Search Results (6,698)

Bladder cancer (BC) is a biologically heterogeneous tumor affected by genetic, metabolic, environmental, and lifestyle factors. Recent research indicates that nutrition can change the way urothelial cancer forms by affecting inflammation, oxidative stress, cellular energy, and the epigenome. It can also change the risk of BC and how well treatment works. Simultaneous progress in precision nutrition (PN) and nutriomic profiling—encompassing nutrigenomics, nutrigenetics, nutriepigenetics, metabolomics, and microbiome science—presents novel options to tailor dietary regimens beyond universal guidelines. In this review, we consolidate existing knowledge regarding the nutritional factors influencing BC, outline pertinent principles of PN for BC prevention and survival, and explore how urine proteomics and molecular subtyping facilitate the integration of PN into precision oncology. Our review examines the methodological, bioinformatic, biomarker, and clinical translation challenges that impede the implementation of PN in BC management; these challenges include the need for validated nutritional biomarkers with mechanistic endpoints, interoperable data platforms, and rigorously designed clinical trials. Finally, we emphasize future prospects for PN-guided medical nutrition therapy and dietary models during and after systemic treatment recovery. We propose research priorities that will facilitate the integration of PN-informed individualized dietary plans with medical and surgical approaches in BC treatment, aiming to decrease the costs associated with expensive or excessively aggressive treatment methods, thereby supporting long-term survival care. This review seeks to establish a conceptual framework for the integration of PN into BC management by delineating the opportunities and challenges, hence promoting hypothesis-driven research in a promising yet underexplored domain. Full article

Background: Pituitary neuroendocrine tumors (PitNETs) are a core manifestation of multiple endocrine neoplasia type 1 (MEN1), yet their true prevalence, biological behavior, and optimal management remain debated. Earlier reports suggested increased aggressiveness compared with sporadic PitNETs, while more recent surveillance-based studies indicate a predominantly indolent phenotype. Methods: We conducted a retrospective single-center study including all patients with clinical, familial, or genetic MEN1 referred to the Endocrinology Unit of the University of Naples “Federico II”, ENETS Center of Excellence, between January 2004 and June 2025. Demographic, clinical, radiological, hormonal, and therapeutic data were systematically collected. PitNETs were classified by size and hormonal activity. Results: Among 103 MEN1 patients (61 women), 50 (48.5%) were diagnosed with PitNETs at a mean age of 35.1 years. Microadenomas predominated (60%), and tumors were equally distributed between functioning and non-functioning lesions. Prolactin-secreting PitNETs were the most common functioning subtype (42%), followed by rare GH-, ACTH-, or mixed-secreting PitNETs. Dopamine agonists, mainly cabergoline, were prescribed in 38% of cases, while neurosurgical intervention was required in 14%, exclusively for macroadenomas. During follow-up, recurrence occurred in 8% of patients. No significant sex-related differences were observed in prevalence, tumor size, functional status, treatment approach, or outcomes. Conclusions: In our MEN1 cohort, PitNETs were frequent but largely indolent, with a predominance of microadenomas and limited need for surgery. Our findings support individualized, subtype-driven surveillance strategies, with conservative management for clinically non-functioning microadenomas and closer monitoring of prolactin-secreting PitNETs due to variable medical responsiveness. Full article

Pathogens causing candidiasis encompass a diverse group of ascomycetous yeasts that have become essential models for studying fungal adaptability, pathogenicity, and host–pathogen interactions. Although many candidiasis-promoting species exist as commensals within host microbiota, several have acquired virulence traits that enable opportunistic infections, positioning them as a leading cause of invasive fungal disease in humans. Deciphering the molecular and genetic determinants that underpin the biology of organisms responsible for candidiasis has long been a central objective in medical and molecular mycology. However, research progress has been constrained by intrinsic biological challenges, including noncanonical codon usage and the absence of a complete sexual cycle in diploid species, which have complicated traditional genetic manipulation. CRISPR-Cas9 genome editing has overcome many of these limitations, providing a precise, efficient, and versatile framework for targeted genomic modification. This system has facilitated functional genomic studies ranging from single-gene deletions to high-throughput mutagenesis, yielding new insights into the mechanisms governing virulence, antifungal resistance, and stress adaptation. Since its initial application in Candida albicans, CRISPR-Cas9 technology has been refined and adapted for other clinically and industrially relevant species, including Nakaseomyces glabratus (formerly referred to as Candida glabrata), Candida parapsilosis, and Candida auris. The present work provides an overview of the evolution of genetic approaches employed in research directed against candidiasis-associated species, with a particular focus on the development and optimization of CRISPR-based systems. It highlights how recent advancements have improved the genetic tractability of these pathogens and outlines emerging opportunities for both fundamental and applied studies in fungal biology. Full article

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from “infection only” to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies. Full article

Cardiovascular health and depression influence each other bidirectionally and negatively, leading to high comorbidity rates, and favouring higher morbidity and mortality. Heart rate variability (HRV) has received much attention as a “biomarker” for major depressive disorder, with studies suggesting its potential both as a diagnostic and as a predictive biomarker. This narrative review offers a first orientation to the evidence base for researchers entering the field. We present and discuss the state-of-the-art evidence of cross-sectional and longitudinal studies (including observational, pharmacological interventions, and non-pharmacological interventions) linking depression and/or depressive symptoms to HRV by highlighting meta-analyses and key studies in the field. We briefly discuss the physiological context for interpretation of HRV and important confounders to consider, including the influence of genetics, age, sex, antidepressant medication, and lifestyle factors. Finally, with this information at hand, we discuss and provide guidance for factors to consider when using HRV in designing a study. Our literature review indicates that while there is potential for vagally mediated HRV to be of value in predicting future depression, more in-depth and stratified research of HRV is beneficial to the field and the understanding of what HRV can mean for depression research. Full article

Background/Objectives: Lynch syndrome (LS), is traditionally managed uniformly despite being caused by pathogenic variants in four distinct mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). This approach fails to leverage gene-specific characteristics for precision healthcare delivery. This review redefines LS as four distinct genetic syndromes and establishes a genotype-guided precision management framework to optimize risk stratification, surveillance, and therapeutic interventions. Methods: We synthesized molecular, clinical, and outcomes data from the Prospective Lynch Syndrome Database (8500+ carriers; 70,000 person-years), genomic studies characterizing gene-specific mutational patterns, and immunotherapy trials while referencing international guidelines [National Comprehensive Cancer Network (NCCN), European Hereditary Tumour Group (EHTG)/European Society of Coloproctology (ESCP), and European Society for Medical Oncology (ESMO)] to formulate genotype-stratified recommendations. Results: Fundamental molecular differences necessitate differentiated management strategies. MLH1 deficiency exhibits unique “two-in-one hit” mechanisms driving aggressive tumorigenesis with high interval cancer rates. MSH2 deficiency presents the highest tumor mutational burden (≈47 mutations per megabase; Mut/Mb) and broadest cancer spectrum. MSH6 deficiency displays distinctive high-single-nucleotide variant (SNV)/low-insertion–deletion (Indel) patterns often presenting as microsatellite instability-low (MSI-low) or microsatellite stable (MSS), complicating conventional detection. PMS2 deficiency demonstrates substantial attenuation due to redundancy. These translate into precision interventions: MLH1/MSH2 carriers require colonoscopy from age 25 at 1–2-year intervals with extended colectomy preferred, while MSH6/PMS2 carriers can defer surveillance to age 35–40 with longer intervals and undergo segmental resection. Immune checkpoint inhibitors (ICIs) are effective in deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors across all four MMR genotypes. Conclusions: Genotype-specific precision management optimizes the benefit–burden balance, enhances early cancer detection, reduces overtreatment, and enables personalized genetic counseling, advancing precision healthcare for LS families and addressing critical gaps in hereditary cancer care. Full article

In genetic disease assessment centers, DNA sequencing can produce results irrelevant to the genetic examination’s purpose. The American College of Medical Genetics and Genomics (ACMG) recommends evaluating and reporting 81 genes discovered using clinical genomic sequencing. While population studies on large cohorts can provide statistics on the prevalence of secondary findings (SFs), no studies have been published yet on large cohorts in Turkiye. We investigated ACMG SF by evaluating clinical exome sequencing data in 1600 individuals from different regions in Turkiye. We detected SF variants reported in ClinVar in 86 individuals (5.375%). Of the SFs, 30% were cardiovascular, 26% were cancer, 16% were neonatal metabolic disorders, and 28% were variants associated with various genetic diseases. In addition, we identified 212 different variants in 226 individuals and 45 different genes, which were not reported in ClinVar. When our results are compared with the Turkish National Genome and Bioinformatics Project database and studies in the literature, the studies vary in terms of participant characteristics, sequencing techniques, and versions of the ACMG SF list. Our findings highlight the importance of expanding and tailoring SF reporting guidelines in populations with high consanguinity and limited cohort-based data. Full article

Breast cancer (BC) remains one of the most prevalent malignancies worldwide, and genetic factors may influence its development. Approximately 10–15% of all BCs are hereditary and known as Hereditary Breast Cancer (HBC). A remarkable family history and young onset are the strongest risk factors of HBC. The rapid development of genetic testing techniques has increased the detection rate of pathogenic and likely pathogenic variants in several genes associated with high, moderate, or low risk of HBC. This allowed us to identify the whole family at risk of HBC. Among hereditary cases, pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are particularly notable, especially in certain populations where founder mutations (specific genetic variants originating from a common ancestor) are more prevalent. In this article, an overview of the current state of knowledge on HBC is provided, focusing on the frequency of founder mutations in the BRCA1 and BRCA2 genes in HBC in Poland compared to other countries. We will also highlight the role of genetic counseling in the diagnosis and treatment of BC, emphasizing its crucial importance in identifying genetic predispositions, selecting appropriate therapeutic strategies, and supporting patients and their families in making informed medical decisions. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with resistance to 5-fluorouracil (5-FU) representing a major therapeutic challenge. Thymoquinone (TQ), a bioactive constituent of Nigella sativa, exhibits anticancer activity; however, the mechanisms underlying TQ-induced cell death appear to be highly context dependent. This study aimed to characterize cell line-specific death pathways triggered by TQ in colorectal cancer models with distinct molecular backgrounds and differential responsiveness to 5-FU. Human CRC cell lines RKO (5-FU-sensitive) and SW1116 (poorly responsive), along with normal colon epithelial cells (CCD-841CoN), were treated with TQ, 5-FU, or their combination for 24 h. Cell viability, DNA fragmentation, caspase-3/7, -8, and -9 activity, cell death phenotypes, and expression of apoptosis- and necroptosis-related genes were evaluated using MTT assays, ELISA, luminescent assays, flow cytometry, and RT-qPCR. TQ significantly reduced viability in both CRC cell lines while exerting minimal cytotoxicity toward normal cells. In RKO cells, characterized by microsatellite instability (MSI), TQ induced DNA fragmentation, caspase activation, and transcriptional upregulation of pro-apoptotic genes, consistent with apoptosis-associated signaling. In contrast, SW1116 cells, which exhibit chromosomal instability (CIN) and reduced responsiveness to 5-FU, displayed decreased viability accompanied by suppressed caspase activity and predominant features of caspase-independent necrotic cell death. This differential response may be attributed to the CIN phenotype, which has been associated with impaired apoptotic signaling and enhanced tolerance to cytotoxic stress. Combined TQ and 5-FU treatment did not produce synergistic cytotoxicity, as confirmed by Bliss independence analysis, but revealed distinct, cell line-dependent death programs. These findings demonstrate that TQ modulates cell death execution in a molecular context-dependent manner rather than enhancing 5-FU efficacy through pharmacological synergy. Full article

Background/Objectives: Cell-free DNA (cfDNA) is a valuable biomarker for cancer diagnosis and therapy monitoring; however, its low abundance and fragmented nature present major challenges for reliable isolation, particularly from limited plasma volumes. Here, we report the development and evaluation of a novel magnetically assisted microfluidic chip with a three-inlet design for efficient cfDNA extraction from small-volume plasma samples. Methods: The platform enables controlled infusion of plasma, lysis buffer, and magnetic nanoparticle suspensions at defined flow rates. An external magnetic field selectively captures cfDNA-bound nanoparticles while efficiently removing background impurities. Results: Direct comparison with two in vitro diagnostic (IVD)-certified commercial cfDNA extraction kits showed that the microfluidic system achieved comparable cfDNA yields at standard plasma volumes and superior performance at reduced input volumes. High DNA purity and integrity were confirmed by quantitative PCR amplification of a housekeeping gene and clinically relevant targets. The complete workflow required approximately 9 min, used minimal equipment, reduced contamination risk, and enabled rapid processing with future potential for parallel multi-chip configurations. Conclusions: These findings establish the proposed microfluidic platform as a rapid, reproducible, and scalable alternative to conventional cfDNA extraction methods. By significantly improving recovery efficiency from small plasma volumes, the system enhances the clinical feasibility of liquid biopsy applications in cancer diagnostics and precision medicine. Full article

Non-traumatic osteonecrosis of the femoral head (ONFH) is a multifactorial disorder in which genetic susceptibility is thought to play an important role, yet the contribution of many candidate genes remains unclear. The catenin beta-1 (CTNNB1) gene encodes β-catenin, a key regulator of the Wnt/β-catenin signaling pathway involved in bone homeostasis and vascular regulation, and may therefore influence susceptibility to non-traumatic ONFH. In this case–control study, genotype data from China Medical University Hospital were analyzed to evaluate the association between CTNNB1 polymorphisms and the risk of ONFH. A total of 609 patients with ONFH and 2436 age- and sex-matched controls were included. Fourteen CTNNB1 single-nucleotide polymorphisms (SNPs) with a minor allele frequency greater than 5% were selected and analyzed using logistic regression under multiple genetic models, with Hardy–Weinberg equilibrium assessed in controls. Two SNPs, rs3774370 and rs11564478, showed significant differences in allele frequencies between cases and controls, with lower minor allele frequencies observed in the ONFH group. Both variants were associated with a reduced risk of ONFH, and these associations remained significant under dominant genetic models. These findings suggest that specific CTNNB1 polymorphisms may confer a protective effect against non-traumatic ONFH and provide further insight into the genetic architecture of this disease. Full article

Background: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by autoimmune-driven inflammation in the central nervous system that damages axons and destroys myelin. It is difficult to diagnose multiple sclerosis due to its complexity, and different people may react differently to different treatments. While the exact cause of multiple sclerosis (MS) and the reasons for its increasing prevalence remain unclear, it is widely believed that a combination of genetic predisposition and environmental influences plays a significant role. Methods: Finding biomarkers for complicated diseases like multiple sclerosis (MS) is made more promising by the emergence of network and system biology technologies. Currently, using tools like Network Analyst to apply network-based gene expression profiling provides a novel approach to finding potential medication targets followed by molecular docking and MD Simulations. Results: There were 1200 genes found to be differentially expressed, with CD44 showing the highest degree score of 15, followed by CDC42 and SNAP25 genes, each with a degree score of 14. To explore the regulatory kinases involved in the protein–protein interaction network, we utilized the X2K online tool. The present study examines the binding interactions and the dynamic stability of four ligands (Obeticholic acid, Chlordiazepoxide, Dextromethorphan, and Hyaluronic acid) in the Hyaluronan binding site of the human CD44 receptor using molecular docking and molecular dynamics (MD) simulations. Docking studies demonstrated a significant docking score for Obeticholic acid (−6.3 kcal/mol), underscoring its medicinal potential. MD simulations conducted over a 100 ns period corroborated these results, revealing negligible structural aberrations (RMSD 1.3 Å) and consistent residue flexibility (RMSF 0.7 Å). Comparative examinations of RMSD, RMSF, Rg, and β-factor indicated that Obeticholic acid exhibited enhanced stability and compactness, establishing it as the most promising choice. Conclusions: This integrated method underscores the significance of dynamic validations for dependable drug design aimed at CD44 receptor-mediated pathways. Future experimental techniques are anticipated to further hone these findings, which further advance our understanding of putative biomarkers in multiple sclerosis (MS). Full article

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by bi-allelic deletions or pathogenic SMN1 variants. Early diagnosis through neonatal screening is essential for timely therapeutic intervention, significantly improving clinical outcomes. In August 2022, a pilot neonatal screening program for SMA was launched in Romania, aiming to assess feasibility and impact. Objectives are to present the preliminary results of the ongoing SMA neonatal screening pilot program in Romania, evaluating its effectiveness in early detection and referral for treatment. The program started in August 2022 with four maternity hospitals and has progressively expanded to 28 maternity hospitals nationwide. Dried blood spot samples from newborns were analyzed for SMN1 gene deletions using real-time PCR. Positive results were confirmed through genetic testing, and affected infants, along with their families, were referred for further medical evaluation and early therapeutic intervention. Approximately 60,000 newborns have been screened since the program’s inception, and 12 newborns tested positive for SMN1 deletions, resulting in an estimated incidence rate of 1 in 5125 live births. All confirmed cases were promptly referred for specialized care, with early access to disease-modifying therapies. The program has faced challenges in logistics, parental awareness, and equitable access to treatment, but its expansion from 4 to 28 maternities demonstrates increasing feasibility, suitability, and acceptance. Conclusions: The Romanian pilot neonatal screening program for SMA has successfully identified affected infants early, proving its feasibility and clinical impact. The ongoing expansion suggests a strong foundation for a future national program, which could significantly improve early SMA diagnosis and patient outcomes in Romania. Full article

Langer–Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPS II; OMIM #150230), is a contiguous-gene deletion disorder caused by haploinsufficiency of TRPS1 and EXT1. Cornelia de Lange syndrome (CdLS) is genetically heterogeneous; heterozygous variants in RAD21 cause the milder CdLS type 4 phenotype (OMIM #614701). Because RAD21 lies between TRPS1 and EXT1, overlapping phenotypes may arise when all three genes are deleted. We report a unique case of a 4-year-old female presenting with a blended phenotype of Langer–Giedion Syndrome (LGS) and Cornelia de Lange Syndrome (CdLS) type 4. This case is distinct from previously reported 8q deletions in three key aspects: (1) Complex Genomic Architecture: Chromosomal microarray revealed a novel complex rearrangement consisting of a 13.01 Mb mosaic interstitial deletion at 8q23.1–q24.12, flanked by two large duplications (21.5 Mb at 8q11.23–q23.1 and 25.78 Mb at 8q24.12–q24.3). (2) Rare Mosaicism: This represents only the second reported case of mosaicism affecting this contiguous gene region. Notably, the patient demonstrates a “mosaic rescue” effect, where the mosaicism appears to have mitigated the neurodevelopmental phenotype (the patient is bilingual and ambulatory) while failing to protect the skeleton. (3) First Bone-Specific Therapy: The patient suffered from severe, recurrent fractures due to a synergistic “double hit” of TRPS1-related osteopenia and EXT1-related exostoses. We report the first successful use of bisphosphonate therapy (pamidronate) in this specific mosaic profile, which resulted in a complete cessation of fractures during a 12-month follow-up. This case underscores the utility of detailed microarray analysis in complex phenotypes and suggests bisphosphonates as a viable rescue therapy for refractory syndromic osteoporosis. Full article

Purpose: Colorectal cancer (CRC) is a highly aggressive malignancy of the digestive system. Somatic variants in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene have a significant influence on CRC progression and serve as key predictors of resistance to anti-epidermal growth factor receptor (EGFR) therapy. This study aimed to determine the prevalence of KRAS variants, with a particular focus on G12D variants, which represent potential for targeted therapy. Methods: A cohort of 73 CRC patients was evaluated between January 2021 and August 2024. Next-generation sequencing (NGS) was performed using the Archer^® VariantPlex^® Solid Tumor Focus v2 (Integrated DNA Technologies, Inc., Boulder, CO, USA) assay on the Illumina NextSeq platform. The gene panel included 20 genes frequently mutated in solid tumors, assessing point variants, insertions/deletions, and microsatellite instability. Results: The cohort of the study comprised 38 female (52%) and 35 males (48%) patients aged 31–83 years (mean, 58.77 ± 12.72). No significant difference in mean age was observed between males and females (60.31 ± 12.32 vs. 57.34 ± 13.08; p > 0.05). KRAS variants were detected in 30 patients (41%). Among these, the variant frequencies for G12D, G12V, and G13D were 7%, 11%, and 11%, respectively. Additionally, one patient (1.4%) harbored an ERBB2 amplification. All KRAS variants were associated with resistance to anti-EGFR therapy. Notably, KRAS G12D variants have potential responsiveness to targeted therapy, while human epidermal growth factor receptor 2 (ERBB2) amplifications are responsive to anti-HER2 treatments and resistant to anti-EGFR therapies. Conclusions: These findings highlight the clinical significance of KRAS variant profiling for prognosis and personalized treatment planning in CRC. Moreover, assessing KRAS variants individually is crucial to better understanding treatment response and exploring the potential targeted therapy in CRC management. Full article