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T cells expressing either alpha-beta or gamma-delta T cell receptors (TCR) are critical sentinels of the adaptive immune system, with receptor diversity being essential for protective immunity against a broad array of pathogens and agents. Programs available to profile TCR clonotypic signatures can be limiting for users with no coding expertise. Current analytical pipelines can be inefficient due to manual processing steps, open to data entry errors and have multiple analytical tools with unique inputs that require coding expertise. Here we present a bespoke webtool designed for users irrespective of coding expertise, coined 'TCR_Explore', enabling analysis either derived via Sanger sequencing or next generation sequencing (NGS) platforms. Further, TCR_Explore incorporates automated quality control steps for Sanger sequencing. The creation of flexible and publication ready figures are enabled for different sequencing platforms following universal conversion to the TCR_Explore file format. TCR_Explore will enhance a user's capacity to undertake in-depth TCR repertoire analysis of both new and pre-existing datasets for identification of T cell clonotypes associated with health and disease. The web application is located at https://tcr-explore.erc.monash.edu for users to interactively explore TCR repertoire datasets., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)

Kinesin family member 20A (KIF20A) is a member of the kinesin family. It transports chromosomes during mitosis, plays a key role in cell division. Recently, studies proved that KIF20A was highly expressed in cancer. High expression of KIF20A was correlated with poor overall survival (OS). In this review, we summarized all the cancer that highly expressed KIF20A, described the role of KIF20A in cancer. We also organized phase I and phase II clinical trials of KIF20A peptides vaccine. All results indicated that KIF20A was a promising therapeutic target for multiple cancer., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Avoidance of immune destruction is recognized as one of the hallmarks of cancer development. Although first predicted as a potential antitumor treatment modality more than 50 years ago, the widespread clinical use of cancer immunotherapies has only recently become a reality. Cancer immunotherapy works by reactivation of a stalled pre-existing immune response or by eliciting a de novo immune response, and its toolkit comprises antibodies, vaccines, cytokines, and cell-based therapies. The treatment paradigm in some malignancies has completely changed over the past 10 to 15 years. Massive efforts in preclinical development have led to a surge of clinical trials testing innovative therapeutic approaches as monotherapy and, increasingly, in combination. Here we provide an overview of approved and emerging antitumor immune therapies, focusing on the rich landscape of therapeutic approaches beyond those that block the canonical PD-1/PD-L1 and CTLA-4 axes and placing them in the context of the latest understanding of tumor immunology., Competing Interests: This work was supported by the Emerson Collective and a Conquer Cancer Foundation Young Investigator Award. Dr Gill is named as an inventor on multiple CAR T–related patents. Dr Welty has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Purpose: Immunotherapy has become an important addition to oncology treatment plans in recent years. As these therapies become more widely employed, many unique side effects have been reported. In ophthalmology the most well-documented side effects of immune checkpoint inhibitors (ICI) include uveitis, macular edema and dry eye syndrome. This manuscript describes a rare case of bilateral choroidal effusions and secondary angle narrowing in the setting of systemic capillary leak syndrome (SCLS) from an HLA-directed vaccine and an ICI, pembrolizumab, for the treatment of stage IV squamous cell carcinoma (SCC) of the lung., Observations: A 67-year-old male with a history of stage IV SCC of the lung status-post pneumonectomy presented to the emergency department due to functional decline, anasarca, and dyspnea after receiving an HLA-directed vaccine in combination with pembrolizumab. Extensive workup revealed that his symptoms were secondary to SCLS. Ophthalmology was consulted due bilateral choroidal detachments seen on magnetic resonance imaging. B-scan ultrasound and ultrasound biomicroscopy revealed large, non-appositional choroidal effusions with anterior rotation of the ciliary body. Given minimal response to oral steroid therapy, sub-Tenon's triamcinolone acetonide, atropine, and intraocular pressure-lowering eyedrops were initiated with a good response., Conclusions and Importance: Choroidal effusions and secondary angle closure can be rare complications of SCLS in the setting of ICIs. Clinicians must be aware of the potentials side effects of ICI therapy, as these medications become more commonly used., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors.)

The relevance of protein-glycan interactions in immunity has long been underestimated. Yet, the immune system possesses numerous classes of glycan-binding proteins, so-called lectins. Of specific interest is the group of myeloid C-type lectin receptors (CLRs) as they are mainly expressed by myeloid cells and play an important role in the initiation of an immune response. Myeloid CLRs represent a major group amongst pattern recognition receptors (PRRs), placing them at the center of the rapidly growing field of glycoimmunology. CLRs have evolved to encompass a wide range of structures and functions and to recognize a large number of glycans and many other ligands from different classes of biopolymers. This review aims at providing the reader with an overview of myeloid CLRs and selected ligands, while highlighting recent insights into CLR-ligand interactions. Subsequently, methodological approaches in CLR-ligand research will be presented. Finally, this review will discuss how CLR-ligand interactions culminate in immunological functions, how glycan mimicry favors immune escape by pathogens, and in which way immune responses can be affected by CLR-ligand interactions in the long term., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Introduction: Mesenchymal stromal cells (MSCs) hold the potential for application as cellular therapy products; however, there are many problems that need to be addressed before the use in clinical settings, these include the heterogeneity of MSCs, scalability in MSC production, timing and techniques for MSC administration, and engraftment efficiency and persistency of administered MSCs. In this study, problems regarding immune rejection caused by human leukocyte antigen (HLA) mismatches were addressed., Methods: Umbilical cord-derived MSCs (UC-MSCs) were gene-edited to avoid allogeneic immunity. The HLA class I expression was abrogated by the knock-out of the beta-2-microglobulin (B2M) gene; instead, the B2M-HLA-G fusion gene was knocked-in using the CRISPR/Cas9 system in combination with adeno-associated virus (AAV)., Results: Cell surface markers on gene-edited UC-MSCs were not different from those on primary UC-MSCs. The gene-edited UC-MSCs also retained the potential to differentiate into adipocytes, osteoblasts, and chondrocytes. B2M gene knock-out alone protected cells from allogeneic T cell immune responses but were vulnerable to NK cells. B2M gene knock-out in combination with B2M-HLA-G knock-in protected cells from both T cells and NK cells. The B2M-HLA-G knock-in MSCs retained a good immunosuppressive ability and the addition of these cells into the mixing lymphocyte reaction showed a significant inhibition of T cell proliferation., Conclusions: The results of this study demonstrated the possibility that the CRISPR/Cas9 system combined with AAV can be used to effectively disrupt/introduce any gene into UC-MSCs. Our findings suggest that the gene-edited cell line produced here using this method may have a higher ability to escape the cytotoxic activity of immune cells than primary cells, thereby being more advantageous for long-term graft survival., Competing Interests: RN is employed by Daiwa Pharmaceutical. SM is employed by Keijinkai Medical Corporation. AT received a research grant from Daiwa Pharmaceutical. TN-I, TO, and MF has no conflicts of interest., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by repeated remissions and relapses. Immunosuppressive drugs have facilitated the induction and maintenance of remission in many patients with UC. However, immunosuppressive drugs cannot directly repair impaired intestinal mucosa and are insufficient for preventing relapse. Therefore, new treatment approaches to repair the damaged epithelium in UC have been attempted through the transplantation of intestinal organoids, which can be differentiated into mucosa by embedding in Matrigel, generated from patient-derived intestinal stem cells. The method, however, poses the challenge of yielding sufficient cells for UC therapy, and patient-derived cells might already have acquired pathological changes. In contrast, human induced pluripotent stem (iPS) cells generated from healthy individuals are infinitely proliferated and can be differentiated into target cells. Recently developed human iPS cell-derived intestinal organoids (HIOs) aim to generate organoids that closely resemble the adult intestine. However, no study till date has reported HIOs injected into in vivo inflammatory models, and it remains unclear whether HIOs with cells that closely resemble the adult intestine or with intestinal stem cells retain the better ability to repair tissue in colitis., Methods: We generated two types of HIOs via suspension culture with and without small-molecule compounds: HIOs that include predominantly more intestinal stem cells [HIO (A)] and those that include predominantly more intestinal epithelial and secretory cells [HIO (B)]. We examined whether the generated HIOs engrafted in vivo and compared their ability to accelerate recovery of the damaged tissue., Results: Findings showed that the HIOs expressed intestinal-specific markers such as caudal-type homeobox 2 ( CDX2 ) and villin, and HIOs engrafted under the kidney capsules of mice. We then injected HIOs into colitis-model mice and found that the weight and clinical score of the mice injected with HIO (A) recovered earlier than that of the mice in the sham group. Further, the production of mucus and the expression of cell proliferation markers and tight junction proteins in the colon tissues of the HIO (A) group were restored to levels similar to those observed in healthy mice. However, neither HIO (A) nor HIO (B) could be engrafted into the colon., Conclusions: Effective cell therapy should directly repair tissue by engraftment at the site of injury. However, the difference in organoid property impacting the rate of tissue repair in transplantation without engraftment observed in the current study should be considered a critical consideration in the development of regenerative medicine using iPS-derived organoids., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Abstract: Background. Microchimerism may play a part in transfusion complications. The aim of this study was to examine whether establishment of post-transfusion microchimerism was related to leukocyte content. Methods. Twenty non-pregnant female patients, without known malignant or immunological diseases, mean age 68 years, receiving 2–4 units of red blood cell concentrates during elective surgery, were included. One or two of the units were from male donors. Ten patients received buffy-coat depleted red blood cell concentrates, leukocyte count 108–109 per unit, and 10 patients received red blood cells leukoreduced by prestorage leukocyte filtration, with a leukocyte count of <106 per unit. EDTA samples were collected in vacuum tubes before and after 1 week and 6 months after transfusion. The tubes were frozen and stored at −400°C. Genomic DNA was isolated and PCR performed using four primer sets amplifying markers on the Y-chromosome. Results. Microchimerism was detected in a total of eight out of the 20 patients. In three patients microchimerism was detected only before transfusion. These patients had given birth to one or two boys each, and had no history of previous transfusion. Two patients receiving buffy-coat depleted red blood cell concentrates and two patients receiving leukoreduced red blood cell concentrates had detectable microchimerism 1 week after transfusion. The age of the transfused red blood cell concentrates was 6, 24, 8 and 7 days, respectively. One patient receiving leukoreduced red blood cell concentrates had detectable microchimerism after 6 months. The age of this concentrate was 22 days. Discussion. This study demonstrates that microchimerism after transfusion does not seem to be dose dependent, and can be induced even by a >3 week old leukoreduced red blood cell concentrate with a very low leukocyte content. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) is a common, systemic autoimmune disease of which the exact etiology is not known. In the past 10 years, substantial progress has been made in the identification of the antigens specifically recognized by the autoantibodies of RA patients. A central factor in this respect is citrullination, a form of post-translational modification that is strongly associated with autoimmunity in RA. Here, we summarize and discuss our current knowledge on (i) autoantibody systems in RA, (ii) the occurrence of peptidylarginine deiminases and (iii) citrullinated proteins in natural and diseased environments, and (iv) genetic factors involved in RA that may influence the generation and presentation of citrullinated proteins and the resulting antibody production against these modified proteins. Citrullination of proteins may play a key role in the initiation and/or the progression of RA. The onset of citrulline-specific autoimmunity in RA is probably mediated by both environmental and genetic factors, and future studies will learn whether therapeutic intervention at the level of citrullination may provide new possibilities to treat RA. [Copyright &y& Elsevier]

This study analyzed the expression of anti-islet autoantibodies and HLA-DR and -DQ genotypes in Korean children with type 1 diabetes mellitus (T1DM). The positivity of the anti-ICA512, anti-GAD65, and anti-insulin autoantibodies in the newly onset T1DM patients (n = 15) was 66.7%, 86.7%, and 46.7%, respectively, and all of them had one or more of the autoantibodies. HLA analysis showed higher frequencies of HLA-DRB1*0301, *0405, *09012 and -DQB1*0201, *0401, *03032 alleles in T1DM patients compared to controls (Pc < 0.05). Because HLA-DQB1*0401, *03032 alleles carry aspartic acid at position 57 of DQB, susceptibility to T1DM in Korean children was not related to the presence of aspartic acid at position 57 of DQB1 locus. We suggest this unique HLA-DR, -DQ allele distribution might be an important factor for the low incidence of T1DM in Korea, and the combined anti-islet autoantibody assays could be valuable screening markers for the early detection of T1DM in Korea. [Copyright &y& Elsevier]

Abstract: Comparison of human leukocyte antigen (HLA) frequencies in patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) and in patients with HCV-associated non-Hodgkin’s lymphoma (NHL) has not been addressed previously. To this aim, we investigated the distribution of HLA class II alleles in two selected groups of HCV-infected patients. Group 1 included 50 patients with HCV-associated NHL; group 2 included 29 patients with HCV-associated HCC. A control group included 144 hospitalized patients without NHL or HCC and who were negative for HCV, hepatitis B virus, and human immunodeficiency virus antibodies. Polymerase chain reaction sequence DRB1 and DQB1 specific-primer methods were used. DRB1*1101/DQB1*0301 haplotype, which mainly favors the spontaneous clearance of HCV infection, was lower in HCC subjects than in controls, whereas HLA-DRB1*1104/DQB1*0301, was higher in NHL patients. These findings suggest different pathogenic pathways in HCC and in NHL development. In patients with HCV-associated HCC, a major protective role of DQB1*0301 allele, rather than DRB1*11, was found, probably because of a better HLA class II-associated virus clearance. By contrast, the same allele as HLA-DRB1*04 showed an increase in HCV-associated NHL. These data suggest that NHL and HCC development may be associated to a different response with respect to chronic HLA class II-restricted antigen presentation (perhaps a switch toward CD4+Th2 response in NHL?) or, alternatively, that these alleles could be in linkage disequilibrium to unrelated gene(s), or are in synergy with other immunomodulatory genes that may confer increased risk for NHL. [Copyright &y& Elsevier]

Idiosyncratic drug reactions represent a major problem. In most cases the mechanisms of these reactions are unknown, but circumstantial evidence points to the involvement of reactive metabolites and the characteristics of the reactions suggest involvement of the immune system. If progress is to be made in dealing with these adverse reactions it is essential that we have a better understanding of their mechanisms, and it is hard to imagine testing mechanistic hypotheses without good animal models. Unfortunately, idiosyncratic reactions are also idiosyncratic in animals so few good models exist. The best models, in which a rodent develops a clinical syndrome similar to that which occurs in humans, appear to be penicillamine-induced autoimmunity in Brown Norway rats and nevirapine-induced skin rash in rats. Sulfamethoxazole-induced hypersensitivity in dogs and propylthiouracil-induced autoimmunity in cats are also similar to adverse reactions that occur in people, but they have practical limitations. Halothane-induced liver toxicity in guinea pigs and amodiaquine-induced bone marrow and liver toxicity in rats represent models in which there is an immune response and mild, reversible toxicity. It is possible that the development of immune tolerance is what limits the toxicity in these models, and if this is true, interventions that prevent tolerance might lead to good models. Although the history of developing animal models of idiosyncratic drug reactions is mostly one of failure, such models are essential. A better understanding of immune tolerance may greatly facilitate the development of better models; transgenic technology may also provide an important tool. [Copyright &y& Elsevier]

Identification of inhibitory killer Ig-like receptor (KIR) genes and their cognate human leukocyte antigen (HLA) class I ligands in donor–recipient pairs for patients undergoing haematopoietic stem cell transplantation (HCT) as treatment for haematopoietic malignancies has recently gained considerable interest. One incentive for these studies is to identify potential donors who are not HLA identical with the recipient but who still could serve as acceptable and potentially preferred donors based on their KIR genotype. It is demonstrated that a majority of individuals have at least one inhibitory KIR gene for which they lack the cognate HLA class I ligand. Therefore, the clinical benefits conferred by ‘missing KIR ligand’ might not be limited only to HLA mismatched donor-recipient combinations but may be applicable also to HLA identical transplants and even autologous HCT. [Copyright &y& Elsevier]

Killer Ig-like receptors (KIRs) are surface inhibitory receptors specific for allelic forms of human leukocyte antigen (HLA) class I molecules, which are expressed by natural killer (NK) cells and a subset of T lymphocytes. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. Cells lacking HLA class I molecules are promptly killed by NK cells because of the predominant effect of several activating NK receptors. The NK-mediated killing of these cells might represent an important defence mechanism, antagonizing spreading of pathogens and tumours. Evidence has been accumulated that KIR-encoding genes have evolved and diversified rapidly in primates and in humans. Similar to HLA loci, KIR sequences are highly polymorphic and, moreover, KIR haplotypes greatly vary in the number of the type of genes they contain. KIR gene expression is regulated by mechanisms of DNA methylation. As recently shown, the HLA class I regulated control of NK cell function can be exploited in an allogeneic bone marrow transplantation setting to eradicate acute myeloid leukaemias. [Copyright &y& Elsevier]

HLA class I antigen defects are frequently found in malignant cells. They appear to play a role in the clinical course of the disease, probably because they provide tumor cells with a mechanism to escape cytotoxic T lymphocyte (CTL) recognition and destruction. Expression of HLA class I antigens, however, is not always associated with the susceptibility of tumor cells to CTL lysis. Many mechanisms may underlie this finding, including the lack of tumor antigen (TA)-derived peptide presentation by a given HLA class I allospecificity, and/or the expression of immunosuppressive molecules such as HLA-G. These findings emphasize the need to develop probes to measure HLA class I allospecificity–TA peptide complex expression in malignant cells. Furthermore, the evaluation of the role of HLA class I antigens in the interaction of malignant cells with host immune cells should take into account the potential interference of tumor-derived immunomodulators. [Copyright &y& Elsevier]

Major histocompatibility complex class I (MHCI) and class II (MHCII) molecules display peptides on antigen-presenting cell surfaces for subsequent T-cell recognition. Within the human population, allelic variation among the classical MHCI and II gene products is the basis for differential peptide binding, thymic repertoire bias and allograft rejection. While available 3D structural analysis suggests that polymorphisms are found primarily within the peptide-binding site, a broader informatic approach pinpointing functional polymorphisms relevant for immune recognition is currently lacking. To this end, we have now analyzed known human class I (774) and class II (485) alleles at each amino acid position using a variability metric (V). Polymorphisms (V>1) have been identified in residues that contact the peptide and/or T-cell receptor (TCR). Using sequence logos to investigate TCR contact sites on HLA molecules, we have identified conserved MHCI residues distinct from those of conserved MHCII residues. In addition, specific class II (HLA-DP, -DQ, -DR) and class I (HLA-A, -B, -C) contacts for TCR binding are revealed. We discuss these findings in the context of TCR restriction and alloreactivity. [Copyright &y& Elsevier]

Pemphigus is a group of autoimmune blistering diseases caused by autoantibodies directed against keratinocyte adhesion molecules. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF), in which autoantibodies bind, respectively, to desmoglein 3 and desmoglein 1, are strongly associated with HLA-class II DR4 and DR14 alleles. In paraneoplastic pemphigus (PNP), a rare variant associated with neoplasia, autoantibodies target proteins of the plakin family in addition to desmogleins 1 and 3. The presence of anti-desmoglein antibodies in all types of pemphigus raises the question of common molecular mechanisms of susceptibility, particularly similar MHC-class II allele associations, in the different forms of the disease. HLA-DRB1 typing was performed in 13 PNP patients and results were compared to those obtained from 84 healthy controls, 37 PV and 31 PF patients. Our data demonstrate a significant association of PNP with HLA-DRB1&ast;03 allele which was found in 61.5% of the patients, whereas DRB1&ast;04 and DRB1&ast;14 appear not to be involved in PNP susceptibility. Therefore, the HLA-genetic background of PNP differs from that of other types of pemphigus, which suggests that distinct mechanism(s) initiate(s) the immunological response in this form of pemphigus. [Copyright &y& Elsevier]

The symptoms of Parkinson’s disease (PD) were first described nearly two centuries ago and its characteristic pathology identified nearly a century ago, yet its pathogenesis is still poorly understood. Parkinson’s disease is the most prevalent neurodegenerative movement disorder and research into its pathogenesis recently accelerated following the identification of a number of causal genetic mutations. The mutant gene products all cause dysfunction of the ubiquitin–proteosome system, identifying protein modification and degradation as critical for pathogenesis. Modified non-degraded intracellular proteins accumulate in certain neuronal populations in all forms of the disease. However, neuronal degeneration is more highly selective and associates with substantial activation of microglia, the inflammatory cells of the brain. We review the current change in thinking regarding the role of microglia in the brain in the context of Parkinson’s disease and animal models of the disease. Comparison of the cellular tissue changes across a number of animal models using diverse stimuli to mimic Parkinson’s disease reveals a consistent pattern implicating microglia as the effector for the selective degeneration of dopaminergic neurons. While previous reviews have concentrated on the intracellular neuronal changes in Parkinson’s disease, we highlight the cell to cell interactions and immune regulation critical for neuronal homeostasis and survival in Parkinson’s disease. [Copyright &y& Elsevier]

Our research has focused on the molecular design of immunotherapeutic vaccines and the advancement of mite-allergy diagnosis. Here, we describe the research history of the major group 1 and group 2 allergens, immunoelectrophoretic analyses covering the complete spectrum of mite allergens, our results on allergens with distinctive characteristics (a conjunctival congestion-eliciting antigen [LM2], an immunotherapeutic antigen [HM2] with high efficacy and without definite adverse reactions, and a potent T-cell stimulatory antigen [HM1] with secretion of IFN-γ), the full spectrum and immunochemical properties of the major and other important mite allergens (including our newly described allergens: a pan-allergen [tropomyosin, group 10], a potent T-cell stimulatory allergen [M-177, apolipophorin, group 14] and its peptide fragments Mag1 and Mag3, a moderate IgE-binding allergen [gelsolin/villin, group 16], an EF-hand Ca2+-binding allergen [group 17], and a less IgE-binding allergen [heat shock protein 70]), and prospects for the development of immunotherapeutic and diagnostic agents. [Copyright &y& Elsevier]

Pemphigus and pemphigoid are cutaneous autoimmune diseases characterised by autoantibodies directed against specific adhesion proteins of the epidermis and dermal–epidermal junction. These proteins are usually associated with desmosomes or hemidesmosomes. Binding of antibodies to their targets leads to the loss of cell–cell or cell–matrix adhesion and subsequently to blister formation. The humoral aspects of the autoimmune responses in pemphigus and pemphigoid have been extensively studied in the past. More recently, the cellular interactions resulting in the formation of autoantibodies and the involvement of autoreactive T cells in these diseases have attracted increased interest. In this review, the current knowledge on T cell involvement in pemphigus and pemphigoid is summarised. [ABSTRACT FROM AUTHOR]

While most immunotherapies for cancer have focused on eliciting specific CD8+ cytotoxic T lymphocyte killing of tumor cells, a mounting body of evidence suggests that stimulation of anti-tumor CD4+ T cell help may be required for highly effective therapy. Several MHC class II-restricted tumor antigens that specifically activate such CD4+ helper T lymphocytes have now been identified, including one from a melanoma tumor that is caused by a single base-pair mutation in the glycolytic enzyme triosephosphate isomerase. This mutation results in the conversion of a threonine residue to isoleucine within the antigenic epitope, concomitant with a greater than five log-fold increase in stimulation of a CD4+ tumor-infiltrating lymphocyte line. Here, we present the crystal structures of HLA-DR1 in complex with both wild-type and mutant TPI peptide antigens, the first structures of tumor peptide antigen/MHC class II complexes recognized by CD4+ T cells to be reported. These structures show that very minor changes in the binding surface for T cell receptor correspond to the dramatic differences in T cell stimulation. Defining the structural basis by which CD4+ T cell help is invoked in an anti-tumor immune response will likely aid the design of more effective cancer immunotherapies. [Copyright &y& Elsevier]

Natural killer (NK) inhibitory receptors are thought to play a critical role in the regulation of cytotoxicity of NK cells and certain self-reactive T cells. In the present study, we investigated whether astrocytoma infiltrating T lymphocytes may be functionally compromised by NK receptors (NKRs). The NK inhibitory receptor CD94/NKG2A was found on a significant proportion of CD8+ astrocytoma infiltrating lymphocytes. The functional consequences of CD94/NKG2A expression were explored at the clonal level, using a T cell clone that exhibited substantial variation in the expression of this heterodimer. Triggering of CD94/NKG2A inhibited the killing properties of T cells with a high level of this receptor, but not those from T cells with a low level. Our data indicate that some astrocytoma infiltrating lymphocytes express functional inhibitory CD94/NKG2A, raising the possibility that they may represent silent T cells specific for self-antigens (Ags) expressed on tumor cells. Understanding the mechanisms of regulation of these receptors may bring new insights for optimizing an anti-tumor immune response. [Copyright &y& Elsevier]

Hodgkin''s disease (HD) has been reported to be rare in Asians. Data sparseness has hindered studies exploring the relative contributions of environment and heredity to HD etiology, and individual risk factors have never been studied in an Asian population. With the most recent, uniformly collected population-based data from the US and Asia, we compared HD incidence rates in Chinese, Japanese, Filipinos, and Asian Indians in the US and in Asia. HD incidence rates were quite low in all Asian subgroups, but approximately double in US Asians as in native Asians. In both, rates were lower for Japanese and Chinese than for Filipinos and Asian Indians. A modest young-adult rate peak occurred for most US Asian groups, but not for any population in Asia. In data from a population-based case–control study of HD in San Francisco area women, young-adult Asian cases, like young-adult cases of other racial/ethnic groups, had childhood social environments indicative of less early contact with children. Given environmental and lifestyle differences between the US and Asia, the consistently low rates of HD in Asians suggest genetic resistance to disease development, possibly associated with HLA type. International and inter-ethnic differences, and risk factor patterns in case–control data, implicate environmental influences in the etiology of HD. [Copyright &y& Elsevier]

Graft verus host disease (GVHD) following Liver transplantation is rare life threatening complication with very high mortality rate around 85%. Due to increased recognition of this condition management approach is rapidly evolving due to newer diagnostic methods and drugs. Etiology, risk factors, pathogenesis, preventive strategies, management approach and newer drugs are discussed. We present our experience of 2 cases from a large cohort of 1052 Liver transplant operations over a decade., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: None disclosed.

Objective: Influenza A virus belongs to the most studied virus and its mutant initiates epidemic and pandemics outbreaks. Inoculation is the significant foundation to diminish the risk of infection. To prevent an incidence of influenza from the transmission, various practical approaches require more advancement and progress . More efforts and research must take in front to enhance vaccine efficacy., Methods: The present research emphasizes the development and expansion of a universal vaccine for the influenza virus. Research focuses on vaccine design with high efficacy. In this study, numerous computational approaches were used, covering a wide range of elements and ideas in bioinformatics methodology. Various B and T-cell epitopic peptides derived from the Neuraminidase protein N1 are recognized by these approaches. With the implementation of numerous obtained databases and bioinformatics tools, the different immune framework methods of the conserved sequences of N1 neuraminidase were analyzed. NCBI databases were employed to retrieve amino acid sequences. The antigenic nature of the neuraminidase sequence was achieved by the VaxiJen server and Kolaskar and Tongaonkar method. After screening of various B and T cell epitopes, one efficient peptide each from B cell epitope and T cell epitopes was assessed for their antigenic determinant vaccine efficacy. Identical two B cell epitopes were recognized from the N1 protein when analyzed using B-cell epitope prediction servers. The detailed examination of amino acid sequences for interpretation of B and T cell epitopes was achieved with the help of the ABCPred and Immune Epitope Database., Results: Computational immunology via immunoinformatic study exhibited RPNDKTG as having its high conservancy efficiency and demonstrated as a good antigenic, accessible surface hydrophilic B-cell epitope. Among T cell epitope analysis, YVNISNTNF was selected for being a conserved epitope. T cell epitope was also analyzed for its allergenicity and cytotoxicity evaluation. YVNISNTNF epitope was found to be a non-allergen and not toxic for cells as well. This T-cell epitope with maximum world populace coverages was scrutinized for its association with the HLA-DRB1*0401 molecule. Results from docking simulation analyses showed YVNISNTNF having lower binding energy, the radius of gyration (Rg), RMSD values, and RMSE values which make the protein structure more stable and increase its ability to become an epitopic peptide for influenza virus vaccination., Conclusions: We propose that this epitope analysis may be successfully used as a measurement tool for the robustness of an antigen-antibody reaction between mutant strains in the annual design of the influenza vaccine., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: Birdshot Retinochoroiditis (BRC) is an uncommon but distinct form of bilateral posterior uveitis. It is generally of indolent onset, making early natural history difficult to study. Our report seeks to expand knowledge on the natural history of the onset of BRC., Observations: Our patient presented with clinical features that were consistent with unilateral BRC, despite it being defined as a bilateral condition. Over the course of one year he developed retinal vasculitis, vitritis and fundus features of BRC in the second eye., Conclusions and Importance: Although BRC is a bilateral disease, our case demonstrates that the onset may sometimes be sequential instead of simultaneous. Unilateral disease that is characteristic of BRC should be monitored for second-eye involvement with multi-modal imaging including fundus photography, angiography, perimetry, electroretinography, and optical coherence tomography of the macula with emphasis on the choroidal thickness., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

The human host immune system wards off attacks by enemies such as viruses by mounting an inflammatory response which may sometimes injure self-tissues. Dysfunctional immune/inflammatory response by the host may affect the functioning of vital organs. The largest number of innate immune cells in the body resides in the liver. On encountering a new insult or injury to the liver, the innate immune system responds quickly to counter it. Acute liver insults may trigger acute liver failure or acute on chronic liver failure; these disorders are associated with a predominant innate immune response. Activation of the reticuloendothelial system (part of the innate immune response) predicts short-term and medium-term survival in patients with acute on chronic liver failure. Liver diseases associated with an aberrant adaptive immune response like autoimmune hepatitis respond well to treatment with steroids and other immunosuppressants, while those associated with innate immune dysfunction like acute on chronic liver failure do not respond well to steroids; recent reports suggest that the latter disorders may respond to therapeutic plasma exchange. How does the immune system in a patient with liver disease respond to SARS CoV2 infection? While commonly used tests in routine clinical practice provide clues to activation of different arms of immune response in patients with cirrhosis, specialized tests may help characterize this further. This review discusses the tests which reflect aberrant immune responses and treatment of patients with cirrhosis., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: None.

Tumor stemness is associated with tumor progression and therapy resistance. The recent advances in sequencing, genomics, and computational technologies have facilitated investigation into the tumor stemness cell-like characteristics. We identified subtypes of lung adenocarcinoma (LUAD) in bulk tumors or single cells based on the enrichment scores of 12 stemness signatures by clustering analysis of their transcriptomic profiles. Three stemness subtypes of LUAD were identified: St-H, St-M, and St-L, having high, medium, and low stemness signatures, respectively, consistently in six different datasets. Among the three subtypes, St-H was the most enriched in epithelial-mesenchymal transition, invasion, and metastasis signaling, genomically instable, irresponsive to immunotherapies and targeted therapies, and hence had the worst prognosis. We observed that intratumor heterogeneity was significantly higher in high-stemness than in low-stemness bulk tumors, but significantly lower in high-stemness than in low-stemness single cancer cells. Moreover, tumor immunity was stronger in high-stemness than in low-stemness cancer cells, but weaker in high-stemness than in low-stemness bulk tumors. These differences between bulk tumors and single cancer cells could be attributed to the non-tumor cells in bulk tumors that confounded the results of correlation analysis. Furthermore, pseudotime analysis showed that many St-H cells were at the beginning of the cell evolution trajectory, compared to most St-L cells in the terminal or later phase, suggesting that many low-stemness cells are originated from high-stemness cells. The stemness-based classification of LUAD may provide novel insights into the tumor biology as well as precise clinical management of this disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)

Competing Interests: None disclosed.

Objectives: Non-invasive biomarkers, for the diagnosis of celiac disease, can reduce the need for biopsy, particularly in pediatric patients. The aim of this study was to investigate the levels tissue transglutaminase antibody (tTG) and plasma citrulline and its correlation with intestinal biopsy., Methods: In this cross-sectional descriptive study, Pediatric patients with celiac disease referred to (XXX)were included. The patients underwent tTG antibody test along with plasma citrulline measurements using HPLC ((high performance liquid chromatography). Biopsy was performed in all the patients and clinical and demographic findings were recorded in a patient form. The data were statistically analyzed using SPSSv22., Results: Of 118 patients with celiac disease, the mean level of citrulline in patients was 17.48 ± 6.92 and the mean tTG titer was 183.17 ± 41.25. The two variables were inversely correlated with each other, p < 0.01. With an increase in Marsh levels, a significant reduction in citrulline levels and an increase in plasma tTG levels were seen, p < 0.01, respectively. The mean citrulline and tTG titer was not associated with gender and the age of the patients., Conclusion: Our findings indicate that citrulline and tTG antibody titer are significant biomarkers for the diagnosis of celiac disease and the severity of intestinal atrophy among pediatric patients., Competing Interests: The authors deny any conflict of interest in any terms or by any means during the study., (© 2022 The Authors.)

Objective: Extraintestinal manifestations in irritable bowel disease (IBD), Crohn's disease and ulcerative colitis are reported in different system of the body. We aimed to investigate the factors determining disease severity and evaluate extraintestinal manifestations in patients with irritable bowel disease based on disease activity scoring system., Methods: This cross-sectional study was conducted on all patients with irritable bowel disease referred to clinic and gastroenterology ward of (XXX). Medical history, gastrointestinal complications and incidence of extraintestinal manifestations were recorded. Disease severity in ulcerative colitis was rated based on PUCAI (Pediatric Ulcerative Colitis Activity Index) score and in Crohn's disease was calculated based on PCDAI (Pediatric Crohn's Disease Activity Index) score., Results: Of 73 children included in our study, 54.80% were diagnosed with ulcerative colitis and 45.20% were diagnosed with Crohn's disease. The most prevalent symptom was weight loss (81.81%), diarrhea (72.72%) and abdominal pain (69.69%) in Crohn's diseases and bloody diarrhea (80%), abdominal pain (77.5%) and weight loss (57.5%) in ulcerative colitis. The average of PCDAI score was 43.44 and PUCAI score was 35.62. The most prevalent extraintestinal manifestation of the disease was arthritis in 7 Crohn's disease patients (21.21%) and 5 patients (12.5%) with ulcerative colitis, oral plague in 5 patients (15.15%) with Crohn's disease and erythema nodosum in 2 patients (6.06%) with Crohn's disease., Conclusion: The severity of oral plaque was positively associated with the severity of the disease. There was no significant association among other parameters. Scoring systems, to determine the extraintestinal manifestation, should be standardized based on the scoring outcomes., Competing Interests: The authors deny any conflict of interest in any terms or by any means during the study. All the fees provided by research center fund and deployed accordingly., (© 2022 The Authors.)

Many risk factors and complications impact the success of liver transplantation, such as ischaemia-reperfusion injury, acute rejection, and primary graft dysfunction. Molecular biomarkers have the potential to accurately diagnose, predict, and monitor injury progression or organ failure. There is a critical opportunity for reliable and non-invasive biomarkers to reduce the organ shortage by enabling i) the assessment of donor organ quality, ii) the monitoring of short- and long-term graft function, and iii) the prediction of acute and chronic disease development. To date, no established molecular biomarkers have been used to guide clinical decision-making in transplantation. In this review, we outline the recent advances in cell-free nucleic acid biomarkers for monitoring graft injury in liver transplant recipients. Prior work in this area can be divided into two categories: biomarker discovery and validation studies. Circulating nucleic acids (CNAs) can be found in the extracellular environment pertaining to different biological fluids such as bile, blood, urine, and perfusate. CNAs that are packaged into extracellular vesicles may facilitate intercellular and interorgan communication. Thus, decoding their biological function, cellular origins and molecular composition is imperative for diagnosing causes of graft injury, guiding immunosuppression and improving overall patient survival. Herein, we discuss the most promising molecular biomarkers, their state of development, and the critical aspects of study design in biomarker research for early detection of post-transplant liver injury. Future advances in biomarker studies are expected to personalise post-transplant therapy, leading to improved patient care and outcomes., Competing Interests: The authors of this manuscript have no conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Introduction: Mature adipocyte-derived dedifferentiated fat cells (DFATs) are mesenchymal stem cell (MSC)-like cells with high proliferative ability and multilineage differentiation potential. In this study, we first examined whether DFATs can be prepared from infrapatellar fat pad (IFP) and then compared phenotypic and functional properties of IFP-derived DFATs (IFP-DFATs) with those of subcutaneous adipose tissue (SC)-derived DFATs (SC-DFATs)., Methods: Mature adipocytes isolated from IFP and SC in osteoarthritis patients (n = 7) were cultured by ceiling culture method to generate DFATs. Obtained IFP-DFATs and SC-DFATs were subjected to flow cytometric and microarray analysis to compare their immunophenotypes and gene expression profiles. Cell proliferation assay and adipogenic, osteogenic, and chondrogenic differentiation assays were performed to evaluate their functional properties., Results: DFATs could be prepared from IFP and SC with similar efficiency. IFP-DFATs and SC-DFATs exhibited similar immunophenotypes (CD73 + , CD90 + , CD105 + , CD31 - , CD45 - , HLA-DR - ) and tri-lineage (adipogenic, osteogenic, and chondrogenic) differentiation potential, consistent with the minimal criteria for defining MSCs. Microarray analysis revealed that the gene expression profiles in IFP-DFATs were very similar to those in SC-DFATs, although there were certain number of genes that showed different levels of expression. The proliferative activity in IFP-DFATs was significantly (p < 0.05) higher than that in the SC-DFATs. IFP-DFATs showed higher chondrogenic differentiation potential than SC-DFATs in regard to production of soluble galactosaminogalactan and gene expression of type II collagen., Conclusions: IFP-DFATs showed higher cellular proliferative potential and higher chondrogenic differentiation capacity than SC-DFATs. IFP-DFAT cells may be an attractive cell source for chondrogenic regeneration., Competing Interests: The authors declare that there is no conflict of interests in this article., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Competing Interests: This work was partially supported by an R01 grant from the National Cancer Institute (CA215134). Dr Majhail has served as consultant for Anthem and Incyte.

Background: Subacute thyroiditis (SAT) followed by Graves disease (GD) is a rare condition. We report the case of a patient with recurrent SAT with human leukocyte antigen (HLA)-associated predisposition to GD., Case Report: A 28-year-old Japanese woman presented with neck pain and hyperthyroidism symptoms. We observed elevated C-reactive protein and thyroid hormone levels, along with a high erythrocyte sedimentation rate. Further, anti-thyroid-stimulating hormone receptor antibody was undetected, and thyroid glands were heterogeneous and hypoechoic. These findings confirmed a diagnosis of SAT. The patient was treated with prednisone (starting dose, 30 mg), and clinical and laboratory data suggested an improvement. Six months later, the patient presented with recurrent clinical and biochemical features of hyperthyroidism (thyroid-stimulating hormone level, 0.003 mIU/mL; free thyroxine level, 3.14 ng/dL; and TSH receptor-stimulating autoantibodies, 220%). The patient was diagnosed with GD and was successfully treated with methimazole. Eleven years later, the patient was diagnosed with simultaneous SAT and GD. HLA-typing revealed that the patient possessed characteristic alleles associated with susceptibility to GD, such as HLA-DRB1∗04:03 and ∗15:01 , DQB1∗03:02:01 and 06:02:01 , and HLA DPB1∗05:01 alleles., Discussion: The occurrence of SAT may trigger thyroid antigen release and lead to the onset of GD in patients who are genetically predisposed to this autoimmune disorder., Conclusion: For certain patients, the diagnosis of GD should be considered in case of recurrent hyperthyroidism and history of resolved SAT., (© 2021 AACE. Published by Elsevier Inc.)

A patient with vascular Behçet's syndrome (BS), a subtype of BS with mainly venous/arterial manifestations, presented with a left main aneurysm/thrombus and cardiogenic shock. The clinical diagnosis of BS includes mucocutaneous, vascular, and neurologic criteria. It is important to consider vascular BS as a nonatherosclerotic cause of coronary aneurysms. ( Level of Difficulty: Intermediate. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, -5, -13, -25, -33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, -5, -13, -25, -33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The outbreak of coronavirus disease 2019 (COVID-19) was caused by the newly emerged corona virus (2019-nCoV alias SARS-CoV-2) that resembles the severe acute respiratory syndrome virus (SARS-CoV). SARS-CoV-2, which was first identified in Wuhan (China) has spread globally, resulting in a high mortality worldwide reaching ~4 million deaths to date. As of first week of July 2021, ~181 million cases of COVID-19 have been reported. SARS-CoV-2 infection is mediated by the binding of virus spike protein to Angiotensin Converting Enzyme 2 (ACE2). ACE2 is expressed on many human tissues; however, the major entry point is probably pneumocytes, which are responsible for synthesis of alveolar surfactant in lungs. Viral infection of pneumocytes impairs immune responses and leads to, apart from severe hypoxia resulting from gas exchange, diseases with serious complications. During viral infection, gene products (e.g. ACE2) that mediate viral entry, antigen presentation, and cellular immunity are of crucial importance. Human leukocyte antigens (HLA) I and II present antigens to the CD8 + and CD4 + T lymphocytes, which are crucial for immune defence against pathogens including viruses. HLA gene variants affect the recognition and presentation of viral antigenic peptides to T-cells, and cytokine secretion. Additionally, endoplasmic reticulum aminopeptidases (ERAP) trim antigenic precursor peptides to fit into the binding groove of MHC class I molecules. Polymorphisms in ERAP genes leading to aberrations in ERAP's can alter antigen presentation by HLA class I molecules resulting in aberrant T-cell responses, which may affect susceptibility to infection and/or activation of immune response. Polymorphisms from these genes are associated, in global genetic association studies, with various phenotype traits/disorders many of which are related to the pathogenesis and progression of COVID-19; polymorphisms from various genes are annotated in genotype-tissue expression data as regulating the expression of ACE2, HLA's and ERAP's. We review such polymorphisms and illustrate variations in their allele frequencies in global populations. These reported findings highlight the roles of genetic modulators (e.g. genotype changes in ACE2 , HLA 's and ERAP 's leading to aberrations in the expressed gene products or genotype changes at other genes regulating the expression levels of these genes) in the pathogenesis of viral infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Purpose and Objectives: Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci., Results: Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score ≤3a and/or eQTL effect) located between 100 kB upstream and downstream of CCR9 and CCL25 are associated with celiac disease and/or selected phenotypes. Of the genotyped SNPs in the CCR9 loci, rs213360 with an eQTL effect on CCR9 expression in blood was associated with celiac disease and all investigated phenotypes except high HLA risk. Rs1545985 with an eQTL on CCR9 expression and rs7652331 and rs12493471, both with RegulomeDB score ≤3a, were all associated with gastrointestinal symptoms and malabsorption and the latter additionally with anemia. The genotyped CCL25 SNPs rs952444 and rs882951, with RegulomeDB scores 1d and 1f respectively and eQTL effect on CCL25 expression in small intestine, were associated with gastrointestinal symptoms and malabsorption. The CCL25 SNP rs2303165 identified in sequencing followed by imputation was associated with partial villous atrophy. However, the association did not pass the permutation based multiple testing correction (P EMP2  > 0.05)., Conclusions: We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Competing Interests: None disclosed.

Objectives: To establish a protocol to prepare and transplant clinical-grade human induced pluripotent stem cell (hiPSC)-derived cardiac tissues (HiCTs) and to evaluate the therapeutic potential in an animal myocardial infarction (MI) model., Methods: We simultaneously differentiated clinical-grade hiPSCs into cardiovascular cell lineages with or without the administration of canonical Wnt inhibitors, generated 5- layer cell sheets with insertion of gelatin hydrogel microspheres (GHMs) (HiCTs), and transplanted them onto an athymic rat MI model. Cardiac function was evaluated by echocardiography and cardiac magnetic resonance imaging and compared with that in animals with sham and transplantation of 5-layer cell sheets without GHMs. Graft survival, ventricular remodeling, and neovascularization were evaluated histopathologically., Results: The administration of Wnt inhibitors significantly promoted cardiomyocyte (CM) ( P  < .0001) and vascular endothelial cell (EC) ( P  = .006) induction, which resulted in cellular components of 52.0 ± 6.1% CMs and 9.9 ± 3.0% ECs. Functional analyses revealed the significantly lowest left ventricular end-diastolic volume and highest ejection fraction in the HiCT group. Histopathologic evaluation revealed that the HiCT group had a significantly larger median engrafted area (4 weeks, GHM(-) vs HiCT: 0.4 [range, 0.2-0.7] mm 2 vs 2.2 [range, 1.8-3.1] mm 2 ; P  = .005; 12 weeks, 0 [range, 0-0.2] mm 2 vs 1.9 [range, 0.1-3.2] mm 2 ; P  = .026), accompanied by the smallest scar area and highest vascular density at the MI border zone., Conclusions: Transplantation of HiCTs generated from clinical-grade hiPSCs exhibited a prominent therapeutic potential in a rat MI model and may provide a promising therapeutic strategy in cardiac regenerative medicine., (© 2021 The Author(s).)

Introduction: Transplantation of IC-2-engineered bone marrow-derived mesenchymal stem cell (BM-MSC) sheets (IC-2 sheets) was previously reported to potentially reduce liver fibrosis., Methods: This study prepared IC-2-engineered cell sheets from multiple lots of BM-MSCs and examined the therapeutic effects of these cell sheets on liver fibrosis induced by carbon tetrachloride in mice. The predictive factors for antifibrotic effect on liver fibrosis were tried to identify in advance., Results: Secreted matrix metalloproteinase (MMP)-14 was found to be a useful predictive factor to reduce liver fibrosis. Moreover, the cutoff index of MMP-14 for 30% reduction of liver fibrosis was 0.918 fg/cell, judging from univariate analysis and receiver operating curve analysis. In addition, MMP-13 activity and thioredoxin contents in IC-2 sheets were also inversely correlated with hepatic hydroxyproline contents. Finally, IC-2 was also found to promote MMP-14 secretion from BM-MSCs of elderly patients. Surprisingly, the values of secreted MMP-14 from BM-MSCs of elderly patients were much higher than those of young persons., Conclusion: The results of this study suggest that the IC-2 sheets would be applicable to clinical use in autologous transplantation for patients with cirrhosis regardless of the patient's age., Competing Interests: G.S. holds more than 5% of the total shares of KanonCure Inc. and receives compensation as a member of KanonCure Inc. The other authors have no competing interests to declare. Tottori university and KanonCure Inc. have the patents for IC-2 sheets (patent registration numbers, US 9,555,061, DE602012040872.3, ES2698365, FR2698365, GB269835, and IT502018000006592), and patent applications (patent application numbers TW107129167, US16/641,874, CN201880054224.7, EP18851336.0, PCT/JP2019/021603, US16/972,285, and EP198156721)., (© 2021 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Left ventricular assist devices (LVADs) are surgically implanted mechanical devices indicated for patients with advanced heart failure and are known to come with several complications. Here we present a case series, and review 1 documented report, of LVAD vasculitis, a presumed new LVAD immune/humoral related phenomenon. ( Level of Difficulty: Advanced. )., Competing Interests: Dr Garcia is supported by the National Heart, Lung, and Blood Institute, Institutes of Health, under Aware Number 5T32HL110837. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 Published by Elsevier on behalf of the American College of Cardiology Foundation.)