Search Results (266)

Cherubism is a rare fibro-osseous disorder of the jaws that typically presents in early childhood and is recognised as genetically heterogeneous. While the condition is well described in non-African populations, African data and molecular confirmation remain limited. Background/Objectives: This structured narrative review aimed to synthesize published African cases of cherubism by describing patterns of presentation, diagnosis, management, and genetic investigation. Methods: A structured narrative literature review was conducted using PubMed, Scopus, Google Scholar, and African Journals Online. Peer-reviewed case reports and case series describing cherubism in African patients were included. Data extraction followed predefined criteria, capturing demographic features, age at onset and presentation, clinical, radiological and histological findings, management strategies, and the use of molecular genetic testing. Findings were synthesised descriptively. Results: Fourteen studies reporting 20 individual cases from eight African countries were identified, with the majority originating from North Africa. Although symptom onset most commonly occurred in early childhood, the median age at presentation for management was 13.75 years, suggesting delayed access to care. Molecular genetic testing was reported in only two cases, while most diagnoses relied on clinical, radiological, and histopathological features. Surgical intervention was commonly described, with fewer cases managed conservatively. Conclusions: Within the limitations of a structured narrative review based predominantly on published case reports and case series, and constrained by the scarcity of molecularly confirmed cases, the available African literature on cherubism remains limited in scope, geographically skewed, and characterised by incomplete genetic reporting. Recurring features include delayed presentation, reliance on clinical diagnosis, and limited use of molecular testing. These observations reflect gaps in reporting and genetic characterisation rather than population-level patterns, underscoring the need for improved molecular diagnostics, multidisciplinary care, and African registries. Full article

Chinese tongue sole (Cynoglossus semilaevis) is an important aquaculture species in China. Under high-temperature conditions, genetically female fish can undergo sex reversal and develop into phenotypic males (pseudomale fish). Previous studies have demonstrated that apoptosis might function in sex differentiation. Based on this, we identified and characterized the functions of six caspase genes (caspase1-like, caspase3a, caspase6, caspase8, caspase8-like, caspase9) in Chinese tongue sole. These six caspase genes were expressed in all analyzed tissues of both males and females. They were detected to be expressed in the gonads at various developmental stages, with expression levels peaking between 7 months and 2 years of age. In situ hybridization (ISH) analysis showed that the caspase genes were mainly localized in spermatocytes and oocytes. Promoter activity analysis indicated that with the exception of caspase3a, the remaining five caspase genes exhibited promoter activity and were regulated by transcription factors, including sp1 and gata4. High-temperature stimulation can significantly affect the expression of caspases in the gonads of both male and female fish, with female fish showing a more pronounced response. An siRNA-mediated knockdown experiment revealed that following caspase knockdown, the expression of sex differentiation-related genes, heat shock transcription factors (hsf), and heat shock proteins (hsp) in Chinese tongue sole was significantly altered. Based on these findings, we speculate that caspases play an important role in the sex differentiation process by responding to temperature stimuli. Full article

Chinese tongue sole (Cynoglossus semilaevis) is an important mariculture product in northern China, exhibiting significant sexual dimorphism: females grow 2–4 times faster than males and ultimately attain much greater body weights. As a well-known transcription factor crucial for regulating sex differentiation, foxl2 has been characterized in various mammals. Herein, we identified and characterized three foxl genes, foxl1, foxl2a and foxl2l. Three foxl genes exhibited a gonad-biased expression pattern, where foxl2a showed higher expression in ovary than in testis, while foxl1 and foxl2l exhibited higher expression in testis. All foxl genes were detected in testes and ovaries by ISH; foxl1/foxl2l were expressed in oocytes and sperm, and foxl2a in granulosa cells and sperm. Overexpression of foxl in testicular cells led to KEGG enrichment in DNA repair, MAPK, FOXO and progesterone-mediated oocyte maturation pathways. In tongue sole testicular cell line, knockdown of foxl1 and foxl2l resulted in upregulation of multiple male-related genes. In contrast, knockdown of foxl2a led to decreased expression of aromatase genes and increased expression of ctnnb1, indicating that foxl2a is more closely associated with female differentiation and maintenance. Our study investigated the functions of the foxl gene family in teleosts and offers valuable insights into their role in sex differentiation and gonadal maintenance in teleost fish. Full article

HER2 testing represents a cornerstone of the treatment algorithm in advanced gastric and gastroesophageal junction adenocarcinoma (GC), yet its evaluation remains complex due to tumor heterogeneity and methodological variability. Unlike breast cancer, HER2 expression in GC is often incomplete and heterogeneous, resulting in discordant results between biopsies, resections, and metastatic sites. Both spatial and temporal HER2 heterogeneity are key determinants of testing reproducibility, diagnostic accuracy, and treatment selection and response in GC. Optimizing sampling through multiple, well-targeted biopsies, standardizing IHC/ISH protocols, and reassessing HER2 status at progression may be crucial steps to ensure diagnostic accuracy. The recognition of HER2-low disease introduces a new pathological and clinical subgroup of GC with potential sensitivity to antibody–drug conjugates, while emerging techniques such as circulating tumor DNA analysis are increasingly applied to detect HER2 amplification and co-existing genetic alterations. Integrating molecular tools and standardized reassessment strategies can enhance HER2 testing reliability and enable more precise treatment strategies, with the potential to minimize HER2 resistance mechanisms. This review provides a practice-oriented guide on the interpretation and optimization of HER2 testing in gastric cancer, while providing insight into the underlying molecular mechanisms driving heterogeneity and resistance. Full article

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2–3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin–melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (LEP, LEPR, POMC, and PCSK1) or autosomal dominant (MC4R, SH2B1, SIM1, GNAS) modes of inheritance. Other gene mutations in heterozygous states (MRAP2, MC3R, SRC1, KSR2) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies. Full article

Background/Objectives: Children and adolescents with intellectual disabilities (ID) have an elevated burden of obesity and cardiometabolic risk, yet factors associated with high blood pressure (BP) in this group remain insufficiently described. This study assessed the prevalence of hypertension (HTN) and isolated systolic hypertension (ISH) at a single visit and examined anthropometric and body composition correlates of elevated BP in children with ID. Methods: A cross-sectional study was conducted among 461 children and adolescents with ID aged 7–18 y attending special education schools in southeastern Poland. Anthropometric indicators (BMI, waist circumference [WC], hip circumference [HC], and waist-to-height ratio [WHtR]) and body composition parameters (BF%, MM%, FFM%, TBW%) were measured using standardized procedures. BP was assessed three times during one visit, and the average of the second and third readings was used. Receiver operating characteristic (ROC) analyses were used for exploratory assessment of discriminatory performance of anthropometric and body composition parameters, and multivariable logistic regression examined associations with elevated BP (HTN + ISH). Results: Overall, 13.9% of participants had HTN and 10.4% had ISH (combined prevalence: 24.3%). Abdominal obesity was present in 39.5% of participants, and elevated HC in 28.2%, both more common in girls. Higher BP categories were associated with greater WC, HC, BMI, and BF%, and lower MM%, FFM%, and TBW% (p < 0.0001). HC showed the highest discriminatory accuracy for HTN + ISH (AUC = 0.844), followed by MM%, BF%, and FFM%, whereas WHtR demonstrated limited discriminatory performance in ROC analyses. In multivariable models, WHtR ≥ 0.5 was associated with increased odds of elevated BP (OR = 4.25), whereas higher TBW% (≥55.38%) was inversely associated with elevated BP (OR = 0.17) in the total sample; similar patterns were observed in sex- and age-stratified analyses. Conclusions: Children with ID show a high prevalence of elevated BP at a single visit, including HTN-range and ISH-range values. Anthropometric indicators, particularly HC and WHtR, and BIA-derived body composition parameters reflecting higher fat mass and lower lean tissue proportion were associated with elevated BP. These exploratory findings suggest that simple anthropometric and body composition measures may help identify individuals who warrant further BP assessment, although longitudinal studies with repeated measurements are required before clinical application. Full article

Introduction: Alcohol consumption is a significant risk factor for hypertension (HTN), a prevalent condition that substantially affects cardiovascular health. In Peru, where various traditional alcoholic beverages exist, the relationship between alcohol consumption and HTN has not been fully explored. Objective: To determine the association between different patterns of alcohol consumption, types of beverages, and various types of HTN. Methods: This cross-sectional analytical study utilized data from the Peruvian Demographic and Family Health Survey (2018–2023), including 236,243 adults (55.95% male; mean age: 41.06 years). General HTN, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH) were evaluated. Alcohol consumption was assessed through self-reported questionnaires evaluating consumption pattern (non-excessive vs. excessive), intensity (light, moderate, heavy), consistency (intermittent vs. consistent), and primary beverage type, including both commercial and traditional Peruvian drinks. Results: Excessive alcohol consumption was significantly associated with an increased risk of HTN (aPR: 1.19, 95% CI: 1.07–1.31), IDH (aPR: 1.61, 95% CI: 1.20–2.16), and SDH (aPR: 1.45, 95% CI: 1.18–1.78). Excessive alcohol consumption was significantly associated with an increased risk of HTN (aPR: 1.19, 95% CI: 1.07–1.31), IDH (aPR: 1.61, 95% CI: 1.20–2.16), and SDH (aPR: 1.45, 95% CI: 1.18–1.78). Consumption of traditional beverages such as chicha and Masato was associated with an elevated risk of various types of HTN. In contrast, wine consumption demonstrated a protective association against general HTN and IDH. Conclusions: Alcohol consumption patterns and beverage types have differential effects on HTN risk in the Peruvian population. These findings underscore the need for culturally adapted prevention strategies and more nuanced public health recommendations regarding alcohol consumption in Peru. Full article

Background: Although the main target of SARS-CoV-2 is the respiratory system, in some patients, it may affect multiple organ systems, leading to multi-organ failure. Acute kidney injury (AKI) remains one of the most frequent and clinically significant complications of severe COVID-19, with clinical importance extending beyond the acute phase due to its association with long-term renal outcomes and persistent morbidity. The incidence of AKI is particularly high among patients admitted to the intensive care unit (ICU), where its development has been consistently associated with prolonged hospitalization and increased mortality. The primary aim of this study was to determine the incidence of COVID-19-associated AKI, identify factors related to its development and severity, and evaluate mortality as a clinical outcome. Methods: Data from 238 COVID-19 patients monitored in the Intensive Care Unit of Ankara University Ibni Sina Hospital (ISH-ICU) between 1 January 2021 and 1 January 2022 were retrospectively reviewed. Patients were divided into two groups according to the presence of AKI. Those with AKI were staged according to KDIGO criteria (stages 1–2–3). Demographic characteristics, comorbidities, disease severity scores, laboratory parameters, and mortality outcomes were analyzed and compared between groups. Results: AKI was identified in 54.6% of patients. Of the patients with AKI, 32 (13.4%) had stage 1, 25 (10.5%) had stage 2, and 73 (30.7%) had stage 3 AKI. Thirteen patients (5.5%) had already developed AKI at ICU admission. AKI developed at a median of 11 days after symptom onset and 3 days after ICU admission. Advanced age, hypertension, cardiovascular disease, and chronic kidney disease were more frequent in patients with AKI (p < 0.001). Higher Charlson Comorbidity Index (CCI) and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) scores were observed in patients with stage 3 AKI. Lymphopenia and elevated levels of D-dimer, ferritin, IL-6, CRP, and procalcitonin were significantly higher in patients with stage 3 AKI than in patients with other AKI stages and the non-AKI group. Mortality rates were higher in patients with AKI and increased with advancing AKI stage (p < 0.001). ICU length of stay was significantly longer in the AKI group (p < 0.001). Conclusions: AKI is a common complication among critically ill patients with COVID-19 and is associated with prolonged ICU stay and higher mortality rates, particularly in advanced stages. Early identification of clinical and laboratory factors associated with AKI may support timely risk stratification and targeted management in this high-risk population. Full article

Transforming growth factor β (TGF-β) superfamily members are critical in teleost sex determination and differentiation. Tgfb2b is an important TGF-β ligand gene exhibiting dominant expression in the ovary of Chinese tongue sole (Cynoglossus semilaevis), yet its function in sex regulation remains unclear. In the present study, the gene expression pattern, transcriptional regulation, and knockdown effect were examined. Its expression persisted and showed a gradual increase throughout ovarian development from 3 months to 1.5 years post-hatching. In situ hybridization (ISH) revealed that the gene was distributed across oocytes at stages I–III, while scarcely detectable in the testis. The transcriptional factors CCAAT/enhancer binding protein α (C/EBPα) and Jun proto-oncogene AP-1 transcription factor subunit (c-Jun) could repress the activity of tgfb2b promoter. In vitro knockdown of tgfb2b in C. semilaevis ovarian cells led to downregulation of its downstream genes (e.g., smad1 and smad2) as well as other sex-related genes (e.g., foxl2 and esr2b). Moreover, multi-omics analysis indicated that, in C. semilaevis gonads, a miRNA named novel-m0083-3p showed an opposite expression pattern with tgfb2b and might have a binding site with the gene. By dual-luciferase assay, tgfb2b was validated to be directly targeted and suppressed by the miRNA. These results demonstrate that tgfb2b plays a significant role in ovarian differentiation and development. Further functional and molecular studies on the interplay between tgfb2b and the foxl2–cyp19a–esr axis will help elucidate the regulatory network underlying sex development in teleost. Full article

Background/Objectives: The Notch–ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch receptor after the Notch receptor binds to a ligand. Crosstalk between Notch and ADAM17 is often altered in pathological situations. Alterations in Notch2 expression, in particular, appears to be correlated with the onset of various autoimmune diseases. In primary Sjögren’s disease (pSjD), an autoimmune disorder characterized by chronic inflammation, the role of ADAM17 has been extensively explored, but a correlation with Notch2 has not yet been evaluated. Methods: To analyze the gene and protein expression of Notch2 in pSjD and a possible correlation with ADAM17 expression and with the patient’s inflammatory grade, we employed an integrated co-detection protocol to analyze salivary gland tissue sections by combining in situ hybridization (ISH) with immunohistochemistry (IHC). Results: combined ISH/IHC allows us to demonstrate an increased expression of Notch2 mRNA and protein in pSjD salivary glands (SGs) biopsies, which appears correlated with an increased expression of ADAM17, both in acinar and duct cells and in infiltrating lymphocytes. Notch2/ADAM17 expression is higher in biopsies of pSjD SGs characterized by a high degree of inflammation. Conclusions: this work demonstrates the correlated expression in pSjD SGs of ADAM17, which plays multiple roles in the pathogenesis of SjD, and Notch2, widely considered a key player in various inflammatory mechanisms, offering a starting point for future therapeutic interventions to investigate. Full article

Purpose: This study investigates receptor status changes following neoadjuvant chemotherapy (NAC) in breast cancer, aiming to identify new therapeutic opportunities and improve human epidermal growth factor receptor 2 (HER2) detection and categorization methods. Methods: This retrospective analysis was conducted on patients with breast cancer who underwent NAC and surgery between July 2022 and June 2024. Chi-square tests and logistic regression models were applied to assess the associations between HER2 status changes and clinicopathological features. Results: Among 508 patients, the receptor discordance rates after NAC were 5.3% for estrogen receptor (ER), 21.3% for progesterone receptor (PR), and 43.7% for HER2. Ki-67 expression decreased in 64.6% of cases and increased in 6.8%. Of the 103 patients with HER2-0, 47 (45.6%) transitioned to IHC 1+, 9 (8.7%) to IHC 2+/ISH−, and 1 (1.0%) to IHC 2+/ISH+. Among 256 patients with HER2 IHC 1+, 58 (22.7%) transitioned to IHC 2+/ISH−, 36 (14.1%) to IHC 0, and 9 (3.5%) to IHC 2+/ISH+. For 149 patients with HER2 IHC 2+/ISH−, 50 (33.6%) transitioned to IHC 1+, 6 (4.0%) to IHC 2+/ISH+, 5 (3.4%) to IHC 0, and 1 (0.7%) to IHC 3+. Univariate analysis revealed that, when compared to grade III tumors, grade I–II tumors exhibited a higher rate of HER2-0 to HER2-low conversion (66.7% vs. 36.8%, p = 0.027). HER2-low to HER2-0 conversion was associated with ER negativity (p = 0.028), PR negativity (p = 0.021), HER2 IHC 1+ (vs. IHC 2+, p = 0.001), and TIL >10% (p = 0.049). Multivariate analysis revealed that tumors with HER2 IHC 1+ were more likely to convert to HER2-0 after NAC than those with HER2 IHC 2+ (p = 0.020). Conclusions: Following NAC, ER gain, PR loss, and Ki-67 reduction were common. HER2 and ER status changes predominantly occurred within adjacent expression intensity levels. Full article

Submesoscale dynamics are critical modulators of upper-ocean biogeochemistry, yet their net influence on chlorophyll concentrations across seasonal to interannual timescales, particularly within productive regions like the Benguela Current Large Marine Ecosystem (BCLME), remains poorly understood. This study quantifies these complex relationships by analyzing 22 years (2001–2022) of physical and biological data. We examined the link between surface chlorophyll (CHL) and key physical drivers: sea level anomaly (SLA) and submesoscale intensity, quantified by the Rossby number (Ro). Using both cross-correlation analysis and Generalized Linear Models (GLMs), our analyses reveal a multi-scale set of spatially dependent and time-lagged biogeochemical responses. At the basin scale, a key finding from cross-correlation is a significant positive correlation where high SLA precedes a rise in CHL by approximately six months, indicating a delayed ecosystem response to large-scale physical forcing. At the event scale, GLMs show the specific impact of eddies is critical: short-lived cyclonic eddies correlate with a significant increase in CHL (~4.6%) in the southern zone, while anticyclonic eddies are associated with a pronounced decrease in CHL (~97.7%) in the central zone during the austral winter. These findings demonstrate that both large-scale preconditions and localized submesoscale features are essential drivers of vertical nutrient transport and the distribution of primary productivity within the BCLME. Full article

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd. Full article

Background: Human papillomavirus (HPV) plays a crucial role in the pathogenesis of oropharyngeal squamous cell carcinomas (OPSCC). Accurate HPV status classification is essential for therapeutic stratification. While p16 immunohistochemistry (IHC) is the clinical surrogate marker, it has limited specificity. Methods: In this study, we implemented a weakly supervised deep learning approach using the Clustering-constrained Attention Multiple-Instance Learning (CLAM) framework to directly predict HPV status from hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) of OPSCC. A total of 123 WSIs from two cohorts (The Cancer Genome Atlas (TCGA) cohort and OPSCC cohort from the University of Naples Federico II (OPSCC-UNINA)) were used. Results: Attention heatmaps revealed that the model predominantly focused on tumor-rich regions. Errors were primarily observed in slides with conflicting p16/in situ hybridization (ISH) status or suboptimal quality. Morphological analysis of high-attention patches confirmed that cellular features extracted from correctly classified slides align with HPV status, with a Random Forest classifier achieving 83% accuracy at the cell level. Conclusions: This work supports the feasibility of deep learning-based HPV prediction from routine H&E slides, with potential clinical implications for streamlined, cost-effective diagnostics. Full article

Background/Objectives: Immunohistochemical (IHC) profiles assessed on core biopsies guide initial therapy in breast cancer; however, paired changes between biopsy and surgical specimens may alter treatment pathways. We aimed to quantify paired biomarker dynamics (ER, PR, HER2, Ki-67) and the proportion of patients undergoing clinically actionable reclassification. Methods: We conducted a single-center retrospective study of 79 patients with paired pre- and post-surgical IHC for ER, PR, HER2 (0/1+/2+/3+ with reflex ISH for 2+), and Ki-67 (20% cut-off). Paired categorical shifts were tested with McNemar’s test; agreement was quantified using Cohen’s κ (95% CI); and multivariable logistic regression examined correlates of neoadjuvant chemotherapy (NACT). Two-sided p < 0.05 denoted statistical significance. Results: Post-surgical reassessment showed measurable conversions: PR-negative increased from 15.19% to 27.85%, while PR-positive decreased 84.81%→72.15%; HER2 3+ contracted 11.39%→6.33% with a parallel rise in 2+ (equivocal) 17.72%→24.05%; Ki-67 < 20% rose 37.97%→56.96%, whereas the >30% category was absent post-surgery. McNemar tests indicated significant paired shifts for PR (p = 0.016) and Ki-67 (p = 0.009); agreement was substantial for ER (κ = 0.70) and lower for PR (κ = 0.49), HER2 (κ = 0.43), and Ki-67 (κ = 0.29). High proliferation (Ki-67 ≥ 20%) independently predicted NACT (OR = 4.36, 95% CI 1.48–12.80). Conclusions: Paired IHC reassessment from biopsy to surgery reveals biomarker conversions that can reclassify therapeutic eligibility (e.g., anti-HER2 candidacy, endocrine strategies). These data support selective confirmation of IHC on resection specimens in routine practice and provide Δ-metrics to inform decision-making; external validation in prospective cohorts is warranted. Full article