Search Results (6,881)

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

Background/Objectives: Inflammatory and oxidative-stress-related processes contribute to post-myocardial infarction (MI) remodeling and may influence long-term cardiovascular outcomes. Recent findings have highlighted the potential role of non-coding RNAs in regulating these processes. LncRNA MALAT1 acts as a ceRNA that “sponges” miR-146a, reducing its ability to repress downstream targets such as COX-2. The aim of this study was to assess MALAT1 and miR-146a expression in PBMCs and plasma COX-2 in controls and patients six months post-MI. In addition, we investigated whether MALAT1 rs3200401 and miR-146a rs2910164 variants were associated with MI susceptibility, MALAT1 and miR-146a expression, plasma COX-2 levels, and left ventricle (LV) echocardiographic parameters. Methods: The study included 534 patients and 381 controls for genetic analyses, while expression analyses were performed in a subset of 89 patients and 39 controls. TaqMan™ assays were used for genotyping and for quantification of MALAT1 and miR-146a expression. Plasma COX-2 levels were measured using ELISA. Results: Compared to controls, patients had higher MALAT1 expression, whereas lower miR-146a expression was observed only in unadjusted analyses. Plasma COX-2 levels were higher in patients with advanced heart failure (NYHA III–IV) compared with NYHA I-II. The rs3200401 TT genotype was more frequent in patients, whereas rs2910164 genotype distributions were similar between groups. The rs3200401-rs2910164 TG allele combination was associated with increased MI risk. Conclusions: MALAT1 may serve as a potential long-term biomarker of post-MI molecular alterations, whereas the role of miR-146a requires further investigation in larger cohorts. The rs3200401 variant may represent a genetic marker associated with MI susceptibility and adverse LV remodeling. Further studies are needed for confirmation. Full article

This study aimed to explore the correlations of nuclear factor erythroid 2-related factor-2 (NRF2) gene polymorphisms, prepregnancy body mass index (BMI) and the interaction between them with the risk of preeclampsia (PE). A case–control study was conducted in which pregnant women with PE (n = 198) and normotensive pregnant women (n = 396) were recruited as the case group and control group, respectively, from two tertiary hospitals in Hunan Province. Data collection was achieved through face-to-face interviews utilizing a standardized questionnaire, along with perinatal health care records. Blood samples were also collected, and genotyping of nine single-nucleotide polymorphisms (SNPs) in the NRF2 gene was subsequently performed using the MassArray platform. Both univariate and multivariate logistic regression analyses were employed to assess the associations of NRF2 gene polymorphisms with prepregnancy BMI and their interactions with the risk of PE. Multivariate logistic regression analyses revealed a significant association between prepregnancy BMI and PE susceptibility. Specifically, prepregnancy overweight/obesity (BMI ≥ 24.0 kg/m²) was associated with an elevated risk of PE (adjusted OR = 4.59, 95% CI: 2.82–7.45), whereas underweight status (BMI < 18.5 kg/m²) was correlated with a reduced PE risk (adjusted OR = 0.38, 95% CI: 0.18–0.78). The NRF2 polymorphism rs13005431 exhibited a protective effect against PE under the additive genetic model (adjusted OR = 0.59, 95% CI: 0.37–0.93). Furthermore, logistic regression analyses revealed a significant effect of the multiplicative interaction between prepregnancy overweight/obesity and polymorphisms rs35652124 (adjusted OR = 0.24, 95% CI: 0.06–0.89) and rs2627765 (adjusted OR = 3.62, 95% CI: 1.07–12.23) on susceptibility to PE. These findings collectively underscore the critical and independent roles of prepregnancy BMI, NRF2 polymorphisms, and their interactions in modulating PE susceptibility, suggesting that the combined effects of metabolic profiles and genetic determinants may act synergistically to shape PE risk. Full article

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, accounting for a substantial proportion of global deaths. Increasing evidence indicates that cardiovascular susceptibility is shaped during fetal development, where the intrauterine environment plays a critical role. Maternal–fetal crosstalk, mediated largely through placental function, coordinates the transfer of metabolic, endocrine, and immune signals that are essential for normal cardiac and vascular development. Disruptions in maternal physiology—including metabolic disorders, hypertensive conditions, inflammation, and environmental stress—can perturb this communication network and alter the intrauterine milieu. These changes induce persistent modifications in cardiomyocyte growth, endothelial function, and key regulatory pathways, thereby contributing to long-term cardiovascular risk. Emerging studies highlight that cardiovascular programming is governed by interconnected mechanisms involving epigenetic regulation, mitochondrial function, immune signaling, and intercellular communication. This review synthesizes current evidence on how maternal–fetal crosstalk shapes cardiovascular development beyond genetic determinants and provides an integrated framework linking early-life exposures to lifelong cardiovascular health. Full article

Congestion is a major driver of symptoms, hospitalization, and adverse outcomes in heart failure (HF), yet its clinical assessment remains challenging. Traditional approaches based on physical examination, biomarkers, and isolated imaging surrogates often fail to capture the complexity of systemic venous congestion and its impact on organ function. In HF, congestion should be interpreted as a multifactorial process resulting from the interaction between intravascular volume burden, venous compliance, cardiac filling pressures, neurohormonal activation, blood volume redistribution, and organ-specific susceptibility. In this context, point-of-care ultrasound has emerged as a promising adjunctive tool for bedside congestion assessment. The Venous Excess Ultrasound (VExUS) score integrates inferior vena cava assessment with Doppler analysis of hepatic, portal, and intrarenal veins, allowing for the evaluation of venous pressure transmission and organ-level congestion. Observational studies suggest that VExUS and related venous Doppler abnormalities correlate with invasive hemodynamic parameters and are associated with acute kidney injury, diuretic response, heart failure hospitalization, and mortality. Serial changes in venous congestion may provide additional information regarding treatment response and clinical trajectory. However, the available evidence remains heterogeneous across acute HF, ambulatory HF, cardiorenal syndrome, and critical care populations, and randomized trials evaluating VExUS-guided management are lacking. Therefore, VExUS should be interpreted as a complementary tool within a multimodal assessment that includes echocardiography, lung ultrasound, biomarkers, renal function, urine output, physical examination, and response to therapy. By integrating fluid burden with venous pressure transmission and organ perfusion, multimodal ultrasound may support more individualized congestion assessment and risk stratification in HF. Full article

(1) Background: The global prevalence of myopia has increased substantially in recent decades. Myopia development is influenced by both environmental factors and a complex genetic architecture involving more than 400 susceptibility loci. The interaction between genetic predisposition and environmental exposures plays a critical role in myopia onset and progression. Unequal access to preventive strategies and eye care services continue to limit effective global myopia control. (2) Methods: This structured narrative review synthesizes evidence identified through systematic database searches, manual reference screening, prospective cohort studies, randomized controlled trials, mechanistic investigations, and genetic analyses identified through the literature search. (3) Results: Environmental factors such as limited outdoor activity, intensive near-work, and academic pressure contribute to myopia progression. Key biometric indicators, such as AL, AL/CR ratio, and choroidal thinning, are strong predictors. Molecular and cellular mechanisms also contribute significantly to myopia progression. Genetics also plays a significant role, with both syndromic and polygenic pathways involved. (4) Conclusions: As precision medicine evolves, individualized therapeutic strategies are becoming important in myopia management. In the treatment of myopia, biomarkers, genetic profiling, and artificial intelligence may support personalized risk assessment and treatment decisions. Full article

Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, immune dysregulation, and increased susceptibility to infections. Obesity may influence these processes and has been proposed as a potential contributor to the so-called “obesity paradox”, although its effects on immune competence, viral burden, and survival are not yet fully understood. Seventy patients with severe to very severe COPD (GOLD stage 3–4) were stratified according to BMI (<30 vs. ≥30 kg/m²). Clinical and functional parameters were assessed together with biomarkers of oxidative stress, DNA damage, systemic inflammation, and T-cell subsets. A comprehensive viral panel, including Torque Teno virus (TTV), was also analyzed. Five-year survival was evaluated using Kaplan–Meier curves and Cox regression models. Patients with BMI ≥ 30 showed higher lymphocyte counts and increased CD4⁺ and CD8⁺ T-cell levels, accompanied by lower systemic inflammatory indices. No significant differences were observed in oxidative stress or DNA damage markers. In addition, TTV viremia (≥4 log₁₀ copies/mL) was more frequently observed among patients with lower BMI. Despite these differences, five-year survival did not significantly differ between the two groups. These findings suggest that BMI alone may have limited value as a predictor of outcomes in patients with advanced COPD. Conversely, immune-inflammatory indices and viral burden, particularly TTV viremia, could provide complementary information for risk assessment and may deserve further investigation as potential tools for personalized patient stratification. Full article

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

Inhalational anesthesia, which includes anesthetics such as sevoflurane, isoflurane, and desflurane, is widely used in clinical settings for surgical interventions across all age groups. Nonetheless, recent findings from preclinical research raise important questions regarding their potential neurotoxic effects, especially within the developing brain, though clinical implications remain to be fully established. This narrative review was conducted through a literature search of the PubMed database and synthesizes preclinical investigations into gene modifications associated with neurotoxicity following exposure to inhalation anesthetics. Emphasis was placed on anesthetic exposure in human and animal-derived cell lines, neurodevelopmental animal models, as well as adult and aged animals. In various models, the neurotoxic mechanisms of inhalational anesthesia involve a complex interaction of apoptosis, oxidative stress, mitochondrial dysfunction, neuroinflammation, and epigenetic remodeling. Developmental studies indicate additional susceptibilities, including impaired neuronal migration, myelination deficits, and transgenerational epigenetic effects, whereas aging models exhibit oxidative stress injury, microglial activation, and heightened perioperative neurocognitive sensitivity. Understanding these neurotoxic mechanisms is essential for identifying risk factors, formulating age-specific neuroprotective strategies, and enhancing the overall safety of anesthetic use, particularly in vulnerable populations. Full article

Cardiovascular disease and cancer remain the leading causes of death worldwide. Although numerous cancer therapies have improved survival rates, they also increase the risk of cardiomyopathy, heart failure, and arrhythmias. These cardiovascular complications can limit treatment options and adversely affect the long-term quality of life of cancer survivors. Ca_V1.3, an L-type calcium channel encoded by CACNA1D, emerges as a central molecular mediator linking cardiovascular disease and cancer. It regulates calcium entry into cardiomyocytes and contributes to sinoatrial pacemaking and atrioventricular conduction. It also contributes to proliferation, migration, and therapy resistance in several cancers. Chemotherapy-induced oxidative stress, inflammatory signaling, hypoxia, and transcriptional changes can modulate the expression, gating, splicing, and trafficking of Ca_V1.3 channels. All these changes destabilize diastolic depolarization and impair conduction, thereby promoting arrhythmias in cancer patients. This review focuses on Ca_V1.3 biology in cardio-oncology, along with the mechanisms of chemotherapy-induced cardiotoxicity. It outlines the role of Ca_V1.3 as a key mediator linking cancer therapies to subsequent nodal dysfunction and increased arrhythmia susceptibility. It also expands on how patient-specific induced pluripotent stem cell-derived cardiomyocytes can model Ca_V1.3 dysregulation as well as support the development of targeted therapies. We propose that Ca_V1.3 represents a mechanistic bridge linking cancer therapy, calcium signaling, and cardiac electrophysiology, and that elucidating its pathophysiology may guide the design of targeted strategies in cardio-oncology. Full article

Buffalo meat is widely consumed in Egypt; however, it may pose serious food safety risks due to microbial contamination during handling, preparation, and processing. This study investigated the prevalence and characterization of multidrug-resistant (MDR) enterotoxigenic Staphylococcus aureus in raw ground buffalo meat and ready-to-eat (RTE) kofta and liver sandwiches marketed in Mansoura, Egypt. S. aureus was detected in 62% (62/100) of raw buffalo ground meat, 41% (41/100) of RTE kofta, and 60% (60/100) of RTE liver samples, with an overall prevalence of 54.3% (163/300). All 660 isolates were confirmed as S. aureus via nuc gene detection, among which 46.8% (309/660) were mecA-positive and verified as methicillin-resistant (MRSA), and 21.8% (144/660) were vanA-positive and verified as vancomycin-resistant (VRSA). Enterotoxigenic strains were identified in 42.7% (282/660) of isolates, with the sea gene being most prevalent (67.7%; 191/282), followed by seb (58.2%; 164/282) and sec (39.7%; 112/282). The highest frequency of enterotoxigenic strains occurred in raw ground meat (47.2%), followed by kofta (45.1%) and liver (36%). Antimicrobial susceptibility testing against 15 antibiotics revealed that 7.6% (50/660) of isolates were extensively drug-resistant (XDR) with a MAR index of 0.9, while 82.9% (547/660) were MDR with MAR values between 0.3 and 0.7, indicating exposure to environments of intensive antibiotic use. The present findings highlight a high contamination level of buffalo meat products with MDR enterotoxigenic MRSA and VRSA, representing a significant public health hazard. Implementation of strict hygiene measures, wise antibiotic usage, and continuous surveillance is essential to control their dissemination through the food chain. Full article

Background/Objectives: Prepubertal localized aggressive periodontitis/LPP is an extremely rare but extremely fast-progressing form of periodontal disease involving systemically healthy children, starting in primary and mixed dentition. Our aim is to synthesize the data (January 2014–April 2026) on LPP progression description in systemically healthy children aged 2–13 years; clinical and biological responses to available treatment strategies, focusing on disease progression pattern, treatment efficacy and factors influencing treatment outcomes; and correlating findings with a report of a 24-month follow-up of a female prepubertal Caucasian patient during the primary and early stages of mixed dentition. Methods: A total of 489 studies were found after deduplication for the selected period. Due to the eligibility criteria, 9 studies plus another 10 contextual publications were included. Additionally, a 24-month follow-up of a previous LPP case was correlated. Results: LPP displayed rapid tissular destruction in primary dentition with risks to transfers to mixed and permanent dentition. The systemic antibiotic treatment reduced tissue loss, enabling fast periodontal regeneration. LPP is rare but severe, with a continuous biological trajectory, and with the window of opportunity remaining when the first symptoms appear. A few months (4–6 months) delay in diagnosis leads to irreversible tooth loss even in young patients with high biological healing potential. Conclusions: Systemic antibiotic treatment is mandatory in LPP/C-MIP cases from the primary dentition phase but does not reset host susceptibility. The Amoxicillin/Augmentin–Metronidazole association is recommended, with caution regarding dosage (adverse reactions). Periodontal gains are radiologically and clinically proven, but rebounding is possible. Full article

Objective: This umbrella review aimed to evaluate the strength and consistency of evidence linking genetic variants to dental caries susceptibility. Methods: An umbrella review was conducted, following PRISMA 2020 guidelines. A comprehensive literature search was performed across six databases. Eligibility criteria included systematic reviews and meta-analyses of human subjects. Study selection, data extraction, and methodological quality assessment were performed systematically, with quality evaluated using the AMSTAR-2 tool. Multilevel meta-analyses were conducted to assess variant-specific and grouped genetic effects. Results: The search identified 29 eligible systematic reviews and meta-analyses for inclusion. The multilevel meta-analysis showed statistically significant associations for polymorphisms in TAS2R38 rs713598 (OR = 0.26, 95% CI: 0.09–0.73) and VDR Cdx-2 rs11568820 (OR = 0.66, 95% CI: 0.46–0.95), both indicating lower odds of dental caries, while MBL2 rs1800450 was associated with increased odds (OR = 1.48, 95% CI: 1.03–2.14). However, pooled effects across the main gene categories, including tooth development and mineralization, salivary composition and function, immune and inflammatory response, taste perception, and signaling, were not statistically significant. Findings were heterogeneous across studies. Conclusions: Current evidence on the association between genetic variants and dental caries susceptibility remains limited and inconsistent, providing insufficient support for the use of genetic markers in risk assessment or personalized prevention. The significant single-nucleotide polymorphism (SNP) associations identified in this review are hypothesis-generating and require validation in larger and more diverse populations using standardized caries definitions and gene–environment approaches. Full article

The topito pepper (Capsicum chinense) is a tropical fruit of economic and gastronomic importance in the Caribbean region, valued for its nutritional content. However, this fruit is susceptible to postharvest fungal diseases, including those caused by the phytopathogenic fungus Penicillium expansum, which can degrade fruit quality and pose a health risk due to the potential presence of mycotoxins such as patulin. In this context, we evaluated the protective effects of coatings with chitosan (CS), clove essential oil (CEO), and their combination (CS+CEO) on sweet peppers stored at 12 °C for 12 days after harvest. The results indicate that the film-forming solution exhibited an acidic pH (5.33–5.44), a density of ~1.0 g/cm³, and viscosities ranging from 2.75 to 32.9 cP. Furthermore, the results indicate that coatings with CS and CS+CEO significantly reduced weight loss, preserved firmness (19.12–30.40 N), and delayed ripening. At the same time, the coatings exhibited inhibitory effects on P. expansum and aerobic mesophiles. The CS+CEO combination demonstrated the greatest inhibitory effect, indicating that it is a sustainable and effective strategy for the postharvest preservation of sweet peppers, thereby enhancing their value, preservation, and food security in the Caribbean region. Full article

Maternal psychoactive substance use during pregnancy represents a major threat to placental integrity and fetal development. As the central interface for maternal–fetal exchange, the placenta is highly susceptible to psychoactive substances, including alcohol, tobacco, cannabis, cocaine, opioids, and synthetic drugs, which can cross the placental barrier and induce structural and functional alterations. This review synthesizes current evidence on the biological mechanisms, diagnostic approaches, and forensic relevance of psychoactive substances-induced placental pathology. We summarize how different substances disrupt placental vascularization, oxidative balance, epigenetic regulation, and cellular viability, leading to impaired nutrient and oxygen transfer and increasing the risk of adverse outcomes such as intrauterine growth restriction, preterm birth, congenital anomalies, and long-term neurodevelopmental impairment. We further discuss the role of placental tissue in identifying prenatal drug exposure and reconstructing exposure timelines. Beyond its clinical relevance, placental examination provides objective evidence with potential forensic value in cases of suspected maternal substance use, while also informing non-punitive, evidence-based interventions. Overall, integrating placental pathology into reproductive health research and prenatal care offers a multidisciplinary framework to improve maternal–fetal outcomes and guide public health strategies addressing substance use during pregnancy. Full article