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关键词： HLA-B leader dimorphism   HLA-Haploidentical hematopoietic cell transplantation   Posttransplant cyclophosphamide  

摘要： Introduction: The graft-versus-leukemia effect of HLA-B leader dimorphism, i.e., methionine (M) or threonine (T) at position -21 of the leader sequence, has been observed in HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo). However, the biological mechanism has been unclear, and the contributions of HLA-B leader genotype to risk reduction of relapse might be dependent on posttransplant cyclophosphamide (PTCy) doses. Methods: To investigate whether the effect of HLA-B leader dimorphism was modified by the PTCy dose, we retrospectively analyzed 99 patients who received PTCy-haplo. Results: In the low-dose PTCy group, the patient M+ HLA-B leader genotype did not significantly affect the cumulative incidence of relapse (CIR) but negatively impacted the overall survival (OS) compared to the M- genotype. In contrast, in the high-dose PTCy group, patients with the M+ genotype had a decreased CIR, but no significant difference in the OS was observed between patients with the M+ and M- genotypes. Regardless of PTCy doses, the patient M+ genotype had detrimental effects on nonrelapse mortality. Conclusion: Our findings suggest that the effect of the patient HLA-B leader genotype is modified by the PTCy dose, providing immunological insight into the PTCy dosage and supporting further studies to investigate the underlying mechanisms.

关键词： 1,3,4-oxadiazole derivative   inflammation   methotrexate   nephroprotective   nephrotoxicity   oxidative stress  

摘要： Nephrotoxicity is a prominent complication of methotrexate (MTX) therapy that limits clinicians in its extensive use. MTX triggers oxidative burden and inflammation, so the nephroprotective potential of the synthetic derivative of 1,3,4-oxadiazole (5b) was explored in this research. Male Wistar rats were divided into four groups i.e., control group, MTX group, 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group, respectively. All treatments were given, intraperitoneally (i.p.) during 12 days of the animal model. The MTX-induced nephrotoxicity was evaluated by renal function markers i.e., serum creatinine (Cret), blood urea nitrogen (BUN), and albumin (Alb). Furthermore, antioxidant markers, catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and oxidative stress, markers lipid peroxidase (LPO) and nitric oxide (NO), were analyzed. Pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), were also calculated. DNA damage was assessed by the comet assay. Histopathological staining (Hematoxylin and eosin, Masson's trichrome) was done and immunohistochemistry was performed against Caspase-3, Nrf2, HO-1, TLR-4, TNF-alpha, and NF-kappa B. A significant improvement in the serum Cret, BUN, and Alb was observed in (5b) treated groups. Antioxidant markers were elevated, oxidative stress markers and pro-inflammatory cytokines were reduced, moreover, histopathological analysis revealed less tissue damage in (5b) administered groups. Immunohistochemistry showed increased immune expression of Nrf2 and HO-1 and decreased expression of TLR-4, TNF-alpha, Caspase-3, and NF-kappa B in 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group as compared to the MTX group. Hence, the results of this study favor the use of (5b) against MTX-induced nephrotoxicity.

关键词： flavonoids   anthocyanins   phlobaphenes   humanized mice   dysbiosis   gut barrier dysfunction   colitis  

摘要： Background: Gut bacterial dysbiosis along with intestinal mucosal disruption plays a critical role in inflammatory disorders like ulcerative colitis. Flavonoids and other food bioactives have been studied in mice models as alternative treatments with minimal side effects. However, most of the research has been carried out with mice-native microbiota, which limits the comprehension of the interaction between flavonoids and human-associated bacteria. Hence, the objective of our study was to determine the effect of healthy human-associated microbiota on the anti-colitic activity of diets rich in anthocyanins (3-HF) and phlobaphenes (3-DF). Methods: In this regard, the interleukin (IL)-10 -/- mice model was utilized. Mice were divided into three groups for inoculation with human gut bacteria from three different healthy donors and assigned to four diets. A purified diet (Diet P) and three diets containing 25% near-isogenic lines (NILs) of corn were evaluated. Diets were substituted with NILs expressing only 3-DFs (diet B), only 3-HFs (diet C), and both 3-DF and 3-HF (diet D). Results: In an overall analysis, flavonoid-rich diets did not affect inflammatory markers, microbiota diversity, or gut metabolites, but diets containing anthocyanins improved barrier function parameters. However, when data was segmented by the recipient's microbiota from different human donors, the diet effects became significant. Furthermore, 3-HFs showed more beneficial effects than 3-DFs across the recipient's microbiota. Conclusions: Our study suggests that the anti-colitic activity of 3-DF and 3-HF and their gut metabolites depends on the donor's microbial composition.

关键词： Drainage   Kidney transplantation   Lymphocele  

摘要： Objective: The routine drain placement following renal transplantation is currently under debate. Its benefit is uncertain and may cause complications, particularly infectious ones. Some renal transplant patients have low- productive drains, that might be unnecessary. The objective of this study is to bring to light factors influencing drain volume in kidney transplantation. Materials and methods: All kidney transplant patients in Tours between 2019 and 2020 were included. The characteristics of the two groups were analyzed: patients with low-productive redons (quantification less than 100 mL/24 h,) and patients with productive redons (> 100 mL/24 h). Univariate and multivariate analyses by logistic regression were performed to look for risk factors associated with productive drainage. Results: One hundred and eighty-nine patients were included (67 in the low-productive group and 122 in the productive group). The results in the productive group showed a significantly higher proportion of retransplantation (P P = 0.015), overweight (P P = 0.012), low residual diuresis (P P = 0.041), and a significantly lower proportion of preemptive transplantation (P P = 0.008) and peritoneal dialysis (P P = 0.037). After an adjustment, the following variables remained significantly associated with greater drainage: overweight (OR = 2.42, P = 0.014;95% CI [1.2- 4.94]);retransplantation (OR = 3.98, P = 0.027;95% CI [1.27-15.45]), and preemptive transplant (OR = 0.22, P = 0.013;95% CI [0.06-0.7]). Conclusion: The non-implementation of a redon in renal transplantation could be considered, in a selected population of non-overweight patients, with significant residual diuresis for a first transplantation which should be preemptive. This could lead to a randomized controlled trial to determine the real benefits of a routine drain replacement in kidney transplantation. Level of evidence: IV. (c) 2024 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI

关键词： biological treatment   biologics   chronic rhinosinusitis with polyps   CRSwNP   dupilumab   secukinumab  

摘要： We identified two CRSwNP patients who had previously failed treatment with an anti-IL-4/IL-13 antibody (dupilumab). Based on their clinical characteristics and blood cytokine levels, we considered them mixed Type II/Type III cases and treated them with an anti-IL-17 antibody (secukinumab). Anti-IL-17 antibody secukinumab was superior in reducing their NPS and SNOT-22 values compared to dupilumab. IL-17 could be a promising target for non-type II and mixed endotype CRS treatment.

关键词： sepsis   septic shock   apoptosis   lymphopenia   CD4+lymphocytes   CD8+lymphocytes   CD19+lymphocytes   natural killer lymphocytes   PD-1/PD-L1 axis   IL-7  

摘要： Sepsis pathophysiology involves a dysregulated immune response to infection, excessive inflammation, and immune paralysis. This study explores the relationships between cell death biomarkers (serum-soluble levels of programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and interleukin-7 (IL-7)) and the percentages of various lymphocyte subsets in relation to the severity and progression of sepsis. This prospective, observational study included 87 critically ill patients. We monitored parameters on days 1 (sepsis was diagnosed according to the Sepsis-3 Consensus) and 5. We established an IL-7 cutoff value of 1.94 pg/mL by comparing levels between a healthy control group and patients with sepsis (p < 0.0001). Lymphopenia was observed in all patients, with negative correlations between helper T lymphocytes and cytotoxic and B lymphocytes, and positive correlations involving cytotoxic lymphocytes across all groups. We found correlations between PD-1/PD-L1 and lymphocyte subsets. IL-7 showed a statistical correlation with PD-1 in non-survivors. Assessing lymphocyte levels shows potential as a biomarker for evaluating the progression of sepsis. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Elevated PD-1/PD-L1 expression impairs costimulatory signalling, reducing T cell responses and lymphopenia, which increases the risk of nosocomial infections.

关键词： Whole genome resequencing   TLR   Functional genomics   Bioinformatics   MHC   Koalas  

摘要： Conservation genomics can greatly improve conservation outcomes of threatened populations, including those impacted by disease. Understanding diversity within immune gene families, including the major histocompatibility complex (MHC) and toll-like receptors (TLR), is important due to the role they play in disease resilience and susceptibility. With recent advancements in sequencing technologies and bioinformatic tools, the cost of generating high-quality sequence data has significantly decreased and made it possible to investigate diversity across entire gene families in large numbers of individuals compared to investigating only a few genes or a few populations previously. Here, we use the koala as a case study for investigating functional diversity across populations. We utilised previous target enrichment data and 438 whole genomes to firstly, determine the level of sequencing depth required to investigate MHC diversity and, secondly, determine the current level of diversity in MHC genes in koala populations. We determined for low complexity, conserved genes such as TLR genes 10 x sequencing depth is sufficient to reliably genotype more than 90% of variants, whereas for complex genes such as the MHC greater than 20 x and preferably 30 x sequencing depth is required. We used whole genome data to identify 270 biallelic SNPs across 24 MHC genes as well as copy number variation (CNV) within class I and class II genes and conduct supertype analysis. Overall, we have provided a bioinformatic workflow for investigating variation in a complex immune gene family from whole genome sequencing data and determined current levels of diversity within koala MHC genes.

关键词： confirmatory alleles   full sequence   HLA   NGS  

摘要： 35 allele sequences were confirmed and extended: 12 HLA-A, 9 HLA-B, 6 HLA-C, 2 HLA-DQB1, and 6 HLA-DRB1.

关键词： antibodies to infliximab   clinical response   endoscopic remission   HLA-DQA1*05   infliximab   small bowel Crohn's disease  

摘要： Carriage of HLA-DQA1*05 is thought to increase the formation of anti-tumour necrosis factor alpha (TNF-alpha) antibodies, reducing the drug efficacy in Crohn's disease (CD) patients. However, little data are currently available for small-bowel Crohn's disease (SB-CD). A specific assessment of the impact of HLA-DQA1*05 on the clinical response to treatment with infliximab (IFX), a TNF-alpha antagonists, in SB-CD patients is necessary. We conducted a single-center retrospective study that included 106 SB-CD patients treated with IFX. The serum samples were collected for antibodies to infliximab (ATI) testing and HLA-DQA1*05 genotyping. Double-balloon enteroscopy (DBE) was performed following the IFX treatment, with endoscopic outcomes evaluated using the partial simple endoscopic score for CD (pSES-CD), whereas the clinical response was assessed with the Crohn's disease activity index (CDAI). Multivariate logistic regression and multivariate COX regression analyses were employed to analyze the correlation of the HLA-DQA1*05 genotypes with other clinical variables. In this study, 30.2% of SB-CD patients carried the HLA-DQA1*05 allele, which significantly increased their risk of ATI generation (odds ratio [OR] = 2.337, p = .043), but it was not associated with the clinical response to IFX and drug persistence (OR = 2.356, p = .145;OR = 0.457, p = .249). The endoscopic remission rates were 40.6% (13/32) and 55.4% (41/74) in HLA-DQA1*05 carriers and non-carriers, respectively. HLA-DQA1*05 was not associated with endoscopic remission (OR = 0.684, p = .414). The HLA-DQA1*05 variant is identified as a significant risk factor of ATI formation in Chinese patients with SB-CD, but is not associated with the clinical response of IFX treatment and endoscopic remission of SB lesions.

关键词： Visceral leishmaniasis   Ascorbate peroxidase   MHC   Immunogenicity   Peptide  

摘要： The control and eradication of any infectious disease is only possible with a potential vaccine, which has not been accomplished for human visceral leishmaniasis (VL). The lack of vaccines may increase the risk of VL outbreaks periodically in endemic zones. Identifying a reliable vaccine candidate for Leishmania is a major challenge. Here, we considered Leishmania donovani ascorbate peroxidase (LdAPx) Ld APx) for its in vitro evaluation with the hope of future vaccine candidates for VL. Ld APx was selected based on its unique presence in Leishmania and virulence in VL pathogenesis. Initially, we found antibodies against recombinant Ld APx (rLdAPx) Ld APx) in the serum of VL patients. Therefore, using bioinformatics, we predicted and selected ten (MHC class I and II) peptides. These peptides, evaluated in vitro with PBMCs from healthy, active VL, and treated VL individuals induced PBMC proliferation, IFN-gamma secretion, and Nitric Oxide (NO) production, indicating host-protective immune responses. Among them, three peptides (PEP6, PEP8, and PEP9) consistently elicited a Th1-type immune response in PBMCs. Treated VL individuals showed a stronger Th1 response compared to active VL patients and healthy subjects, highlighting these peptides' potential as vaccine candidates. Further studies are on the way toward evaluating the Ld APx- derived peptides or sub-unit vaccine in animal models against the L. donovani challenge.