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Nature Reviews. Cancer Apr 2021The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest... (Review)
Review
The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
Topics: ADAM Proteins; ADAMTS Proteins; Bone Morphogenetic Protein 1; Cathepsins; Cell Movement; Collagen; Cystatins; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillins; Glucuronidase; Glycoproteins; Humans; Hyaluronoglucosaminidase; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Protein Processing, Post-Translational; Proteoglycans; Serpins; Tissue Inhibitor of Metalloproteinases; Tolloid-Like Metalloproteinases; Tumor Microenvironment
PubMed: 33589810
DOI: 10.1038/s41568-020-00329-7 -
Nature Jun 2021Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to...
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre;Ercc1 or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre;Ercc1 mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Topics: Aging; Animals; DNA Damage; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Healthy Aging; Homeostasis; Immune System; Immunosenescence; Male; Mice; Organ Specificity; Rejuvenation; Sirolimus; Spleen
PubMed: 33981041
DOI: 10.1038/s41586-021-03547-7 -
Transplant International : Official... Nov 2021The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to... (Review)
Review
The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.
Topics: Animals; Heterografts; Humans; Models, Animal; Organ Transplantation; Transplantation, Heterologous; Transplants
PubMed: 34459040
DOI: 10.1111/tri.14031 -
Frontiers in Immunology 2019The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective... (Review)
Review
The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective approach for the treatment of end-stage organ failure; however, the imbalance between organ supply and the demand for human organs is a bottleneck for clinical transplantation. Therefore, xenotransplantation might be a promising alternative approach to bridge the gap between the supply and demand of organs, tissues, and cells; however, immunological barriers are limiting factors in clinical xenotransplantation. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable. In this review, we focus on the evolution and current status of xenotransplantation research, including our current understanding of the immunological mechanisms involved in xenograft rejection, genetically modified pigs used for xenotransplantation, and progress that has been made in developing pig-to-pig-to-non-human primate models. Three main types of rejection can occur after xenotransplantation, which we discuss in detail: (1) hyperacute xenograft rejection, (2) acute humoral xenograft rejection, and (3) acute cellular rejection. Furthermore, in studies on immunological rejection, genetically modified pigs have been generated to bridge cross-species molecular incompatibilities; in the last decade, most advances made in the field of xenotransplantation have resulted from the production of genetically engineered pigs; accordingly, we summarize the genetically modified pigs that are currently available for xenotransplantation. Next, we summarize the longest survival time of solid organs in preclinical models in recent years, including heart, liver, kidney, and lung xenotransplantation. Overall, we conclude that recent achievements and the accumulation of experience in xenotransplantation mean that the first-in-human clinical trial could be possible in the near future. Furthermore, we hope that xenotransplantation and various approaches will be able to collectively solve the problem of human organ shortage.
Topics: Animals; Animals, Genetically Modified; Biomarkers; Blood Coagulation Disorders; Disease Management; Gene Expression Regulation; Graft Rejection; Graft Survival; Haplorhini; Humans; Immunity, Cellular; Immunity, Humoral; Models, Animal; Species Specificity; Swine; Translational Research, Biomedical; Transplantation Immunology; Transplantation, Heterologous
PubMed: 32038617
DOI: 10.3389/fimmu.2019.03060 -
Clinical Transplantation Sep 2019These guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of... (Review)
Review
These guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of post-operative surgical site infections (SSIs) in solid organ transplantation. SSIs are a significant cause of morbidity and mortality in SOT recipients. Depending on the organ transplanted, SSIs occur in 3%-53% of patients, with the highest rates observed in small bowel/multivisceral, liver, and pancreas transplant recipients. These infections are classified by increasing invasiveness as superficial incisional, deep incisional, or organ/space SSIs. The spectrum of organisms implicated in SSIs in SOT recipients is more diverse than the general population due to other important factors such as the underlying end-stage organ failure, immunosuppression, prolonged hospitalizations, organ transportation/preservation, and previous exposures to antibiotics in donors and recipients that could predispose to infections with multidrug-resistant organisms. In this guideline, we describe the epidemiology, clinical presentation, differential diagnosis, potential pathogens, and management. We also provide recommendations for the selection, dosing, and duration of peri-operative antibiotic prophylaxis to minimize post-operative SSIs.
Topics: Communicable Diseases; Humans; Organ Transplantation; Practice Guidelines as Topic; Societies, Medical; Surgical Wound Infection
PubMed: 31077619
DOI: 10.1111/ctr.13589 -
American Journal of Transplantation :... Feb 2023The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting... (Review)
Review
The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols.
Topics: Humans; United States; Tissue and Organ Procurement; Organ Transplantation; Tissue Donors; Cardiovascular System; Perfusion; Death; Organ Preservation
PubMed: 36695685
DOI: 10.1016/j.ajt.2022.10.009 -
Hematology/oncology Clinics of North... Dec 2020Please add expansion for AL. Hematologic disease control combined with solid organ transplantation can result in long-term survival in selected patients with light chain... (Review)
Review
Please add expansion for AL. Hematologic disease control combined with solid organ transplantation can result in long-term survival in selected patients with light chain (AL) amyloidosis and limited other organ involvement. Restoration of critical cardiac function with organ transplantation can render patients eligible for effective disease-directed therapies, including high-dose therapy and autologous stem cell transplantation. Access to directed-donor organs, exchange programs for renal transplantation, and extended-donor organs for cardiac transplantation improves the availability of organs for patients with AL amyloidosis. Disease recurrence in the graft and progression in other organs remain concerns but often can be managed with a variety of effective plasma cell-directed therapies.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Organ Transplantation; Transplantation Conditioning; Transplantation, Autologous
PubMed: 33099431
DOI: 10.1016/j.hoc.2020.08.006 -
Transplant International : Official... Nov 2021In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We... (Meta-Analysis)
Meta-Analysis
In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.
Topics: Death; Graft Survival; Humans; Organ Preservation; Organ Transplantation; Perfusion; Retrospective Studies; Tissue Donors; Tissue and Organ Procurement
PubMed: 34570380
DOI: 10.1111/tri.14121 -
Clinical Transplantation Sep 2019These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice provide recommendations for the diagnosis and management...
These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice provide recommendations for the diagnosis and management of Candida infections in solid organ transplant recipients. Candida infections manifest primarily as candidemia and invasive candidiasis and cause considerable morbidity and mortality. Early diagnosis and initiation of treatment are necessary to reduce mortality. For both candidemia and invasive candidiasis, an echinocandin is recommended for initial therapy. However, early transition to oral therapy is encouraged when patients are stable and the organism is susceptible. Candida prophylaxis should be targeted for high-risk patients in liver, small bowel, and pancreas transplant recipients. Future research should address which patient groups may benefit most from preventative antifungal therapy strategies.
Topics: Antifungal Agents; Candida; Candidiasis; Humans; Organ Transplantation; Practice Guidelines as Topic; Societies, Medical; Transplant Recipients
PubMed: 31155770
DOI: 10.1111/ctr.13623