📋 Browse Articles

Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to steatohepatitis (MASH), which is closely associated with obesity and insulin resistance. Resmetirom, and semaglutide, have been shown to have therapeutic effects in clinical studies. We compared these mechanisms in western diet (WD)-fed melanocortin 4 receptor knockout (MC4R-KO) mice, a human MASH pathology model. Male MC4R-KO mice were fed WD for 6 weeks starting from 22 weeks of age for disease induction and were administered drugs for 7 weeks with WD feeding, for a total duration of 13 weeks. Both resmetirom and semaglutide treatments for 7 weeks substantially improved these parameters. Although resmetirome and semaglutide improved liver hydroxyproline deposition and total fat mass, semaglutide markedly suppressed total lean mass. Moreover, resmetirom enhanced oxygen consumption, whereas semaglutide reduced energy expenditure. Histopathological evaluation showed that resmetirom significantly and semaglutide tended to improve liver steatosis score. On the fibrosis score, semaglutide significantly reduced it. Resmetirom and semaglutide have different mechanisms of action against MASH. Similar to clinical evidence, semaglutide treatment, might cause muscle mass reduction due to food intake suppression. This is the first study to simultaneously compare the effects of resmetirom and semaglutide on MASH phenotypes and reveal the differences on their mechanisms of action in WD-fed MC4R-KO mice. Show less

Cervical Cancer is the second most common gynecological malignancy affecting a large group of women worldwide. The molecular mechanism of cervical cancer progression is still not very clear. As a result, diagnosis of cervical cancer occurs at a very advanced stage when the disease has spread to its malignant stage, causing death in the majority of women. EMT is a major culprit associated with the malignant transformation of tumor cells during cancer progression and metastasis. Hence, identification of new biomarkers to detect cervical cancer at an early stage is essential to minimize incidence and mortality. The present study aims to identify Common Differentially Expressed Genes (DEGs) and early biomarkers associated with EMT in cervical cancer. The Datasets were downloaded from the Gene Expression Omnibus (GEO) database, with Accession numbers GSE26511, GSE67522, and GSE9750. Then, the Gene Ontology (GO), KEGG pathway enrichment analysis, and protein-protein interactions (PPI) were done. Further hub genes were identified by molecular interaction networks using Cytoscape from the constructed network of DEGs. Afterwards, survival analysis was performed to assess the prognostic significance of eight hub genes associated with EMT in cervical cancer. A total of 11,339 overlapping DEGs were identified from all three datasets, among all the total 61 DEGS, and 8 hub genes were linked to the EMT pathway. Our study suggests that these eight hub genes, CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2, may be critically associated with EMT progression. Among the eight identified EMT hub genes, CDH2 (N-cadherin) demonstrated a significant association with overall survival, while FN1 (fibronectin) was notably linked to disease-free survival, underscoring their prognostic value in cervical cancer. Based on these findings, our study suggests that CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2 hold potential diagnostic and prognostic significance in the progression of cervical cancer. Show less

Mitochondrial unfolded protein response (UPR The data were sourced from the cancer genome atlas (TCGA) and GSE31210 dataset and MRGs were retrieved to identify those with prognostic relevance, which were applied to recognize the molecular clusters in LUAD. The cluster-specific differentially expressed genes (DEGs) were identified for the functional enrichment analysis. The independent differentially expressed MRGs were sorted out to develop a risk model. Besides, the tumor immune microenvironment was analyzed using the ESTIMATE, TIMER, MCP-counter, and ssGSEA algorithms. The data were processed with Mutect2 to evaluate the genetic mutation landscape, while the IMvigor210 cohort and pRRophetic package were utilized to predict immunotherapeutic responses and drug sensitivity. Finally, in vitro validation was performed via quantitative real-time PCR (qRT-PCR), cell counting kit-8 (CCK-8), wound healing, and Transwell assays. Most MRGs were higher expressed in LUAD, and CREB binding protein (CREBBP), lysine demethylase 6B (KDM6B) and leucine rich pentatricopeptide repeat containing (LRPPRC) were the top 3 genes with mutation frequency. 8 MRGs were applied to identify 2 molecular clusters, with the worst prognosis seen in cluster C1. The clusters-specific DEGs were mainly enriched in cell proliferation-related pathways and the established risk model based on 4 hub genes (ANLN, FAM83A, CPS1 and KRT6A) showed satisfying efficacy in predicting the prognosis and was negatively correlated with most immune cells. Besides, the tumor mutation burden tended to be stronger in high risk group with high gene mutation frequency. In IMvigor210 cohort, higher RiskScore was seen in patients with progressive disease and stable disease and related to a worse survival. 3 drug candidates, including Roscovitine, Rapamycin and PHA.665752 were positively correlated with RiskScore. Besides, all 4 MRGs were highly expressed in LUAD cells and the silencing of ANLN repressed the LUAD cell proliferation, migration and invasion. The established 4-MRGs signature not only serves as a robust prognostic indicator but also highlights the significant involvement of mitochondrial unfolded protein response in shaping tumor microenvironment and influencing immunotherapy outcomes in LUAD. The 4 MRGs may contribute to the understanding on UPR Show less

Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse causality. Furthermore, the underlying mediating factors and potential therapeutic targets underlying this association are poorly understood. This study aimed to investigate the causal effect of visceral adipose tissue (VAT) on asthma risk, identify potential mediators, and quantify their effects using a Mendelian randomization (MR) framework. In this study, we employed MR approach to elucidate the impact of VAT on asthma and to assess the potential mediators. Subsequently, the association between seven lipid-lowering medication targets and asthma risk was investigated using the drug target MR method. Lastly, we conducted an observational study involving 12,120 participants to evaluate the relationship between visceral adiposity index (VAI) and asthma. The univariable MR analysis demonstrated that each standard deviation increase in genetically predicted VAT was associated with a 46 % higher risk of asthma (IVW: OR = 1.460, 95 % CI: 1.351-1.578, p = 1.471E-21). This association remained significant after adjusting for BMI in multivariable MR (OR = 1.137, 95 % CI: 1.023-1.262, p = 0.017). Mediation analysis revealed that HDL-C accounted for 4.3 % of this effect (OR = 1.016, 95 % CI: 1.001-1.033, p = 0.038). Drug-target MR indicated that activation of HMGCR and LDLR reduced asthma risk (OR = 0.846 and 0.866, respectively; both p < 0.01), whereas LPL activation increased risk (OR = 1.080, p = 0.015). Observational analysis of NHANES data (n = 12,120) confirmed that higher VAI was associated with increased asthma prevalence (OR = 1.290, 95 % CI: 1.101-1.479, p = 0.010). Our results reveal a significant association between increased visceral adipose tissue and elevated risk of asthma, which is partially mediated by high-density lipoprotein cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase, low-density lipoprotein receptor, and lipoprotein lipase exhibit potential as therapeutic targets for asthma. Show less

The 808-nm wavelength laser has emerged as a promising non-invasive tool with significant therapeutic potential in various medical fields. This review highlights its biological mechanisms, including anti-inflammatory effects, tissue repair, and pain modulation. The laser inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, reducing pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)) and increasing interleukin-10 (IL-10), an anti-inflammatory mediator that accelerates healing. The laser also activates the transforming growth factor-beta (TGF-β) pathway to stimulate collagen synthesis and fibroblast activity, enhancing tissue regeneration. Additionally, by promoting vascular endothelial growth factor (VEGF) expression, and improves neovascularization and tissue oxygenation as well. The modulation of transient receptor potential vanilloid 1 (TRPV1) channels, increased adenosine triphosphate (ATP) production, and activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and the brain-derived neurotrophic factor (BDNF) pathways further support neuroprotection and cellular recovery. Importantly, recent insights suggest the laser's interaction with glial cells particularly astrocytes and microglia plays a critical role in managing neuro-inflammation and improving outcomes in neurological disorders such as hydrocephalus. The ability to influence cerebrospinal fluid regulation and enhance brain barrier permeability positions the 808-nm laser as a potential therapeutic option for improving life quality in affected individuals. Despite its potential, further clinical studies are required to validate and standardize its application across medical protocols. Show less

Arrhythmogenic cardiomyopathy (ACM) is typically linked to variants in desmosomal genes (eg, DSG2), whereas MYBPC3 variants are associated with hypertrophic cardiomyopathy. Concurrent variants from both pathways are rare and poorly characterized. A 35-year-old man who presented with congestive heart failure fulfilled the criteria for biventricular ACM. Genetic analysis identified 3 heterozygous variants, in DSG2 (c.136C>T, p.Arg46Trp and c.806T>C, p.Ile269Thr) and MYBPC3 (c.529C>T, p.Arg177Cys; variant of uncertain significance). The patient was treated with guideline-directed therapy, remained clinically stable with reduced premature ventricular complex burden and improved biventricular function on cardiac magnetic resonance, and was listed for heart transplantation. Concurrent DSG2 and MYBPC3 variants represent an uncommon genetic profile in ACM, contributing to variable phenotype and adverse outcomes. This case highlights the value of genetic testing combined with advanced imaging in refining the characterization of inherited cardiomyopathies. Concurrent genetic variants may influence phenotype and prognosis. Comprehensive testing and longitudinal follow-up are essential for risk stratification and personalized care. Show less

Sub-optimal metabolism is linked to dementia risk, yet metabolic traits rarely occur in isolation. Using data from 308,019 UK Biobank participants, we examined associations of six diverse metabolic subgroups (I-VI) - previously derived via a self-organising map (SOM) that captures patterns of co-occurring metabolic biomarker traits in the population - and 39 individual biomarkers, with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Biomarker associations were assessed using both linear and nonlinear (restricted cubic spline) models. After adjusting for age, sex, socioeconomic, and lifestyle factors, subgroup analyses showed that participants in the two leanest and two most adipose subgroups had higher risk of dementia outcomes compared to others. Subgroups with high adiposity exhibited elevated VaD risk, which was linked to hypertension, hyperglycaemia, and liver stress (Subgroup II); inflammation, microalbuminuria, and low apolipoprotein A1 (III). For AD, the risk was elevated in the lean subgroups (IV, V), characterised by low body mass index (BMI), triglycerides, and urate, and high sex-hormone binding globulin; as well as for adipose Subgroup II. APOE-ε4 allele count had limited influence on dementia associations with metabolic subgroups and biomarkers. This marked metabolic heterogeneity in dementia risk suggests that metabolic profiling could inform targeted prevention strategies. Interpretation of these findings is supported by previously reported MRI profiles of the metabolic subgroups, providing biological context. Show less

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL) [...]. Show less

Impaired cerebral glucose metabolism is a hallmark of Alzheimer's disease (AD). Lactate is an alternative brain fuel; however, whole-body lactate metabolism has not been measured in AD. The Lactate for Energy and Neurocognition Trial (NCT05207397) was a single-arm trial that enrolled 24 cognitively healthy (CH) older adults and 12 cognitively impaired (CI) participants. Subjects underwent a stable isotope lactate infusion to evaluate lactate metabolism, cognitive testing, and blood biomarker analyses. pTau217, brain-derived tau (BD-tau), pTau181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total tau, and brain-derived neurotrophic factor (BDNF) were analyzed by Simoa HD-X (Quanterix). Lactate metabolic clearance rate did not differ between CH and CI subjects (p = 0.988). After infusion, global cognition was improved (p < 0.001) and plasma pTau217 (-33.8%, p < 0.001), BD-tau (-32.6%, p < 0.001), pTau181 (-21.4%, p < 0.001), GFAP (-39.7%, p < 0.001), and NfL (-19.5%, p < 0.001) were reduced. Lactate turnover was not different between diagnosis groups. Lactate infusion improved cognition and reduced AD fluid biomarkers. Individuals with Alzheimer's disease (AD) can metabolize lactate as well as healthy controls. Lactate infusion might improve global cognition and processing speed. Lactate infusion results in significant decrease of AD fluid biomarkers. Show less

Cognitive impairment is acknowledged as an early stage between normal aging and Alzheimer's disease, emphasizing the need for prompt intervention. There is growing evidence that the gut-brain axis plays a role in regulating cognitive function, indicating that probiotics and their derivatives may impact cognitive functions through the brain-gut axis. In this study, we isolated and identified a novel bacterial strain Show less

Depression and obesity are amongst the most serious global health challenges. Each of them is associated with high morbidity, chronicity, and socioeconomic burden. Increasing evidence suggests that these conditions are not merely comorbid but share convergent biological pathways (e.g., hypothalamic-pituitary-adrenal axis dysregulation, chronic inflammation, gut dysbiosis, and mitochondrial dysfunction). All these components contribute together to the development and persistence of depressive symptoms as well as to an increase in adiposity. Within this framework, adipose tissue has emerged as an essential endocrine organ that has a deep impact on neuroimmune signalling and mood regulation through its secreted molecules, such as leptin, adiponectin, resistin, omentin, apelin, chemerin, and visfatin. The current management of depression involves a comprehensive, multidisciplinary approach that includes pharmacological treatment and psychotherapeutic support, alongside lifestyle changes. Here we highlight the molecular crosstalk between adipose tissue and the brain, summarising the evidence of adipokines' dysregulation role in connecting metabolic dysfunction to depressive neurobiology. By integrating metabolic, immunological, and neuroendocrine perspectives, this narrative review underscores the need to reconceptualise depression as an immunometabolic disorder. Understanding adipokine-mediated pathways may reveal new biomarkers and therapeutic targets, fostering interdisciplinary approaches. This would allow for the development of new treatment strategies, which include recombinant adipokines, anti-inflammatory agents, and microbial modulation. These new strategies might provide a significant benefit in selected patients, in addition to conventional antidepressants. Show less

Cardiovascular-Kidney-Metabolic (CKM) syndrome is characterized by the interrelatedness of chronic kidney disease, cardiovascular disease, and metabolic disorders. Although physical activity is widely acknowledged as an effective intervention for improving the prognosis of chronic diseases, its impact on all-cause mortality among patients with CKM syndrome remains unclear. To investigate the impact of physical activity on all-cause mortality among patients with CKM syndrome. Data from the 2011 wave of the China Health and Retirement Longitudinal Study were used as the baseline, with follow-up conducted until 2013. According to the International Physical Activity Questionnaire criteria, weekly physical activity levels were divided into three categories: light-volume physical activity (LPA), moderate-volume physical activity (MPA), and vigorous-volume physical activity (VPA). Cox proportional hazards regression models were employed to assess the impact of varying levels of physical activity on all-cause mortality. Restricted cubic spline analysis was used to explore possible nonlinear relationships. A total of 3343 patients with CKM syndrome were enrolled in this study. During the 2-year follow-up period, 44 deaths were recorded. After adjusting for potential confounders, VPA was associated with a 54% lower risk of all-cause mortality (adjusted hazard ratios, 0.46; 95% confidence interval: 0.24-0.89). Dose-response relationships demonstrated that all-cause mortality decreased as physical activity increased, with a 5.8% reduction in all-cause mortality risk for every 1000 MET-min/week increment in physical activity levels. VPA was significantly associated with reduced all-cause mortality in patients with CKM syndrome. Encouraging patients with CKM syndrome to engage in increased physical activity may improve clinical outcomes. Key messages What is already known on this topic: Cardiovascular-Kidney-Metabolic (CKM) syndrome involves a complex interplay between cardiovascular disease, metabolic disorders, and chronic kidney disease. While prior studies have established that physical activity can decrease mortality risk in the general population as well as in patients with cardiovascular and metabolic syndromes, the evidence regarding its impact on individuals with CKM syndrome remains limited. Additionally, there is a lack of detailed dose-response analyses of physical activity specifically targeting this high-risk population. What this study adds: This study provides novel evidence indicating that vigorous-volume physical activity (>3000 MET-minutes/week) significantly decreases all-cause mortality by 54% among patients with CKM syndrome, whereas moderate-volume, and light-volume physical activities show no significant effects. Notably, a linear dose-response relationship was established, demonstrating that each 1000-MET increment corresponds to a 5.8% reduction in mortality risk. These findings address a critical knowledge gap by quantifying both the threshold and incremental benefits of physical activity specifically for individuals with CKM syndrome, a population characterized by unique multisystem pathophysiology. How this study might affect research, practice, or policy: The findings of this study have the potential to substantially impact clinical practice by offering evidence-based thresholds for physical activity recommendations in the management of CKM syndrome. The benefits associated with vigorous-volume physical activity (>3000 MET-minutes/week) may encourage guideline committees to formulate more precise exercise prescriptions tailored to this high-risk population. Additionally, these results can be incorporated into a multidisciplinary care framework designed for managing complex chronic conditions. Show less

Despite widespread use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, substantial atherosclerotic cardiovascular disease risk persists, especially in people with heterozygous familial hypercholesterolemia or elevated lipoprotein(a) [Lp(a)] levels. Cholesteryl ester transfer protein (CETP) inhibitors block the transfer of hydrophobic cholesteryl esters from high-density lipoprotein to apolipoprotein B (apoB)-containing particles. This process raises high-density lipoprotein-C and lowers low-density lipoprotein-C, apoB, and Lp(a) levels. The first-generation of CETP inhibitors was limited by toxicity, neutral outcomes, or unfavorable pharmacokinetics. Obicetrapib is a next-generation amphipathic CETP inhibitor that selectively targets both CETP's hydrophobic and hydrophilic tunnels. It reduces low-density lipoprotein-C by about 30-51%, apoB by 20-33%, and Lp(a) by 30-57% without causing tissue accumulation or toxicity. Phase 3 trials (BROOKLYN, BROADWAY, TANDEM) show that obicetrapib is effective when added to maximized therapy, with a safety profile similar to placebo. Its consistent reduction of Lp(a) addresses an important unmet need. In addition to lowering atherogenic lipoproteins, early data suggest potential for neuroprotection, such as reductions in p-tau217 seen among APOE4 carriers. A 2025 pooled analysis offers initial evidence that major adverse cardiovascular events are reduced, as studied in the ongoing PREVAIL outcomes trial. This review covers CETP biology and tunnel mechanics, outcomes from earlier CETP inhibitor studies, obicetrapib's pharmacology, and current efficacy and safety data, and will clarify its potential place in lipid management today. Show less

Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive impairment, increased adverse cardiac events, and even death. This study aimed to investigate the correlation between plasma lipid levels and the characteristics of atherosclerotic plaques in adult patients with type 2 diabetes mellitus. A retrospective analysis was conducted on adult patients with type 2 mellitus who were hospitalized in the Department of Endocrinology at Affiliated Hospital of Hebei University between January 2017 and December 2021.Patients were categorized into two groups based on arterial ultrasound results. Statistical analyses were performed to compare plasma lipid levels and plaque characteristics across the groups. 1) Statistically significant differences were observed among the two groups in terms of gender, hypertension, age, duration of diabetes mellitus, plaque location, triglycerides (TG),total cholesterol (TC), Apolipoprotein A1 (Apo A1),very-low-density lipoprotein (VLDL), VLDL/apolipoprotein B(ApoB), high-density lipoprotein cholesterol (HDL)/ApoA1 ( In clinical practice, the characteristics of atherosclerotic plaques and lipid profiles should be jointly evaluated to guide targeted treatment and effectively reduce the risk of atherosclerotic cardiovascular disease. Show less

An increasing number of university students report feeling lonely, a negative experience arising from a mismatch between perceived and actual social relationships. Loneliness has been linked to poorer mental health. However, the relationship between qualitative (sources of loneliness) and quantitative (high or low) differences in loneliness and mental health is under researched. The aims of this research were to (a) identify profiles of loneliness among university students across three indicators of loneliness, namely, social, family, and romantic indicators, using latent profile analysis (LPA); (b) examine the differences among identified profiles based on dimensions of mental health indicators (depression, anxiety, and stress), social support, and life satisfaction; and (c) assess profile membership based on demographic variables (gender, social isolation, relationship status, and education characteristics) and the Big Five personality traits (extraversion, agreeableness, openness, conscientiousness, and neuroticism). A cross-sectional survey was conducted on 912 university students from five cities in Uttar Pradesh, India. Participants completed questionnaires covering demographic details and validated measures assessing loneliness, depression, stress, anxiety, social support, life satisfaction, and the Big Five personality traits. Data were analyzed using the latent profile module in Jamovi and fit indices, namely, BIC, AIC, and BLRT, and entropy was used to select the best profile. The latent profile analysis identified four profiles for university student loneliness, including Social and emotional lonely (31.4%), Moderate romantic lonely (23.8%), Moderate social lonely (8.2%), and Severe romantic lonely (36.6%). Moreover, the Social and emotional lonely profile scored the highest on depression, anxiety, and stress. The Moderate romantic lonely profile scored the highest on life satisfaction and social support. Being in a relationship decreased the likelihood of being categorized as Severe romantic lonely. In terms of personality, neuroticism was the strongest predictor of profile membership. This study is a step towards identifying at-risk lonely individuals with varying sources of loneliness. Identifying different profiles of lonely individuals will have direct implications for designing interventions that cater to a particular group rather than a one-size-fits-all approach. Show less

To investigate the dynamic genetic regulatory mechanisms of CD4 This study integrated context-specific expression quantitative trait locus analysis, Mendelian randomization, colocalization analysis, single-cell RNA sequencing, and qPCR experimental validation. A systematic investigation was conducted on gene expression and genetic variation in CD4 The study identified multiple genes demonstrating a causal relationship with OSA risk, such as The immune regulation mediated by CD4 Show less

The feeding rhythm is a major temporal regulator of metabolic physiology, yet its impact on microbiome-derived functional traits relevant to cardiometabolic disease remains insufficiently understood. Our previous work demonstrated that ad libitum, daytime-restricted, and nighttime-restricted feeding produce markedly different atherosclerotic outcomes in Apoe Show less

The purpose of this study was to identify the functional characteristics of blood proteins which are important in assessing reproductive health due to their immunoregulatory effects in women residing in the European North and Arctic regions of the Russian Federation. A total of 557 women aged 21-55 (36.89 ± 0.54), engaged in intellectual professions, born and long-term residents of the European North (Arkhangelsk Oblast) and Arctic (Murmansk Oblast, Svalbard archipelago) participated. The hemogram, phagocytic activity of neutrophils, erythrocyte aggregation, lymphocyte content with CD3, CD4, CD8, CD10, CD19, CD16, CD71, CD95 phenotypes, cytokines: TNF-α, IFN-γ, IL-6, IL-10, extracellular receptors: sCD71, sCD62L, sApo-1/Fas, sFasL, circulating immune complexes, sex hormones, and as well as immunoregulatory blood proteins: haptoglobin, transferrin, immunoglobulins, lipoproteins, apoproteins, were evaluated. In women from Arkhangelsk Oblast, transferrin levels showed a substantial increase, while IgA levels decreased relative to the reference range. In women from Murmansk Oblast, haptoglobin, IgM, and IgA levels increased, and a reduction in IgG levels was observed. In women from the Svalbard Archipelago, transferrin and IgM concentrations increased, whereas IgG and IgA levels decreased. Additionally, in women from the European North and Arctic, a decrease in ApoB and ApoA-I content was observed. Elevated levels of transferrin and a decrease in lymphocytes with a transferrin receptor CD71+ and an increase in soluble transferrin receptor sCD71 levels were noted. Elevated haptoglobin levels are related to lymphocyte activation. The frequent occurrence of reduced IgA and IgG levels suggests impaired immunoglobulin class switching. Reduced levels of ApoB and ApoA-I indicate the early stages of lipid metabolism disorders. The immunoregulatory role of blood proteins determines their functional characteristics in women living in the European North and the Arctic. Reduced antioxidant protection, metabolic disorders, and dysregulation of the immune response in women living in Northern and Arctic regions can lead to reproductive health risks. Show less

Indigenous Australians have an increased risk of type 2 diabetes mellitus (T2DM) and premature cardiovascular disease. Subpopulations of high-density lipoprotein (HDL) have been associated with increased cardiovascular risk, but HDL composition, size, or function have not been studied in Indigenous Australians. The study consisted of 86 non-Indigenous participants, 43 of whom had T2DM, and 75 Indigenous participants, 36 of whom had T2DM. HDL lipid and apolipoprotein content were determined using enzymatic assays and enzyme-linked immunosorbent assays, respectively, and HDL size and distribution were investigated using nuclear magnetic resonance spectroscopy. Transporter-independent, ATP-binding cassette transporter (ABC)A1- and ABCG1-specific cholesterol efflux capacity (CEC) were determined using cell lines stably expressing human ABCA1 or ABCG1. Indigenous participants had significantly lower concentrations of large (10.3-12.0 nm), small (7.4-7.8 nm), and total HDL particles, which persisted after adjustment for serum triglyceride (TG), body mass index (BMI), and T2DM. HDL from Indigenous Australians was also highly enriched in TG, apolipoprotein (apo) E, and apoCIII (all P < .001). Transporter-independent and ABCG1-mediated CEC were not different between the populations. ABCA1-specific CEC per HDL particle was higher in Indigenous than in non-Indigenous subjects (P < .001), and persisted after adjustment for TG, BMI, and T2DM. Multivariable analysis identified that ABCA1-specific CEC was independently and positively associated with HDL-apoCIII and HDL-apoE levels. Indigenous Australians demonstrate significant compositional, size, and functional changes in circulating HDL, which is only partially explained by BMI, hypertriglyceridemia, or T2DM. Remodeled HDL may serve as a biomarker of increased cardiovascular risk in Indigenous Australians. Show less

Next-generation sequencing (NGS) is instrumental for clinical decisions on molecularly targeted therapy (TT). In pediatric oncology, TT is a relatively rare choice administered chiefly on a tumor-agnostic basis. The investigation enrolled 304 pediatric patients with extracranial solid tumors that were diagnosed and treated in 2018-2023. Tumor DNA was sequenced using a customized QiaSeq panel (Qiagen, Hilden, Germany) of genes known to be relevant for pediatric solid tumors, including Show less

The aim of this study was to explore the prospective association between compositions of accelerometry-measured occupational physical behaviors and the risk of knee pain among eldercare workers. We performed a prospective study among 377 eldercare workers employed across 20 Danish nursing homes. Occupational physical behaviors were measured using thigh-worn accelerometers over 1-4 working days. Workers reported intensity of and days with knee pain in a questionnaire at baseline and after one year. We explored associations between compositions of occupational physical behaviors [ie, sedentary, standing, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA)] and knee pain, adjusting for potential confounders. No significant associations were found. Trends were found for increased occupational time spent in MVPA and decreased risk of days with knee pain [relative risk (RR) 0.58, 95% confidence interval (CI) 0.32-1.05, P=0.07] in main analyses, and for decreased risk of knee pain intensity among non-knee pain cases (RR 0.36, 95% CI 0.12-1.13, P=0.08) in sensitivity analyses. No significant associations were found between baseline occupational physical behaviors and knee pain at one-year follow-up. However, a non-significant trend suggested that increasing occupational MVPA might be associated with reduced risk of knee pain at follow-up, though studies with larger samples are needed to confirm this finding. Show less

Lipoprotein(a) (Lp(a)) is a plasma lipoprotein with atherogenic, prothrombotic, and proinflammatory properties. Elevated Lp(a) levels are linked to the development of early atherosclerosis in childhood and contribute to a higher risk of cardiovascular disease (CVD) in adulthood. This study aimed to assess the clinical significance of Lp(a) levels in Portuguese pediatric patients who underwent serum Lp(a) testing as part of a lipid disorder screening prompted by obesity, hypercholesterolemia, and/or a family history of premature CVD. We also evaluated the correlation between Lp(a) levels and CVD risk factors. This cross-sectional retrospective study included 792 pediatric patients. Data on demographics, clinical history, body mass index, and laboratory values, including Lp(a), were collected. Lp(a) levels were categorized into 3 groups: <75 nmol/L, 75-125 nmol/L, and >125 nmol/L. A multivariate analysis was used to identify factors associated with Lp(a) ≥ 75 nmol/L. The most prevalent comorbidities in this sample were obesity and associated low-grade inflammation, each affecting at least one-third of participants. The median Lp(a) level was 31.80 nmol/L, with 9.1% and 21.6% of children having intermediate (75-125 nmol/L) and high (>125 nmol/L) Lp(a) levels, respectively. Higher total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C) levels were correlated with elevated Lp(a) levels. The multivariate analysis identified an elevated LDL-C level as a predictor of a higher Lp(a) level. This study highlights the alarming prevalence of elevated Lp(a) levels in Portuguese pediatric patients who underwent serum Lp(a) testing due to lipid disorder screening, with >30% at intermediate/high CVD risk. As Lp(a) levels are mostly genetically determined and tend to persist into adulthood, these findings emphasize the importance of including Lp(a) screening in the cardiovascular risk assessment of children with CVD risk factors to enable timely prevention strategies for adultonset CVD. Show less

Pharmaceutical and personal care products (PPCPs), as ubiquitous emerging contaminants, present undercharacterized neuropsychiatric hazards through environmental exposure. This investigation employs convergent multi-omics strategies - integrating toxicogenomic discovery, disease-associated genomic mapping, and transcriptomic profiling - to elucidate mechanistic linkages between PPCPs bioactivity and depressive pathogenesis. Through systematic analysis of Nanjing's aquatic chemical burden (prioritizing dimenhydrinate, ibuprofen, padimate-O, caffeine, and roxithromycin), we identified 3073 conserved molecular targets bridging PPCPs toxicity and depression etiology via Comparative Toxicogenomics Database and GeneCards interrogation. Functional ontology revealed dysregulated pathways encompassing lipidomic remodeling, IL-17-mediated neuroinflammation, and synaptic transmission deficits. Ensembled machine learning algorithms (Lasso regression, XGBoost, random forest) converged on seven high-fidelity candidate biomarkers (HSPA8, CBX1, CD59, CHAF1A, CUX1, ID2, RPL3) demonstrating stress-adaptive, chromatin regulatory, and immunomodulatory functions. Molecular docking predicted strong binding affinities between PPCPs and depression-related proteins, notably dimenhydrinate with CHAF1A (- 6.1 kcal/mol) and HSPA8 (- 6.1 kcal/mol), suggesting multi-target modulation. This work proposes a computational framework to map molecular interactions between specific PPCPs and depression-associated pathways. Candidate targets highlight testable hypotheses for future experimental validation. These findings suggest selected PPCPs with neuroactive properties may warrant further investigation as environmental modifiers of depression risk. Show less

Mitochondrial dysfunction critically impacts lung adenocarcinoma (LUAD) progression and tumor microenvironment (TME) remodeling, highlighting the urgent need to identify predictive biomarkers with clinical utility. RNA-seq data sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify mitochondrial-related (MTR) genes associated with LUAD progression. A three-gene prognostic signature, consisting of SFXN1, CPS1, and MTFR2, was developed through univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. Functional enrichment, immune infiltration, and tumor mutation burden (TMB) analyses were performed to characterize the TME. Experimental studies were conducted in LUAD cell lines The signature stratified patients into high-risk and low-risk groups with significant survival differences (TCGA: HR = 1.476, This study has successfully established a mitochondrial-related prognostic signature that predicts survival outcomes and immune phenotypes of LUAD patients, providing a clinically relevant predictive tool and laying the foundation for developing mitochondrial-targeted therapeutic strategies. Show less