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This study investigated the relationship between apolipoprotein B (apoB), "excess apoB" (apoB beyond low-density lipoprotein cholesterol (LDL-C)), and apoB/apolipoprotein A1 (apoA1) ratio with 20-year atherosclerotic cardiovascular disease (ASCVD) incidence, using an age- and sex-specific approach. In 2002, a cohort of 3042 adults, free of cardiovascular disease (CVD) residing in the greater Athens area (Greece) was recruited. A 20-year follow-up was conducted in 2022, comprising of 2169 participants, of whom 1988 had complete data for CVD incidence. Cox proportional hazards models were used to assess the association of apoB, excess apoB, and apoB/apoA1 with 20-year ASCVD risk and residual risk (events not predicted by standard factors). Older participants and males had higher levels of apoB, excess apoB, and apoB/apoA1. In the overall cohort, only apoB was significantly associated with ASCVD risk (hazard ratio (HR), 1.006; p = 0.003). However, age- and sex-dependent associations were observed as apoB, excess apoB, and apoB/apoA1 significantly predicted increased ASCVD incidence only in males under 40 years (HR 1.025, p = 0.005; 1.052, p = 0.003; 1.396, p = 0.002; respectively). Significant associations were observed with residual ASCVD risk in the overall cohort, with the most pronounced associations seen in males under 40 (HR 1.023, p = 0.001; 1.039, p < 0.001; 1.285, p = 0.002; respectively). The association of apoB, excess apoB, and apoB/apoA1 with long-term ASCVD incidence and residual risk demonstrates age- and sex-dependent variations, with younger males showing elevated risk, highlighting the value of these markers beyond traditional risk factors and emphasizing the need for age- and sex-specific considerations in ASCVD risk assessment. Show less

Obesity is a well-established risk factor for asthma pathogenesis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic interventions are currently lacking, making asthma management in obese individuals particularly challenging. Asthma is characterized by chronic airway inflammation, eosinophilic infiltration, and airway hyperresponsiveness (AHR). In this study, we investigated the novel role of fibroblast growth factor 21 (FGF21), a stress-inducible hepatokine with pleiotropic metabolic regulatory functions, in obesity-associated AHR using a diet-induced obesity mouse model (n = 10). Serum samples were collected from obese and lean asthma patients, along with relevant clinical indicators, including body mass index (BMI), forced expiratory volume in 1 second (FEV1%), and the FEV1/forced vital capacity (FVC) ratio, to facilitate the investigation. Moreover, diet-induced obese mice with innate AHR (male, n = 10) were employed to clarify the effects of FGF21 and FGF21-neutralizing antibody on obesity induced AHR. In vitro, LAD2 human mast cells and P815 murine mast cells activated by compound 48/80 were used to elucidate the underlying mechanisms. Our findings demonstrate that serum FGF21 levels exhibit reportedly elevated in participants with obesity and are associated with impaired pulmonary function. In diet-induced obese (DIO) mice, FGF21 levels were increased in both serum and bronchoalveolar lavage fluid (BALF). In vivo investigations demonstrate that administration of recombinant FGF21 exacerbated AHR in DIO mice, whereas FGF21-neutralizing antibody treatment ameliorated obesity-induced AHR and suppressed mast cell infiltration. Mechanistically, FGF21 was found to potentiate mast cell activation through cholesterol biosynthesis modulation. Crucially, pharmacological inhibition of FGFR1 abrogated FGF21-induced mast cell hyperactivity and cholesterol synthesis, indicating FGFR1-dependent signaling in this process. These findings may represent the FGF21/FGFR1 axis as a potential therapeutic target for obesity-related AHR and asthma. Show less

This review examines the rapidly evolving landscape of myeloproliferative hypereosinophilic syndromes (HES) and related neoplasms. We aim to synthesize current understanding of their diverse molecular drivers, evaluate the efficacy of established and novel targeted therapies, and identify critical research gaps. The goal is to provide a clinically relevant update on how molecular precision is reshaping the diagnosis and management of these rare, often aggressive hematologic malignancies beyond the established standard of imatinib. The field has moved beyond generic HES diagnoses to a molecularly defined classification. While imatinib remains the standard for The management of myeloproliferative HES has transitioned from empirical therapy to a precision medicine paradigm. Early comprehensive molecular profiling is essential to guide therapy selection. While imatinib remains a cornerstone for select patients, novel agents like pemigatinib and avapritinib have filled critical therapeutic gaps. Future progress depends on the routine integration of comprehensive next-generation sequencing, the validation of minimal residual disease monitoring to guide therapy de-escalation, and international collaboration to conduct innovative trials for these rare patient populations. Show less

Recent advances in molecular pathology have transformed the diagnostic landscape and management of human cancer. Increasingly, integration of genomic and epigenomic data with conventional histopathology has improved tumor classification, refined prognostic assessment, and revealed previously unsuspected therapeutic targets. High-throughput techniques such as next-generation sequencing, gene fusion panels, and methylation arrays have expanded applicability to formalin-fixed tissue and enabled simultaneous evaluation of multiple cancer-defining alterations/genetic drivers. In optic nerve gliomas, MAPK pathway activation through BRAF or FGFR1 alterations, or NF1 inactivation, is a basic biological feature with diagnostic implications, while MEK inhibitors may be of clinical benefit in selected patients. Optic nerve sheath/orbital meningiomas demonstrate divergent molecular landscapes depending on location, with NF2-driven and non-NF2-driven pathways informing recurrence risk and behavior. In the orbit, characteristic genetic drivers facilitate diagnosis of mesenchymal tumors such as solitary fibrous tumor (NAB2::STAT6) and alveolar rhabdomyosarcoma (PAX3/7::FOXO1), while molecular profiling assists in distinguishing challenging peripheral nerve and melanocytic lesions. Similarly, lacrimal gland neoplasms parallel salivary gland counterparts, with recurrent fusions such as PLAG1, HMGA2, and MYB::NFIB of great diagnostic utility. These advances underscore the growing role of molecular diagnostics in improving accuracy, guiding prognostication, and refining the classification of rare ocular tumors. As high-throughput techniques continue to mature, integration with evolving spatial and single-cell-based approaches promises to expand our understanding and further personalize diagnostic and therapeutic strategies. Show less

Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity. Show less

Accurately predicting the bioactivity of small molecules against cancer therapeutic targets remains a significant challenge at the intersection of cheminformatics and drug discovery. This study comprehensively evaluates chemical representations, including AtomPair Counts (APC),Avalon (AVN), Extended-Connectivity Fingerprint diameter 4 (ECFP4), Extended-Connectivity Fingerprint diameter 6 (ECFP6), Feature-based Morgan 2 (FM2), Feature-based Morgan 3 (FM3), Mol2Vec (M2V), Molecular ACCess System (MACCS), Mordred 2D Chi Kappa (MK2), RDKFingerprint (RDF), Rdkit PhysChem (RDC), Torsion (TSN) combined with machine learning algorithms (Bayesian Ridge (BRG), Elastic Net (ENT), Extra Trees (ETT), Hist Gradient Boosting (HGT), K-Nearest Neighbors (kNN), Lasso (LSS), Multi-layer Perceptron (MLP), Partial least squares (PLS), Random Forest (RFT), Ridge (RDG), Support Vector Regressor (SVR), and XGBoost (XGB)) for predicting cancer bioactivities. The results show that while AVN chemical representation, in conjunction with SVR algorithm, achieved the highest predictive accuracy, with R2 of 0.735 in FGFR1 dataset; The mTOR dataset demonstrated the highest average performance across all models and chemical representations, with an R2 of 0.592 across various cancer datasets. These findings demonstrate how cheminformatics tools like molecular fingerprints and quantitative structure-activity relationship (QSAR) modeling can significantly enhance bioactivity prediction, ultimately contributing to more efficient and targeted cancer drug discovery. Show less

This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer's disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ Show less

To explore the association between apolipoprotein E (APOE) gene polymorphisms and the risk of premature (age of onset: men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). This study retrospectively collected the medical records (age, gender, hypertension, diabetes mellitus, smoking, drinking, and serum lipid) of 379 PMI patients and 628 age-matched non-AMI individuals (controls), from December 2018 to March 2024. The relationship between APOE polymorphisms and PMI was analyzed. 15(1.5%) individuals carried ɛ2/ɛ2, 147(14.6%) had ɛ2/ɛ3, 16(1.6%) presented with ɛ2/ɛ4, 670(66.5%) were ɛ3/ɛ3 carriers, 149(14.8%) had ɛ3/ɛ4, and 10 (1.0%) carried ɛ4/ɛ4. The proportion of ɛ2/ɛ3 genotype was significantly lower in the PMI group than in controls (7.7% vs. 18.8%, p < 0.001), whereas the prevalence of ɛ3/ɛ4 genotype was substantially higher in the PMI group (20.6% vs. 11.3%, p < 0.001). Logistic regression analysis identified some associated factors: smoking (odds ratio [OR]: 3.057, 95% confidence interval [CI]: 2.098-4.455, p < 0.001), hypertension (OR: 4.474, 95% CI: 3.273-6.117, p < 0.001), and dyslipidemia (OR: 1.805, 95% CI: 1.333-2.443, p < 0.001). Additionally, genetic factors were associated with PMI: the APOE ɛ3/ɛ4 genotype (vs. ɛ3/ɛ3, OR: 1.548, 95% CI: 1.038-2.309, p = 0.032) and the presence of ɛ4 allele (vs. ɛ3, OR: 1.521, 95% CI: 1.033-2.241, p = 0.034) were confirmed as independent associated factors. APOE ε3/ε4 genotype was significantly associated with PMI, suggesting that this genotype could serve as a potential genetic marker for PMI risk assessment. Show less

Genetic forms of obesity, including monogenic (MO) and syndromic (SO) obesity, are characterised by severe, early-onset weight gain due to disrupted central regulation of body weight, typically involving key pathways such as the leptin-melanocortin axis. These alterations result in marked hyperphagia and complex eating behaviours, yet clinical characterisation remains limited. This review aimed to describe the multidimensional eating behaviour profiles across genetically confirmed obesity, explore their variability, and evaluate existing assessment tools to support early diagnosis, personalised care, and therapeutic monitoring. We conducted a systematic review following PRISMA guidelines including publications up to 4 September 2025. A total of 162 studies involving individuals with genetically confirmed SO or MO were analysed. Eating behaviours were categorised into nine dimensions: food-centred thinking, food-seeking/stealing, hunger/satiety, ingestive/oral behaviours, nutritional quality, food preferences, food acceptability, loss of control eating, and eating restraint. Assessment tools and methodologies were systematically reviewed. Hyperphagia was consistently reported across genetic aetiologies, though definitions and measures remain heterogeneous. Prader-Willi syndrome (PWS), the most studied condition, was associated with early-onset hyperphagia, increased hunger, pronounced food preoccupation, compulsive food-seeking/stealing and strong preferences for carbohydrate-rich, large quantities and unusual food items. Similar behavioural traits were found in other SO and MO, including Bardet-Biedl syndrome, Alström syndrome, Fragile X syndrome, WAGR syndrome, pseudohypoparathyroidism Ia, 16p11.2 deletion and LEPR, POMC, and MC4R deficiencies. Behavioural traits appeared relatively consistent across sex, age, and genotypes within syndromes. Most studies relied on caregiver reports; existing tools such as the Hyperphagia Questionnaire (HQ) and Food-Related Problem Questionnaire (FRPQ), developed primarily for PWS, did not fully capture the behavioural spectrum or suit all cognitive profiles. Tools applicable to individuals without intellectual developmental disorders, particularly adults living independently, remain scarce. This is the first systematic review to comprehensively map eating behaviours across rare genetic obesity using a multidimensional approach. It highlights the shared feature of disrupted appetite regulation and emphasises the need for standardised, multidimensional tools suitable for both clinical and research contexts. Better behavioural characterisation will support targeted therapies and improve outcome monitoring in these high-need populations. Show less

Inhibitors of the menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged leukemias. We evaluated menin inhibition in patient-derived xenografts of KMT2A-rearranged leukemias with high-risk features. Three acute myeloid leukemias with high-risk fusion partners (mixed-lineage leukemia-10 [MLLT10] and mixed-lineage leukemia-4 [MLLT4]) and two infant acute lymphocytic leukemia (ALL) samples were sensitive to menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared with cells obtained earlier in the same patients' disease course. Because none of the patients had been treated with a menin inhibitor, resistance in these highly pretreated samples was acquired in the absence of menin-inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy toward the canonical targets of the menin inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple comutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patient; inactivation of KMT2C/D has been reported to result in menin-inhibitor resistance, and KMT2C-edited cells from this patient were selected for in menin-inhibitor-containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data support using menin inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred. Show less

In the present study, a systematic revision in the Medline was conducted to determine the somatic mutation in gangliogliomas. A Medline search for relevant publications up to October 2024 using the key phrase "ganglioglioma mutation" led to the retrieval of 297 studies. This corpus provided the basis for the present review. The records without abstract or descriptions of somatic mutations were excluded. Only records in the English language were considered. A total of 43 papers were evaluated, reporting a total of 1360 cases of ganglioglioma. Among them, 528 cases presented mutations in 6 genes: BRAF BRAF Show less

Embryos produced in vitro exhibit heightened cryosensitivity due to excessive lipid accumulation. Previous studies demonstrated that cyclic guanosine monophosphate (cGMP) modulates intracellular lipid metabolism through cGMP-dependent protein kinase (PKG) signaling in various cell types. This study investigated the effects of cGMP on (i) cryosurvival in sheep embryos, (ii) embryonic quality, and (iii)lipolysis-related parameters. Specifically, we quantified lipid droplet content, free fatty acid levels, and hormone-sensitive lipase (HSL) phosphorylation status as key indicators of lipolytic activity. The results showed that cGMP pretreatment (0.5 mM) for 10 min prior to slow freezing significantly improved post-thaw embryo recovery rates and upregulated the mRNA expression of key developmental genes (POU5F1, SOX2, CDX2, and NANOG). cGMP pretreatment significantly upregulated the expression of multiple lipid catabolism genes (ACSL4, HMGCR, HMGCS1, LIPE, LPL, LIPF, and PLIN2), with LIPE (encoding HSL) exhibiting the most pronounced induction (27.10-fold increase vs. control). Following cGMP pretreatment, PKG activation triggered significant increases in the intracellular Ca Show less

This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, IL-8 and PAD4 in papillary thyroid carcinoma (PTC) tissues and adjacent non-cancerous thyroid tissues. Effects of DUSP6 on the proliferation, apoptosis, migration, and invasion of thyroid cancer cell lines TPC-1 and IHH4 were performed through in vitro experiments. A rescue experiment was performed to verified DUSP6 regulated the migration and invasion of thyroid cancer cells TPC-1 and IHH4 through IL-8 and neutrophil extracellular traps (NETs) formation. In addition, in vitro cell experiments were conducted to analyze the regulation of NETs formation by DUSP6 through IL-8. Finally, the effect of sh-DUSP6 on the growth of thyroid cancer tumors in mice were conducted through in vivo experiments. DUSP6 expression was significantly upregulated in PTC tissues. Moreover, the expression of DUSP6 in tumor tissues of TPC patients is positively correlated with the expression of IL-8 and PAD4. Overexpression of DUSP6 promotes the proliferation, migration, and invasion of thyroid cancer cells (TPC-1 and IHH4) while inhibiting apoptosis. Conversely, silencing DUSP6 exerts opposing effects. Knockdown of IL-8 reverses the enhanced migratory and invasive capabilities induced by DUSP6 overexpression in these cell lines. NETs treatment enhances the migration and invasion of TPC-1 and IHH4 cells, whereas the application of sh-DUSP6 or sh-IL-8 counteracts this NETs-mediated promotion. Furthermore, DUSP6 overexpression facilitates NETs formation by upregulating IL-8 expression. In vivo experiments demonstrate that sh-DUSP6 suppresses thyroid cancer tumor growth in mouse models. Conclusion: DUSP6 promotes the metastasis of thyroid cancer by facilitating the formation of neutrophil extracellular traps via IL-8. Show less

Hypertriglyceridemia (HTG) increases cardiovascular and pancreatitis risk. Antisense oligonucleotide (ASO) therapies like volanesorsen and olezarsen target ApoC-III mRNA to reduce ApoC-III, enhancing lipoprotein lipase activity and lowering triglycerides (TGs). This meta-analysis evaluates the efficacy and safety of these ASOs in severe HTG. A systematic review (PROSPERO: CRD42024577110) was conducted following PRISMA, sourcing studies from PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov until July 2024. Randomized controlled trials (RCTs) involving severe HTG (≥200 mg/dL) treated with volanesorsen or olezarsen vs. placebo were included. Data were synthesized using a random effects model in RevMan 5.4, and bias was assessed with the Cochrane tool. Of 31 identified articles, 9 RCTs (341 patients treated with ASOs, 209 controls) were included. ASOs significantly reduced TG levels [mean difference (MD): -53.72; 95% confidence interval (CI): -77.04 to -30.40; p<0.00001]. Reductions were also seen in very low-density lipoprotein cholesterol (MD: -55.76; p<0.00001), ApoC-III (MD: -74.78; p<0.00001), and APOB48 (MD: -69.45; p<0.00001). Olezarsen uniquely reduced APOB (MD: -15.60; p<0.00001). Non-high-density lipoprotein cholesterol (HDL-C) decreased (MD: -23.25; p<0.00001), while HDL-C increased (MD: +42.14; p<0.00001). Volanesorsen was linked to higher low-density lipoprotein-cholesterol (MD: +62.74; p=0.004). For safety, local injection reactions, thrombocytopenia, and nausea were more common with volanesorsen. Acute pancreatitis occurred only in the placebo group (relative risk: 0.15; p=0.0004), indicating ASO protection. This meta-analysis confirms that ASOs effectively lower TGs and improve lipid profiles in severe HTG. Show less

Hypoparathyroidism is a rare endocrine condition characterized by insufficient secretion of parathyroid hormone (PTH), resulting in abnormally low calcium levels (hypocalcemia) and elevated phosphate levels (hyperphosphatemia) in the blood. This report describes a man in his late 30s with a chronic skin condition marked by dryness and desquamation. He occasionally experienced mild perioral numbness. Over the past year, he developed recurrent neuromuscular irritability, including worsening perioral numbness, tingling or numbness in the hands and feet, and muscle spasms consistent with tetany. He was diagnosed with hypoparathyroidism, and his symptoms improved markedly after calcium and calcitriol supplementation. Genetic testing revealed a novel heterozygous c.2298C>G (p. Tyr766Ter) mutation in exon 18 of the fibroblast growth factor receptor 1 gene. This case report aimed to describe this novel mutation and its potential role in the pathogenesis of primary hypoparathyroidism and to discuss relevant diagnostic and therapeutic management strategies. In addition, it broadens our understanding of genetic mutations associated with hypoparathyroidism and provides clinically relevant diagnostic information that may benefit future patients with the similar genetic alteration. Furthermore, it underscores the importance of genetic analysis in elucidating the heterogeneity and complexity of hypoparathyroidism, thereby supporting the development of more precise and tailored treatment approaches. Show less

The discovery of dual acetylcholinesterase (AChE) and β-secretase (BACE1) inhibitors remains a promising strategy against multifactorial Alzheimer's disease. Here, rigorously curated ChEMBL-derived data were used to develop explainable QSAR (Quantitative structure-activity relationship) models for dual-inhibition prioritization. Molecules were standardized, near-duplicates were removed using a Tanimoto similarity threshold (≥ 0.80), and physicochemical outliers were filtered prior to modeling. Multiple classifiers (including Light Gradient-Boosting Machine, eXtreme Gradient Boosting, Random Forest, Support Vector Machine, k-Nearest Neighbors and Gradient Boosting Decision Trees) and fingerprints (e.g., RDKit fingerprints, Extended Connectivity Fingerprint) were benchmarked under scaffold-based nested cross-validation to prevent data leakage. Class imbalance was handled with SMOTETomek applied strictly within training folds. Model selection relied on F-Score, Area Under the Precision-Recall Curve, Matthews Correlation Coefficient (MCC), and Recall, and performance was accompanied by bootstrap confidence intervals, calibration curves, and Y-randomization controls. In classification, the top model (GBDT + ECFP6) achieved strong generalization (Recall ≈ 1.00, PR-AUC ≈ 0.84, MCC ≈ 0.81, F1 Score ≈ 0.84). Shapley Additive Explanations (SHAP) analysis highlighted aromatic and hydrogen-bonding substructures as key positive contributors. Prospective candidates (e.g., CHEMBL5082250, CHEMBL1651126, CHEMBL1651127) were evaluated by active-site-focused docking against AChE (PDB: 4EY7) and BACE1 (PDB: 2G94) with essential waters retained; docking scores (ΔG, kcal·mol⁻ Show less

Important pathophysiological characteristics of human tumors are the presence of hypoxia and of an extracellular acidosis. Both metabolic parameters can affect the malignant behavior of tumors but also the response to treatments. Here the modulation of the ERK1/2 signaling plays a relevant role. ERK1/2 activation is controlled by the dual-specificity phosphatase 6 (Dusp6) and by this modulates cellular processes. For this reason, the study analyzed the impact of hypoxia and/or extracellular acidosis on the expression of Dusp6. Several tumor cell lines were exposed to control conditions (room air, pH = 7.4), hypoxia (pO Show less

Despite the rapid development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in recent decades, resistance remains a significant challenge in managing advanced non-small cell lung cancer (NSCLC). Elucidating the mechanisms underlying EGFR-TKI resistance and developing novel strategies are therefore crucial. In this study, we investigated the role of polo-like kinase 1 (PLK1) in EGFR-mutant NSCLC and evaluated the therapeutic potential of combining EGFR-TKIs with PLK1 inhibitors. We demonstrated that high PLK1 expression correlates with STAT3 signaling activation and decreased survival probability in EGFR-mutant NSCLC patients. Subsequent studies revealed that PLK1 inhibitors effectively reversed the activation of STAT3 induced by EGFR-TKIs. When used in combination with EGFR-TKIs, they promoted cell apoptosis, inhibited cell proliferation in vitro, and induced tumor regression in animal models. Mechanistically, our data demonstrated that PLK1 regulated STAT3 activity through protein-protein interactions and JAK1-mediated phosphorylation, while STAT3 reciprocally regulated PLK1 transcription, establishing a positive feedback loop between these signaling molecules. This PLK1/STAT3 loop was further reinforced by FGFR1 upregulation and directly linked to EGFR-TKI resistance. Targeting this axis with combinatorial inhibitors exerted synergistic anti-tumor effects, suppressing proliferation and migration in osimertinib-resistant models. In conclusion, concurrent inhibition of EGFR and FGFR1/STAT3/PLK1 signaling pathways provides a promising therapeutic strategy for NSCLC patients with EGFR mutations, enhancing efficacy and overcoming resistance. Show less

MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). MYBPC3-deleted hiPSC-CMs revealed the characteristics of heart failure, which exhibited increased contractility at 30 days but decreased at 40 days. Furthermore, at 40 days, it also shows abnormal calcium handling, increased ROS levels, and mitochondrial damage. Further RNA sequencing revealed that the oxidative stress pathway was aberrant, in addition to alterations linked to hypertrophic cardiomyopathy. Moreover, after adding melatonin to hiPSC-CMs at 30 days, MYBPC3-deleted hiPSC-CMs showed restored calcium handling capacity, decreased ROS levels, and improved myocardial contractility. In summary, reducing ROS can improve the phenotype of hypertrophic cardiomyopathy. Show less

Alzheimer's Disease (AD) is the leading cause of dementia, accounting for 60-70 % of cases worldwide. Early diagnosis remains challenging due to the limitations of current diagnostic tools, which are costly, invasive, and suffer from low patient compliance. Blood-based biomarkers, particularly plasma brain-derived exosomes (BDEs), have emerged as a promising alternative since they carry AD-related molecules and can be isolated non-invasively. In this study, an immunoassay was developed to isolate BDEs using magnetic particles functionalized with an anti-neuroligin-3 (NLGN3) antibody, while the AD-related marker β-secretase (BACE-1) was detected on the captured exosomes. This is the first report combining NLGN3 for for the isolation of BDEs with BACE-1 as a detection target, establishing a novel biomarker panel for AD diagnostics. The assay was evaluated across three readout platforms-optical, chemiluminescent, and electrochemical-with detection limits in the range of 10 Show less

Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis to establish causality between them, offering clinical treatment and prediction insights. Apoptosis-related genes are sourced from GeneCards, and 6 transcriptomic datasets from the cells in the circulation are obtained from GEO. Meta-analysis integrated differentially expressed apoptosis-related genes (DEGs) from the above 6 datasets. Causality between gene expressions, epigenetic changes, and OP is examined using OP genome-wide association study (GWAS), plasma expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data, while analysis of skeletal muscle eQTL and OP GWAS data is conducted. External validation is performed with the UK Biobank datasets. Meta-analysis of 6 GEO datasets identified 384 DEGs, including 78 apoptosis-related genes. The three-step analysis indicates 8 candidate causal genes in blood, including MAP3K3, DPP8, RPL3, PPP2CA, CD86, LRRFIP1, TRAP1, and DUSP6, with LRRFIP1 influenced by four methylation sites. Analysis of skeletal muscle data reveals 4 causal genes, including SIPA1L3, PDLIM7, CTNNB1, and DPP8. Among apoptosis-related genes causally linked to OP in both circulation and skeletal muscle, LRRFIP1 was validated based on methylation-associated regulation and demonstrated consistent, reproducible expression patterns. This study uses a multi-omics strategy to clarify the roles of apoptosis-related gene expressions and their corresponding methylation in OP, providing targets and a basis for early diagnosis, personalized treatment, and monitoring of OP. Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction. Show less

Generation of specific antibodies against peptides by immunization requires their covalent conjugation to protein carriers to override their inherently weak immunogenicity. The vast majority of bioconjugation approaches to achieve peptide-protein constructs rely on thiol-maleimide chemistry and capitalize on a wide array of commercial maleimide-functionalized protein carriers. Disulfide-rich peptides (DRPs) possess a rigid, constrained structure that makes them ideal for designing synthetic mimics of protein regions/domains. For bioconjugation purposes, the introduction of a single spare thiol moiety into a linear peptide antigen is straightforward, while DRPs' disulfide bonds are prone to intramolecular thiophilic attack by the reactive thiolate. This unintended reactivity competes with the desired Michael addition to the maleimide moiety, ultimately disrupting the native disulfide bridging framework. As a result, DRP's tertiary structure will be altered, affording an immunogen that is a poor mimic of the native target. Although a few studies have explored the late-stage introduction of thiol-containing cross-linkers into DRP antigens for their conjugation onto protein carriers, the stability of DRPs' disulfide pattern in the presence of an extra thiol has never been examined. In this study, we systematically evaluated the influence of different spacers in "DRP-spacer-thiol" constructs under thiol-maleimide reaction conditions. Our results highlight how both linker length and flexibility are key to maintaining DRP disulfides unaltered, providing a general approach to achieve DRP bioconjugation by thiol-maleimide chemistry. We have applied our approach to a small DRP predicted to closely mimic a surface-accessible epitope of the full LINGO-1 protein and obtained a very specific antibody response upon immunization; the resulting polyclonal IgG was able to selectively bind the full-length protein in a cellular context, with stringent selectivity across its four homologs. Show less

Muscular strength is a marker of current health and a predictor of long-term health outcomes in young populations, supporting the inclusion of muscle-strengthening activities into current guidelines and recommendations. Over the last decade, muscular strength has been included in several fitness-test batteries in children and adolescents. However, little is known about its relevance and the feasibility of assessing it in preschool children aged 3-5 years. Therefore, in this cross-sectional study, we aimed to generate reference values for handgrip strength in Swedish preschool children and to examine the associations of device-measured movement behaviours (sedentary time [ST], light physical activity [LPA], moderate-to-vigorous physical activity [MVPA], and sleep duration) with handgrip strength using compositional data analysis. A total of 3,218 preschool children (48.53% female) aged 3.0-5.5 years from Sweden were included. Handgrip strength was measured using a validated analog dynamometer following standardized procedures. Movement behaviours were assessed in a subsample of 2,328 children who had both handgrip data and valid accelerometer recordings. Compositional data analysis was used to examine associations between handgrip strength and the 24-hour time-use composition, adjusting for age, sex, body mass index, parental education, and wear time. Age- and sex-specific percentiles for handgrip strength were developed. Boys showed higher handgrip values than girls at all ages (e.g., median increased from 4.08 to 7.42 kg in boys and from 3.45 to 6.87 kg in girls between ages 3 and 5 years). When the proportion of time spent in MVPA increased relative to the other behaviours, handgrip strength rose by + 1.22 kg; the opposite was observed for ST, which related to - 0.84 kg lower handgrip strength. No significant associations were observed for LPA or sleep duration (LPA: β =-0.48 kg, 95% CI: -1.23, 0.27; sleep: β = 0.10 kg, 95% CI: -0.37, 0.57). This study provides the first normative reference values for handgrip strength from Northern Europe. These values offer a useful reference for screening and contextual interpretation of muscular strength in preschool children. Show less

Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple-negative breast cancer (TNBC) lung metastasis in an immune-dependent pattern by improving tetracosatetraenoic acid (C24:4 (n-6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8 Show less

Fibroblast growth factor 19 (FGF19) is a key intestinally secreted factor in mammals, its physiological role in teleost remains largely unclear. This study aimed to investigate the function and underlying mechanisms of FGF19 in the regulation of lipid metabolism in large yellow croaker. Results revealed that FGF19 was predominantly expressed in the liver. Treatment with recombinant FGF19 protein significantly reduced triglyceride (TG) levels in hepatocytes in a dose-dependent manner. Both in vitro treatment and in vivo injection of FGF19 significantly downregulated lipogenic genes and upregulated lipolytic genes expression in hepatocytes and liver tissue. Further investigation demonstrated that FGFR1 inhibition attenuated the TG-lowering effects of FGF19 and reversed the suppression of lipogenic gene expression. Additionally, FGF19 treatment enhanced the phosphorylation of ERK, P38, AMPK, and AKT. Inhibition of P38, AMPK, or AKT significantly increased triglyceride levels which were reduced by FGF19. Inhibition of ERK, P38, and AKT impaired the FGF19-mediated regulation of lipolysis-related genes, whereas AMPK inhibition predominantly affected the regulation of lipogenic genes. Moreover, results showed that high linoleic acid (LA) intake induced endoplasmic reticulum stress and elevated expression of FGF19. The expression of XBP1s protein was significantly increased by LA treatment, while co-expression of XBP1s significantly induced the promoter activity of FGF19. In summary, these results suggest that FGF19 is primarily expressed in the liver and plays a crucial role in regulating lipid metabolism to prevent excessive lipid accumulation in large yellow croaker, while high LA intake can increase FGF19 expression through ER stress-induced XBP1s. This study will enhance the understanding of FGF19 in lipid metabolism, offering insights into the evolution of these processes in vertebrates. Show less