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关键词： endometrial adenocarcinoma   interleukin 6   signal transducer and activator of transcription 3   programmed death ligand 1  

摘要： Endometrial cancer is a common type of cancer in women, with endometrial adenocarcinoma (EA) being the most common type. Monitoring the expression levels of signal transducer and activator of transcription 3 (STAT3), the protein levels of interleukin 6 (IL-6) and soluble programmed death ligand 1 (sPD-L1), and their differences in patients with various pathological characteristics is beneficial for accurately evaluating the disease stage and differentiation degree of patients in clinical practice. The aim of the present study was to assess the expression levels of STAT3, and the protein levels of IL-6 and sPD-L1 in EA. In the present retrospective study, data were retrieved from the medical records of 137 patients with EA who received surgical treatment at The First Affiliated Hospital of Hebei North University from January 2017 to December 2022. Of the 137 cases, 90 met the inclusion criteria. The patients with EA were matched with a cohort of 30 patients with atypical endometrial hyperplasia in a ratio of 3:1. Among the 90 patients with EA, 30 patients with well-differentiated EA were matched with 30 patients with moderately differentiated EA and 30 patients with poorly differentiated EA in a 1:1:1 ratio. Expression level of STAT3, and protein levels of IL-6 and sPD-L1 were recorded preoperatively and compared between patients with different pathological characteristics [such as differentiation degree, disease stage, depth of myometrial invasion and lymph node metastasis (LNM)] and prognosis. Levels of IL-6, STAT3 and sPD-L1 in the observation group were significantly higher compared with the control group (P<0.001). Additionally, there were significant differences in IL-6, STAT3 and sPD-L1 levels between patients with different differentiation degrees, disease stages, myometrial invasion and LNM (P<0.001). The increase in IL-6, STAT3 and sPD-L1 levels were significantly associated with the decrease in the differentiation degree and the increase in the disease sta

关键词： Interleukin 21 signaling   JAK/STAT3   AKT   IgM plus B cells   Cell proliferation   Antibody secretion  

摘要： IL-21 is a type I cytokine that is produced by activated CD4+ T cells and has a significant impact on the growth, survival, and functional activation of B lymphocytes. While IL-21 has been identified in several teleost fish species, its function and associated mechanisms focus on teleost fish B cells remain largely unknown. In this study, we aimed to investigate the effects of IL-21 (OnIL-21) on IgM+ B cells from Nile tilapia (Oreochromis niloticus), as well as the intracellular signaling transduction pathway involved. Through intraperitoneal injection of recombinant OnIL-21 (rOnIL-21), we observed that IL-21 exerted significant effects on Nile tilapia IgM+ B cells, including the promotion of IgM+ B cell proliferation, induction of IgM secretion, and up-regulation of inflammatory cytokines. These findings suggest that OnIL-21 enhances the ability of IgM+ B cells in humoral immunity. Furthermore, when IgM + B cells were stimulated with rOnIL-21 in vitro, we observed a significant upregulation in antibody secretion ability (sIgM), as well as increased expression of IFN-gamma and IL-10. To further understand the regulatory mechanism of OnIL-21, we demonstrated that OnIL-21 binds to its heterodimer receptor complex (OnIL-21R/On gamma c) to exert its function. This binding triggers the conserved JAK/STAT3 and AKT pathways, which in turn regulate the expression of genes involved in B cell proliferation, antibody secretion, and cytokine expression. Collectively, our findings establish that IL-21 plays a crucial role in the regulation of humoral immunity in lower vertebrates, and this regulation is mediated through conserved signaling pathways across vertebrates.

关键词： Childhood exposure   disease onset   IL17   IL23   maternal smoking   multiple sclerosis   onset symptoms   passive smoking  

摘要： Introduction: The aim of the study was to investigate whether there is any effect of smoking status or passive exposure on different subtypes of multiple sclerosis (MS) and their association with the IL17 & IL23 levels. Methods: Blood samples were obtained from patients diagnosed with clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS) and healthy controls. Smoking habits and passive exposure were questioned via a specifically created questionnaire. Patients and controls were grouped into three subgroups according to smoking status as active smokers, former smokers and never smokers. Results: There were 60 patients and 20 age and sex-matched healthy controls. Active smoking was associated with a higher relapse rate per year. Smoking was inversely proportional to IL23 levels. Passive smoking was associated with atrophy in the follow-up cranial MRI. In utero exposure was associated with a polysymptomatic disease onset. The onset symptoms differed between patients whose mothers smoked during their childhood. Conclus & imath;on: This study shows the effects of smoking and passive smoking on the presenting symptoms and course of MS. The relationship between these adverse effects and the Th17 pathway is not clear. It is evident that MS patients should be advised against smoking and should be directed to programs for quitting smoking.

关键词： HSCT   GVHD   MTHFR C677T   MTHFR A1298C  

摘要： The impact of non-HLA drug-metabolizing gene polymorphisms on post-transplant outcomes is well recognized. We aimed to evaluate the impact of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1982C and CYP3A4 A290G polymorphisms on the outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from fully matched siblings. Using PCR-RFLP and according to DNA availability, MTHFR and CYP3A4-V polymorphisms were evaluated. In total 60 patient/donor pairs were investigated. The MTHFR genotypes exhibited similar frequencies in both patients and donors;the MTHFR wild-type in patients correlated with a trend towards reduced incidence of GVHD and improved overall survival rates. Most patients (84.9 %) and donors (76.8 %) had CYP3A4 A wild type. Acute GVHD occurred only in patients with the wild type (10/45 AA vs 0/8 AG or GG) and 9/43 vs 1/13 in recipients from donors with AA vs. AG + GG. GVHD prophylaxis regimens that do not include methotrexate demonstrated a 5.5-fold increased risk of acute GVHD (p = 0.03). Alternative conditioning regimens to Busulphan/Cyclophosphamide exhibited a 19.1-fold increase in the risk of transplant-related mortality (TRM), with statistical significance (p = 0.007). Severe oral mucositis was correlated with male gender (p = 0.03) and a diagnosis of leukaemia (p = 0.007). Renal toxicity is correlated with an age of >= 18 years (p = 0.04) and male gender (p = 0.04). In conclusion, methotrexate in GVHD prophylaxis correlates with a reduced risk of GVHD, while the Busulphan/Cyclophosphamide conditioning regimen is linked to a lower incidence of TRM. Although statistical significance was not achieved due to the predominance of the CYP3A4 wild type, its nearly exclusive association with GVHD may hold clinical significance. Therefore, genotyping patients and adjusting the CsA dose for individuals with the CYP3A4 wild type is recommended.

关键词： HLA-DRB1*11:340   HLA   novel allele   sequencing-based typing  

摘要： HLA-DRB1*11:340 differs from HLA-DRB1*11:01:01:01 by one nucleotide substitution in codon 36 in exon 2.

关键词： Premature menopause   Prophylactic surgical   procedure   Fimbriectomy   Ovarian neoplasm   HBOC syndrome   Adnexa uteri  

摘要： Risk reducing salpingo-oophorectomy has long been the gold standard for preventing the development of tubo-ovarian cancers in high-risk population such as BRCA1/2 mutation carriers. Although a clear survival benefit has been demonstrated of these prophylactic procedures, important side effect from the associated surgical menopause have been described. Given that recent evidence suggests that most high-grade serous carcinomas (HGSC), the majority of all ovarian carcinomas, and especially for patients with a genetic predisposition originate in the fallopian tube, where also precursor lesions such as STIC can be found, an alternative risk reduction strategy has emerged, the prophylactic fimbriectomy with delayed oophorectomy. Multiple studies have already investigated the acceptability, side effects and safety of this procedure, with promising results. And currently multiple studies are ongoing to investigate the long-term effects on sexuality and the risk of developing subsequent tubo-ovarian carcinomas. A long-term follow-up in a large population is essential given the latency of 4-5 years between precursor lesions and HGSC. In this review, we provide an overview of the current knowledge on the origin, screening, and risk-reducing surgery for the prevention of tubo-ovarian cancers in high-risk women.

摘要： INTRODUCTION:Cardiovascular diseases (CVDs) are the leading cause of death worldwide, significantly contributing to increased healthcare costs and deteriorated health. In Malaysia, CVDs account for 20.79% of deaths in government hospitals. Key risk factors include high blood sugar levels, elevated blood pressure, and increased cholesterol levels. Atherosclerosis frequently serves as the underlying condition for coronary heart disease (CHD), with CCL2 and TNF-α playing a crucial role in recruiting immune cells to inflammation sites. Early diagnosis of CVDs risk is important for preventing severe complications. This crosssectional study aims to investigate the relationship between biomarker CCL2 and TNF-α expression levels and Framingham Risk Score (FRS) categories in a Malaysian cohort. MATERIALS AND METHODS:A total of 333 patients from the Family Medicine Specialist Clinic at Hospital Sultan Abdul Aziz Shah were recruited between March 2022 and February 2023. Blood samples were taken after a 12-hour fasting period, and levels of fasting blood sugar (FBS), triglycerides (TG), total cholesterol (TC), HDL cholesterol, and LDL cholesterol were measured. 150 plasma samples were randomly selected for cytokine analysis of CCL2 and TNF-α using the Human Magnetic Luminex Assay. Patients' cardiovascular risk was assessed using the FRS calculator. The Kruskal-Wallis test was used to analyze the relationship between cytokine levels and FRS categories, followed by a post hoc test with Bonferroni correction. A logistic regression model was implemented to assess the independent effects of these variables. RESULTS:The results demonstrated a significant association between the level of chemokines CCL2 and proinflammatory TNF-α, and FRS categories (low-risk, moderate-risk, and high-risk). CCL2 levels were notably higher in the high-risk group, as were TNF-α levels, with both biomarkers showing increasing trends with higher risk categories, (p<0.001, effect size=0.32) and (p<0.001, ef

关键词： HLA   HLA-B*51:01:01:125   NGS   novel allele   splice site  

摘要： HLA-B*51:01:01:125 differs from HLA-B*51:01:01:61 by a single substitution at the genomic nucleotide position 199 in intron 1.

关键词： oncotherapy   exosome   IL24   NKG2D  

摘要： Natural killer (NK) cell-derived exosomes (NK-Exos) are emerging as a promising avenue in cancer immunotherapy due to their inherent tumor-targeting properties and their capacity to deliver therapeutic agents directly to malignant cells. This research delves into the boosted anti-tumor potency of NK-Exos that has been genetically enhanced to overexpress NKG2D, a vital activating receptor, along with interleukin-24 (IL24), a cytokine renowned for its selective suppressive impact on tumor cells. NKG2D facilitates the recognition of tumor cells by binding to stress-induced ligands, while IL24 induces apoptosis and modulates immune responses to enhance tumor destruction. The NK-Exos engineered to express both NKG2D and IL24 significantly enhanced tumor targeting and increased the apoptosis rate of tumor cells by 30% in A549 and by 20% in HELA at 48 h compared with non-modified NK-Exos, respectively. Furthermore, this enhancement also impacted cell proliferation, with inhibition rates increasing by 30%, 15%, and 15% in A549, HELA, and MCF-7 cells, respectively, and it reduced A549 cell migration by 10%. The integration of NKG2D and IL24 within NK-Exos confers a dual therapeutic mechanism, synergistically amplifying their efficacy in cancer treatment. The utility of NK-Exos co-expressing NKG2D and IL24 offers a novel approach to overcome the limitations of current therapies, providing prolonged tumor suppression and precise targeting of malignant cells and holding great promise for clinical application.