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关键词： genetics   population diversity   precision medicine   type 1 diabetes   type 2 diabetes  

摘要： Aims: We have reported that a 9SNPs type 1 diabetes (T1D) Genetic Risk Score (GRS) developed from European data had a lower power in Indians to distinguish T1D from type 2 diabetes (T2D). We explore the performance of an improved (67SNPs) T1DGRS and also the potential reasons for lower discriminative ability to classify types of diabetes in Indians. Methods: We studied the discriminative ability of a 67SNPs European T1DGRS in 611 clinically diagnosed T1D and 1153 T2D patients, and 321 non-diabetic controls, using receiver operating characteristic (ROC) area under the curve (AUC). We also compared the frequency and effect sizes of HLA risk haplotypes between Indians and Europeans. Results: The T1DGRS was discriminative of T1D from T2D and controls. However, the ability is lower in Indians than Europeans (AUC, Europeans 0.92, Indians all T1D 0.83, AA-positive 0.86). The T1DGRS was higher in AA-positive than in AA-negative persons [13.01 (12.79-13.23) vs. 12.09 (11.64-12.56)], p < 0.0001. The association of common HLA-DQA1 similar to HLA-DQB1 haplotypes was broadly similar;however, important differences were noted in the frequency, direction and magnitude of effect for some haplotypes between Indians and Europeans. Conclusions: We confirm broad applicability of European 67SNPs T1DGRS to Indian T1D persons. However, differences in HLA allele frequencies, magnitude and directional differences reduced the predictive value. Our results stress the need to generate ancestry-specific GRS, which we plan to do in the near future.

关键词： peginterferon alfa-2b   chronic hepatitis B virus infection   liver function   immune factors   prognosis  

摘要： Aims/Background Hepatitis B virus (HBV) infection poses a challenge to global healthcare. Peginterferon alfa-2b (PEG-IFNa-2b) is an effective treatment for HBV infection. This study aimed to explore the efficacy of PEG-IFNa-2b combined with entecavir in the treatment of HBV infection, its effect on liver function and immune factors, and the risk factors affecting the prognosis of patients with HBV infection. Methods The clinical data of 184 patients with HBV infection who were treated at Jinhua Central Hospital from January 2021 to January 2024 were collected for retrospective analysis. Patients were divided into a control group (not receiving antiviral treatment, n = 34), a standard treatment group (receiving entecavir, n = 85), and a combination treatment group (PEG-IFNa-2b and entecavir, n = 65) according to the treatment approach. Treatment efficacy, liver function indicators (albumin [ALB], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]), immune factor indexes (tumour necrosis factor alpha [TNF-a] and interferon gamma [IFN-'y]), hepatitis B surface antigen [HBsAg] and HBV DNA levels were compared among the three groups. All patients were followed up after treatment. According to their prognosis, the patients were divided into good prognosis group (n = 118) and poor prognosis group (n = 66). Logistic regression analysis was performed to explore the risk factors affecting the prognosis of HBV patients. Results The efficacy in the combination treatment group was higher (92.31%) than that in the control group (8.82%) and the standard treatment group (78.82%) (p G 0.05). After treatment, the HBsAg and HBV DNA levels were decreased in the standard treatment and combination treatment groups (p G 0.05). Compared with the control and standard treatment groups, the combination treatment group exhibited significantly lower HBsAg and HBV DNA levels after treatment (p G 0.05). Besides, the combination treatment group had lower ALT and AST levels (p G 0

关键词： 多囊卵巢综合征   先兆流产   血清糖类抗原 125   孕激素诱导的阻断因子   人绒毛膜促性腺激素   雌二醇  

摘要： 目的:探究血清糖类抗原 125(CA125)、孕激素诱导的阻断因子(PIBF)、人绒毛膜促性腺激素(HCG)、雌二醇(E2)在多囊卵巢综合征(PCOS)伴先兆流产孕妇中的表达及其预测价值.方法:选择 2023 年 7 月至 2024 年 7 月本院收治的 80 例PCOS孕早期患者为研究对象,根据是否伴有先兆流产分为观察组(n=33,伴先兆流产)和对照组(n=47,不伴有先兆流产),对比两组的一般资料及血清CA125、PIBF、HCG、E2 表达水平,分析CA125、PIBF、HCG、E2 与PCOS的关系,绘制ROC曲线探讨血清CA125、PIBF、HCG、E2预测PCOS患者出现先兆流产的价值.结果:观察组的继续妊娠率、P、PIBF、HCG、E2 水平均低于对照组,CA125 水平高于对照组(P<0.05);多因素二元Logistic回归分析显示,CA125 高表达及PIBF、HCG、E2 低表达为影响PCOS伴先兆流产的独立危险因素;CA125、PIBF、HCG、E2 四项指标联合的(ROC)曲线下面积(AUC)最大(AUC=0.952),灵敏度、特异度均更高,分别为 97.15％、89.57％(P<0.05).结论:CA125 在PCOS伴先兆流产患者中的呈低表达,PIBF、HCG、E2 呈高表达,是PCOS患者出现先兆流产的危险因素,将血清CA125、PIBF、HCG、E2 联用于PCOS患者的先兆流产预测中能提高结果的准确度.

关键词： myeloperoxidase   Interleukin-6   TNF-alpha   cardiotoxicity   atherosclerosis   computed tomography   anthracycline   computed tomographic angiography   coronary artery calcium score   cancer therapy-related cardiovascular toxicity  

摘要： Interleukin-6, myeloperoxidase, and tumor necrosis factor alpha are proinflammatory cytokines that play a role both in cardiovascular and oncological diseases. The study aimed to prospectively investigate the clinical value of interleukin-6, myeloperoxidase, and tumor necrosis factor alpha as potential biomarkers of cancer therapy-related cardiac dysfunction (CTRCD) in patients receiving anthracycline treatment. A total of 80 patients were included, with 77 (96.25%) followed for an average for 11.5 months. The mean age at baseline was 60.5 years, and 72 (93.51%) were women. Clinical risk factors were documented for all patients, and laboratory assessments, including measurements of IL-6, MPO, and TNF-alpha, were conducted. All participants also underwent echocardiography with assessment of global longitudinal strain (GLS). In the study group, coronary CT angiography with coronary artery calcium (CAC) score calculation was performed once at the beginning of the study. During observation, any degree of CTRCD was diagnosed in 48 (62.4%) patients. Mild CTRCD occurred in 38 (49.4%) patients, moderate CTRCD was diagnosed in 7 (9.1%), and severe in 3 (3.9%). In patients with high baseline risk, IL-6 levels were significantly elevated compared to those with moderate risk (p = 0.018). Higher levels of IL-6 were found to correlate with an increased grade of CTRCD. In a multivariate repeated measures model of the biomarkers studied, only a higher level of IL-6 was significantly associated with the diagnosis of CTRCD. Among the novel biomarkers studied, we found evidence for IL-6 for its potential use in the detection of cardiac dysfunction related to cancer therapy in patients treated with anthracyclines.

关键词： ankylosing spondylitis   HLA-B13   HLA-B37   non-HLA-B27 spondylarthritis   pathogenesis   cross-reactivity  

摘要： Background and Objectives: Spondylarthritis is a complex group of inflammatory diseases closely associated with the HLA-B27 antigen. However, the role of non-HLA-B27 alleles in the disease's pathogenesis has gained significant scholarly attention in recent years. Case presentation: This case study presents a 49-year-old male with a history of progressive inflammatory back pain, characterized by morning stiffness and restricted spinal mobility developed over several years. Initially presenting with non-specific symptoms, the patient eventually experienced persistent axial pain and deteriorating functional limitations, which required further evaluation. Radiographic imaging supported the diagnosis of ankylosing spondylitis (AS) by identifying bilateral sacroiliitis. HLA genotyping revealed a negative result for HLA-B27 but positive results for HLA-B13 and HLA-B37. This finding serves as a foundation for exploring alternative genetic factors contributing to spondylarthritis (SpA). HLA-B13 and HLA-B37 exhibit structural and functional similarities to HLA-B27, particularly in their peptide-binding grooves. This resemblance may lead to overlapping peptide repertoires and increased T cell cross-reactivity. Moreover, these alleles belong to overlapping cross-reactive groups (CREGs) and share the Bw4 epitope. This suggests that they may contribute to disease pathogenesis via similar mechanisms, such as molecular mimicry and the dysregulation of natural killer (NK) cell interactions, as observed in HLA-B27. Conclusions: This case emphasizes the necessity of expanding diagnostic criteria to incorporate non-HLA-B27 markers, particularly for patients who are HLA-B27-negative. Enhancing our understanding of the roles of alternative genetic markers can improve diagnostic accuracy, enable personalized treatment approaches, and enhance outcomes for the diverse SpA patient population.

摘要： Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2 alpha expression in resistant tumor cells through inducing c-Myc. cPLA2 alpha inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2 alpha loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2 alpha, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2 alpha effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer.

关键词： biomimetic strategy   glioblastoma   immunotherapy   NIR-II fluorescence imaging   photothermal therapy  

摘要： It is a big challenge for precision therapy of glioblastoma, mainly due to the existence of blood-brain barrier (BBB), tumor immunosuppressive microenvironment (TIM), and lack of efficient treatment paradigms. Herein, a theranostic nanoplatform for the second near-infrared window (NIR-II) fluorescence imaging-guided membrane-targeted mild photothermal-immunotherapy of glioblastoma using genetically engineered CSF1R/IL12-macrophage membrane (MM)-liposome hybrid nanovesicles, is reported. By mimicking lipophilic membrane probe (Dil) with octadecyl chains, a NIR-II emissive photothermal dye (IRC18), which realizes labeling of nanovesicle lipid bilayers for biodistribution tracing, glioblastoma diagnosis, and molecular imaging of tumoral microenvironment, is synthesized. Importantly, MM and c-RGD-decorated liposome together offer BBB crossing, tumor targeting, and long-term circulation;while, the genetically overexpressed CSF1R and IL12 on MM surface contribute to effective modulation of M2-to-M1 macrophage repolarization and local promotion of T cell cytotoxicity in glioblastoma microenvironment, respectively. Notably, through membrane fusion, IRC18 dyes translocate from nanovesicle lipid bilayers to glioblastoma membranes, which achieve membrane-targeted mild photothermal therapy to ablate primary tumor and induce immunogenic cell death to promote antigen presentation. More importantly, the combined blockade of the CSF1-CSF1R axis and IL-12 enrichment not only reprograms the tumor microenvironment through macrophage M1 repolarization but also activates cytotoxic T cells, ultimately achieving complete glioblastoma eradication. This research provides an efficient theranostic paradigm for glioblastoma treatment.

关键词： TNF-alpha blockers   thrombosis   FAERS database   adverse event   adalimumab   infliximab  

摘要： Objective This research is designed to explore the connection between tumor necrosis factor-alpha (TNF-alpha) blocker drugs and thrombotic adverse *** The study included data from the FDA Adverse Event Reporting System (FAERS) spanning from the first quarter of 2004 to the first quarter of 2024. We employed the disproportional analysis approach to analyze the signals of thrombosis-related adverse events associated with TNF-alpha blockers. Moreover, subgroup analyses were conducted to investigate the circumstances of different age and gender groups. Additionally, the induction time and Weibull distribution were utilized for the further interpretation of the *** During the study period, among 1,382,627 patients in the FAERS database who had adverse events linked to TNF-alpha inhibitors, 9,714 could be attributed to thrombosis-related adverse events. In the remaining patients, different types of infection events accounted for a large proportion of the proportion. (N = 165,765) Thrombosis-related adverse event signals were detected in all five types of TNF-alpha inhibitor drugs. Among them, in the analysis of adalimumab, the adverse event signal of postpartum thrombosis was the strongest, and the positive signal of axillary vein thrombosis was the weakest. The analysis based on gender subgroups discovered some positive signals of adverse events that were not observed in the overall population. The Weibull distribution analysis indicated that all five drugs exhibited an premature aging type characteristic, and their induction decreased gradually over *** This study suggests that TNF - alpha blockers are associated with various adverse events of thrombosis, with different risks in different patient groups and treatment stages. Clinical doctors should assess individual thrombosis risk and closely monitor coagulation related indicators when using TNF - alpha inhibitors. This study offers valuable insights for optimizing treatment and improvin

关键词： endothelium   inflammation   MitoTEMPOL   vascular dysfunction  

摘要： Chronic inflammation is a major contributor to the development of endothelial dysfunction. Circulating concentrations of the proinflammatory cytokine interleukin-6 (IL-6) have been shown to predict cardiovascular disease risk and are associated with the development of vascular dysfunction. However, the mechanisms that underlie inflammation-induced endothelial dysfunction are not fully understood. Vascular endothelial dysfunction is characterized by blunted nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS), with mitochondrial ROS suggested to play a primary role. Therefore, we tested the hypothesis that IL-6 induces mitochondrial ROS production and blunts NO bioavailability in endothelial cells. To study the effect of IL-6, we treated the human aortic endothelial cells (HAECs) with IL-6, MitoTEMPOL (MT;a mitochondria-targeted antioxidant), and/or a nitric oxide synthase (NOS) inhibitor (l-NAME) with and without ACh stimulation. Results are expressed as means +/- SD (n = 4 replicates), one-way ANOVA, and Bonferroni's post hoc tests were performed. IL-6 treatment resulted in greater mitochondrial ROS (IL-6: 2.94 +/- 0.93 a.u.) when compared with the untreated cells (Control: 1 +/- 0;P = 0.0021) and also blunted NO bioavailability at baseline (Control: 1 +/- 0;IL-6: 0.57 +/- 0.08 a.u. P = 0.0008) and with acetylcholine stimulation (Control Ach: 1.27 +/- 0.09;IL-6 Ach: 0.60 +/- 0.13 a.u. P < 0.0001). Scavenging mitochondrial ROS with MT restored NO bioavailability in the IL-6-treated cells (IL-6: 0.57 +/- 0.08;IL-6 MT: 1.16 +/- 0.20 a.u. P < 0.0001). These findings indicate that IL-6 has a direct effect on mitochondrial ROS in human aortic endothelial cells, which leads to reduced nitric oxide bioavailability.

关键词： Immobilized catalyst   Ionic liquid   Lignin   Biscoumarin  

摘要： Herein, a new nanocomposite was prepared by immobilizing ionic liquid on magnetic lignin as a support with a core-shell structure (Fe3O4-Lignin-SO3/IL). The properties of the prepared catalyst were studied using various analyses such as FE-SEM, FT-IR, TEM, VSM, EDS, XRD, and TGA techniques. The resultant nanocomposite exhibits remarkable catalytic activity for synthesizing biscoumarin derivatives. The magnetic nanocatalyst can be readily and quickly separated from the reaction mixture and can be reused for at least five successive reaction cycles without a significant reduction in efficiency.