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关键词： Genomics   Single nucleotide polymorphisms   Major histocompatibility complex   3' UTR   5' UTR   Genome sequencing   Genotyping   Haplotypes  

摘要： In addition to the classical HLA genes, the major histocompatibility complex (MHC) harbors a high number of other polymorphic genes with less established roles in disease associations and transplantation matching. To facilitate studies of the non-classical and non-HLA genes in large patient and biobank cohorts, we trained imputation models for MICA, MICB, HLA-E, HLA-F and HLA-G alleles on genome SNP array data. We show, using both population-specific and multi-population 1000 Genomes references, that the alleles of these genes can be accurately imputed for screening and research purposes. The best imputation model for MICA, MICB, HLA-E, -F and -G achieved a mean accuracy of 99.3% (min, max: 98.6, 99.9). Furthermore, validation of the 1000 Genomes exome short-read sequencing-based allele calling against a clinical-grade reference data showed an average accuracy of 99.8%, testifying for the quality of the 1000 Genomes data as an imputation reference. We also fitted the models for Infinium Global Screening Array (GSA, Illumina, Inc.) and Axiom Precision Medicine Research Array (PMRA, Thermo Fisher Scientific Inc.) SNP content, with mean accuracies of 99.1% (97.2, 100) and 98.9% (97.4, 100), respectively.

关键词： alcohol   CAGE   drug survival   effectiveness   Psoriasis  

摘要： BackgroundAlcohol abuse is correlated with the onset and worsening of psoriasis, but its effects, as for smoking, on biological therapies are still poorly *** and methodsThis study aimed to determine the prevalence of alcohol abuse and other discretionary habits (such as smoking and sedentary lifestyle) in patients with psoriasis treated with topicals, conventional systemic and biologic therapies. The second objective is to investigate the impact of discretionary habits, focusing on alcohol abuse, on the response to biological therapy. To identify alcohol dependence, the CAGE questionnaire was distributed among patients of our ***305 patients were included with 18% at high risk of alcohol abuse. Clinically, guttate psoriasis and psoriatic arthritis were more common in patients at higher risk of alcohol abuse. Furthermore, patients with an alcohol problem who started biological therapy reported a higher PASI than those who drank less. None of the considered variables seemed to correlate with discontinuation of medication or with lower achievement of the analyzed outcomes (PASI100, PASI90, and PASI <= 3). There was a stronger association between alcohol dependence and patients receiving conventional therapy than with patients receiving *** efficacy of biologicals did not seem to be impacted by alcohol consumption, smoking, or sedentary lifestyle.

关键词： Donor age   B-leader   Mismatched unrelated   donor   Haploidentical donor  

摘要： HLA-mismatched unrelated donors and haploidentical related donors are suitable stem cell sources for hematopoietic cell transplantation (HCT) when patients lack HLAmatched donors. Clinical outcome after mismatched HCT is influenced by HLA factors including the similarity of peptide-binding motifs (PBMs) between the patient and unrelated donor, and of the HLA-B leader in unrelated and haploidentical donors. Whether these factors can aid in the selection between mismatched unrelated and haploidentical donors is not known. To address this question, we investigated outcomes between the two donor types defined by matching for the PBM and leader peptide. We compared PBM-matched (n = 614) and mismatched (n = 958) MMUDs with calcineurin-inhibitorbased prophylaxis to four haploidentical groups that received post-transplant cyclophosphamide (PTCy)-based prophylaxis. The haploidentical groups were B-leader matched/ DRB1-mismatched (n = 722), B-leader matched/DRB1-matched (n = 154), B-leader mismatched/DRB1-mismatched (n = 493), and B-leader mismatched/DRB1-matched (n = 63). Multivariate analysis showed that the B-leader matched/DRB1-mismatched haploidentical group had the best overall survival (OS) compared to the PBM-matched MMUD, while other haploidentical groups had comparable OS. The PBM-mismatched MMUD showed the poorest outcomes, similar to the B-leader mismatched/DRB1-matched haploidentical group. Among non-HLA factors, donor age was the most significant predictor of OS. These results suggest that a B-leader matched/DRB1 mismatched haploidentical donor might be the preferred choice among donors of similar age. If such a donor is not available, the youngest donor from either PBM-matched unrelated or other haploidentical groups could be a beneficial choice. These findings need validation with both donor groups receiving PTCy-based graft-versus-host disease prophylaxis. (c) 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All r

关键词： age-related macular degeneration   gene polymorphisms   ARMS2 (rs10490924)   TNFRSF1B (rs1061622)   TNFRSF1A (rs4149576)   VEGFA (rs3024997)   ARMS2   TNFRSF1B   TNFRSF1A   VEGFA   ELISA   anti-VEGF therapy  

摘要： Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEG

关键词： rare earth elements (REEs)   polymer inclusion membranes (PIM)   bifunctional ionic liquid extractant   Cyphos IL 104   separation  

摘要： In this study, an ionic liquid-based polymer inclusion membrane (IL-PIM) made of (50% polymer-50% CyphosIL104) was used to extract and separate the rare earth elements (REEs) Y, La, Nd, and Sm in chloride solutions. The effect of extraction time and pH was studied to optimize the extraction and separation conditions. The four REEs were effectively extracted at pH 4-5 from both single and mixed metals solutions. However, at pH 2, only Y was extracted. The recovery of the extracted REEs from the loaded PIM was achieved using HNO3 and H2SO4. In the case of La, it was quantitatively back-extracted with H2SO4 after a contact time of 1 h, while up to 4 h was necessary to recover 70% of the extracted Y, Sm, and Nd. Extraction isotherms were studied, and the Freundlich isotherm model was the most adequate to describe the interaction between the PIM and the REEs. Finally, the developed PIM was investigated for the extraction of REEs from mixtures containing other metals, which showed great selectivity for the REEs.

关键词： Brazil   HLA   HLA-B   new allele   next-generation sequencing   Rio de Janeiro  

摘要： The novel HLA-B*18:37:03 allele, first described in a potential bone marrow donor from Brazil.

关键词： hepatocellular carcinoma   IL-6/STAT3 pathway   ropivacaine   sorafenib  

摘要： The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth in vivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.

关键词： Inflammation   TNF alpha   Database   Molecular docking   Anti-inflammatory lead   Diclofenac  

摘要： Any pathogenic attack, infection, or disease can initiate inflammation. It results in significant adverse consequences like inflammatory bowel disease, rheumatoid arthritis, etc. TNF alpha is one of the major pro-inflammatory cytokines for the progression of inflammation-the present study designed a series of hybrid compounds consisting of the pyrazole-pyridine moiety. Virtual screening was performed utilizing the e-pharmacophore hypothesis with the co-ligand of TNF alpha, screening, docking, and ADMET study. Induced fit docking, DFT analysis, and molecular dynamic simulation showed that the four best molecules - Dh1- Dh4-showed crucial interaction with Tyrosine, higher dock scores, and better stability than Diclofenac. Following the synthesis of hit molecules, an in vitro albumin denaturation IC50 of Dh1 was found to be 118.01 mu M. Further in-depth in vitro and in vivo analyses of these pyrazole-pyridine small compounds may serve as potential space for creating new anti-inflammatory leads. image

关键词： HLA-DRB3/4/5   next-generation sequencing   novel allele  

摘要： Two novel alleles that appear to be generated from recombination between exons 2 and 3.

关键词： CD28   GVHD   HSCT   Tunisians  

摘要： Graft-versus-host disease (GVHD) is a potentially serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Graft-contaminating T cells (donor T cells) are crucial for the development of GVHD since they are able to react against the recipient's antigens. In this study we aim to evaluate the potential association between the IVS3 + 17 T/C gene variation in the CD28 molecule, a T cells costimulatory factor, and the GVHD occurrence in a Tunisian group of recipients of allo-HSCTs. Results show that there is an association between the presence of this polymorphism and the occurrence of grades II-IV acute GVHD (OR: 2.470, I.C: 1.027-5.938, p = 0.043). As for the chronic GVHD, it seems that the studied gene variation has no impact on the occurrence of this complication, which appeared likely to be affected by the HSCT graft source (PBSC: peripheral blood stem cells) (OR: 5.141, I.C: 1.590-16.620, p = 0.006). Based on these data, we believe that the CD28 IVS3 + 17 T/C polymorphism is a significant factor in the pathogenesis of acute GVHD.