Correlation of MicroRNA-125b, Sirtuin, and Signal Transducer and Activator of Transcription 3 with Biochemical Parameters and Risk Factors in Atherosclerosis Patients.

Background: Atherosclerosis (AS) is an inflammatory disease linked to vascular events, with dysregulation of microRNA (miR)-125b, contributing to cardiovascular disease pathogenesis. Moreover, there is evidence of the involvement of signal transducer and activator of transcription 3 (STAT3) and sirtuin 6 (SIRT6) in AS. This study aimed to survey the expression levels of miR-125b, STAT3, and SIRT6 in the peripheral blood mononuclear cells (PBMCs) of AS patients and controls, and to find their correlations with biochemical parameters and risk factors. Methods: This study included blood samples from 45 controls and 45 AS patients, with PBMCs isolated using Ficoll solution. Expression levels of miR-125b, STAT3, and SIRT6 were determined via quantitative Real Time-PCR. Results: The findings revealed a significant increase in miR-125b levels in patients compared to controls (P = 0.017). However, alterations in STAT3 and SIRT6 expression were not significant (P> 0.05). There was no substantial relationship between miR-125b and STAT3 (P = 0.522) or SIRT6 (P = 0.88). miR-125b showed a significant relationship with atherogenic indexes and creatinine (P<0.05), while the association of SIRT6 with HDL and creatinine was significant (P<0.05). STAT3 exhibited high diagnostic power for identifying individuals at risk of heart disease and hypertension (P<0.05). Conclusion: STAT3 can serve as a valuable biomarker for detecting AS and AS-related risk factors. miR-125b and SIRT6 may be associated with AS lipid metabolism. However, further studies with larger sample sizes are recommended to mechanistically elucidate the association of these genes.

An overview of early genetic predictors of IgA deficiency.

INTRODUCTION: Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown. AREAS COVERED: This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells. EXPERT OPINION: A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.

Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

Understanding the Correlation between Blood Profile and the Duration of Hospitalization in Pediatric Bronchopneumonia Patients: A Cross-Sectional Original Article.

Introduction: Pediatric bronchopneumonia is a prevalent life-threatening disease, particularly in developing countries. Affordable and accessible blood biomarkers are needed to predict disease severity which can be based on the Duration of Hospitalization (DOH). Aim of the Study: To assess the significance and correlation between differential blood profiles, especially the Neutrophil-Lymphocyte Ratio (NLR), and the DOH in bronchopneumonia children. Material and Methods: A record-based study was conducted at a secondary care hospital in Indonesia. After due ethical permission, following inclusion and exclusion criteria, 284 children with confirmed diagnoses of bronchopneumonia were included in the study. Blood cell counts and ratios were assessed with the DOH as the main criterion of severity. Mann-Whitney test and correlation coefficient were used to draw an analysis. Results: Study samples were grouped into DOH of ≤ 4 days and > 4 days, focusing on NLR values, neutrophils, lymphocytes, and leukocytes. The NLR median was higher (3.98) in patients hospitalized over 4 days (P<0.0001). Lymphocyte medians were significantly higher in the opposite group (P<0.0001). Thrombocyte medians were similar in both groups (P=0.44481). The overall NLR and DOH were weakly positively correlated, with a moderate positive correlation in total neutrophils and DOH, and a moderate negative correlation in total lymphocytes and DOH. The correlation between the DOH ≤ 4 days group with each biomarker was stronger, except for leukocyte and thrombocyte. Analysis of the longer DOH group did not yield enough correlation across all blood counts. Conclusions: Admission levels of leukocyte count, neutrophil, lymphocyte, and NLR significantly correlate with the DOH, with NLR predicting severity and positively correlated with the DOH.

Pathological and functional significance of aging mouse kidneys: clinical implications to reduce the risk of hyper- or hypokalemia in the elderly.

Elderly patients are prone to develop hyper- or hypokalemia, since they are susceptible to drugs or diets that affect the urinary or fecal potassium (K+) excretion. In aging mouse kidneys, in addition to glomerulosclerosis, proximal tubular atrophy, and atherosclerosis in renal arterioles, there was diffuse tubulointerstitial fibrosis with a number of inflammatory leukocytes infiltrating into the cortical interstitium. Since these pathological features greatly influence renal K+ handling, slowing the progression of kidney aging would fundamentally reduce the risk of developing hyper- or hypokalemia. Immunohistochemistry demonstrated the overexpression of K+ channels (Kv1.3) in leukocytes within the cortical interstitium, which was strongly associated with "chronic inflammation" in aging kidneys and the subsequent progression of renal fibrosis. In our basic studies, antihypertensive drugs (benidipine, nifedipine, verapamil, diltiazem) and anticholesterol drugs (lovastatin, simvastatin, pravastatin) strongly suppressed the leukocyte Kv1.3 channels and thus exerted anti-inflammatory effects. Given such pharmacological properties of these drugs, they may also be useful in slowing the progression of tubulointerstitial fibrosis in aging kidneys and reducing the risk of hyper- or hypokalemia in elderly patients.

Subcutaneous G-CSF administration improves IVF outcomes in patients with recurrent implantation failure presenting a KIR/HLA-C mismatch.

RESEARCH QUESTION: Despite advances in assisted reproductive technologies, many blastocysts are lost unexpectedly during implantation. Alterations in maternal immune tolerance towards fetal antigens may contribute to adverse IVF outcomes. The purpose of this study is to evaluate whether administering Granulocyte Colony-Stimulating Factor (G-CSF) to couples with a Human Leukocyte Antigen/Killer-Cell Immunoglobulin-Like Receptor (HLA/KIR) mismatch could positively modulate the implantation process in patients with recurrent implantation failure (RIF). A KIR/HLA-C mismatch occurs when the interaction between KIRs and HLA-C causes an inhibition of NK cells, which may result in reduced G-CSF secretion leading to impaired placentation and increased risk of miscarriage, pre-eclampsia and fetal growth restriction. DESIGN: A retrospective monocentric cohort study conducted at the IVI Clinic in Rome, including women with a history of at least two failed blastocyst transfers. Couples underwent KIR and HLA-C testing. Couples with a KIR/HLA-C mismatch received G-CSF subcutaneously up to week nine of gestation. The mismatch included cases with inhibitory KIR genotypes and HLA-C2C2 females with HLA-C1C1, or C1C2 males or HLA-C1C2 females with male HLA-C2C2. The reproductive outcomes were assessed, and the logistic regression models controlled for potential confounders affecting IVF outcomes. RESULTS: 79 patients with RIF and a KIR/HLA-C mismatch were included in the study. 30 patients were administered G-CSF, and 49 received no treatment. In the univariate analysis, no statistically significant differences were reported in the reproductive outcomes after IVF between the women treated with G-CSF and the control group. However, the logistic regression analysis that controlled for confounding factors showed that patients treated with subcutaneous G-CSF had statistically significant higher ongoing-pregnancy (aOR=3.808) and live-birth (aOR=4.998) rates, and a lower miscarriage rate (aOR=0.057). No statistically significant differences were found in other reproductive outcomes. CONCLUSION: The use of subcutaneous G-CSF in patients with a KIR/HLA-C mismatch undergoing IVF may reduce miscarriage and improve live-birth rates. G-CSF may modulate NK-mediated immune mechanisms and improve trophoblast invasion and development. Randomized trials are warranted to validate these findings and enhance the chances of successful pregnancies in couples with an immunological mismatch.

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors.

BACKGROUND: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. METHODS: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). RESULTS: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. CONCLUSION: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

Clues of HLAs, metabolic SNPs, and epigenetic factors in T cell-mediated drug hypersensitivity reactions.

Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24-72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.

Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study.

Background: The link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed. Methods: We extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode. Results: Genetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes. Conclusion: This study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.

Effect of Trehalose Disaccharide on Activation of Microglia and Indices of Systemic Inflammation in an Experimental Model of Alzheimer's Disease.

In an experimental model of Alzheimer's disease in mice, oral administration of trehalose disaccharide reduces neuroinflammation assessed by the expression level of microglia activation marker Iba1 and affects the neutrophil degranulation activity. A potential anti-inflammatory effect of 4% trehalose solution associated with a decrease in the activity of leukocyte elastase in plasma was revealed.

Differential composition and yield of leukocytes isolated from various blood component leukoreduction filters.

In Flanders, an estimated 300,000 leukoreduction filters are discarded as biological waste in the blood establishment each year. These filters are a possible source of fresh donor leukocytes for downstream purposes including research. We investigated leukocyte isolation from two types of filters either used for the preparation of platelet concentrates (PC-LRF) or erythrocyte concentrates (EC-LRF). Outcome parameters were leukocyte yield, differential count, turnaround time and effect of storage conditions. Leukocytes were harvested by reverse flow of a buffer solution. Control was the gold standard density gradient centrifugation of buffy coats. Total leukocyte number isolated from PC-LRF (1049 (± 40) x 106) was almost double that of control (632 (± 66) x 106) but the differential count was comparable. Total leukocyte number isolated from EC-LRF (78 (± 9) x 106) was significantly lower than control, but the sample was specifically enriched in granulocytes (81 ±â€¯4%) compared to control (30 ±â€¯1%). Isolation of leukocytes from either PC- or EC-LRF takes 20 min compared to 240 min for control density gradient centrifugation. Leukocyte viability is optimal when harvested on day 1 post donation (95 ±â€¯0.9%) compared to day 3 (76.4 ±â€¯2.4%). In conclusion, our study demonstrates that leukoreduction filters from specific blood component processing are easy to use and present a valuable source for viable leukocytes of all types.

Depressive symptom as a risk factor for cirrhosis in patients with primary biliary cholangitis: Analysis based on Lasso-logistic regression and decision tree models.

BACKGROUND: Depressive symptoms are frequently observed in patients with primary biliary cholangitis (PBC). The role of depressive symptoms on cirrhosis has not been fully noticed in PBC. We aimed to establish a risk model for cirrhosis that took depressive symptoms into account. METHODS: Depressive symptoms were assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). HAMD-17 score was analyzed in relation to clinical parameters. Least absolute shrinkage and selection operator (Lasso)-logistic regression and decision tree models were used to explore the effect of depressive symptoms on cirrhosis. RESULTS: The rate of depressive symptom in patients with PBC (n = 162) was higher than in healthy controls (n = 180) (52.5% vs. 16.1%; p < .001). HAMD-17 score was negatively associated with C4 levels and positively associated with levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TB), Immunoglobulin (Ig) G, and IgM (r = -0.162, 0.197, 0.355, 0.203, 0.182, 0.314, p < .05). In Lasso-logistic regression analysis, HAMD-17 score, human leukocyte antigen (HLA)-DRB1*03:01 allele, age, ALP levels, and IgM levels (odds ratio [OR] = 1.087, 7.353, 1.075, 1.009, 1.005; p < 0.05) were independent risk factors for cirrhosis. Elevated HAMD-17 score was also a discriminating factor for high risk of cirrhosis in patients with PBC in decision tree model. CONCLUSIONS: Depressive symptoms were associated with disease severity. Elevated HAMD-17 score was a risk factor for cirrhosis in patients with PBC.

Comprehensive analysis of L-PRF exudate components and their impact on whole blood platelets.

OBJECTIVE: This study assessed the cellular composition and effects of leukocyte-platelet-rich fibrin (L-PRF) exudate on whole blood platelets from healthy volunteers. Key objectives included evaluating leukocyte subpopulations, platelet activation markers, platelet-leukocyte interactions and quantifying inflammatory cytokines within the L-PRF exudate. MATERIALS AND METHODS: L-PRF was obtained from 20 healthy donors. Flow cytometry methodologies were used to assess intracellular calcium kinetics and activated GPIIbIIIa, and P-selectin expression. Leukocyte subpopulations and platelet-leukocyte interactions were characterized using monoclonal antibodies. Inflammatory cytokines (IL-8, IL-1ß, IL-6, IL-10, TNF, IL-12p70) within L-PRF exudate were quantified using a cytometric bead array. RESULTS: The expression of activated GPIIbIIIa, and P-selectin exhibited a significant increase (p < 0.001) when L-PRF exudate was added to platelets of whole blood. Regarding intracellular Ca2+ mobilization, the L-PRF exudate elicited significant responses (p < 0.001). L-PRF exudate contained different leukocytes populations, being TCD4 + the most representative of T cells. It was possible to stablish a profile of cytokines produced by the L-PRF exudate, with human IL-8 cytokine exhibiting the highest average (16.90 pg/mL). CONCLUSIONS: Despite the study limitations, the research yielded important insights: 1- L-PRF exudate can stimulate platelet activation, essential in healing, tissue inflammation and remodeling. 2-The presence of leukocyte subpopulations within L-PRF exudate reflexes its complexity and potential to enhance immune responses. 3-The analysis of inflammatory cytokines within L-PRF exudate revealed its immunomodulatory potential. These findings are valuable evidences for understanding the potential role of L-PRF exudate in regenerative dentistry and medicine, offering innovative therapeutic strategies. CLINICAL RELEVANCE: This research highlights crucial aspects that could significantly influence the clinical use of L-PRF exudate in the oral cavity. The findings support the application of L-PRF exudate in both surgical and regenerative dentistry, facilitating the development of innovative therapeutic strategies to enhance patient outcomes.

Revealing the effect of X-ray or proton brain irradiation on systemic inflammation and leukocyte subpopulation interplay in rodents.

The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.

Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

SCARF2 is a target for chronic obstructive pulmonary disease: Evidence from multi-omics research and cohort validation.

Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.

Adolescent sleep patterns, genetic predisposition, and risk of multiple sclerosis.

STUDY OBJECTIVES: Shift work, insufficient sleep, and poor sleep quality at young age have been associated with increased risk of multiple sclerosis (MS). This study aimed to investigate the potential interaction between aspects of inadequate sleep (short sleep, phase shift, and poor sleep quality) during adolescence and HLA-DRB1*15:01 in relation to MS risk. METHODS: We used a Swedish population-based case-control study (1253 cases and 1766 controls). Subjects with different sleep patterns during adolescence and HLA-DRB1*15:01 status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Additive interaction between aspects of inadequate sleep and HLA-DRB1*15:01 status was assessed by calculating the attributable proportion due to interaction (AP) with 95% CI. RESULTS: Short sleep duration (<7 hours/night) during adolescence acted synergistically with HLA-DRB1*15:01, increasing the risk of MS (AP 0.38, 95% CI 0.01-0.75, p=0.04). Similarly, subjective low sleep quality during adolescence interacted with HLA-DRB1*15:01 regarding risk of MS (AP 0.30, 95% CI 0.06-0.56, p=0.03), whereas phase shift did not significantly influence the risk of the disease, irrespective of HLA-DRB1*15:01 status. CONCLUSIONS: Our findings underscore the importance of addressing inadequate sleep during adolescence, particularly in the context of the HLA-DRB1*15:01 allele, as it appears to amplify the risk of subsequently developing MS.

Role of leukocyte parameters in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with high thrombus burden.

Objective: Leukocyte parameters are associated with cardiovascular diseases. The aim of the present study was to investigate the role of leukocyte parameters in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) with high thrombus burden (HTB). Methods: A total of 102 consecutive STEMI patients with HTB who underwent PPCI within 12 h from the onset of symptoms between June 2020 and September 2021 were enrolled in this study. In addition, 101 age- and sex-matched STEMI patients with low thrombus burden (LTB) who underwent PPCI within 12 h from the onset of symptoms were enrolled as controls. Leukocyte parameters, such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), were calculated at the time of admission. Results: The value of NLR and MLR were significantly higher in the HTB group than in the LTB group (6.24 ± 4.87 vs. 4.65 ± 3.47, p = 0.008; 0.40 ± 0.27 vs. 0.33 ± 0.20, p = 0.038). A cutoff value of >5.38 for NLR had a sensitivity and specificity of 53.9% and 74.3%, respectively, and MLR >0.29 had a sensitivity and specificity of 60.8% and 55.4%, respectively, for determining the STEMI patients with HTB [area under the receiver operating characteristic curve (AUC): 0.603, 95% confidence interval (CI): 0.524-0.681, p = 0.012; AUC: 0.578, 95% CI: 0.499-0.656, p = 0.046]. There was no significant difference of all-cause mortality rate and major adverse cardiac events (MACEs) between the STEMI patients with HTB or with LTB (3.92% in HTB group vs. 2.97% in LTB group, p = 0.712; 10.78% in HTB group vs. 8.91% in LTB group, p = 0.215). Compared with the HTB patients in the low NLR group, C-reactive protein, baseline troponin I, baseline brain natriuretic peptide, and leukocyte parameters, such as white blood cell, neutrophil, lymphocyte, NLR, PLR, and MLR, were also significantly higher in the high NLR group in STEMI patients who underwent PPCI with HTB (18.94 ± 19.06 vs. 35.23 ± 52.83, p = 0.037; 10.99 ± 18.07 vs. 21.37 ± 19.64, p = 0.007; 199.39 ± 323.67 vs. 430.72 ± 683.59, p = 0.028; 11.55 ± 3.56 vs. 9.31 ± 2.54, p = 0.001; 9.77 ± 3.17 vs. 5.79 ± 1.97, p = 0.000; 1.16 ± 0.44 vs. 2.69 ± 1.23, p = 0.000; 9.37 ± 4.60 vs 1.31 ± 2.58, p = 0.000; 200.88 ± 89.90 vs. 97.47 ± 50.99, p = 0.000; 0.52 ± 0.29 vs. 0.26 ± 0.14, p = 0.000, respectively). MACEs and heart failure in the high NLR group were significantly higher than that in the low NLR group of STEMI patients who underwent PPCI with HTB (20.45% vs. 4.25%, p = 0.041; 10.91% vs. 2.13%, p = 0.038). Conclusion: The value of NLR and MLR were higher in STEMI patients who underwent PPCI with HTB. In STEMI patients who underwent PPCI with HTB, a raised NLR could effectively predict the occurrence of MACEs and heart failure.

A causal link between circulating leukocytes and three major urologic cancers: a mendelian randomization investigation.

Purpose: This study aimed to explore the influence of serum leukocytes on urologic cancers (UC) using observation-based investigations. In the present study, Mendelian randomization (MR) was employed to assess the link between leukocyte count (LC) and the risk of UC development. Methods: Five LC and three major UC patient prognoses were obtained for MR analysis from genome-wide association studies (GWAS). Furthermore, in order to evaluate reverse causality, bidirectional studies were conducted. Finally, a sensitivity analysis using multiple methods was carried out. Results: There was no significant correlation found in the genetic assessment of differential LC between the co-occurrence of bladder cancer (BCA) and renal cell carcinoma (RCC). Conversely, an individual 1-standard deviation (SD) rise in neutrophil count was strongly linked to a 9.3% elevation in prostate cancer (PCA) risk ([odd ratio]OR = 1.093, 95% [confidence interval]CI = 0.864-1.383, p = 0.002). Reverse MR analysis suggested that PCA was unlikely to cause changes in neutrophil count. Additional sensitivity studies revealed that the outcomes of all MR evaluations were similar, and there was no horizontal pleiotropy. Primary MR analysis using inverse-variance weighted (IVW) revealed that differential lymphocyte count significantly influenced RCC risk (OR = 1.162, 95%CI = 0.918-1.470, p = 0.001). Moreover, altered basophil count also affected BCA risk (OR = 1.249, 95% CI = 0.904-1.725, p = 0.018). Nonetheless, these causal associations were not significant in the sensitivity analysis. Conclusion: In summary, the results revealed that increased neutrophil counts represent a significant PCA risk factor. The current research indicates a significant relationship between immune cell activity and the cause of UC.

HLA-B*35:01-mediated activation of emodin-specific T cells contributes to Polygonum multiflorum thunb. -induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: HLA-B*35:01 has been identified as a risk allele for Polygonum multiflorum Thunb.-induced liver injury (PMLI). However, the immune mechanism underlying HLA-B*35:01-mediated PMLI remains unknown. AIM OF THE STUDY: To characterize the immune mechanism of HLA-B*35:01-mediated PMLI. MATERIALS AND METHODS: Components of P. multiflorum (PM) bound to the HLA-B*35:01 molecule was screened by immunoaffinity chromatography. Both wild-type mice and HLA-B*35:01 transgenic (TG) mice were treated with emodin. The levels of transaminases, histological changes and T-cell response were assessed. Splenocytes from emodin-treated mice were isolated and cultured in vitro. Phenotypes and functions of T cells were characterized upon drug restimulation using flow cytometry or ELISA. Emodin-pulsed antigen-presenting cells (APCs) or glutaraldehyde-fixed APCs were co-cultured with splenocytes from emodin-treated transgenic mice to detect their effect on T-cell activation. RESULTS: Emodin, the main component of PM, could non-covalently bind to the HLA-B*35:01-peptide complexes. TG mice were more sensitive to emodin-induced immune hepatic injury, as manifested by elevated aminotransferase levels, infiltration of inflammatory cells, increased percentage of CD8+T cells and release of effector molecules in the liver. However, these effects were not observed in wild-type mice. An increase in percentage of T cells and the levels of interferon-γ, granzyme B, and perforin was detected in emodin-restimulated splenocytes from TG mice. Anti-HLA-I antibodies inhibited the secretion of these effector molecules induced by emodin. Mechanistically, emodin-pulsed APCs failed to stimulate T cells, while fixed APCs in the presence of emodin could elicit the secretion of T cell effector molecules. CONCLUSION: The HLA-B*35:01-mediated CD8+ T cell reaction to emodin through the P-I mechanism may contribute to P. multiflorum-induced liver injury.