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Cytokines are essential for regulating immune cell activity during pregnancy. Research shows that CD4+ T-cells exhibit specific cytokine secretion patterns, resulting in polarized immune responses. This study aims to compare the gene expression levels of Th1, Th2, and Th17 cytokines in women with normal pregnancies versus those with a history of recurrent spontaneous abortion (RSA). In this case-control study, 20 patients with RSA within 24 h of their last abortion were compared to 20 pregnant women with no history of abortion (Control Group). Cytokine levels of IL-2, IL-17, and IL-27 were quantified using real-time polymerase chain reaction (RT-PCR). Overall cytokine levels were similar between the groups, but the cytokine levels in both groups were generally similar. However, higher IL-17 and IL-2 levels were observed in the healthy pregnancy group ( Elevated IL-2 levels may be a risk factor for RSA. Consistent with recent studies, our findings emphasize the role of IL-17 and IL-27 as crucial regulatory cytokines for maintaining a successful pregnancy. Show less

The diagnosis and treatment of Waldenstrom macroglobulinemia (WM) are the subjects of this two-part review, which aims to provide current and thorough knowledge of these topics. The first portion of the study, previously published, investigated the epidemiology, etiology, clinicopathological aspects, differential diagnosis, prognostic factors, and impact on WM-specific groups. Specifically, this second section examines both the standard consolidated method and the new therapeutic strategy to handle the complex topic of the treatment of WM. WM has no cure, but therapies can improve survival. Treatment for WM/LPL patients should be initiated when they exhibit symptoms, and the IgM level should not determine WM treatment.Current guidelines suggest various initial personalized therapy treatments, typically chemoimmunotherapy (CIT) or BTK inhibitors (BTKi).Patients with WM can be put into three groups based on their MYD88 and CXCR4 mutational status: those with MYD88 mutations but no CXCR4 mutations (MYD88MUT/CXCR4WT), those with both MYD88 and CXCR4 mutations (MYD88MUT/CXCR4MUT) and those who do not have both MYD88 and CXCR4 mutations (MYD88WT/CXCR4WT).The objective of treatment is to alleviate symptoms and mitigate the risk of organ impairment.The timing of response evaluations, including BM, should be established on a case-by-case basis, informed by clinical and laboratory assessments.Patients with relapsed/refractory WM following chemotherapy and covalent Bruton tyrosine kinase inhibitors may choose non-covalent Bruton tyrosine kinase inhibitors, novel anti-CD20 monoclonal antibodies, BCL-2 inhibitors, or more intensive chemotherapy regimens.Patients who are younger and healthier and have not responded to both CIT and BTKi may be good candidates for an autologous stem cell transplant (ASCT).Second-generation anti-CD19 CAR T cells exhibit anti-WM activity in both in vitro and in vivo settings.From 2.4% to 11% of patients with WM undergo histological transformation, predominantly to diffuse large B-cell lymphoma (DLBCL). The median duration between diagnosis and transformation is 4.6 years.WM patients have a higher risk of secondary cancers.HSV and HZV prophylaxis may be beneficial for patients needing extensive treatment. Screening for Hepatitis B is necessary. Pneumocystis jiroveci prophylaxis is highly recommended. SARS-CoV- 2 and seasonal flu vaccines should be available to all WM patients. Show less

Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4 pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation, thereby slowing the course of CAVD. Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification. Show less

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases. Show less

Pilocytic astrocytoma (PA) is the most common pediatric tumor, typically located in the cerebellum, with spontaneous regression observed mainly in patients with neurofibromatosis type 1 (NF1). However, spontaneous regression of PA without NF1 is rarely reported. Here, we describe a case of spontaneous regression of PA without NF1, located in the left frontal lobe with FGFR1-TACC1 fusion, in a 14-year-old boy who presented with epilepsy. Initial MRI revealed a lesion in the left middle frontal gyrus, and subsequent follow-up MRI demonstrated spontaneous regression. Despite this regression, the patient's seizures persisted, leading to epileptic focus resection. Pathological examination confirmed PA with characteristic histological findings and FGFR1-TACC1 fusion. This case suggests that FGFR1-TACC1 fusion may be linked to spontaneous regression of PA, even in the absence of NF1. Surgical intervention may remain necessary in cases of epilepsy associated with PA, regardless of tumor regression. Show less

The comorbidity of major depressive disorder (MDD) and Parkinson's disease (PD) were prevalent and has a profound impact on patients. However, whether this comorbidity results from specific pathological processes or a mutual cause-and-effect relationship was largely controversial. Additionally, although MDD can appear before or after PD, the health impact of the comorbidity sequence is poorly understood. We used mendelian randomization (MR) and UK biobank (UKB) cohort to explore the associations between MDD and PD. MR was also utilized to investigate potential confounders. By classifying UKB patients into MDD first and PD first groups, we evaluated the health impact of the comorbidity sequence using Cox regression. Bidirectional MR and cohort study showed conflicting results. MR did not find associations between MDD followed by PD (odds ratio [OR] = 1.28, 95 % confidence interval [CI] = 0.85-1.94) or PD followed by MDD (OR = 0.99, 95 % CI = 0.97-1.01). However, the cohort study found a significant effect of MDD on PD (hazard ratio [HR] = 1.75, 95 % CI = 1.55-1.97) and PD on MDD (HR = 4.35, 95 % CI = 3.65-5.19). By performing MR on 4709 proteins, we identified ESD, LEAP2, NDRG3, NRXN3, and PLXNB2 as potential common causes of MDD and PD. Additionally, PD first group had higher risks of all-cause mortality (HR = 1.65, 95 % CI = 1.03-1.90), dementia (HR = 1.88, 95 % CI = 1.16-3.04), and aspiration pneumonia (HR = 1.89, 95 % CI = 1.09-3.27). Our study suggested the comorbidity of MDD and PD is likely the result of certain pathological processes. Additionally, patients with PD first had higher risks of several adverse outcomes. Show less

This systematic review examines the discordance between low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B-100 (apoB) in individuals with metabolic diseases, such as metabolic syndrome and type 2 diabetes, and evaluates the implications for atherosclerotic cardiovascular disease (ASCVD) risk assessment. A systematic literature search was conducted using Academic Search Complete, CINAHL Complete, and MEDLINE databases from 10 January 2024 to 28 May 2024. Studies were selected based on pre-defined inclusion and exclusion criteria, focusing on observational studies that compared LDL-C, non-HDL-C, and apoB levels in individuals with metabolic disease. Studies were included if they assessed fasted blood samples and reported lipid measurements, excluding those involving drug therapies or dietary interventions. Nine studies met the inclusion criteria, revealing significant discordance between LDL-C and apoB levels in individuals with metabolic syndrome or type 2 diabetes. These individuals often achieve optimal LDL-C levels while exhibiting elevated apoB and non-HDL-C concentrations, highlighting the limitations of LDL-C as the sole marker for ASCVD risk. The discordance is largely attributed to differences in LDL particle size and density, with metabolic disease contributing to a higher proportion of small, dense, atherogenic LDL particles. Elevated triglyceride-rich lipoproteins (TRLs), such as very low-density lipoproteins (VLDL), were also identified as contributing to ASCVD risk underestimation by traditional LDL-C measurements. While LDL-C remains a central marker for ASCVD, apoB quantification provides a more accurate assessment of ASCVD risk, particularly in individuals with metabolic diseases. Incorporating apoB levels into therapeutic strategies for lipid reduction is recommended to improve cardiovascular risk management in this population. Show less

Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell barrier. This process allows the heart to obtain fatty acids (FAs), its chief source of energy and apolipoprotein B (apoB)-containing lipoproteins to cross the arterial endothelial barrier leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial triglyceride-rich lipoproteins (TRLs) as an independent risk factor for cardiovascular disease (CVD). We explored how chylomicrons affect ECs and transfer their FAs across the EC barrier. We had reported that media from chylomicron-treated ECs leads to lipid droplet (LD) formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid and microRNA (miR) content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of scavenger receptor-BI (SR-BI) altered these responses. In addition, using chylomicrons labeled with [ Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage LD accumulation. The EVs contained little free fatty acids and triglyceride, but abundant phospholipids and diacylglycerols. In concert with this, [ EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. FAs within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition. Show less

This study, for the first time, sought to investigate whether the interaction between the GRS consists of three SNPs (CAV-1, CRY-1, MC4R) and fat intake is associated with inflammatory markers among Iranian overweight and obese women. This cross-sectional study was conducted with 246 overweight and obese women, aged 18-48 years. Three SNPs, including CAV-1 rs3807992, CRY-1 rs2287161, and MC4R rs17782313, were genotyped using PCR-RFLP to calculate the genetic risk score (GRS) for each participant. Dietary fat intake was measured using a validated semi-quantitative food frequency questionnaire (FFQ). C-reactive protein (CRP), interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and Galectin-3 (Gal-3) were assessed as the primary outcomes of the study. After controlling for confounding variables, a significant interaction between high total fat intake and high GRS, compared to the reference group, was found for TGF-β level ( Consuming different types of fats can influence the interaction between GRS and inflammatory markers, suggesting further research is needed to fully understand this relationship. The online version contains supplementary material available at 10.1007/s40200-024-01542-z. Show less

While the impact of COVID-19 on bone metabolism has been extensively studied, the inverse relationship remains less understood. This study investigates whether impaired bone metabolism is associated with an increased risk of COVID-19 infection. We conducted a nested case-control study within a population-based cohort, incorporating Kaplan-Meier analysis (KMA) to assess time to infection (TTI) differences. Propensity score matching (1:2) was performed and validated through standardized mean differences (<0.10), variance ratio (=1), and McFadden's pseudo- We analysed 294 COVID-19 cases and 528 controls. AOMI+ individuals had a higher prevalence of COVID-19 (41.5% vs. 33.2%; Impaired bone metabolism was found to be associated with increased COVID-19 risk, in a relationship potentially mediated by underlying inflammation. Elevated osteoclastic activity and a defined lipid profile with high ApoB, TC, LDL levels, played a crucial role in the results. Bone quality parameters more accurately captured COVID-19-related bone changes than BMD. Show less

Suboptimal diets are linked to higher cardiometabolic risks and influenced by socioeconomic status. In 2019, Health Canada released an updated Canda's Food Guide (CFG) supported with Canada's Dietary Guidelines (CDG) to help Canadians achieve healthy diet. This study aims to investigate the association between food choices assessed by a Food Choices Assessment Score (FCAS) according to 2019 CFG/CDG, and socioeconomic status and cardiometabolic risk factors among Canadian adults. Dietary choices of Canadian adults ( Show less

Plozasiran, an investigational siRNA targeting hepatic apoC-III, reduces triglyceride-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein particle numbers and sizes is unknown. However, reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected. This study aimed to determine the impact of plozasiran on lipoprotein particle concentration and subclass distribution using nuclear magnetic resonance (NMR) in 2 phase 2 studies. Patients (N = 403) from SHASTA-2 (severe hypertriglyceridemia) and MUIR (mixed hyperlipidemia) were administered 2 total subcutaneous doses of plozasiran (10, 25, or 50 mg) or placebo at baseline and week 12. Comprehensive lipoprotein profiling was conducted with NMR. In SHASTA-2, there was a dose-dependent reduction in TRL-P, with placebo-adjusted total TRL-P reductions of -46% and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large LDL-P concentration increased by +53% and medium by +56%; small LDL-P trended lower (-13%). Total HDL-P increased by +8%, primarily driven by a +36% increase in large high-density lipoprotein particles (HDL-Ps). Similarly, in MUIR, there were dose-dependent reductions in TRL-P, with total TRL-P significantly reduced by -48% (pooled plozasiran) and reductions across all TRL subclasses with plozasiran. While total LDL-P was unchanged, large and medium LDL-P levels increased by +88% and +46%, respectively; small LDL-P levels decreased by -28%. Total HDL-P increased by +12%, driven by a +83% increase in large HDL-P. Plozasiran induced reductions in apoC-III and showed potentially favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in patients with hypertriglyceridemia and mixed hyperlipidemia. Plozasiran reduced TRL-P by ∼50%, shifted LDL to larger particles, and modestly increased HDL-P concentration. While high-potency TRL-lowering therapies can lead to an overall LDL-C increase, plozasiran did not increase LDL-P or apoB but shifted LDL particle size distribution from small dense LDL toward larger sizes. The ∼50% reduction in TRL-P with no increase in apoB and possibly beneficial qualitative changes in LDL suggests the potential of plozasiran to lower cardiovascular risk, which may be evaluated in a prospective outcomes trial. Show less

Hereditary multiple osteochondromas (HMO) is an autosomal dominant disorder caused by heterozygous deleterious variants in the EXT1 or EXT2 genes. While the clinical core phenotype is well established and mainly consists of bone deformities, limb length discrepancies, multiple benign bone neoplasms, and increased risk of chondrosarcoma, the association of HMO with malignancies remains undefined. Only two cases have been reported to date. We report a third patient with HMO and leukemia. New research suggests that EXT1 and EXT2 genes may influence leukemogenesis through several mechanisms, including protein-protein interactions with leukemia-associated genes and modulation by specific microRNAs (miRNAs). Dysregulation of heparan sulfate biosynthesis, a pathway involving exostosin proteins, may disrupt the bone marrow microenvironment, impacting hematopoietic cell growth and differentiation. Show less

Contributing factors for the development of heart failure (HF) involve both apolipoprotein B (ApoB) and coronary microvascular dysfunction (CMD). Although ApoB has been linked to diverse cardiovascular risks, its association with CMD remains unclear. A total of 145 patients undergoing cardiac single-photon emission computed tomography (SPECT) scan was enrolled into this retrospective study. Based on ApoB serum level, all subjects were classified into three groups (Group 1-3). Myocardial flow reserve (MFR) was calculated using myocardial blood flow (MBF) tested in different contexts. ApoB serum level was positively correlated to rest MBF but inversely associated with stress MBF and MFR. Following adjustment for covariates, a significant relationship was observed between increased ApoB and decreased MFR. The predictive value of ApoB was test by Receiver Operating Characteristic Curve (ROC) analysis, showing an area under curve (AUC) of 0.87. The findings indicated that a higher level of ApoB correlated with the severity of CMD. Show less

Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway. To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C-lowering variants is associated with a reduction in the risk of coronary heart disease (CHD). This was a population-based genetic association study with 2 × 2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024. Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D). This study included 401 548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216 901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97). Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C-lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies. Show less

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field. Show less

Small dense low-density lipoprotein (sdLDL) is atherogenic and associated with atherosclerotic cardiovascular diseases (ASCVD). The aim of this study was to perform the prospective evaluation of sdLDL-c in new ASCVD over 18 years of follow up, and to compare the association of sdLDL-c and conventional lipids and apolipoproteins with ASCVD in the elderly. This prospective study included a total of 1770 subjects ≥ 64 years of age with an 18-year follow-up period. The determination of sdLDL-c was measured by a homogenous, selective enzymatic method. Levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG) were determined by enzymatic methods. Apolipoproteins, ApoA1 and ApoB, were analyzed by immunonephelometric methods. Low-density lipoprotein cholesterol (LDL-c) levels were calculated using the Friedewald formula. According to Pearson's correlation coefficients, sdLDL-c concentration was positively correlated with LDL-c, nonHDL-c, TC and ApoB concentrations. During follow up, sdLDL-c was significantly associated with new ASCVD in men aged 64-76 years in both unadjusted and adjusted Cox regression models. The adjusted hazard ratio (95 % CI) for sdLDL-c was 1.61 (1.13-2.28). No significant associations between sdLDL-c and ASCVD were observed in men aged 77-97 years, nor in women aged 64-79 or 80-100 years. Lipid and apolipoprotein concentrations of the elderly were high compared to the recommended target values. In addition, lipid and apolipoprotein baseline concentrations were not higher in the ASCVD group than in the control group. Our results indicated that sdLDL-c is as good a marker as ApoB and better than LDL-c. Show less

Seven compounds, comprising three anthraquinones and four stilbenoids, were isolated from the roots of Rheum palmatum L. These compounds include chrysophanol (1), aloe-emodin (2), aloe-emodin 8-O-β-D-glucopyranoside (3), desoxyrhapontigenin (4), rhapontigenin (5), desoxyrhaponticin (6), and piceatannol 3'-O-β-D-glucopyranoside (7). Among these, compound 5 showed potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activity with an IC Show less

Estrogens can modulate energy balance by regulating food intake and energy expenditure. Hayashi et al. revealed that hypothalamic neuroestrogens, especially E2 from aromatase Cyp19a1, regulate appetite and body weight. In ovariectomized mice, elevated hypothalamic Cyp19a1 and Mc4r expression coincided with reduced food intake and weight loss. Pharmacological or genetic disruption of aromatase in mice lowered Mc4r expression and increased food intake, whereas neuronal Cyp19a1 overexpression enhanced Mc4r expression and suppressed appetite, independent of leptin. Therefore, neuroestrogens critically maintain metabolic equilibrium, positioning aromatase-derived E2 as a promising anti-obesity target. Show less

Cisplatin is a chemotherapy drug used to treat different solid tumors, including ovarian, bladder, lung, and head and neck cancers. One of its significant side effects is ototoxicity, especially when high doses are required. Cisplatin-induced ototoxicity is associated with increased cochlear cell death resulting from DNA damage, caspase activation, oxidative stress, inflammation, and glutamate excitotoxicity. The regulator of G protein signaling 17 (RGS17), a member of the RGS-RZ subfamily, hastens the hydrolysis of GTP to GDP on the G Show less

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy (LVH =15 mm) in the absence of other causes. It affects 1 in 500 individuals, with an autosomal dominant inheritance pattern involving MYH7 and MYBPC3, the most commonly affected genes. Diagnosis relies on echocardiography, with cardiac magnetic resonance providing additional insights, including late gadolinium enhancement, aneurysms, and microvascular dysfunction linked to adverse outcomes. Risk stratification for sudden cardiac death includes the HCM Risk-SCD (adults) and HCM Risk-Kids (pediatrics) models, guiding implantable cardioverter defibrillator therapy. Management depends on phenotype: 1. Obstructive HCM: First-line therapy includes beta-blockers or non-dihydropyridine calcium channel blockers. Myosin inhibitors offer new options for symptom control. In refractory cases, surgical myectomy or alcohol septal ablation is recommended. 2. Non-Obstructive HCM: Treatment focuses on diastolic dysfunction and arrhythmia management, with emerging pharmacologic options under investigation. 3. Atrial fibrillation: Common in HCM, requiring anticoagulation, rate control, or ablation. Advances in genetic testing, imaging, and targeted therapies have significantly reduced HCM-related mortality to 0.5% per year, transforming it into a manageable condition. Future research will enhance precision medicine, surgical expertise, and equitable access to care. Show less

Bladder cancer (BC) is one of the most common urological malignancies, ranking as the eleventh most common cause of cancer-related deaths worldwide. The lack of specific and sensitive prognostic biomarkers presents a significant challenge in the early diagnosis and treatment of BC. We used the Gene Expression Omnibus (GEO) dataset GSE13507 and the Cancer Genome Atlas (TCGA) database to screen differentially expressed genes related to BC. By using Weighted Gene Co-expression Network Analysis (WGCNA), two modules associated with BC were investigated in GSE13507 and TCGA. Hub genes were identified through Protein-Protein Interaction (PPI) network analysis and their functions were validated through multiple approaches, including Gene Expression Profiling Interactive Analysis (GEPIA), Western Blotting (WB) assay, Human Protein Atlas (HPA), Oncomine analysis, and quantitative Real-Time PCR (qRTPCR) analysis. Additionally, miRNAs associated with hub gene expression were identified using various databases to predict the progression and prognosis of BC. WCGNA and differential gene expression analysis identified 171 common genes as target genes. Ten genes (MYH11, ACTA2, TPM2, ACTG2, CALD1, MYL9, TPM1, MYLK, SORBS1, and LMOD1) were identified using the PPI tool and the CytoHubba plugin of Cytoscape. The CALD1 and MYLK genes showed a significant prognostic value for overall survival and diseasefree survival in patients with BC. According to the HPA and Oncomine databases, CALD1 and MYLK expression levels were significantly lower in BC tissues than in normal tissues. Additionally, qRT-PCR analysis, WB assay, and immunohistochemical analysis confirmed CALD1 and MYLK as tumor suppressor genes in BC. Furthermore, miR-155 showed a significant positive correlation with MYLK. This study established MYLK as a direct target gene of miR-155, functioning as an actionable survival-related gene correlated with BC development. Show less

Hepatoblastoma (HB) is a rare embryonal liver tumor, with an increasing global incidence that underscores the need to understand its genetic etiology. Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case-control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases. Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10-6), FADS1 (P value = 4.01 × 10-6), and UGDH (P value = 5.29 × 10-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10-13, 3.62 × 10-3, and 1.95 × 10-9, respectively). We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study. We conducted the largest HB TWAS to date, prompting further exploration of genes. Show less

To evaluate optic nerve head (ONH) morphology in children with craniosynostosis versus healthy controls. Single-center, prospective cohort study. Handheld optical coherence tomography (OCT) was performed in 110 eyes of 58 children (aged 0-13 years) with craniosynostosis. Inclusion criteria were as follows: normal intracranial pressure on invasive overnight monitoring, or clinically stable intracranial pressure. The latter was defined as stable VA within 1 logMAR line and no papilledema on fundoscopy for at least 4 months following OCT, and normal/stable visual evoked potentials. Control data for 218 eyes of 218 children were obtained from a published normative dataset. The main outcome measures were disc width, cup width, rim width, and retinal nerve layer thickness (nasal and temporal). Outcome measures were compared using three-way linear mixed model regression analysis (fibroblast growth factor receptor [FGFR] 1/2-associated craniosynostosis, non-FGFR 1/2-associated craniosynostosis, and controls). Out of 63 eligible children with craniosynostosis, handheld OCT imaging was successful in 110 eyes of 58 children (92%). Of these, 22 (38%) were female. Median subject age at OCT examination was 53 months (range: 2-157; IQR: 39-73). Twelve children (21%) had FGFR1/2-associated syndromes (Crouzon, n = 6; Apert, n = 4; Pfeiffer, n = 2). Control data were available for 218 eyes of 218 healthy children. 122 controls (56%) were female. Median control age at OCT examination was 20 months (range: 0-163; IQR: 6-59). When comparing ONH morphology in craniosynostosis (n = 58) versus controls (n = 218), disc width was 6% greater (P = .001), temporal cup width was 13% smaller (P = .027), rim width was 16% greater (P < .001) and temporal retinal nerve fiber layer was 11% smaller (P = .027). When comparing FGFR1/2-associated syndromes (Crouzon, Apert, and Pfeiffer syndromes, n = 12) to the rest of the craniosynostosis group (n = 46), disc width was 10% smaller (P = .014) and temporal cup width was 38% smaller (P = .044). This cohort demonstrated morphological differences of the ONH in craniosynostosis, most markedly in Crouzon, Apert, and Pfeiffer syndromes. These findings could help improve ophthalmological monitoring and surgical decision-making in children with craniosynostosis. Further work on longitudinal ONH changes in syndromic and nonsyndromic craniosynostosis would be valuable. Show less

Apart from biochemical signals, tumour cells respond to biophysical and mechanical cues from their environment. The mechanical forces from the tumour microenvironment could be in the form of shear stress, tension, or solid stress compression. In this study, we explore the effects of solid stress compression on tumour cells. Solid stress compression, a prevalent biomechanical stimulus accumulated during tumour growth, has been shown to enhance invasive and metastatic phenotypes in cancer cells. However, the underlying molecular mechanism that elicits this aggressive metastatic phenotype, especially in breast cancer, is not extensively studied. Using an established 2D Show less

MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers. Show less

Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin-myosin interaction and its calcium regulation and cause myocardial hypercontractility. About half of such mutations are found in the Show less

To investigate the molecular mechanisms underlying EA(elaidic acid)-induced lipid accumulation in VSMCs(vascular smooth muscle cells). CCK-8 assay determined the effects of EA(0-2.8 mmol/L) on MOVAS(murine aortic vascular smooth muscle cells)to select experimental concentrations. Oil Red O staining combined with quantitative lipid droplet analysis was conducted to examine the effects of EA on intracellular lipid droplet accumulation. Intracellular total cholesterol(TC) and triglyceride(TG) levels were quantified spectrophotometrically to assess EA's effects on intracellular lipid levels. Western blot analyzed protein expression of PPARγ, LXRα, ABCA1, and ABCG1 to delineate EA's pro-foamogenic mechanism. EA dose-dependently suppressed MOVAS viability(P<0.01). EA-treated groups exhibited significant increases in lipid droplet area/number and TC/TG content versus controls(P<0.01). EA downregulated PPARγ and LXRα protein expression(P<0.05), subsequently suppressing downstream targets ABCA1 and ABCG1(P<0.05). EA disrupts lipid metabolism in VSMCs by inhibiting the PPARγ-LXRα-ABCA1/ABCG1 signaling pathway, thereby inducing lipid accumulation and promoting foam cell formation. Show less

Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mechanisms in human Sertoli cells remain unclear. In this study, immortalized human Sertoli cells were exposed to BPS, and cell viability, proliferation, and transcriptomic changes were assessed, with bulk RNA sequencing integrated with single-cell transcriptomic profiles from non-obstructive azoospermia (NOA) testes to identify key regulatory factors. Potential BPS targets were predicted via pharmacophore mapping and confirmed through molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations, while functional validation was performed using NR1H3 knockdown and overexpression assays with luciferase reporter and Western blot analyses. BPS significantly inhibited cell viability and proliferation at concentrations ≥ 20 μM, inducing transcriptomic dysregulation involving cell cycle suppression, metabolic pathway alterations, and steroid biosynthesis disruption. Integration of computational and transcriptomic analyses identified NR1H3 as a direct BPS target, with docking and dynamics simulations demonstrating stable binding (-20.64 ± 2.26 kcal/mol), and experimental data showing that BPS reduced NR1H3 protein levels and transcriptional activity, while NR1H3 knockdown impaired cell survival and overexpression partially rescued BPS-induced cytotoxicity. These findings provide the first evidence that BPS impairs human Sertoli cell function by targeting NR1H3, revealing a critical role of NR1H3 in Sertoli cell survival and suggesting that BPS exposure may contribute to male infertility through NR1H3-mediated pathways. Show less