Search Results (4,279)

Background: Early diagnosis of familial hypercholesterolemia (FH) is crucial to improve long-term outcomes. FH diagnosis relies on elevated low-density lipoprotein cholesterol (LDL-C) levels, familial clinical characteristics, and identification of pathogenic variants in FH-related genes. Secondary factors, such as overweight and obesity, are known to influence lipid profiles in the general population. More recently, polygenic risk scores based on single-nucleotide polymorphisms (SNPs) have been proposed as additional determinants of LDL-C levels. Methods: We enrolled 214 pediatric subjects with LDL-C levels ≥95th percentile (after 6 months of dietary intervention) and with at least one parent with LDL-C levels ≥ 95th percentile. All participants underwent biochemical and auxological assessment and genetic testing for FH. In a subgroup of 60 subjects, LDL-C polygenic scores based on 6- and 12-SNPs were calculated. Results: Pathogenic variants confirming heterozygous FH were identified in 190 subjects (variant-positive, V+); 17 were variant-negative (V−), yielding a mutation detection rate of 91.8%. An additional seven patients carrying variants of uncertain significance were excluded from the primary analysis. LDL-C was modestly higher in V+ than V− subjects using both Friedewald (212 vs. 188 mg/dL; p = 0.035) and Martin–Hopkins formulas (208 vs. 187 mg/dL; p = 0.041), while the other main clinical and laboratory parameters were similar. In V+, LDL-C was higher in subjects with null variants, compared to those with defective variants. Body mass index (BMI SDS) was inversely correlated with HDL-C (p < 0.001), and obesity (BMI z-score > 2 SDS) was associated with lower HDL-C and higher LDL-C, non-HDL-C, and ApoB. With regard to the polygenic scores, 12- and 6-SNP scores showed overlap between V+ and V−, and published cut-offs did not discriminate lipid severity in our population; however, in V+ subjects, the 12-SNP score acted as a phenotype modifier, being independently associated with higher LDL-C and non-HDL-C levels after adjustment for age, sex, and BMI SDS. Conclusions: In children selected by LDL-C ≥ 95th percentile, together with autosomal dominant familial hypercholesterolemia, genetic confirmation of FH is achieved in the vast majority of cases. Variant type (null vs. defective), BMI, and polygenic background contribute to phenotypic heterogeneity, supporting the need to address other factors alongside genetic diagnosis. Further validation is needed before polygenic scores can be implemented in routine clinical practice. Full article

Background/Objectives: There is a lack of cohesion in integrating current knowledge on the genetic and environmental etiology of dental impaction. The primary aim of this article is to review the current literature to identify candidate genes involved in the pathogenesis of dental impaction. Methods: A scoping review was conducted following PRISMA-ScR guidelines to identify and organize the available body of evidence. Relevant literature was searched in MEDLINE (via PubMed), Scopus, and Web of Science, with the final search conducted on 03 January 2026. Eligibility criteria included case–control, cohort, cross-sectional observational, and case report studies in humans. Selected studies focused on syndromic and non-syndromic variants, inheritance patterns, and genetic analyses. Risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists and AMSTAR 2. Results: Only 18 studies met the eligibility criteria. Most articles were case reports and retrospective observational studies, revealing a multifaceted genetic landscape underlying dental impaction, with mutations affecting transcription factors and signaling pathways critical for odontogenesis, particularly RUNX2, FGFR1, MSX1, PAX9, and AXIN2. Overall, the included studies showed moderate methodological quality. Conclusions: Current evidence does not clearly support specific genes as causal factors in dental impaction, but instead suggests a complex, likely polygenic susceptibility that modulates the anatomical threshold for tooth eruption. This review highlights RUNX2, FGFR1, MSX1, PAX9, and AXIN2, as well as emerging candidates involved in eruption and bone remodeling pathways. Future progress depends on standardized phenotyping, large replicated cohorts, and functional studies linking genetic variation to dental follicle-mediated eruptive remodeling. Full article

Java deserialization vulnerabilities remain a critical security threat, with existing detection tools facing significant challenges in generating functional exploit payloads due to semantic blindness and constraint complexity. This paper presents LLM-JDFuzz, the framework that leverages Large Language Models for automated Java deserialization payload generation. By reframing payload generation as a constraint-aware code synthesis problem, LLM-JDFuzz introduces three key innovations: (1) an Autoprompting engine that transforms Gadget Chain specifications into structured natural language instructions, (2) an adaptive multi-strategy fuzzing loop that dynamically selects between generation, mutation, and semantic exploration based on execution feedback, and (3) a fine-grained feedback mechanism that performs error classification and root cause attribution to guide iterative refinement. We evaluate LLM-JDFuzz on 34 Gadget Chains from the ysoserial benchmark. Results show that LLM-JDFuzz achieves a 70.6% success rate. While maintaining comparable effectiveness to the state-of-the-art static tool JDD, LLM-JDFuzz demonstrates superior performance in processing cross-language scripting engine chains and achieves a 4× improvement in generation efficiency. Our work demonstrates that LLMs possess inherent semantic understanding capabilities for security-critical code generation, opening new research directions for AI-assisted vulnerability exploitation. Full article

Ovarian cancer remains a leading cause of gynecologic cancer–related mortality worldwide, and long-term outcomes with conventional cytotoxic chemotherapy remain limited. The integration of targeted therapies has substantially reshaped treatment paradigms by exploiting key molecular pathways involved in angiogenesis, DNA damage repair, and folate receptor signaling. This review synthesizes evidence from pivotal phase II and III clinical trials, translational studies, and meta-analyses evaluating inhibition of the VEGF, PARP, and folate receptor-alpha (FRα) pathways, with a focus on bevacizumab, rucaparib, and mirvetuximab soravtansine. Across disease settings, these agents have demonstrated clinically meaningful improvements in progression-free survival, durability of response, and tolerability when deployed in biomarker-selected populations. Bevacizumab has shown consistent benefit when combined with platinum-based chemotherapy and as maintenance therapy in advanced disease. PARP inhibitors, including rucaparib, exploit homologous recombination deficiency (HRD) to induce synthetic lethality and are now central to frontline and recurrent treatment strategies for BRCA-mutated and HRD-positive tumors. Mirvetuximab soravtansine has emerged as an effective and well-tolerated option for patients with FRα-high, platinum-resistant ovarian cancer, addressing a longstanding unmet clinical need. Collectively, VEGF-, PARP-, and FRα-targeted therapies have enabled more rational treatment sequencing, informed combination strategies, and personalized clinical decision-making in ovarian cancer. Ongoing efforts to define optimal sequencing, overcome acquired resistance, and refine predictive biomarkers are expected to further enhance the durability and breadth of benefit from targeted therapies and advance precision oncology in gynecologic malignancies. Full article

Background/Objectives: The incidence of early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is increasing worldwide; however, comparative data between patients with EO-CRC and late-onset colorectal cancer (LO-CRC) in Asian populations remain limited. We compared the clinicopathological, molecular, and prognostic characteristics of EO-CRC and LO-CRC in a tertiary-center cohort. Methods: This retrospective cohort study included patients with histologically confirmed colorectal adenocarcinoma treated at a single tertiary referral center between January 2011 and December 2024. Patients were classified as having EO-CRC (<50 years) or LO-CRC (≥50 years). Demographic and lifestyle factors, clinicopathological characteristics, laboratory findings including blood tests and tumor markers, and molecular profiles such as microsatellite instability (MSI) status and selected gene mutations were compared. Overall survival and associated prognostic factors were evaluated using multivariate analysis. Results: Among 1383 patients, 104 had EO-CRC and 1279 had LO-CRC. Patients with EO-CRC reported smoking and alcohol consumption more frequently, had fewer comorbidities, and showed a higher prevalence of distal tumors, particularly rectal cancer, with a lower T stage. Nodal and distant metastatic stages were comparable between the groups, with no difference in the proportion of stage IV disease. Laboratory parameters, tumor marker levels, MSI status, and other available molecular markers were not significantly different. Overall survival did not differ significantly between EO-CRC and LO-CRC. Conclusions: EO-CRC exhibited distinct clinical features; however, molecular characteristics and survival outcomes were similar to those of LO-CRC. Prognosis is primarily determined by disease stage rather than the age at diagnosis, supporting the importance of early detection strategies in high-risk populations. Full article

In the long-term operation of canals in loess areas, instability and landslides frequently occur due to the effect of wetting–drying cycles, which severely restricts the long-term safe operation of engineering projects. To reveal the evolution law of loess strength under wetting–drying cycles and establish a strength prediction model, this study conducted wetting–drying cycle tests and direct shear tests, analyzing the effects of different cycle times, dry densities, and initial water contents on the shear strength and its parameters. A combined model of improved adaptive genetic algorithm and backpropagation neural network (IAGA-BP) was adopted for shear strength prediction. An adaptive crossover and mutation operator based on the Sigmoid function, which combines the fitness value with the population iteration number, was proposed. By optimizing the parent selection strategy and the uniform crossover genetic method, the population diversity was effectively maintained, and premature convergence was avoided. The test results show that with the increase in the wetting–drying cycle times, both the shear strength and strength parameters of loess exhibit a trend of gradual attenuation and eventually tend to be stable. The increase in the dry density and initial water content can reduce the degradation amplitude of soil cohesion after five wetting–drying cycles. The model verification results indicate that all evaluation indicators of the IAGA-BP neural network model (MAPE = 3.75%, MAE = 0.95 kPa, MSE = 9 × 10⁻⁴, R² = 0.975) are significantly superior to those of the traditional BP and GA-BP models, with the comprehensive prediction performance improved by 62% and 46%, respectively. This model not only effectively overcomes the defect that traditional models are prone to fall into local extremum but also shows significant advantages in prediction accuracy and convergence speed. This study can provide a theoretical reference for the calculation of loess strength degradation and the prediction of long-term stability under the environment of wetting–drying alternation. Full article

Craniopharyngiomas are rare, histologically benign but locally aggressive intracranial tumors that are associated with substantial visual, endocrine, and hypothalamic morbidity. Advances in molecular characterization have enabled the use of systemic molecularly targeted therapies, particularly in the recurrent or refractory setting, with the goal of limiting further surgical or radiation-related injury to the hypothalamic–pituitary axis. Papillary craniopharyngioma (PCP), defined by near-universal BRAF V600E mutations, exhibits profound and rapid responses to combined BRAF and MEK inhibition, with objective response rates exceeding 90% in prospective studies. These responses can facilitate less extensive surgery, enable de-escalation of radiotherapy, or allow deferral of local treatment. In contrast, adamantinomatous craniopharyngioma (ACP), characterized by CTNNB1 mutations and a cystic phenotype with a prominent inflammatory microenvironment, lacks a single actionable oncogenic driver. Early clinical experience suggests that Interleukin-6/Interleukin-6 receptor (IL-6/IL-6R) blockade, alone or in combination with bevacizumab, may stabilize or reduce cystic components in selected patients, although evidence remains limited to small case series. Other systemic approaches for ACP, including MAPK pathway inhibition and immune-directed strategies, are still under investigation. Across subtypes, adverse events have generally been class-expected and manageable, but data on long-term endocrine, hypothalamic, and neurocognitive outcomes are sparse. This review synthesizes current evidence for neoadjuvant, adjuvant, and palliative craniopharyngioma systemic targeted therapies and highlights the ongoing clinical considerations of this therapy. Full article

Directed grey-box fuzzing (DGF) is central to vulnerability reproduction, patch testing, static analysis, and information-flow detection. However, most existing DGF tools rely on largely random mutation strategies and thus produce many ineffective inputs. To address this, we present SpeedDGF, a directed grey-box fuzzer that employs a lightweight per-byte mutation strategy. At runtime, SpeedDGF dynamically identifies path-sensitive bytes—those most influential for reaching target code regions—and assigns them higher byte-energy, increasing their likelihood of selection during mutation. The effectiveness of SpeedDGF was systematically evaluated across 26 real-world vulnerabilities. The experimental results demonstrate that SpeedDGF is 4.63× faster in reaching the target locations and 5.78× more effective in reproducing target vulnerabilities compared with existing fuzzing tools. This approach significantly enhances the capability of the fuzzing tool to reach specified target locations and efficiently reproduce vulnerabilities. Full article

Background/Objectives: The SARS-CoV-2 virus frequently undergoes mutations to evade the human immune system. Vaccines for new strains are developed each season, and an identification test confirming the specific strain is essential for vaccine quality control, as stated by the U.S. Food and Drug Administration. However, a shorter timeline of antibody discovery was required to adjust vaccine development schedules. Therefore, anti-SARS-CoV-2 strain-specific, single-domain antibodies (sdAbs) for SARS-CoV-2 vaccines were discovered using alpaca synthetic libraries without animal immunization. Methods: A synthetic sdAb library was developed based on conserved alpaca sdAb frameworks, with a degree of freedom in the three complementarity-determining regions. Specific and high-affinity sdAb clones were selected from the library by one ribosomal display round, followed by two phage display selections using a biotinylated strain-specific SARS-CoV-2 receptor-binding domain (RBD) of the spike protein as bait and non-biotinylated RBD variants to block. The sdAbs clones were applied to the identification test using Western blotting. The binding epitopes were determined by hydrogen–deuterium exchange mass spectrometry. Results: Five clones of XBB.1.5 and two clones of JN.1-specific sdAbs were discovered. Anti-JN.1 sdAb clone 1B9 detected JN.1 vaccine products but no other previously produced vaccine strains, Wuhan, BA.5 and XBB.1.5, by WB for vaccine identification test. Four binding epitopes for anti-JN.1 sdAb clone 1B9 were identified, including the L455S mutation, a critical amino acid to evade neutralizing antibodies for the JN.1 strain. Conclusions: Anti-XBB.1.5 and JN.1-specific sdAbs were discovered from a synthetic single-domain antibody library within 8–9 weeks, and these sdAbs were applied to vaccine identification testing. Full article

Molnupiravir induces mutations that render severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication-competent through error catastrophe mechanisms. Previous studies showed no resistant virus emergence during prolonged molnupiravir treatment, with no resistant variants reported. However, these approaches were limited by genetic uniformity at passage initiation. To investigate viral population dynamics under enhanced genetic diversity, we employed mutagenic pre-treatment using 5-fluorouracil (5-FU) and favipiravir to generate diverse quasi-species populations before molnupiravir selection pressure. Viral populations were treated with stepwise increasing molnupiravir concentrations (10 μM ⟶ 25 μM ⟶ 40 μM) over ten serial passages. Viral detectability, plaque morphology, and mutation accumulation were analyzed using molecular and sequencing approaches. Only high-concentration favipiravir (1000 μM) pre-treatment maintained detectable viral RNA through ten passages under 40 μM molnupiravir, while favipiravir (500 μM) and 5-FU groups became undetectable after passage 6. Surviving populations formed extremely small plaques with markedly reduced replication capacity. Next-generation sequencing revealed extensive mutation accumulation across viral proteins, including polymerase proteins. Individual viable virus isolation was unsuccessful, and large-scale propagation could not be achieved. These findings demonstrate apparent survival rather than true resistance to molnupiravir, characterized by severely compromised viral fitness. Full article

Mucinous appendiceal and colorectal tumors represent a biologically and clinically distinct subset of gastrointestinal malignancies, defined by abundant extracellular mucin, characteristic molecular alterations, and a strong predilection for peritoneal dissemination. Despite these distinctive features, they remain relatively underrepresented in biomarker-driven clinical frameworks, and evidence specific to liquid biopsy performance in this subgroup is fragmented. These features complicate clinical assessment and limit the applicability of tissue-based and circulating biomarkers that perform well in non-mucinous colorectal cancer. Although liquid biopsy is now integral to precision oncology across multiple solid tumors, its role in mucinous disease remains incompletely defined. This review synthesizes evidence on liquid biopsy and molecular biomarkers in mucinous appendiceal and colorectal tumors, with emphasis on circulating tumor DNA (ctDNA) and emerging multi-analyte approaches. Rather than extrapolating from non-mucinous colorectal cancer paradigms, we examine liquid biopsy performance through the lens of mucinous tumor biology and peritoneal compartmentalization. We summarize how peritoneal-dominant spread, limited vascular access, low tumor cellularity, and sequestration of malignant cells within mucin pools constrain biomarker shedding into peripheral blood and contribute to low ctDNA detectability. We discuss the clinical implications for postoperative surveillance after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, molecular profiling when tissue is limited, and longitudinal monitoring in selected patient subsets. A central focus is the context-dependent interpretation of positive versus negative plasma findings, particularly in low-shedding disease, where false reassurance may occur. We also review strategies beyond plasma ctDNA, including compartment-specific sampling and non-mutational platforms that may improve sensitivity in low-shedding settings. By integrating biological rationale with comparative findings across studies, we identify key evidence gaps and priorities for prospective, biologically stratified validation. We further outline practical considerations for integrating liquid biopsy results into multidisciplinary decision-making in mucinous malignancies. Aligning biomarker class and sampling compartment with mucinous tumor biology may improve interpretability and support more precise clinical management. Full article

Differential wavefront sensing (DWS) is widely adopted for high-precision angular detection in interferometric systems, yet its measurement range is constrained by the nonlinear implicit phase–angle relationship. This paper proposes a strategy-enhanced differential evolution algorithm, termed Bi-inheritance and Tournament-Selection-based Differential Evolution (BiTsDE), to suppress nonlinear angular errors. The method introduces fitness-guided inheritance of mutation and crossover factors and tournament-based elite parent selection, enabling adaptive balance between global exploration and local exploitation. Unlike conventional DE variants that mainly tune control parameters, BiTsDE optimizes the evolutionary search strategy, enhancing early-stage diversity and late-stage convergence stability. Simulations demonstrate angular resolution better than 0.06 nrad within ±1 mrad. Experiments show that up to 600 μrad, BiTsDE reduces demodulation error by 99.9% compared with linear DWS, achieving 17.9 nrad precision and 42% faster convergence. These results validate BiTsDE as an effective solution for nonlinear error suppression in DWS-based high-precision optical metrology, particularly for space-based gravitational wave detection. Full article

Background: Chromosome 3p (chr3p) is frequently deleted in multiple cancers, indicating the presence of shared tumor suppressors. In aggressive uveal melanomas (UVM), this deletion often co-occurs with chr8q amplification (8q+), suggesting strong selection pressure during UVM evolution. Methods: To understand the pattern of genomic alterations mediated by chr3p deletion, we have developed an algorithm for detecting isochromosomes in 10,632 TCGA cancer patients. We further perform integrative genomics analysis to investigate how chr3p deletion could affect subsequent cancer genome evolution and synthetic lethality in UVM. Results: Analysis of genomic alterations in 33 different cancer types implicates the deletion or deleterious mutations of SET-domain-containing 2 (SETD2) at chr3p21 in significantly facilitating the formation of isochromosomes, thereby promoting genomic instability conducive to rapid cancer genome evolution. Fracturing of dicentric isochromosomes during cell division is pervasive and follows the dynamic fragmentation pattern of solids under impulse. In the most aggressive UVM subtype, chr3 deletion includes MITF, a master regulator of melanocyte survival and differentiation, and co-occurs with 8q+. We demonstrate that MITF is a master transcriptional regulator of GNAQ/GNA11 and associated synthetic-lethal genes in UVM. MITF maintains MAPK and calcium homeostasis in UVM, and its hemizygous deletion is thus accidental, likely creating an early crisis during oncogenesis. We further show that MITF, MYC, and GNAQ/GNA11 form coupled regulatory feedback loops in the melanocyte lineage, and MITF deletion in UVM creates acute dependency on MYC-mediated rescue via 8q+. The discovered feedback loops predict both overall and relapse-free patient survival within the most aggressive UVM subtype, explain sensitivity to therapeutic gene perturbations, and inform effective combinatorial therapies. Conclusions: SETD2 deletion potentiates isochromosome formation across diverse cancers. Combinatorial targeting of MITF together with a previously identified synthetic lethal gene may benefit UVM patients harboring both chr3 deletion and 8q+. Full article

The treatment landscape for endometrial carcinoma (EC) is undergoing a paradigm shift from traditional histopathological dualism to precision medicine grounded in the Cancer Genome Atlas (TCGA) molecular classification. The “No Specific Molecular Profile” (NSMP) subgroup, the largest molecular cohort, has emerged as a particularly promising target for endocrine-based strategies. While endocrine therapy (ET) has been a mainstay for over 60 years due to its favorable safety profile, its efficacy as monotherapy remains modest. This review provides a comprehensive overview of current endocrine strategies, including traditional agents like progestins and aromatase inhibitors, and focuses on novel combination therapies designed to overcome resistance. Recent clinical trials have demonstrated that integrating molecularly targeted agents, such as CDK4/6 and mTOR inhibitors, significantly improves clinical outcomes. Specifically, patients with TP53 wild-type status and CTNNB1 mutations exhibit exceptional responses to these combinations. Furthermore, we discuss the potential of next-generation selective estrogen receptor degraders (SERDs) and the importance of refining patient selection through robust predictive biomarkers. Driven by molecular insights, endocrine therapy is transitioning from a secondary palliative option into a definitive cornerstone of precision oncology, offering a personalized and effective treatment for patients with advanced or recurrent endometrial carcinoma. Full article

Background: Skipper butterflies (Hesperiidae) are a morphologically distinctive lineage within Papilionoidea, yet relationships among many groups remain difficult to resolve, and mitochondrial genomic resources remain limited for some tribes, including Celaenorrhinini. Methods: We sequenced and characterized the complete mitochondrial genome of Celaenorrhinus victor using Illumina short-read sequencing. Gene content and organization were annotated, codon-usage patterns were assessed across Celaenorrhinus using relative synonymous codon usage and multiple compositional/selection tests (ENC–GC3s, neutrality, and PR2 analyses), selective constraints were evaluated using Ka/Ks for 13 protein-coding genes, and phylogenetic relationships were inferred with a partitioned maximum-likelihood analysis of 66 complete hesperiid mitogenomes. Results: The circular mitogenome of C. victor is 15,180 bp and contains the typical 37 genes (13 protein-coding genes, 22 tRNAs, and two rRNAs) plus an A + T-rich control region, with an overall A + T content of 79.64%. Gene order and orientation match those of other Celaenorrhinus and hesperiid mitogenomes. All protein-coding genes use standard invertebrate mitochondrial start codons (with cox1 initiating with TTG) and terminate with complete TAA stop codons. Codon usage is strongly biased toward A/U-ending codons and is broadly similar among five sampled Celaenorrhinus mitogenomes; ENC–GC3s, neutrality, and PR2 analyses indicate a predominant influence of A + T-directed mutational pressure with additional effects beyond base composition. Ka/Ks values for all 13 protein-coding genes were <1, consistent with pervasive purifying selection; cox genes were the most conserved, whereas several NADH dehydrogenase subunit genes evolved comparatively faster. The phylogeny recovered monophyletic Celaenorrhinini and a well-supported Celaenorrhinus clade, placing C. victor as sister to Celaenorrhinus consanguineus, while deeper nodes among major hesperiid lineages showed only moderate support in parts of the tree. Conclusions: This study provides a new mitogenomic resource for Celaenorrhinini and a comparative reference for codon usage and selective constraints within Celaenorrhinus, supporting the placement of C. victor within Hesperiidae while highlighting remaining uncertainty at deeper hesperiid divergences. Full article