Despite considerable progress to increase our understanding of muscle genetics, pathophysiology, molecular and cellular partners involved in muscular dystrophies and muscle ageing, there is still a crucial need for effective treatments to counteract muscle degeneration and muscle wasting in such conditions. This review focuses on cell-based therapy for muscle diseases. We give an overview of the different parameters that have to be taken into account in such a therapeutic strategy, including the influence of muscle ageing, cell proliferation and migration capacities, as well as the translation of preclinical results in rodent into human clinical approaches. We describe recent advances in different types of human myogenic stem cells, with a particular emphasis on myoblasts but also on other candidate cells described so far [ CD133+ cells, aldehyde dehydrogenase-positive cells ( ALDH+), muscle-derived stem cells ( Mu Stem), embryonic stem cells ( ES) and induced pluripotent stem cells (i PS)]. Finally, we provide an update of ongoing clinical trials using cell therapy strategies. [ABSTRACT FROM AUTHOR]

The article presents the draft guideline of the British Committee for Standards in Haematology (BCSH) on the best practise in clinical apheresis and collection of cellular therapy products. An overview of the objectives of the guideline and the clinical use of apheresis procedures is offered. Key recommendations on therapeutic apheresis and the indications and technical aspects of cellular therapy products including plasma exchange, lipoprotein apheresis, and red cell apheresis are offered.

Gene transfer into haematopoietic stem cells ( HSCs) has now come to the stage where it can be recognized as a form of established therapy for patients with a certain range of genetic diseases. Primary immunodeficiency disease ( PID) represents an ideal pathological target for this type of genetic medicine, that is HSC gene therapy, as exemplified well by the successful cases with adenosine-deaminase ( ADA) deficiency. Other diseases including X-linked severe combined immunodeficiency disease ( X- SCID), chronic granulomatous disease ( CGD) and Wiskott- Aldrich syndrome ( WAS) have also been the targets of gene therapy, but the efficacy reportedly varies considerably. In addition, all those diseases except ADA deficiency have been demonstrated to be subject to an inherent risk of insertional leukaemogenesis as long as gene transfer accompanies genomic insertion. Researchers therefore should continue to aim for further improvement of HSC gene therapy to maximize both safety and efficacy. To achieve this aim, an ideal model system is desired, by which faithful recapitulation of the disease-related pathophysiology is feasible. Recently, a new model system possibly constituting such an ideal platform has come to reality; that is, patient-/disease-specific induced pluripotent stem cells ( iPSCs). iPSCs should particularly be useful for modelling genetic disorders, because of their excellent potential to differentiate into any types of somatic cells while retaining the patient-specific genetic mutations. These model cells should allow testing various kinds of genetic manipulation and also detailed analysis of the target cells before/after differentiation, thus providing a disease-specific platform for preclinical studies to test safety and efficacy of each gene-modification procedure. [ABSTRACT FROM AUTHOR]

Tissue-engineered therapies are being developed across virtually all fields of medicine. Some of these therapies are already in clinical use, while others are still in clinical trials or the experimental phase. Most initial studies in the evaluation of new therapies focus on demonstration of clinical efficacy. However, cost considerations or economic viability are just as important. Many tissue-engineered therapies have failed to be impactful because of shortcomings in economic competitiveness, rather than clinical efficacy. Furthermore, such economic viability studies should be performed early in the process of development, before significant investment has been made. Cost-minimization analysis combined with sensitivity analysis is a useful model for the economic evaluation of new tissue-engineered therapies. The analysis can be performed early in the development process, and can provide valuable information to guide further investment and research. The utility of the model is illustrated with the practical real-world example of tissue-engineered constructs for corneal endothelial transplantation. WIREs Syst Biol Med 2015, 7:91-100. doi: 10.1002/wsbm.1292 For further resources related to this article, please visit the . Conflict of interest: The authors have declared no conflicts of interest for this article. [ABSTRACT FROM AUTHOR]

The article focuses on the Production Assistance for Cellular Therapies (PACT) program through funding by the National Institutes of Health, National Heart, Lung and Blood Institute (NHLBI) to provide clinical cell therapy product manufacturing support. Topics discussed include management of data by the bone marrow transplant (BMT) community, approval for the data collection forms by the U.S. Food and Drug Administration, and manufacturing of cellular therapy products by biotechnology firms.

Clinicians have long reported that hair-bearing areas tend to heal more rapidly than those lacking hair follicles. In the past decade, numerous scientific studies have corroborated clinical evidence, showing a direct nexus between the human hair follicle and the wound healing process. The migration of epithelial follicular stem cells to the skin surface to help in the wound re-epithelialization and the effect of the hair cycle on the wound healing rate underline the influence of the hair follicle in the healing process. In clinical practice, non-healing wounds are pathologies of high prevalence with significant associated burden costs for the healthcare system. As the population ages, the prevalence of this pathology is expected to increase in future years. The recent advances in understanding the biology of hair follicle stem cells have created the challenges of using this newly acquired knowledge in practical therapeutic applications. Chronic leg ulcers are an example of the targeted pathologies that urgently need better therapies. In this essay, our aim is to raise interest in this question, reviewing what is known in relation to the connections between hair follicles and wound healing, and elaborating on future directions that the field might take, including implications for clinical practice. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics related to training and education including blended learning in blood centers, transfusion education for doctors, and certification of transfusion medicine and cell therapy.

Chemical encapsulation of microbes in threedimensional polymeric microcapsules promises various applications, such as cell therapy and biosensors, and provides a basic platform for studying microbial communications. However, the cytoprotection of microbes in the microcapsules against external aggressors has been a major challenge in the field of microbial microencapsulation, because ionotropic hydrogels widely used for microencapsulation swell uncontrollably, and are physicochemically labile. Herein, we developed a simple polydopamine coating for obtaining cytoprotective capability of the alginate capsule that encapsulated Saccharomyces cerevisiae. The resulting alginate/ polydopamine core/shell capsule was mechanically tough, prevented gel swelling and cell leakage, and increased resistance against enzymatic attack and UV-C irradiation. We believe that this multifunctional core/shell structure will provide a practical tool for manipulating microorganisms inside the microcapsules. [ABSTRACT FROM AUTHOR]

Background Potent immunomodulatory effects have been reported for mesenchymal stem/stromal cells (MSCs), multipotent adult progenitor cells (MAPCs), and fibroblasts. However, side-by-side comparisons of these cells specifically regarding immunophenotype, gene expression, and suppression of proliferation of CD4+ and CD8+ lymphocyte populations have not been reported. Methods We developed MAPC and MSC lines from rhesus macaque bone marrow and fibroblast cell lines from rhesus dermis and assessed phenotypes based upon differentiation potential, flow cytometric analysis of immunophenotype, and quantitative RT- PCR analysis of gene expression. Using allogeneic lymphocyte proliferation assays, we compared the in vitro immunomodulatory potency of each cell type. Results and Conclusions Extensive phenotypic similarities exist among each cell type, although immunosuppressive potencies are distinct. MAPCs are most potent, and fibroblasts are the least potent cell type. All three cell types demonstrated immunomodulatory capacity such that each may have potential therapeutic applications such as in organ transplantation, where reduced local immune response is desirable. [ABSTRACT FROM AUTHOR]

Many studies in the field of cell-based cartilage repair have focused on identifying markers associated with the differentiation status of human articular chondrocytes (HAC) that could predict their chondrogenic potency. A previous study from our group showed a correlation between the expression of S100 protein in HAC and their chondrogenic potential. The aims of the current study were to clarify which S100 proteins are associated with HAC differentiation status and to provide an S100-based assay for measuring HAC chondrogenic potential. The expression patterns of S100A1 and S100B were investigated in cartilage and in HAC cultured under conditions promoting dedifferentiation (monolayer culture) or redifferentiation (pellet culture or BMP4 treatment in monolayer culture), using characterized antibodies specifically recognizing S100A1 and S100B, by immunohistochemistry, immunocytochemistry, Western blot, and gene expression analysis. S100A1 and S100B were expressed homogeneously in all cartilage zones, and decreased during dedifferentiation. S100A1, but not S100B, was re-expressed in pellets and co-localized with collagen II. Gene expression analysis revealed concomitant modulation of S100A1, S100B, collagen type II, and aggrecan: down-regulation during monolayer culture and up-regulation upon BMP4 treatment. These results strongly support an association of S100A1, and to a lesser extent S100B, with the HAC differentiated phenotype. To facilitate their potential application, we established an S100A1/B-based flow cytometry assay for accurate assessment of HAC differentiation status. We propose S100A1 and S100B expression as a marker to develop potency assays for cartilage regeneration cell therapies, and as a redifferentiation readout in monolayer cultures aiming to investigate stimuli for chondrogenic induction. J. Cell. Physiol. 229: 1106-1117, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Nanofiber-expanded human umbilical cord blood-derived CD34+ cell therapy has been shown to have potential applications for peripheral and myocardial ischaemic diseases. However, the efficacies of expanded CD34+ cell therapy for treating cutaneous wounds and its mechanisms of action have yet to be established. Using an excisional wound model in non-obese diabetic/severe combined immune deficient mice, we show herein that CD34+ cells accelerate the wound-healing process by enhancing collagen synthesis, and increasing fibroblast cell migration within the wound bed. Concomitantly, reduced levels of matrix metalloproteinase ( MMPs) such as MMP1, MMP3, MMP9 and MMP13 were detected in the wound beds of animals treated with CD34+ cells compared with vehicle-treated controls. CD34+ cells were found to mediate enhanced migration and proliferation of dermal fibroblast cells in vitro. Moreover, CD34+ cells secrete collagen in a serum-deprived environment. In mechanistic studies, co-culture of CD34+ cells with primary skin fibroblasts increased the expression of collagen1A1, a component of type 1 collagen, and decreased the expression of MMP1 in fibroblast cells in the presence of a proteasome inhibitor. Finally, CD34+ cell-mediated functions were transcriptionally regulated by the c-Jun N-terminal kinases pathway. Collectively, these data provide evidence of therapeutic efficacy and a novel mechanism of nanofiber-expanded CD34+ cell-mediated accelerated wound healing. [ABSTRACT FROM AUTHOR]

During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini-review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof-of-principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α-synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union-funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Experimental neural cell therapies, including donor neural stem/progenitor cells ( NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system ( CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-β was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair. [ABSTRACT FROM AUTHOR]

Umbilical cord blood ( UCB) hematopoietic stem cells ( HSC- CD34+) are valuable for treating malignant or nonmalignant disease. Processing UCB by HESPAN-6% and anti- CD34- Miltenyi particles provides insufficient cells for treating adults. Physicochemical-electrokinetic studies on UCB-mononuclear cells (MNCs) under conditions of delayed processing, ice or very low temperatures, and some cell separation media identified artifacts introduced by procedures. Adsorption of biomaterials from cell damage by temperature, degradation products after using enzymes, harsh reagents, dithiothreitol, and HESPAN affect cell properties and distribution. Miltenyi particles internalized by cells could release iron that accumulating in liver or spleen would then risk toxicity. Summary topics included the effects of temperature, HESPAN (fast sedimenting agent), glycoproteases, DNase, and dithiothreitol risk affecting cell receptors in recognition, 'homing,' leading to possible unintended iatrogenic bioeffects should such cells be transfused into humans. The loss of undetectable and uncaptured low CD34 antigen-bearing cells by Miltenyi particles seems to occur when the current methods of isolation of CD34+ cells and other cells are critically assessed. The purpose here is to highlight and suggest avoiding the procedural flaws involved. Preventing ice temperatures avoids ice-damaged platelets releasing biomaterials that are adsorbed on cells altering UBC- MNCs/ HSC properties and cell loss. Omitting the positive selection with antibody-linked Miltenyi particles obviates the use of harsh reagents to release the cells. Internalized Miltenyi particles are a toxicity hazard that needs investigations. Achieving approximately 5% yields of CD34+ cells (153 × 105/110 mL cord-placenta blood) is a major advance holding great promise, for the first time increasing the prospect of stem cell therapy of 70-kg adults, using a single UCB donation (with dose of 1.5 × 105 cells/kg) and considerably cheaper cultured red blood cells manufacture (multiple packs/2 × 1012). [ABSTRACT FROM AUTHOR]

Critical to patient safety is the capability of rapidly tracing a medical product of human origin (MPHO) from donor to recipient and vice versa. Traceability requires that each product be uniquely identified in order to provide a clear, unambiguous path between donor and recipient. While historically an identifier was unique only to the facility that assigned it, it is becoming increasingly important that such identifiers be unique globally because some MPHO, especially cells and tissues, are distributed across national borders. This requires a coding system that supports the assignment of internationally unique identifiers. ISBT 128 is the terminology, coding and labelling system used by facilities across to world to ensure traceability. It is managed by ICCBBA, a non-governmental organization in official relations with the World Health Organization. [ABSTRACT FROM AUTHOR]

Stem cells have been shown to have the potential to provide a source of cells for applications to tissue engineering and organ repair. The mechanisms that regulate stem cell fate, however, mostly remain unclear. Mesenchymal stem cells ( MSCs) are multipotent progenitor cells that are isolated from bone marrow and other adult tissues, and can be differentiated into multiple cell lineages, such as bone, cartilage, fat, muscles and neurons. Although previous studies have focused intensively on the effects of chemical signals that regulate MSC commitment, the effects of physical/mechanical cues of the microenvironment on MSC fate determination have long been neglected. However, several studies provided evidence that mechanical signals, both direct and indirect, played important roles in regulating a stem cell fate. In this review, we summarize a number of recent studies on how cell adhesion and mechanical cues influence the differentiation of MSCs into specific lineages. Understanding how chemical and mechanical cues in the microenvironment orchestrate stem cell differentiation may provide new insights into ways to improve our techniques in cell therapy and organ repair. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics wich include the use of low-powered HoLEP in treating benign prostatic hyperplasia, assessment on monarc suburethral sling in women with stress urinary, and the effectivenees of cell therapy for stress urinary incontinence incontinence.

Despite decades of research, remaining safety concerns regarding disease transmission, heterotopic tissue formation, and tumorigenicity have kept stem cell-based therapies largely outside the standard-of-care for musculoskeletal medicine. Recent insights into trophic and immune regulatory activities of mesenchymal stem cells (MSCs), although incomplete, have stimulated a plethora of new clinical trials for indications far beyond simply supplying progenitors to replenish or re-build lost/damaged tissues. Cell banks are being established and cell-based products are in active clinical trials. Moreover, significant advances have also been made in the field of pluripotent stem cells, in particular the recent development of induced pluripotent stem cells. Their indefinite proliferation potential promises to overcome the limited supply of tissue-specific cells and adult stem cells. However, substantial hurdles related to their safety must be overcome for these cells to be clinically applicable. [ABSTRACT FROM AUTHOR]

Stem cells and their malignant counterparts require the support of a specific microenvironment or 'niche'. While various anti-cancer therapies have been broadly successful, there are growing opportunities to target the environment in which these cells reside to further improve therapeutic efficacy and outcome. This is particularly true when the aim is to target normal or malignant stem cells. The field aiming to target or use the niches that harbor, protect, and support stem cells could be designated as 'nichotherapy'. In this essay, we provide a few examples of nichotherapies. Some have been employed for decades, such as hematopoietic stem cell mobilization, whereas others are emerging, such as chemosensitization of leukemia stem cells by targeting their niche. [ABSTRACT FROM AUTHOR]

The Schneider membrane is the mucosa that covers the inner part of the maxillary sinus cavities. The free surface is a ciliated pseudostratified epithelium, while the deeper portion is a highly vascularized connective tissue. The stromal fraction, bordering the bony wall of the sinus, after tooth loss can exhibit increased osteoclastic activity resulting in resorption of the bone in the posterior maxilla. Goal of our study was to isolate and characterize mesenchymal progenitors in the Schneider's membrane connective net and to evaluate their self ability to differentiate toward osteoblastic lineage, in absence of osteoinductive factors and osteoconductive biomaterials of support. This should indicate that maxillary sinus membrane represents an useful an approachable source of MSCs for bone tissue engineering and cell therapy and owns the intrinsic capacity to restore maxillary bone after tooth loss without the needing of biomaterials. J. Cell. Physiol. 227: 3278-3281, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Cell-based therapy is considered a novel and potentially new strategy in regenerative medicine. But the efficacy of cell-based therapy has been limited by the poor survival of the transplanted cells in an ischaemic environment. The goal of the present study is to present a possibility to increase survival of the transplanted cardiomyocytes, by increasing the vascularization of the infarcted area. First, we injected endothelial progenitor cells (EPCs) to augment the vascular density in infarcted areas and to improve the benefit of a subsequent Tx of foetal cardiomyocytes. Serial echocardiography indeed showed significant improvement of the left ventricular function after application of EPC and a significant additive improvement after Tx of foetal cardiomyocytes. In contrast, repetitive EPC transplantation as a control group did not show an additional improvement after the second transplantation. Histologically, cells could be readily detected after Tx by BrdU-staining for EPC and by carboxy-fluorescein diacetate succinimidyl ester (CFSE)-staining for foetal cardiomyocytes. Staining for CD31 revealed a significant increase in vessel density in the infarction area compared with medium controls, possibly contributing to the benefit of transplanted foetal cardiomyocytes. Notably, a significant increase in the number of apoptotic cells was observed in cell-transplanted hearts accompanied by an increase in proliferation, collagen content and neutrophil infiltration, suggesting an active remodelling concomitant with sustained inflammatory processes. In conclusion, repetitive Tx of different cell types after myocardial infarction in rat hearts significantly improved left ventricular function and could represent a feasible option to enhance the benefit of cell therapy. [ABSTRACT FROM AUTHOR]

The relative merits of reduced-intensity allogeneic stem cell transplantation ( RISCT) for high-risk indolent lymphoid malignancies are emerging, although the preferred conditioning regimen to manage the risks of graft-versus-host disease ( GVHD) is not clearly defined. Here we report the outcome of 73 patients with lymphoid malignancies who received RISCT with a fludarabine/cyclophosphosphamide conditioning regimen and a median follow-up of 3 years. Median age was 54 years. Forty-eight per cent of patients had previously undergone autologous stem cell transplantation with a median of three prior therapies. Non-relapse mortality at 3 years was 19% but only 5% for patients with multiple myeloma ( MM). Three-year overall survival and current progression-free survival was 67% and 63% respectively. Grade 2-4 acute GVHD occurred in 14% of patients while 49% had chronic GVHD requiring systemic immunosuppression. The preparatory regimen in this study has the advantage of reduced acute GVHD and low mortality, notably in patients with MM. In addition, this strategy provides long-term disease control in a significant proportion of patients with particular benefit in those with high-risk follicular lymphoma. [ABSTRACT FROM AUTHOR]

The article offers information on the children with juvenile myelomonocytic leukaemia (JMML) and the haematological improvement observed after the chemotherapy. It is suggested that allogeneic haematopoietic stem cell transplantation (HSCT) is only curative treatment for JMML. It also presents the chart related to the number of patients who showed long-term haematological improvement despite no chemotherapy or after non-intensive chemotherapy is indicated in parenthesis.

The path to induced pluripotency, Discovery of a pan-species pluripotency network, Animal iPSCs and disease modelling, Issues with large animal iPSCs, Conclusions, The derivation of human embryonic stem cells and subsequently human induced pluripotent stem cells (iPSCs) has energized regenerative medicine research and enabled seemingly limitless applications. Although small animal models, such as mouse models, have played an important role in the progression of the field, typically, they are poor representations of the human disease phenotype. As an alternative, large animal models should be explored as a potentially better approach for clinical translation of cellular therapies. However, only fragmented information regarding the derivation, characterization and clinical usefulness of pluripotent large animal cells is currently available. Here, we briefly review the latest advances regarding the derivation and use of large animal iPSCs. [ABSTRACT FROM AUTHOR]

Myelofibrosis ( MF) is a heterogeneous disease for which long-term, effective medical therapeutic options are currently limited. The role of allogeneic haematopoietic stem cell transplant ( AHSCT) in this population, many of whom are elderly, often provides a challenge with regard to the identification of suitable candidates, timing of transplantation in the disease course and choice of conditioning regimen. This review summarizes key findings from published data concerning AHSCT in MF and attempts to provide a state of the art approach to MF- AHSCT in 2012. In addition, we postulate on how the era of JAK inhibition might impact on transplantation for MF. [ABSTRACT FROM AUTHOR]

Aging has less effect on adipose-derived mesenchymal stem cells (ADSCs) than on bone marrow-derived mesenchymal stem cells (BMSCs), but whether the fact holds true in stem cells from elderly patients with osteoporotic fractures is unknown. In this study, ADSCs and BMSCs of the same donor were harvested and divided into two age groups. Group A consisted of 14 young patients (36.4 ± 11.8 years old), and group B consisted of eight elderly patients (71.4 ± 3.6 years old) with osteoporotic fractures. We found that the doubling time of ADSCs from both age groups was maintained below 70 hrs, while that of BMSCs increased significantly with the number of passage. When ADSCs and BMSCs from the same patient were compared, there was a significant increase in the doubling time of BMSCs in each individual from passages 3 to 6. On osteogenic induction, the level of matrix mineralization of ADSCs from group B was comparable to that of ADSCs from group A, whereas BMSCs from group B produced least amount of mineral deposits and had a lower expression level of osteogenic genes. The p21 gene expression and senescence-associated β-galactosidase activity were lower in ADSCs compared to BMSCs, which may be partly responsible for the greater proliferation and differentiation potential of ADSCs. It is concluded that the proliferation and osteogenic differentiation of ADSCs were less affected by age and multiple passage than BMSCs, suggesting that ADSCs may become a potentially effective therapeutic option for cell-based therapy, especially in elderly patients with osteoporosis. [ABSTRACT FROM AUTHOR]

Autologous AD-MSC [adipose-derived MSC (mesenchymal stem cell)] therapy involves harvesting fat from the patient by isolating the stem and regenerative cells and administering the cells back to the patient. This study evaluated the production of canine AD-MSCs and their possible application in cellular therapy for dogs. To assess whether cellular therapy can replace drug therapy, the clinical effect of a single intra-articular injection of AD-MSCs was evaluated on 4 dogs with lameness associated with OA (osteoarthritis) of the humeroradial joints. MSCs were readily isolated from adult dog adipose tissue, and their ability to form colony and differentiate into various phenotypes was confirmed. AD-MSCs expressed OCT4, NANOG and SOX2 at the mRNA level, pluripotency markers usually ascribed to embryonic stem cells. The results suggest the stemness of the cells isolated from canine fat, and good quality control made them available for both experimental and clinical use. Follow-up studies to evaluate the effects of AD-MSC therapy showed that OA of the elbow joints improved with time, indicating significant potential for clinical use in the treatment of lameness, particularly when administered before the injury becomes severe. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) with ex vivo expanded tumour-infiltrating lymphocytes (TILs) in combination with IL-2 is an effective treatment for metastatic melanoma. Modified protocols of cell expansion may allow the treatment of most enrolled patients and improve the efficacy of adoptively transferred cells. The aims of this study were to establish and validate the novel 'Young TIL' method at our institution and perform a head-to-head comparison of clinical-grade products generated with this protocol opposed to the conventional 'Standard TIL', which we are currently using in a pilot ACT trial for patients with melanoma. Our results confirm that 'Young TILs' display an earlier differentiation state, with higher CD27 and lower CD56 expression. In addition, CD8+ TILs expressing CD27 had longer telomeres compared with the CD27−. A recently described subset of NK cells, endowed with a high expression of CD56 (CD56bright), was detected for the first time in both types of cultures but at a higher frequency on Young TILs. Young and Standard TILs' reactivity against autologous tumours was similar, with significant expression of TNF-α/IFN-γ/CD107a by CD8+ TILs detected in all cultures analysed. However, either slow expansion with high-dose IL-2 only or large numerical expansion with a rapid expansion protocol, which is required for current therapeutic protocols, significantly modified TIL phenotype by reducing the frequency of less differentiated, cancer-specific TILs. These studies further support the adoption of the Young TIL method in our current ACT trial and highlight the importance of continuous quality control of expansion protocols. [ABSTRACT FROM AUTHOR]

Background and Objectives TGF-β1 exerts important physiological functions in osteogenesis and chondrogenesis and may be of therapeutic interest. The aim of this work was to develop a scalable purification process of TGF-β1 from virally inactivated human platelets. Study Design and Methods Apheresis platelet concentrates ( N = 12) were solvent/detergent (S/D) treated (1% TnBP/1% Triton X-45; 31 °C) and the resulting platelet lysates were clarified by oil extraction and centrifugation, then chromatographed on an anion-exchange DEAE-Sepharose Fast-Flow column equilibrated in a PBS buffer, pH 7·5. The column was washed to eliminate unbound proteins and the S/D agents. Bound proteins were eluted using a 1 M NaCl-PBS buffer pH 7·5 (DEAE-eluate). The content in TGF-β1, PDGF-AB, VEGF, IGF-1, EGF, and b-FGF was measured by ELISA. Proteins, lipids, and S/D agents were assessed. Protein profile was determined by SDS-PAGE under reduced or non-reduced conditions. Results Most proteins, including albumin and immunoglobulins G, A, and M did not bind to the DEAE column as evidenced also by SDS-PAGE. Essentially all PDGF, VEGF, and IGF were in the breakthrough. The DEAE-eluate contained close to 60% of the TGF-β1 at a mean concentration of about 102 ng/ml, whereas EGF, b-FGF were at about 0·72 and 0·18 ng/ml, respectively. The content in TnBP and Triton X-45 was <2 ppm. Conclusion A fraction enriched in TGF-β1 can be prepared from virally inactivated human platelet lysates using an easily scale process. Its interest in regenerative medicine and cell therapy will be evaluated in further studies. [ABSTRACT FROM AUTHOR]

Fibrin is a natural biopolymer with many interesting properties, such as biocompatibility, bioresorbability, ease of processing, ability to be tailored to modify the conditions of polymerization, and potential for incorporation of both cells and cell mediators. Moreover, the fibrin network has a nanometric fibrous structure, mimicking extracellular matrix, and it can also be used in autologous applications. Therefore, fibrin has found many applications in tissue engineering, combined with cells, growth factors, or drugs. Because a major limitation of cardiac cell therapy is low cell engraftment, the use of biodegradable scaffolds for specific homing and in situ cell retention is desirable. Thus, fibrin-based injectable cardiac tissue engineering may enhance cell therapy efficacy. Fibrin-based biomaterials can also be used for engineering heart valves or cardiac patches. The aim of this review is to show cardiac bioengineering uses of fibrin, both as a cell delivery vehicle and as an implantable biomaterial. [ABSTRACT FROM AUTHOR]

Summary Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18 years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260 mg/m2 per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6·8 years, range, 1·2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow-up of 109 and 39 months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29·6% and 78·7%, respectively ( P = 0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL. [ABSTRACT FROM AUTHOR]

Human embryonic stem cells (hESCs) hold great promise for ushering in an era of novel cell therapies to treat a wide range of rare and common diseases, yet they also provide an unprecedented opportunity for basic research to yield clinical benefit. HESCs can be used to better understand human development, to model human diseases, to understand the contribution of specific mutations to the pathogenesis of disease, and to develop human cell-based screening systems to identify novel therapeutic agents and evaluate potential toxicity of therapeutic agents under development. Such basic research will benefit greatly from efficient methods to perform targeted gene modification, an area of hESC investigation that is currently in its infancy. Moreover, the reality of hESC-based cellular therapies will require improved methods for generating the specific cells of interest, and reporter cell lines generated through targeted gene modifications are expected to play an important role in developing optimal cell-specific differentiation protocols. Herein, we review the current status of homologous recombination in hESCs, a gene targeting technique that is sure to continue to improve, and to play an important role in realizing the maximal human benefit from hESCs. Clin Trans Sci 2011; Volume 4: 298-305 [ABSTRACT FROM AUTHOR]

Background and Objectives Recently, it was reported that leucocytes obtained from leucoreduction system chambers (LRSCs) after plateletapheresis show excellent quality due to culture of dendritic cells. This study analysed apoptosis of mononuclear cells derived from LRSCs of single platelet units (SPUs) and double platelet units (DPUs) during storage. Materials and Methods This randomized prospective study compared eighteen single and double platelet units produced with the Trima Accel cell separator. Buffy coat was drained from the LRSCs and analysed after 1, 6, 24, 48 and 72 h. CD45 + lymphocytes and CD14 + monocytes cells as well as Annexin-V+ and 7-AAD+ mononuclear cells were measured by flow cytometry. Results The WBC concentration of LRSCs obtained from SPUs and DPUs differed significantly (SPUs: 0∙93 ± 0∙32 × 105 per μl WBCs; DPUs: 1∙71 ± 0∙55 × 105 per μl WBCs; P < 0∙001). Processed blood volume (PBV) correlated significantly with WBC concentration (r2 = 0∙75, P < 0∙001). Fifty percent of monocytes were Annexin-V-positive 1 h after production decreasing to 30% during 24 h of storage. Compared to that, the part of late apoptotic or necrotic PBMCs increased later on, after 24 h. After 24 h, Annexin-V- and 7-AAD-positive, late apoptotic and necrotic lymphocytes and monocytes doubled. Conclusion PBMCs stored in autologous plasma in PVC-bags at room temperature did not show an increase of 7-AAD-positive PBMCs during 24 h prior to cell processing but increased significantly thereafter. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to compare different magnet arrangements for magnetic cell delivery to human lower leg arteries and investigate the theoretical targeting efficiency under realistic flow conditions as a possible treatment after angioplasty. Additionally the potential of scaling down or translating the magnetic actuation device for preclinical studies was explored.Methods: Using finite element methods, the magnetic field distribution was calculated in 3D for the optimization of magnet arrangements. Computational fluid dynamics simulations were performed for the human posterior tibial artery with the geometry and boundary condition data derived from magnetic resonance imaging (MRI) studies. These simulations were used to trace the trajectories of cells for an optimized magnet arrangement. Additionally the behavior of cells close to the vessel wall was investigated using a fluid-structure interaction model.Results: The optimal magnet for the lower leg arteries was a Halbach cylinder k3 variety (12 elements with 90° rotation steps for the magnetization orientation). With this magnet, numerical simulations predict a targeting efficiency of 6.25% could be achieved in the posterior tibial artery for cells containing 150 pg iron. Similar simulations, which were scaled down to rabbit dimensions while keeping the forces acting on a cell constant, lead to similar predicted targeting efficiencies. Fluid dynamic and fluid-structure interaction simulations predict that magnetically labeled cells within a 0.5% radii distance to the vessel wall would be attracted and remain at the wall under physiological flow conditions.Conclusions: First pass capture of magnetically labeled cells under pulsatile flow conditions in human lower leg arteries leads to low targeting efficiencies. However, this can be increased to almost 100% by stopping the blood flow for 5 min. A magnetic actuation device can be designed for animal models that generate magnetic forces achievable for cells in human leg arteries. [ABSTRACT FROM AUTHOR]

The use of stem cells derived from adipose tissue as an autologous and self-replenishing source for a variety of differentiated cell phenotypes, provides a great deal of promise for reconstructive surgery. In this article, we review available literature encompassing methods of extraction of pluripotent adipose stem cells (ASCs) from lipoaspirate locations, their storage, options for culture, growth and differentiation, cryopreservation and its effect on stem cell survival and proliferation, and new technologies involving biomaterials and scaffolds. We will conclude by assessing potential avenues for developing this incredibly promising field. [ABSTRACT FROM AUTHOR]

In this article the author discusses the effect of the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) on transplant rejection risk. The author reveals that anti-Neu5Gc antibodies are significant in xenotransplantation, allotransplantation and autotransplantation provided that methods are integrated with an ex vivo culturing phase using animal stem-cell-based therapies. Confusions and misconceptions on the value of Neu5Gc in biological therapies are also offered.

International regulatory authorities view risk management as an essential production need for the development of innovative, somatic cell-based therapies in regenerative medicine. The available risk management guidelines, however, provide little guidance on specific risk analysis approaches and procedures applicable in clinical cell therapy manufacturing. This raises a number of problems. Cell manufacturing is a poorly automated process, prone to operator-introduced variations, and affected by heterogeneity of the processed organs/tissues and lot-dependent variability of reagent (e.g., collagenase) efficiency. In this study, the principal challenges faced in a cell-based product manufacturing context (i.e., high dependence on human intervention and absence of reference standards for acceptable risk levels) are identified and addressed, and a risk management model approach applicable to manufacturing of cells for clinical use is described for the first time. The use of the heuristic and pseudo-quantitative failure mode and effect analysis/failure mode and critical effect analysis risk analysis technique associated with direct estimation of severity, occurrence, and detection is, in this specific context, as effective as, but more efficient than, the analytic hierarchy process. Moreover, a severity/occurrence matrix and Pareto analysis can be successfully adopted to identify priority failure modes on which to act to mitigate risks. The application of this approach to clinical cell therapy manufacturing in regenerative medicine is also discussed. [ABSTRACT FROM AUTHOR]