Search Results (20,487)

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, with clear cell renal cell carcinoma (ccRCC) accounting for more than 75% of RCC cases and representing the primary cause of mortality in renal cancer patients. CDC6 exhibits oncogenic characteristics and plays a significant role in tumor grading and prognosis prediction. Analysis of The Cancer Genome Atlas (TCGA) data shows that the CDC6 gene is significantly overexpressed in 97.22% (70/72) of paired clinical samples in ccRCC tissues compared to adjacent normal tissues. Consistent with this, elevated CDC6 protein levels were observed across all four paired tumor tissues examined. Functional experiments further confirm that CDC6 expression levels directly influence cellular proliferation, as its knockdown suppresses cell viability by ~60% in CCK-8 assays (p < 0.001) and reduces EdU incorporation by ~50%. Mechanistically, in tumor tissues, CDC6 transcription is epigenetically regulated by histone acetylation and methylation, which in turn modulates downstream effectors, e.g., the exosome complex protein EXOSC5. Our findings indicate that in ccRCC, increased histone H3K4 trimethylation near the CDC6 transcriptional start site enhances its expression. The methyltransferase SETD1A may act as a potential upstream regulator mediating the transcriptional activation of CDC6, thereby driving tumor progression through the regulation of EXOSC5. We have further investigated the relationship between the CDC6-associated gene network and tumor development and clarified the diagnostic and prognostic relevance of the SETD1A–CDC6–EXOSC5 axis in ccRCC. The outcomes of this research are expected to provide novel insights into the pathogenesis of renal cell carcinoma and establish a theoretical foundation for new diagnostic strategies. Full article

Endometrial polyps are common benign lesions of the uterine cavity characterized by localized overgrowth of endometrial glands, stroma, and vasculature. They are mostly asymptomatic, although in some cases they cause abnormal uterine bleeding and infertility. Increasing evidence indicates that endometrial polyps represent genetically heterogeneous lesions with a multifactorial molecular basis. This review aims to analyze current knowledge on the genetic background of endometrial polyps. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the role of genetics in endometrial polyps, published in the English language with no time restrictions. References of the selected articles for possible additional articles were also screened in order to include most of the key recent evidence. This review highlights the multifactorial genetic landscape underlying the development of endometrial polyps. Current data suggest that these lesions cannot be explained by a single pathogenic mechanism, but rather arise through the interaction of chromosomal changes, somatic and germline genetic variants and dysregulated gene expression. Understanding and integrating these genetic and molecular alterations may improve future diagnostic evaluation, risk stratification, and clinical management of endometrial polyps, although most findings are not yet ready for routine clinical application. Full article

Background: Early-stage seizures caused by an undetermined etiology cannot be treated with effective antiepileptic drugs in a timely manner, leading to poor seizure control and severely affecting long-term prognosis. Therefore, early clarification of the cause and targeted timely treatment are crucial. Objective: To characterize the clinical features and genetic mutations in neonatal seizures, particularly those of unknown cause. Methods: Clinical data from 56 neonates with seizures were retrospectively analyzed. Family-based whole-exome sequencing was performed in six cases of undetermined etiology. The KCNQ2 variant was classified according to the ACMG guidelines. Basic statistical comparisons were performed using the chi-square test. Results: Hypoxic-ischemic encephalopathy (HIE) was the most common cause (23.21%, 13/56), with most seizures occurring within the first three days of life. Subtle seizures were the predominant type (46.42%, 26/56). Abnormal amplitude-integrated EEG findings were observed in 58.82% (30/51). The HIE group had a significantly higher proportion of seizures occurring within the first three days of life compared to the non-HIE group (p = 0.01). A novel heterozygous KCNQ2 mutation (c.766G>T, p.Gly256Trp) was identified and classified as likely pathogenic according to the ACMG guidelines. Conclusions: HIE remains a leading cause of early-onset neonatal seizures. A novel likely pathogenic KCNQ2 mutation expands the genetic spectrum of neonatal seizures, highlighting the value of genetic testing. Full article

Introduction: Biological invasions constitute one of the main threats to freshwater ecosystems, causing significant ecological changes through the introduction of exotic species that compete with or prey upon native species. In Portugal, the introduction and spread of exotic species in lotic and lentic ecosystems, such as pike (Esox lucius), European catfish (Silurus glanis), and largemouth bass (Micropterus salmoides), all top predators, may have a big impact on autochthonous species. In contrast, bleak (Alburnus alburnus), European perch (Perca fluviatilis), and common carp (Cyprinus carpio) compete aggressively for food resources. In the Sousa River basin, gudgeon (Gobio lozanoi) is considered an exotic species with potential ecological impact, with the minnow (Phoxinus phoxinus) stand having been recently identified in Portugal and, so far, recorded only in this river basin, and not yet being classified as an invasive species in Portugal. Public knowledge regarding invasive aquatic biodiversity remains a significant bottleneck for conservation. Because recreational angling is a prominent dispersal vector, initiatives that directly target this community are relevant. Objective: The aim is to carry out a bibliographic review on the exotic ichthyofauna species present in the Sousa River, with special focus on the invasion potential of the minnow (P. phoxinus). Methodology: The literature review was conducted based on the ScienceDirect, Springer Nature Link, and Fauna Norvegica databases, selecting publications between 2006 and 2025 concerning relevant studies on the potentially invasive characteristics of the minnow (P. phoxinus). The methodology is based on the analysis of studies regarding the impacts caused on riparian ecosystems. Results: The species P. phoxinus presents a generalist diet and high adaptive capacity, allowing it to colonise new habitats and compete aggressively with native species for trophic resources. Its presence is associated with negative impacts on brown trout populations (Salmo trutta), reducing growth and productivity, especially in mountain ecosystems. Increased species density also causes a significant decrease in benthic macroinvertebrate biodiversity. Studies conducted in the Douro basin indicate that the arrival of minnow in Portugal resulted from human action, probably associated with its use as live bait in recreational fishing. Conservation programmes use diverse tactics to bridge the awareness gap. Recent initiatives feature electrofishing demonstrations to visually differentiate species, theatrical performances, and even culinary show-cooking events using invasive predators like the European catfish to promote harvesting. Conclusions: The potential transition of P. phoxinus into an exotic and invasive species may be associated with the ecological pressure exerted on native communities, particularly through competition for trophic resources, highlighting the need to assess its dispersion in the Sousa basin and its impacts on fish fauna and benthic macroinvertebrates. It is important to do more sampling to understand its real distribution in the Sousa Basin. Additionally is important to explain to recreational anglers and the general population the impacts of fish transfer and the adverse effects of invasive species on freshwater Portuguese ecosystems. Full article

The agricultural and environmental application of Miscanthus × giganteus biomass ash (MBA) as a soil amendment requires a thorough assessment of its properties, nutrient potential, and associated risks. This study characterizes the elemental composition, pH, cation exchange capacity (CEC), and polycyclic aromatic hydrocarbons (PAHs) content of MBA in comparison with other common biomass ashes (crops, wood, and sewage sludge) referred to the international regulatory standards. The ash exhibits a strong alkaline pH (11.03), suggesting potential to improve soil pH in acid soils, but requires careful controlled application to prevent excessive alkalization. The main nutrients detected include K (5.54%), Ca (2.07%), Mg (0.37%), and P (0.86%), indicating its potential as a soil amendment, though long-term use may cause nutrient imbalances. Micronutrients such as Zn (240.67 mg·kg⁻¹), Mn (297 mg·kg⁻¹), and Cu (33.5 mg·kg⁻¹) are found in concentrations suitable for agricultural use, while potentially toxic elements (PTEs), including Cd, Cr, Ni, and Pb, are below detection limits, thereby reducing the risk of pollution. As (8.3 mg·kg⁻¹) and ΣPAHs (1.63 mg·kg⁻¹) remain within safety thresholds, suggesting a low environmental toxicity of MBA. The low Na content (0.12%) indicates a minimal risk of salinity accumulation, distinguishing MBA from high-sodium biomass ashes. Soil alkalization, disruptions in nutrient balance, and element leaching are risks to be considered. Despite these concerns, its composition is in agreement with established safety guidelines, supporting its feasibility for valorization as a sustainable soil amendment and remediation material. To maximize agronomic benefits and mitigate environmental risks, it is important to utilize the ash, considering site conditions and carry out regular monitoring of the soil. Full article

Lateral epicondylitis (LE), commonly referred to as tennis elbow, remains a frequent cause of lateral elbow pain, yet its optimal management and risk profile are still debated. Therefore, this review aimed to summarize current evidence on its definition, diagnosis, and treatment while addressing common misconceptions. A non-systematic review of major medical databases, including PubMed, Cochrane Library, and Google Scholar, was conducted using predefined inclusion criteria to identify relevant review articles. The analyzed literature highlights that LE is primarily diagnosed clinically and managed through a spectrum of conservative and interventional approaches. Evidence suggests that structured physiotherapy and load modification remain the cornerstones of treatment, while modalities such as platelet-rich plasma and autologous blood injections may offer longer-term benefits compared with corticosteroids, which are effective mainly for short-term symptom relief. In contrast, interventions such as acupuncture and shock wave therapy show limited or inconsistent efficacy. Identified risk factors include female sex, smoking history, repetitive or forceful manual work, and higher cardiovascular risk burden. Overall, conservative management should be the first-line approach, with biologic therapies considered in refractory cases and surgery reserved as a last option; however, further high-quality randomized controlled trials are required to establish optimal treatment algorithms and clarify long-term outcomes. Full article

Bacillus anthracis is endemic in the United States causing periodic outbreaks in wildlife and domestic animals. Currently, human anthrax cases in the U.S. are rare but were common in the 1950s–1960s due to industrial work with imported B. anthracis-contaminated animal products. Multiple-locus variable-number tandem repeat analysis (MLVA) initially differentiated B. anthracis into 89 genotypes and two major clades. Recently, whole-genome sequencing (WGS) was implemented to differentiate B. anthracis which allows for higher resolution and can eliminate risk of homoplasy. To assess the molecular diversity of U.S.-established isolates, we performed MLVA and WGS on 81 B. anthracis isolates from domestic animals or soil. By MLVA, most isolates (n = 58, 72%) were in the Western North America (WNA)/A1.a cluster. Isolates were also observed in the Ames (A3.b), Vollum (A4), and Group B clusters. Using WGS, two major clades (A and B) and four clusters (WNA, Ames, Vollum, Group B) were identified. The four WGS clusters correlated with previously established MLVA clusters (A1a, A3b, A4, and B1, respectively). Further differentiation of the WNA cluster showed that isolates collected from the same state generally clustered together and more broadly by region (west, central, Texas). In the current study, we provide an update on the genetic diversity of domestically established B. anthracis strains using MLVA and WGS. WGS was able to provide additional differentiation, particularly within the WNA cluster, which can lend assistance in epidemiological investigations. Full article

Background: Following the coronavirus disease 2019 (COVID-19) pandemic, increased reports of severe acute hepatitis of unknown etiology in children have raised concerns about virus-associated liver injury. Acute respiratory tract infections (ARTIs) are a common cause of pediatric hospitalization and may be accompanied by reactive hepatitis; however, virus-specific patterns of hepatic involvement remain incompletely defined. This study aimed to evaluate liver involvement associated with ARTIs in hospitalized children. Methods: This retrospective study included pediatric patients (<18 years) hospitalized with ARTIs between October 2021 and May 2023. Respiratory viruses were identified via multiplex real-time polymerase chain reaction assays. Liver function tests were systematically evaluated during hospitalization. Transaminase elevations were categorized according to the upper limit of normal (ULN = 40 U/L). Acute hepatic failure was defined according to the Pediatric Acute Liver Failure criteria. Results: A total of 179 patients were analyzed (median age: 38 months; 59.2% male). Elevated AST and ALT levels were observed in 24.0% and 8.4% of patients, respectively. Adenovirus was the most frequently detected virus (11.2%), followed by influenza A (7.3%) and parainfluenza virus (6.7%). Severe transaminase elevations (>5 × ULN and >500 U/L) were observed in patients with influenza infection. All cases of acute hepatic failure (n = 3) were associated with influenza infection. Other respiratory viruses were associated with mild or transient liver enzyme abnormalities. Conclusions: Severe hepatic involvement—including severe transaminase elevation and acute hepatic failure—occurred exclusively in children with influenza infection, particularly influenza B, while mild and transient liver enzyme abnormalities were common across other respiratory viral infections. These findings highlight the importance of targeted liver function monitoring in pediatric influenza patients and provide clinically relevant data on virus-specific hepatic involvement in the post-COVID-19 era. Full article

The belief that the moon disturbs sleep is widespread, but the factors associated with it remain poorly understood. I therefore examined how frequently poor sleep is attributed to moon phases, whether this varied across the lunar cycle, and which personal and environmental factors were associated with “moon blaming”. Data were derived from an ongoing online survey. At the time of analysis, 1815 participants had completed a 16-item questionnaire assessing sleep quality, sleep duration, sleep timing on workdays and free days, alarm clock use, environmental and personal sleep-disturbing factors, residential setting, age, gender, attention to lunar phases, and whether the moon was perceived as a cause of poor sleep. The primary outcome was endorsement of the moon as a sleep-disturbing factor. Logistic regression with stepwise Akaike information criterion selection was used to identify the strongest predictors of attributing the moon for poor sleep. Questionnaire timing was also examined across the lunar cycle. Among environmental factors, the moon was the most frequently endorsed cause of poor sleep (36%), followed by outdoor temperature (31%), indoor noise (26%), and bad weather (22%). Rumination was the most commonly reported personal factor (73%), but it did not predict moon attribution. Instead, the strongest correlates were weather-related sleep complaints, tracking lunar phases, age, and gender, with endorsement increasing with age and being more common among women. Moon-related complaints also peaked during the week after the full moon. These findings suggest that perceived lunar effects on sleep are shaped, at least in part, by attributional and expectation-related processes. Full article

Background and Objectives: Transcatheter aortic valve implantation (TAVI) is the standard therapy for patients with severe aortic stenosis at intermediate or high surgical risk. Mitral annular calcification (MAC) is frequently observed in this population and has been linked to adverse cardiovascular outcomes. This study evaluated the association between MAC and TAVI-related complications and mortality, and identified predictors of all-cause mortality and permanent pacemaker implantation (PPI) following TAVI. Materials and Methods: Patients undergoing self-expanding TAVI between January 2010 and June 2020 were retrospectively analyzed. Outcomes included TAVI-related complications, in-hospital and long-term mortality, and predictors of all-cause mortality and PPI. Results: A total of 245 patients (98 men [40%], mean age 76.3 ± 8.3 years) were included. Mean left ventricular ejection fraction was 54.8 ± 11.4%, and aortic valve area was 0.74 ± 0.14 cm². MAC was present in 148 patients (60.4%). Pericardial effusion (26.4% vs. 12.4%, p = 0.013) and acute kidney injury (21.6% vs. 7.2%, p = 0.005) were significantly more frequent in patients with MAC. PPI was required in 42 patients (17.8%). In-hospital mortality occurred in 14 patients (5.7%), and all-cause mortality was observed in 89 patients (36.3%) during a median follow-up of 23.1 months (IQR, 11.6–44.3). MAC extension into the left ventricular outflow tract was the only independent predictor of PPI (OR: 3.32, p = 0.002). Independent predictors of all-cause mortality included use of renin–angiotensin–aldosterone system blockers (HR: 0.54, p = 0.012), hemoglobin level (HR: 0.79, p = 0.006), severe MAC (HR: 1.94, p = 0.024), and post-TAVI atrial fibrillation (HR: 2.39, p = 0.002). Conclusions: MAC is common in TAVI patients and is associated with increased procedural complications, including higher rates of pericardial effusion and acute kidney injury. Greater MAC severity independently predicts higher all-cause mortality. In addition, MAC extension into the left ventricular outflow tract is an independent predictor of PPI following self-expanding TAVI, emphasizing the importance of comprehensive pre-procedural imaging. Full article

Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2–F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies. Full article

Background: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), and colorectal surveillance has been shown to reduce death from CRC in this high-risk population. This study aimed to examine adherence to recommended endoscopic surveillance intervals in a LS cohort and identify factors associated with adherence. Methods: A retrospective review was performed of 1403 lower endoscopic procedure (LEP) reports from 540 individuals with LS completed between May 2001 and September 2023. Adherence was calculated by comparing the endoscopists’ recommended interval to the actual date of the subsequent procedure. Reports from individuals with ≥2 LEPs and those with follow-up intervals within the study period were included (n = 1170). A mixed-effect logistic regression analysis identified factors associated with adherence. Results: Among 1170 LEPs from 295 LS carriers, 67.4% were performed within the recommended interval. However, 68.8% of individuals had at least one procedure that was delayed. Increased adherence was significantly associated with prior detection of CRC (OR 9.30, 95% CI 1.16–74.32, p = 0.035) on an LEP. Marital status was significantly associated with adherence, with higher rates among married (OR 1.73, 95% CI 1.05–2.85, p = 0.030) and divorced/widowed individuals (OR 2.32, 95% CI 1.14–4.72, p = 0.020). Current smokers had a lower rate of adherence (OR 0.33, 95% CI 0.13–0.82, p = 0.018). No significant associations were observed with age, biological sex, race, or insurance status. Conclusions: Nearly one third of LEPs in our LS cohort were delayed. Efforts to address barriers and enhance adherence are essential to optimize outcomes for this high-risk population. Full article

High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)—Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)—apo(a)—which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV₂) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI). Full article

Multiple sclerosis is an immune-driven neurological disease that affects myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire hyper-react to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion nor the cause of the immune hyper-reactivity is known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. In this concept paper, we propose the novel paradigm that the trigger of autoimmunity in MS comprises a conspiracy of three common herpesviruses: human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein−Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells. Full article

Deep dermatophytosis is a rare, life-threatening fungal infection characterised by the invasion of dermatophytes beyond the superficial layers of keratinised tissue into the dermis and subcutaneous tissues. The present review aimed to identify the current knowledge on the role of Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in the pathogenesis, clinical spectrum, diagnosis, and management of deep dermatophytosis. For innate immune activation, CARD9 acts as an adaptor molecule. Basically, CARD9 helps mediate the connection between the fungal pattern recognition receptor (Dectin-1) and the NF-κB and MAPK signalling pathways, and it mediates cytokine production, thereby activating phagocytic activities. Thereby, any change or mutation in the CARD9 gene may disrupt these pathways, leading to dysfunctional neutrophils and impaired Th17-mediated antifungal immunity. Clinically, patients with CARD9 deficiency are immunocompetent but susceptible to recurrent and/or severe fungal infections [Candida, dermatophytes (Trichophyton spp.), and phaeohyphomycetes]. Deep dermatophytosis in these patients is usually chronic, treatment-resistant, and characterized by erythematous papules, nodules, plaques, ulcers, or necrotic lesions, most of which occur on the lower limbs. It usually occurs in adulthood and is more common in males. There have been instances of geographic clustering of CARD9 deficiency in Asia, North Africa, and the Middle East. Early recognition and genetic diagnosis of CARD9 mutations in patients with recurrent or atypical deep dermatophytosis. Although antifungal therapy is essential, hematopoietic stem cell transplantation can be a definitive treatment for selected patients with CARD9 deficiency. Thus, CARD9 deficiency is a critical factor in the better management of patients but remains an underrecognized cause of severe, treatment-resistant deep dermatophytosis, and early genetic diagnosis is essential for guiding targeted management and improving patient outcomes. This review emphasises the importance of CARD9 in antifungal immunity and underscores the need for greater clinical awareness and the incorporation of genetic evaluation into the management of deep dermatophytosis. Full article