Search Results (556)

Generative adversarial networks (GANs) are increasingly applied to mitigate extreme class imbalance in intrusion detection systems, yet reported improvements often obscure role augmentation intensity and adversarial stability. This paper presents a controlled ablation study that isolates the impact of adversarial objective choice, augmentation ratio, and training duration on GAN-based minority data augmentation for highly imbalanced tabular cybersecurity data. Using the UWF-ZeekData22 dataset, nine MITRE ATT&CK tactic-versus-benign classification tasks are evaluated under augmentation ratios of 0.25 and 0.50 and training durations of 400 and 800 epochs. Four GAN variants—Vanilla GAN, Conditional GAN (cGAN), WGAN, and WGAN-GP—are assessed using stratified cross-validation and five classical classifiers representing diverse inductive biases. The results reveal consistent structural patterns. Moderate augmentation (r = 0.25) with controlled training (400 epochs) yields the most stable and reliable improvement in minority recall. Wasserstein-based objectives demonstrate superior stability under aggressive augmentation and prolonged training, while conditional GANs frequently exhibit recall collapse in ultra-sparse regimes. Increasing augmentation volume does not uniformly improve performance and may introduce distributional overlaps that degrade linear and margin-based classifiers. Tree-based classifiers remain largely invariant once sufficient minority density is achieved. These findings demonstrate that adversarial calibration is more important than architectural complexity for improving the detection of rare attacks. The study provides practical guidance for designing robust GAN-based augmentation pipelines under extreme cybersecurity class imbalance. Full article

Pancreatic cancer (PC) is a highly aggressive malignancy characterized by limited opportunities for early diagnosis and poor clinical outcomes, underscoring the need for minimally invasive biomarkers to improve detection and patient stratification. Given emerging evidence that mitochondrial DNA (mtDNA) alterations reflect cancer-related biological processes, this study investigated whether blood-derived mtDNA profiles could provide clinically relevant information in PC. In this exploratory study, whole-blood mtDNA from 33 PC patients and 10 healthy individuals were analyzed using next-generation sequencing to assess single-nucleotide variants (SNVs), allele frequencies, and mtDNA copy number. A total of 252 unique mtDNA SNVs were identified, including variants exclusive to PC patients, variants unique to controls, and variants shared between groups. While the overall SNV burden did not differ significantly between groups, PC patients showed distinct mutation distributions and allele frequency patterns, with cancer-exclusive variants occurring predominantly at low allele frequencies. Mutation hotspots were observed in the ND5, COI, and D-loop regions, implicating genes involved in oxidative phosphorylation and mtDNA maintenance. Although mtDNA copy number did not differ significantly between groups, greater variability was observed among PC patients and was associated with differences in survival outcomes. Overall, these findings indicate that blood-based mtDNA profiling captures biologically relevant variation associated with PC and supports further development of integrated mtDNA-based approaches for improved risk assessment and patient stratification. Full article

Patients with nephronophthisis caused by nephrocystin 3 (NPHP3) variants rapidly progress to end-stage kidney disease. However, existing Nphp3 mouse models fail to fully recapitulate the characteristics of this disease. We generated a renal tubule-specific Nphp3 knockout mouse model that more accurately mirrors the human disease course. The mouse model was first validated by confirming the loss of Nphp3 protein expression in renal tubules. Comprehensive phenotypic analyses were then performed to assess both renal and extrarenal manifestations. The origin of renal cysts was investigated, and the underlying mechanisms were further validated. We successfully generated a renal tubule-specific Nphp3 knockout mouse model (Cdh16-Cre; Nphp3^flox/flox). These mice exhibited a markedly shortened lifespan (5–8 weeks) and developed key features of infantile nephronophthisis, including early-onset renal cysts originating from distal tubules and collecting ducts, progressive interstitial fibrosis that was evident by postnatal week 2, a rapid decline in kidney function, and increased urinary protein levels. Importantly, treatment with the vasopressin V2 receptor antagonist tolvaptan or the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040) significantly attenuated cyst growth and improved kidney morphology, confirming shared pathogenic pathways with other Nphp3 models. We established a renal tubule-specific Nphp3 knockout mouse model that accurately recapitulates the aggressive infantile form of nephronophthisis characterized by early cystogenesis, progressive fibrosis, and a shortened lifespan, and is ideal for evaluating novel interventions against this currently untreatable ciliopathy. Full article

Background/Objective: Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. Methods: We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. Results: MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell–matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (ANO4) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in ANO4 was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced ANO4 expression levels in prostate cancer tissues and improved survival in patients with high ANO4 expression levels. Pathway analyses linked low ANO4 expression levels with enhanced cell cycle activity and compromised cell adhesion. Conclusions: Our findings suggest that ANO4 may act as a mediator of MEHP-associated prostate cancer progression and support a gene–environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease. Full article

Optimal surgical scheduling necessitates a strategic balance between elective efficiency and responsiveness to stochastic emergency arrivals. This study evaluates a Genetic Algorithm alongside discretized variants of Particle Swarm Optimization, the Secretary Bird Optimization Algorithm, and the Mantis Shrimp Optimization Algorithm. These algorithms are assessed within a dynamic three-stage flexible flow shop model under no-buffer blocking constraints. Findings from 300 Monte Carlo replications demonstrate that while the Genetic Algorithm achieves peak global efficiency, discretized bio-inspired algorithms reach a comparable statistical efficiency frontier. Notably, the discretized Secretary Bird Optimization Algorithm facilitates superior emergency integration by maintaining natural capacity buffers, whereas the aggressive local optimization characteristic of alternative methods often triggers resource saturation in recovery units. These results indicate a potential recovery of 90 annual operating hours per theater.These results indicate a potential recovery of 90 annual operating hours per theater, representing a 6.7% increase in resource utilization efficiency. This improvement provides a critical data-driven capacity margin to mitigate the non-prioritized (Non-GES) surgical backlog in Chilean public hospitals. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare, clinically heterogeneous neoplasms with rising incidence linked to improved diagnostics. This review examines pNET management, addressing epidemiology, classification, diagnosis, treatment, and emerging therapies. Epidemiologically, pNETs show higher prevalence in Western populations, with emerging associations to metabolic disorders. The 2022 WHO classification highlights distinct prognoses for well-differentiated NETs versus poorly differentiated NECs, guided by Ki-67 and mitotic indices. Non-functional tumors often present late, while functional variants manifest hormonal syndromes, necessitating tailored approaches. Advanced imaging (contrast-enhanced CT/MRI, ⁶⁸Ga-DOTATATE PET) and endoscopic ultrasound-guided biopsy enable precise localization and grading. Surgical resection remains curative for localized disease, with minimally invasive techniques reducing morbidity. Active surveillance is favored for small (<2 cm), low-grade, non-functional tumors, while larger or aggressive lesions require resection. Systemic therapies, including mTOR inhibitors (everolimus), anti-angiogenics (surufatinib), and peptide receptor radionuclide therapy (PRRT), extend survival in advanced cases, though immunotherapy efficacy remains limited. Future strategies emphasize molecular profiling, biomarker development, and multidisciplinary integration to optimize outcomes. This evolving paradigm prioritizes precision medicine, balancing oncologic control with quality of life and functional preservation. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a chief cause of cancer-related mortality throughout the world. SIRT6 is a fundamental sirtuin that governs several disease processes encompassing inflammation and cancer, including HCC. Longevity in centenarian Ashkenazi Jews was recently associated to novel allelic variants of SIRT6 (N308K/A313S), which ameliorate genome maintenance and DNA repair, and suppress cancer cells. It is currently unknown whether the above-mentioned SIRT6 variants display divergent or similar roles in HCC pathogenesis, compared to the wild-type (WT) counterpart. Methods: Our goal was to elucidate how these new centenarian-associated SIRT6 genetic variants may modulate HCC cell lines’ (HepG2 and Huh-7) aggressiveness and behavior, using functional and transcriptomic approaches. Results: We demonstrate that adeno-associated virus (AAV2/8)-mediated overexpression of centenarian-associated SIRT6 variants hampered HCC cell proliferation, with transcriptomic data showing the modulation of hallmark genes involved in the turnover of collagen/extracellular matrix (ECM). In addition, we found that AAV2/8-mediated overexpression of SIRT6 N308K/A313S decreased invasion and also increased stiffness in HCC cells, as measured by nanoindentation, in a more pronounced fashion compared to SIRT6 WT. Intracellular stiffness is a property of the cancer cells themselves, which, along with ECM invasiveness, plays a significant role in the progression of HCC. Conclusions: These data suggest that increased intracellular stiffening mirrors increased cell motility and invasive behavior; it can be indicative of suppressed cancer development and progression by the centenarian-associated SIRT6 N308K/A313S mutant. Full article

Background/Objectives: Aggressive variants of prostate cancer pose significant diagnostic and prognostic challenges due to atypical imaging appearances, variable prostate-specific antigen behavior, and distinct molecular features. Conventional imaging may underestimate their biological aggressiveness. This review aimed to synthesize current evidence on imaging characteristics, biomarker dynamics, tumor localization, histology, and radiomic features of aggressive prostate cancer variants, and to evaluate the potential role of radiomics in early recognition and risk stratification. Methods: A structured narrative review was performed of studies reporting imaging, clinical, and molecular features of aggressive prostate cancer variants. Imaging modalities included multiparametric magnetic resonance imaging, positron emission tomography with prostate-specific membrane antigen or fluorodeoxyglucose, bone scintigraphy, and transrectal ultrasound. Data on prostate-specific antigen levels and kinetics, intraprostatic tumor location, tumor size, metastatic patterns, and molecular alterations were extracted. Evidence for rare entities such as basaloid and primary squamous carcinomas was derived from published case reports and series, while selected variants were complemented by institutional imaging and histopathologic observations. Results: Neuroendocrine and small cell carcinomas frequently showed low prostate-specific antigen levels, high fluorodeoxyglucose uptake, low prostate-specific membrane antigen expression, and central or transitional zone involvement with large tumor size at diagnosis. Ductal adenocarcinoma demonstrated marked diffusion restriction and elevated prostate-specific antigen, whereas basal cell carcinoma often appeared inconspicuous on conventional imaging. Radiomic analysis consistently captured tumor heterogeneity and spatial complexity beyond standard qualitative metrics. Conclusions: Aggressive prostate cancer variants represent a diagnostic blind spot in routine imaging. Radiomics offers complementary quantitative information that may improve early detection, subtype differentiation, and risk stratification when integrated into multimodal imaging workflows. Further prospective and radiogenomic studies are warranted to validate these findings. Full article

Background/Objectives: Micropapillary urothelial carcinoma of the urinary bladder (MPUC) represents a rare but highly aggressive histological variant of urothelial carcinoma (UC), frequently presenting at an advanced stage of disease. Although data on histological variants consistently suggest inferior oncological outcomes, the independent prognostic role of the micropapillary variant remains controversial. Methods: The present work synthesizes the findings of a large meta-analysis evaluating histological variants of UC and a separate meta-analysis focusing exclusively on MPUC, and further examines the most recent cohort-based evidence published between 2016 and 2025. Results: The presence of any histological variant in UC treated with radical cystectomy is associated with significantly worse recurrence-free survival, disease-specific survival, and overall survival, as reflected by pooled hazard ratios (HRs). For the micropapillary variant specifically, a modest increase in overall mortality has been demonstrated (pooled HR ≈ 1.20); however, results from adjusted analyses dedicated to MPUC remain inconsistent. Conclusions: Micropapillary urothelial carcinoma is consistently associated with adverse pathological features and poorer oncological outcomes. However, whether micropapillary morphology independently predicts prognosis beyond established factors such as pathological stage and nodal status remains uncertain, as adjusted analyses across studies have yielded inconsistent results. Part of the observed survival disadvantage may be explained by stage migration, although an intrinsic residual risk cannot be definitively ruled out. This review integrates contemporary population-based registry analyses with prior meta-analytic evidence to provide a clinically oriented synthesis of the prognostic and therapeutic implications of MPUC. In addition, we propose minimal reporting standards aimed at improving comparability across future studies and strengthening risk stratification and treatment decision-making. Full article

Background/Objectives: Colorectal cancer (CRC) liver metastases present a significant clinical challenge due to high recurrence risks post-resection. Traditional diagnostics often fail to detect early-stage minimal residual disease (MRD). This preliminary pilot study evaluated ctDNA dynamics in 10 patients with liver metastases using a personalized multistep approach. Methods: Following primary tumor Next-Generation Sequencing (NGS) to identify somatic mutations in KRAS, NRAS, TP53, RET, APC, and WRN, custom TaqMan assays were designed for longitudinal plasma analysis. Four methodologies were compared: HRM-PCR, PNA-enhanced qPCR, and two digital platforms (dPCR and ddPCR). Results: While HRM-PCR sensitivity was limited in plasma, digital platforms demonstrated 100% qualitative concordance. MRD-negative status (VAF 0.00%) was identified in 70% of cases (P01, P03, P06, P07, P08, P09, P10), while detectable ctDNA in patients P02, P04, and P05 strongly correlated with aggressive progression. Digital PCR enabled the ultra-low detection of Variant Allele Frequencies (VAFs), identifying high molecular burdens (e.g., P05, VAF 49%) correlating with rapid decline, and capturing early molecular residue in P04 (VAF 0.62%). Conclusions: Our preliminary findings confirm that personalized longitudinal VAF tracking via digital PCR provides superior prognostic value, serving as a robust tool for recurrence monitoring in personalized CRC therapy. Full article

Caudal type homeobox 2 (CDX2) is an intestine-specific transcription factor that serves as a diagnostic marker of enteric differentiation and may also reflect tumor behavior and therapeutic susceptibility. Emerging evidence suggests that CDX2 expression may predict sensitivity to fluoropyrimidine-based therapy independent of tissue of origin. We report a retrospective case series of three patients with metastatic adenocarcinoma (aggressive variant prostate, minor salivary gland, and intestinal-type sinonasal tract) exhibiting strong CDX2 nuclear expression. In all cases, tumors were refractory to or lacked established standard systemic therapy. Treatment decisions were informed by the CDX2-positive enteric phenotype, leading to the initiation of fluoropyrimidine-based regimens. Response was assessed using PET-CT and MRI. All three patients achieved marked metabolic and clinical responses, including a sustained complete metabolic response in the prostate cancer case and durable disease control in the salivary gland and sinonasal tumors. These findings highlight CDX2 as a potential biomarker requiring validation, which may identify tumors intrinsically susceptible to fluoropyrimidines regardless of anatomical origin. CDX2 immunohistochemistry is widely available and inexpensive, and may complement genomic profiling in rare malignancies or in settings where standard treatment algorithms are limited. This report is hypothesis-generating and not intended to estimate response rates or treatment efficacy. Full article

In recent years, several studies have highlighted the ability of malignant cells to use acetate as an alternative energy and biosynthetic source to glucose. In this context, the present study aimed at characterizing the expression profile of genes involved in acetate metabolism in thyroid carcinomas. To this end, we analyzed molecular and clinical data from 496 papillary thyroid cancers (PTCs) and 59 normal thyroid tissues from The Cancer Genome Atlas (TGCA). In addition, we examined 57 PTCs and matched normal tissues, and six anaplastic thyroid carcinomas (ATCs) collected in our institutions, using real time RT-PCR. The results show a downregulation of ACSS1, ACSS2, ACACB, PDHA1, SLC16A3 and SLC16A7 genes in PTCs compared with normal tissues, some of which were significantly lower in BRAF-mutated tumors, the more aggressive tall cell variant, and larger and/or metastatic PTCs. Overall, these findings point to a reduction in mitochondrial oxidative pathways that was more evident in advanced or aggressive disease forms. In ATCs, ACSS2 was the only upregulated gene, suggesting further tumor adaptation to the metabolic stress of rapidly growing cancers. In conclusion, our study demonstrates a dysregulated expression pattern of multiple genes involved in acetate metabolism, which could be exploited for the development of new therapeutic strategies. Full article

Anaplastic thyroid carcinoma (ATC) is an aggressive and lethal malignancy that carries a poor prognosis. Moreover, there are limited therapeutic options for managing ATC. There is increasing evidence that implicates the role of cancer stem cells (CSCs) in the processes of dedifferentiation in the progression, therapeutic resistance, and metastatic potential of ATC. In this review, we integrate the molecular and cellular insights into the CSCs paradigm in ATC to highlight the role of stemness-associated markers that include CD44, CD133, and ALDH1. We put special emphasis on the role of CD44 and its variant isoforms (CD44v), which play a role in the interface of cancer stemness, tumour microenvironment crosstalk, modulation of epithelial–mesenchymal transition (EMT), chemoresistance, and metastasis. The contribution of signalling pathways (PI3K/AKT/mTOR, MAPK, Notch, Wnt/β-catenin, and Hedgehog) to hypoxia, cancer-associated fibroblasts (CAFs), and tumour-associated macrophages (TAMs) in sustaining CSC niches will be discussed. The review explores advances in molecular diagnostics, imaging technologies, and targeted therapeutic strategies with the potential to disrupt CSC-driven tumour maintenance. Through integration of multigenic, epigenetic, and microenvironmental perspectives, this review highlights the potential necessity of CSC-targeted and combination therapies to improve disease outcomes in ATC. Full article

Programmed death-ligand 1 (PD-L1) has become a central biomarker and therapeutic target across multiple solid tumors, yet its clinical meaning in prostate cancer (PCa) remains unsettled. PCa is commonly described as an immunologically ‘cold’ malignancy, characterized by limited baseline cytotoxic T-cell infiltration and a tumor microenvironment (TME) shaped by myeloid-driven suppression and low neoantigen load in many cases. Against this background, PD-L1 expression in PCa is typically low in untreated primary tumors but can increase in aggressive variants, advanced stages, and metastatic castration-resistant disease, where therapy pressure and microenvironmental cues may select for immune-evasive phenotypes. The literature is further complicated by major analytic variability, including differences in antibody clones and platforms, scoring algorithms (tumor proportion score, combined positive score, immune-cell scoring), cut-offs, tissue sites and timing, and pre-analytical variables such as fixation and decalcification. Collectively, available studies suggest that higher PD-L1 expression tends to be associated with adverse clinicopathological features and may enrich for responses to immune checkpoint inhibitors in selected settings, but PD-L1 immunohistochemistry alone is insufficient as a stand-alone predictive tool in unselected patients. This review synthesizes the biological drivers of PD-L1 regulation in PCa, dissects key methodological sources of heterogeneity in PD-L1 assessment, summarizes clinicopathological and therapeutic correlations, and outlines emerging biomarkers and approaches (including mismatch repair deficiency/microsatellite instability, tumor mutational burden, gene-expression signatures, liquid biopsies, and neuro-immune interactions) that may enable more actionable patient stratification. Full article

Background and Clinical Significance: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that may arise through dedifferentiation from pre-existing differentiated thyroid carcinomas. The tall cell subtype of papillary thyroid carcinoma (TC-PTC) represents an aggressive variant that has been involved in this tumor progression pathway. Case Presentation: We report on a rare case of ATC developed in association with a high-grade TC-PTC. A 67-year-old man presented with an enlarging anterior cervical mass. Imaging identified a suspicious nodule in the right thyroid lobe, and total thyroidectomy was performed. Histologic examination revealed a biphasic tumor composed of a nodular TC-PTC with high-grade features, contiguous with an infiltrative anaplastic carcinoma component. The anaplastic component showed marked pleomorphism, loss of thyroid differentiation markers, and an increased ki67 proliferation index. Multinucleated giant cells exhibited aberrant CD68 expression, without proliferative activity. Conclusions: This case illustrates the morphologic association between tall cell papillary thyroid carcinoma with high-grade features and anaplastic thyroid carcinoma, emphasizing diagnostic considerations within the framework of the WHO 5th edition classification. Full article