Search Results (430)

The primary aim of this review is to summarize current evidence from clinical and pre-clinical studies on endogenous molecular biomarkers associated with radiosensitivity and radioresistance in cervical cancer, including patients treated with photon-based radiotherapy, cervical cancer cell lines, and xenograft models, and to evaluate the association of these biomarkers with radiotherapy response, residual disease, recurrence and survival, and experimental measures of radiosensitivity. A systematic literature review was conducted for studies published over the last 10 years that evaluated associations between genomic, epigenetic, or protein biomarkers and radiotherapy response or survival outcomes in cervical cancer. Eligible studies included in the current analysis summarize clinical, translational, and pre-clinical studies in correlation with photon-based radiotherapy. Research focusing exclusively on non-coding RNAs, exogenous radiosensitizers, or non-photon modalities was excluded. In total, 112 studies were identified, and 46 of them met the inclusion criteria. The identified biomarkers clustered into several key biological processes: DNA damage response and cell cycle regulation, cancer stemness, hypoxia and microenvironment, epigenetic and transcriptional regulation, and signaling pathways, including exosome-mediated communication. Most markers were linked to radioresistance and adverse outcomes, whereas a smaller subset was associated with increased radiosensitivity. A limited group of biomarkers was linked to clinical outcomes such as local control, residual disease, or survival, and emerging multi-marker protein signatures suggested that combinatorial approaches may outperform single-marker strategies. Radiosensitivity in cervical cancer is regulated by a network of biological pathways. Validated, integrated biomarker panels that capture DNA repair proficiency, stemness, hypoxia adaptation, and key signaling pathways are needed to improve risk stratification and enable biomarker-guided radiosensitization. Full article

This paper develops a reliability-oriented resource-allocation framework for a single-cell uplink sparse code multiple access (SCMA) system with fixed low-projection codebook (LPCB) constellation components. Link-level SCMA–message-passing-algorithm (MPA) samples calibrate a compact bit-error-rate (BER) surrogate, enabling repeated candidate evaluation without embedding MPA decoding in the search loop. The proposed two-stage method combines a subcarrier allocation whale optimization algorithm (SAWOA), equipped with stochastic binary mapping and exact degree-feasibility repair, with an exact Karush–Kuhn–Tucker (KKT) active-set power allocator. For the $J=6$, $K=4$ setting, exact enumeration over all 210 main conditions shows that the SAWOA attains the enumerated equal-power ${\mathcal{P}}_1$ oracle objective within relative tolerance ${10}^{-10}$ in every case. Across 30 paired channel/optimizer blocks, each aggregating the seven power points, the SAWOA reduces the initial-gap-normalized convergence area under the curve by 47.5% relative to the Standard Binary WOA (Holm-adjusted $p=1.19\times {10}^{-5}$); its oracle-hit rate by iteration 20 is 93.3% versus 75.7%, while no significant AUC difference is detected relative to particle swarm optimization. After 100 iterations, the three population methods approach the same oracle plateau, whereas random is significantly worse at the midpoint ($p=7.45\times {10}^{-9}$). Exact KKT refinement improves every recorded SAWOA solution and reduces the equal-power surrogate by 3.64–56.27% on average across the sweep, with a maximum relative KKT residual of $1.01\times {10}^{-16}$. A single-point direct Rayleigh SCMA–MPA check confirms the executable transfer of the selected allocation and returns the same decoded BER for the SAWOA and Standard Binary WOA; it remains a bounded transfer sanity check. The results demonstrate finite-budget stage-1 search efficiency, reliable feasible support recovery, and effective exact power refinement for the investigated quasi-static configuration. Full article

Background/Objectives: CRISPR/Cas9-mediated genome editing enables efficient generation of knockout mouse models; however, frameshift mutations do not always result in complete loss of function. The factors influencing functional inactivation following frameshift mutations remain incompletely understood. Here, we tested whether frameshift-dominant targeting of exon 1 is sufficient to generate a null allele of Fgf10, a gene essential for limb formation. Methods: Guide RNAs (gRNAs) were selected using a machine learning-based pipeline to favor microhomology-mediated end joining (MMEJ)-dominant repair. Editing efficiency and indel profiles were assessed via amplicon sequencing in mouse embryonic stem cells (mESCs) and preimplantation embryos. Edited embryos were transferred to surrogate females and analyzed at embryonic day 15.5 (E15.5). Results: Amplicon sequencing confirmed >97% editing efficiency and >80% frameshift alleles in both mESCs and preimplantation embryos, with a predominant 7 bp deletion. Despite highly efficient frameshift-dominant editing, most of the E15.5 embryos were morphologically normal, indicating that exon 1 targeting did not reliably produce null phenotypes. In silico analysis suggested the possible presence of alternative downstream translation initiation sites, and our secretion assay supported this possibility. Initiation from a downstream ATG in a +2 reading frame (e.g., 7 bp deletion) may restore the downstream coding sequence and partially preserve protein function. Conclusions: Frameshift mutations in exon 1 of Fgf10 do not consistently result in functional knockout. The functional outcome depends on the specific reading frame and may be influenced by alternative translation initiation and protein domain architecture. These findings highlight important considerations for designing genome editing strategies to achieve complete gene inactivation. Full article

The rising prevalence of cardiovascular diseases (CVDs) worldwide imposes a substantial economic burden on healthcare systems. Despite major advances in evidence-based therapies and modern healthcare, the demand for novel, time- and cost-effective treatment options continues to grow. Extracellular vesicles (EVs), including apoptotic bodies, microvesicles, and exosomes, are released by numerous cell types and mediate intercellular communication in both physiological and pathological contexts. To date, researchers have amassed compelling evidence for the functional roles of EVs in the development and progression of myocardial disease, supporting their exploration for clinical applications. In this review, we examine the multifunctional roles of EVs from diverse cellular origins in prominent CVD manifestations, highlighting publications of the last eight years and their key findings. They confirm that EVs carry disease-specific molecular cargo, particularly microRNAs, long non-coding RNAs, proteins, and other bioactive molecules, contributing to inflammation, oxidative stress, fibrosis, endothelial dysfunction, and cardiac remodeling, while also serving as promising diagnostic and prognostic biomarkers. Furthermore, emerging preclinical evidence demonstrates the therapeutic potential of engineered or tissue-derived EVs for promoting cardiac repair and limiting adverse cardiac remodeling. Full article

Domain-Specific Languages (DSLs) are essential in software engineering for safely expressing complex domain logic. However, Large Language Models (LLMs) struggle to generate syntactically and semantically correct code for niche DSLs due to sparse representation in pre-training corpora. While Grammar-Constrained Decoding (GCD) resolves syntactic hallucinations by masking logits through a formal Context-Free Grammar (CFG), empirical evidence shows that strict GCD disrupts the autoregressive Chain-of-Thought (CoT) reasoning of modern models, frequently forcing them into irreversible semantic dead-ends. To overcome the friction between internal neural reasoning and external symbolic constraints, we propose a Dual-Phase Cascaded Neurosymbolic framework. In the first phase, the model is provided with dynamically injected grammar rules and is permitted to reason unconstrained, producing an optimistic code draft. If the draft fails native compiler checks, the system enters a second phase: it preserves the successful semantic reasoning from Phase 1 but re-generates the code under strict GCD enforcement. This cascaded architecture utilizes the formal FSM not as an adversarial constraint, but as a localized syntax repair engine guided by the model’s own prior reasoning. We construct a comprehensive benchmark of 100 MiniZinc constraint programming tasks and evaluate our approach using a $pass@k$ metric with a strict semantic LLM judge. Our findings demonstrate that this dual-phase “think-then-constrain” approach significantly outperforms zero-shot, pure few-shot, and pure GCD baselines, achieving highly reliable, training-free code generation for unseen DSLs. Full article

Vulnerable-code auditing is critical within the Software Development Life Cycle (SDLC) as timely remediation reduces exploitation risks from sensitive-data exposure to full system compromise. Although Automatic Program Repair (APR) has advanced through Machine Learning (ML), Deep Learning (DL), and Transformer-based generative models, current approaches remain limited by reduced language coverage, weak grounding in documented vulnerabilities, incomplete patch validation, and lack of explicit normative guidance for secure-coding compliance. This study introduces FocalVulNORM, a normatively conditioned Multi-Task repair model that generates a secure patch from vulnerable code while simultaneously verifying whether the vulnerable pattern is removed, the patch preserves observable behavior, and the repair aligns with the applicable security control. FocalVulNORM uses a shared Transformer encoder, a Focal Attention Layer, and four jointly optimized objectives: Repair, Detection, Normative Compliance, and Semantic Equivalence. The normative text is derived from CWE descriptions and SDLC secure-coding guides and standards, providing the security condition used to guide and evaluate each repair. Using this normative input, FocalVulNORM is trained on 11,503 vulnerability–patch pairs across seven programming languages and eight Common Weakness Enumeration (CWE) types. The model achieves CodeBLEU $=0.8247$ and Token-Level Accuracy (TLA) $=0.8976$ for Repair, $F1=0.9926$ for Detection, $F1=0.9820$ for Normative Compliance, and $F1=0.9921$ for Semantic Equivalence. The results indicate that FocalVulNORM extends APR beyond patch generation by attaching each repair to explicit evidence of vulnerability removal, behavioral preservation, and security-control alignment. Full article

Malignant gliomas are highly aggressive primary brain tumors for which the therapeutic efficacy of cisplatin is frequently limited by intrinsic or acquired drug resistance. Despite advances in adjuvant therapies, overcoming chemoresistance remains a major challenge in the treatment of these malignancies. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of non-protein-coding transcripts involved in gene regulation, play important roles in modulating treatment responses. Several lncRNAs, including differentiation antagonizing non-protein-coding RNA (DANCR), HOXD antisense growth-associated long non-coding RNA (HOXD-AS1), MEG3, MALAT1, and HOTAIR, have been implicated in pathways associated with glioma progression and therapeutic resistance. In particular, DANCR has been reported to promote cisplatin resistance in glioma cells through suppression of apoptosis and activation of pro-survival signaling pathways. This review summarizes current evidence regarding the roles of lncRNAs in cisplatin resistance, highlighting mechanisms such as regulation of drug transport, DNA damage repair, apoptosis, cancer stem-cell maintenance, and signaling pathways associated with treatment adaptation. We also discuss current limitations, challenges for clinical translation, and gaps in the existing evidence. A better understanding of lncRNA-mediated resistance mechanisms may facilitate the identification of novel therapeutic targets and inform future studies aimed at overcoming cisplatin resistance in malignant gliomas. Full article

Background: Abdominal aortic aneurysm (AAA) remains an important cause of cardiovascular mortality in the United States despite advances in screening, surveillance, and aneurysm repair. Contemporary national analyses evaluating long-term AAA mortality trends across demographic and geographic subgroups remain limited, particularly following the COVID-19 pandemic period. Objective: To evaluate temporal trends in AAA-related mortality among U.S. adults aged ≥ 65 years from 1999 to 2024 and characterize demographic and geographic disparities. Methods: A retrospective population-based study was conducted using the CDC WONDER Multiple Cause of Death database. AAA-related deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes I71.3 and I71.4. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Mortality trends were stratified by sex, age, race/ethnicity, census region, and urbanization status. Joinpoint regression analysis was used to estimate annual percent change (APC) and average annual percent change (AAPC). Results: Between 1999 and 2024, a total of 208,476 AAA-related deaths among U.S. adults aged ≥ 65 years were recorded. Overall AAMR declined significantly from 32.61 per 100,000 population in 1999 to 12.17 per 100,000 population in 2024 (AAPC −3.86%; 95% confidence interval [CI]: −4.43 to −3.30; p < 0.001). Mortality rates remained consistently higher among males, adults aged ≥ 85 years, non-Hispanic White individuals, residents of the Midwest, and non-metropolitan populations. Joinpoint analysis demonstrated sustained declines across most demographic groups. Although several subgroups exhibited a temporary plateau in declining mortality trends during the pandemic era, these trend changes did not reach statistical significance. Following 2021, mortality rates resumed a significant downward trend. Conclusions: AAA-related mortality among U.S. adults aged ≥ 65 years declined substantially between 1999 and 2024; however, important demographic and geographic disparities persist. Continued efforts aimed at risk factor reduction, equitable screening access, and preventive vascular care remain essential to further reduce AAA-related mortality among older adults. Full article

This article offers a case-illustrative socio-legal analysis of five decisions of German ordinary courts concerning Muslim prayer and halal food in prison, Islam-coded public performance in urban space, minority community mediation in criminal justice and male circumcision as a ritual controversy involving Muslim and Jewish communities. Building on comparative work on “moderate secularism” and using cases identified through the CUREDI database, it develops a focused account of selective secularism by examining how courts translate minority claims into legal categories within Germany’s formally cooperative framework for governing religion. The analysis distinguishes this wider Christian-centred recognition architecture from the more specific legal and institutional baselines operative in the selected disputes. Within this framework, the argument examines how, in the selected decisions, minority practices are assessed through arena-specific legal standards and institutional routines presented within legal reasoning as neutral, administrative or secular, including security, public order, ordinary institutional diet, restorative justice, bodily integrity and child welfare. Non-religion is approached as an implicit baseline within disputes legally framed as religious. The article contributes to debates on Islam and religious diversity in Germany by analysing prison accommodation, urban public order, criminal mediation and bodily-integrity controversies together. It shows how each legal arena defines what counts as ordinary, which minority claims require justification, and which forms of accommodation or restriction become possible. It argues that, across these decisions, minority claims receive less restrictive legal treatment when they can be translated into goals legible to state institutions, such as order, repair, child welfare or regulated inclusion. Full article

Thrombospondin-2 (TSP-2) is an extracellular matrix glycoprotein involved in angiogenesis, vascular remodeling, cell adhesion, and tissue repair. Its expression is induced by pathological stimuli, including mechanotransduction, hypoxia, and TGF-β signaling, and has been associated with several cardiovascular diseases (CVDs), such as heart failure, coronary artery disease, abdominal aortic aneurysm, and hypertension. Elevated circulating TSP-2 levels, particularly in combination with NT-proBNP, as well as alterations in THBS2 and its regulatory non-coding RNAs, have been linked to disease severity and adverse cardiovascular outcomes. This review summarizes current evidence on the role of TSP-2 in cardiovascular pathophysiology and its involvement in cardiovascular homeostasis. Although accumulating data suggest that TSP-2 may have diagnostic, prognostic, and therapeutic relevance, its clinical utility as a biomarker or therapeutic target has not yet been established. Further large-scale studies and standardized assessment methods are required to validate its potential and support future clinical translation. Full article

The multifaceted oncogenic role of teratocarcinoma-derived growth factor 1 (TDGF1) in colon cancer remains incompletely understood. Through integrative bioinformatic and functional analyses, we identified a novel competing endogenous RNA (ceRNA) axis wherein the long non-coding RNA OLMALINC directly sponges hsa-miR-3614-5p, leading to the derepression of TDGF1. This OLMALINC/miR-3614-5p/TDGF1 axis promoted colon cancer cell proliferation, migration, invasion, and anti-apoptosis in vitro, whereas TDGF1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, TDGF1 co-activated oncogenic signaling via the Thr88-dependent Nodal/Smad2 cascade and the Glypican-1-mediated MAPK/AKT pathway. Beyond cell-autonomous effects, transcriptomic and single-cell analyses revealed that elevated TDGF1 correlates with an immunosuppressive microenvironment, characterized by reduced immune infiltration and altered LGALS9-CD44 malignant-T cell communication. Clinically, high TDGF1 expression in a tissue microarray cohort was significantly associated with advanced T stage, reduced expression of specific mismatch repair proteins (MLH1/PMS2), and poor overall survival. Collectively, this study delineates the OLMALINC/miR-3614-5p/TDGF1 regulatory circuit and establishes TDGF1 as a multifaceted driver of tumor progression, highlighting its potential as a prognostic biomarker and therapeutic target in colon cancer. Full article

This study conducts a comparative analysis of surgical outcomes in patients who underwent FSF repair by a plastic surgeon versus an ENT using a national database. A retrospective analysis was conducted on patients who underwent surgical treatment of FSFs by a plastic or ENT surgeon using the de-identified American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Patients were identified based on surgical CPT codes. Data extracted included primary surgeon specialty and patient demographics, comorbidities, and surgical outcomes. Statistical analysis was performed using Fisher’s Exact test and the Wilcoxon Rank-Sum test, with a p-value < 0.05 representing statistical significance. A total of 111 patients were analyzed, of which 85.6% were male. The mean age was 30.0 years [22.0, 48.0]. There were 70 patients (63.1%) treated by an ENT and 41 (36.9%) by a plastic surgeon. The median operative time was 131.0 min for ENT and 115.0 min for plastic surgery (p = 0.19). The median length of postoperative stay was 1.0 day for both groups. Postoperative complications included surgical site infection (SSI), wound disruption, and sepsis in five patients (4.5%). There was no statistically significant difference in the rate of complications between patients who underwent surgery with an ENT surgeon versus a plastic surgeon (p = 0.16). There were no statistically significant differences in operative time, length of stay, or complications between patients who underwent FSF repair by an ENT or by a plastic surgeon. Surgeon specialty training does not appear to influence intraoperative or postoperative outcomes. Studies with larger sample sizes may demonstrate statistically significant differences in outcomes. Full article

Background/Objectives: Cervical cancer is mainly driven by persistent infection with high-risk human papillomaviruses (HPV), particularly HPV16 and HPV18. Despite advances in cytology, HPV-DNA testing and vaccination, challenges remain in the triage of HPV-positive individuals, prognostic stratification and prediction of treatment response. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, together with host genetic factors influencing ncRNA expression and emerging lncRNA-encoded peptides, are increasingly recognized as regulators of HPV-associated carcinogenesis. This review summarizes their biological and potential clinical relevance. Methods: A structured literature search was conducted in PubMed and Scopus. Eligible studies included experimental, clinical, observational, genomic and translational investigations on ncRNA dysregulation, circulating or exosomal ncRNAs, treatment-response signatures, host genetic variation and lncRNA-encoded peptides in HPV-associated cervical precancer and cancer. Results: HPV oncoproteins can reshape host ncRNA networks through transcriptional and epigenetic mechanisms. Several miRNAs, lncRNAs and circRNAs are involved in cell-cycle control, apoptosis, senescence, epithelial–mesenchymal transition, immune regulation, DNA repair and treatment resistance. Circulating, exosomal and urinary ncRNA signatures have shown diagnostic or prognostic potential in exploratory cohorts. Specific lncRNAs, including ENSG00000267838/lnc-LENG9-5 and lncRNA-EME1, have been associated with chemoradiotherapy response and radioresistance. The lncRNA-encoded peptide TUBORF represents a novel preclinical therapeutic candidate, while genetic variation may further modulate lncRNA function in HPV-related cervical cancer. Conclusions: ncRNAs are promising candidates for risk stratification, non-invasive diagnosis, treatment-response prediction and therapeutic development in HPV-associated cervical disease. However, evidence remains exploratory, requiring prospective multicentre validation and standardized workflows before clinical implementation. Full article

Multimodal large language models can read architectural images and design instructions but they still struggle to turn architectural rules into editable, executable models in professional modeling environments. To address this limitation, this paper presents MLLMto3D, an MCP-driven closed-loop framework that connects multimodal reasoning with Rhino-based modeling, feedback, and revision. The framework consists of five phases: visual parsing, JSON-based intent serialization, code synthesis, MCP-driven Rhino execution and feedback, and verification with bounded repair. Its core mechanism is JSON-based intent serialization, which converts image-derived architectural information into machine-readable modeling parameters under a predefined JSON schema. The schema separates geometric and compositional constraints, including height, bay rhythm, facade zones, and alignment rules, from design variables such as materials, openings, and ornament. Building on this mechanism, Skills modules externalize facade typology knowledge and safe Rhino scripting patterns, providing callable professional constraints for code synthesis to reduce design-intent deviation and API hallucination. The framework is evaluated through an experimental design case study on a site in Shanghai’s Hengfu Historic District, where the generation of new façades is informed by a nearby heritage architectural reference. The results show that MLLMto3D can generate a parametrically adjustable Rhino model while preserving the main compositional constraints, thereby advancing AI-assisted architectural 3D generation toward a controllable, verifiable, and iterative modeling process. Full article

Background: Oral squamous cell carcinoma (OSCC) remains a major public health challenge, particularly in South Asian populations where environmental exposures such as tobacco and areca nut consumption contribute significantly to disease burden. Although genomic studies have improved understanding of oral cancer biology, population-specific genomic data from high-risk Indian populations remain limited. This study aimed to characterize the genomic landscape of OSCC using whole-exome sequencing (WES) of fresh biopsy specimens obtained from patients residing along the southwest coast of Karnataka, India. Methods: Paired tumor and adjacent normal tissues from ten OSCC samples (total n = 20 samples) were subjected to WES to identify somatic and germline-associated variants. Matched tumor–normal comparative analysis, variant annotation, and population frequency assessment using established genomic databases, including gnomAD, were performed to characterize the mutational profile. The findings were further compared with a previously analyzed regional cohort comprising 66 OSCC patients to evaluate recurrence patterns and population relevance. Results: The analysis identified a broad background of recurrent germline-associated variants alongside a comparatively limited number of tumor-specific somatic mutations, consistent with the expected predominance of constitutional genetic variation relative to acquired coding alterations in tumor samples. Recurrent variants were observed in genes associated with DNA repair, immune signaling, inflammatory responses, and pharmacogenomic pathways, including XRCC1, ITPKB, ABCB1, and OPRM1, whereas somatic alterations were primarily detected in established cancer-associated genes such as TP53, CDKN2A, and TERT. Conclusions: Several recurrent variants demonstrated high frequencies in South Asian populations, suggesting that they may represent recurrent population-associated variants of potential biological or pharmacogenomic relevance that require validation in larger cohorts. KEGG pathway enrichment analysis identified pathways related to cancer, chemical carcinogenesis, metabolic regulation, and xenobiotic response. Overall, these findings provide preliminary insights into the population-specific genomic characteristics of OSCC in this regional cohort and highlight the need for larger validation studies to determine the biological significance and reproducibility of these findings. Full article