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关键词： B-leader   donor age   haploidentical   HLA matched sibling donor   post-transplantation cyclophosphamide   PTCy  

关键词： HLA-E*01:01:46   next-generation sequencing   novel allele  

摘要： HLA-E*01:01:46 differs from HLA-E*01:01:01:01 by a single nucleotide substitution at position 12 A>C.

关键词： Major depressive episode   Th1   Th17   Exhausted CD8 (+) lymphocytes   CD4+CD10+lymphocytes  

摘要： Depression is a highly prevalent psychiatric condition referred to as a major depressive episode (MDE). The underlying causes and mechanisms of depression remain poorly elucidated and, in consequence, the efficacy of the current therapies. Inflammation has been proposed to contribute to the pathophysiology of MDE with altered innate and adaptive immune responses. The present work aimed to shed light on the effector CD4(+) T helper (Th) cell subsets response and the activation and exhaustion condition of CD8(+) lymphocytes in the peripheral blood of patients with MDE. Patients with MDE (n = 57) and healthy controls (HCs) (n = 34) were recruited. The intracellular production of interferon (IFN) gamma (Th1), interleukin (IL)-17 (Th17), and IL-10 (CD4(+) IL-10(+)) as the activation and exhausted status of CD8(+) lymphocytes were evaluated by flow cytometry. The frequencies of Th1 and Th17 cells did not show statistical differences, but a lower percentage of CD4(+)IL-10(+) cells (P < 0.05) and CD4(+)IFN gamma+IL-10(+) cells (P < .01) were found in patients with MDE compared with HCs. The reduction in the CD4(+)IL-10(+) and CD4(+)IFN gamma+IL-10(+) population negatively correlated with the number of depressive episodes (P < .05 and P < .01) and duration of illness (P < .01). A higher proportion of activated CD8(+)CD69(+) (P < .0001) with potentially exhausted phenotype CD8(+)PD1(+)LAG3(+) (P < .0001) were observed, which positively correlated with the severity, number of episodes, and duration of illness in MDE compared with HCs. Altogether, patients with MDE are characterized by unbalanced Th1/Th17/CD4(+)IL-10(+) cells and increased activation and exhaustion of cytotoxic CD8(+) T cells. Therapeutic strategies restoring this balance and effective control of inflammatory responses may be beneficial in MDE.

关键词： diverse ethnicity   HLA imputation   reference panel  

摘要： HLA molecules are produced by genes within the Major Histocompatibility Complex (MHC). Although the identification of HLA genotype is costly, fortunately, recent computational methods have made it possible to impute HLA genotypes using inexpensive single nucleotide polymorphism (SNP) markers. These imputation methods perform well if ethnicity-matched reference panels are provided. However, the availability of large-sized panels specific to each ethnicity remains limited. As a result, to achieve better imputation for each population, we need to utilise available multiple reference panels together. In this study, we introduce MultiCook, which enables users to simultaneously utilise existing multiple HLA imputation methods with multiple reference panels. MultiCook is versatile in that panels typed with different SNP genotyping platforms can seamlessly be merged, outputs from multiple imputation methods can be combined and the output from the Michigan imputation server with a multiethnic reference panel can also be incorporated. We compared MultiCook to the existing single-reference-panel approaches and the Michigan HLA imputation server. In evaluation with a cohort of 413 Koreans, MultiCook reduced the imputation error rate by about one third, from 4.70% to 3.31%, by combining 1KG EAS (N = 504) and HAN Chinese (N = 9773) reference panels compared to the single-panel approach. Moreover, MultiCook achieved better accuracy for imputing low-frequency alleles in evaluation benchmarks.

关键词： PLOD1   HCC   NF-KB   STAT3   TCA cycle   Tumor stem cell  

摘要： Background & Aims: Procollagen lysyl hydroxylase 1 (PLOD1) is crucial in regulating collagen synthesis and cross-linking. However, its roles and underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we aimed to investigate the underlying biological functions and mechanisms of PLOD1 in HCC. Methods: The expression levels of PLOD1 in HCC were measured by qPCR, Western blot, and immunohistochemistry. Cell proliferation, apoptosis, and stemness were examined by CCK8, flow cytometry, sphere formation, and aldehyde dehydrogenase activity assays. The subcutaneous tumorigenicity model, orthotopic tumorigenicity model, and hepatotoxin-induced HCC model were used for in vivo experiments. RNA-sequence and untargeted metabolomics analysis were performed to identify underlying mechanisms. Results: PLOD1 is found to be highly expressed in both human (p <0.0001) and mouse HCC (p <0.01) and is associated with a poor prognosis (p = 0.047). In vitro and in vivo experiments reveal that overexpression of PLOD1 promotes the proliferation and stemness of HCC cells. Meanwhile, the depletion of PLOD1 attenuates the occurrence and growth of HCC, leading to cell cycle arrest (p <0.01) and apoptosis (p <0.001) in HCC. Mechanistically, PLOD1 positively regulates the NF-jB/IL-6/STAT3 signaling pathway and accelerates TCA cycle metabolic reprogramming. Blocking the NF-jB/IL-6/STAT3 signaling pathway and TCA cycle can effectively mitigate PLOD1-induced proliferation and stemness of HCC cells. Conclusions: Our study uncovers the PLOD1/NF-jB/IL-6/STAT3 axis as a therapeutic target for inhibiting the progression and stemness of HCC. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

摘要： HLA-DPB1*1782:01 differs from HLA-DPB1*04:02:01:01 by a non-synonymous nucleotide substitution at codon 87.

关键词： Acute transverse myelitis   COVID-19   Tumor necrosis factor-alpha inhibitor   Ulcerative colitis  

摘要： We report a case of acute transverse myelitis (ATM) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a 59-year-old man. This patient had been treated for ulcerative colitis (UC) for 4.5 years with several medications, including a tumor necrosis factor (TNF)-alpha inhibitor. Because this patient developed ATM almost concurrently with the onset of coronavirus disease 2019, SARS-CoV-2 infection was considered the likely cause of ATM, although TNF-alpha inhibitor therapy and the autoimmune condition UC might also have played a role.

关键词： SARS-CoV-2   MERS-CoV   Interferon lambda   Therapeutics   Variants of concern  

摘要： Therapeutic options against pathogenic human coronaviruses remain limited. In a recent clinical trial, we demonstrated the therapeutic efficacy of pegylated-IFN-lambda in COVID-19 outpatients. However, the emergence of variants that have the potential to evade IFN-mediated antiviral responses raises concerns regarding the continued efficacy of this approach. In this work, we compared the sensitivity of SARS-CoV-2 variants and MERSCoV to IFN-lambda treatment in vitro and explored the potential of combination therapy with other FDA-authorized or approved antiviral agents. We observed that in contrast to the ancestral strain, all other SARS-CoV-2 lineages showed varying, but increased resistance to IFN-lambda treatment, from a 5.7-fold increase in EC50 value for the P.1 strain to a 32.7-fold increase for the B.1.1.7 variant. We further show that combination treatment with remdesivir or nirmatrelvir enhanced the antiviral effect of IFN-lambda against both SARS-CoV-2 and MERS-CoV. These findings justify the initiation of further in vivo testing that ultimately can help inform the development of more effective therapeutic guidelines against pathogenic coronaviruses.

关键词： Autoimmunity   Shared epitope   Cardiovascular disease  

摘要： Objective: Rheumatoid arthritis (RA) has been considered an independent risk factor for cardiovascular disease (CVD), where RA and CVD later manifest following genetic predisposition and an extended preclinical phase. The HLA-DRB1 Shared Epitope (SE) alleles predispose for RA and are associated with higher risk of CV mortality in RA patients, but have not been evaluated in a community-living population. Thus, we evaluated whether HLA-DRB1 (SE) alleles were associated with subclinical CVD, CV events, and mortality in the MultiEthnic Study of Atherosclerosis (MESA). Methods: We performed HLA typing in 955 MESA participants and evaluated associations of SE alleles with coronary artery calcium (CAC) and abdominal aortic calcium (AAC);risk difference for CAC, AAC severity, and carotid intima media thickness (cIMT);and associations of SE with all-cause mortality, CVD and nonCVD death, and CV events. Results: Among 955 participants, 30 % were HLA-DRB1 SE positive. SE positivity was not significantly associated with higher risk of CAC, AAC, cIMT, CV events, or mortality. DRB1*10:01 demonstrated 2.63-fold higher risk for CAC (95 % CI 1.17-5.99);DRB1*14:02 demonstrated 42 % higher risk for AAC (95 % CI 1.17-1.74);and DRB1*04:05 demonstrated 24 % lower risk for AAC (95 % CI 0.58-0.99). Conclusion: In a multi-ethnic community-living population, HLA-DRB1 SE alleles were not associated with subclinical CVD, CV events, or mortality. However, individual allele-associations with subclinical CVD suggested variability in risk.

关键词： Unconventional T cell receptor   gamma S TCR   Superantigen   SEA   TRGV9/TRDV2  

摘要： Bacterial toxins, called superantigens, are produced by Staphylococcus aureus and are known to activate gamma S T cells. gamma S T cells contribute to long-lasting immunity against bacterial skin infections caused by S. aureus. gamma S T cells are a distinct subgroup of T cells containing the T cell receptor (TCR) gamma and S chains. The gamma S TCR harbouring the variable chains TRGV9/TRDV2 is the most common TCR in human peripheral blood and is known to be activated by superantigens and are also promising candidates for tumor immunotherapy. However, detailed analyses of antigen binding to gamma S TCR have been severely hampered by difficulties in producing large amounts of gamma S TCR. In this study, we report a protocol to produce recombinant gamma S TCR (TRGV9/TRDV2) by fusing the variable domains gamma S TCR with the constant domains of alpha(3 TCR. Subsequently, binding analyses were executed applying microscale thermophoresis showing a clear binding between superantigen and the gamma S TCR in the micro molar range. In addition, the superantigen SEA was shown to induce cytokine expression in gamma S T cells with moderate MHC dependence, suggesting that other receptors can act as antigen presenting molecules upon gamma S T cell activation. These results pave the way towards a better understanding of superantigen recognition by the gamma S T cells and facilitates the future use of gamma S TCR in cellular tumor immunotherapy.