Search Results (1,835)

Background: Endometriosis is a chronic inflammatory condition affecting 10–15% of women of reproductive age. Genome-wide association studies (GWASs) have accounted for only a fraction of its high heritability, indicating the need for alternative approaches to identify rare genetic variants contributing to its etiology. To this end, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: A multigenerational family was studied, comprising three sisters, their mother, grandmother, and a daughter, all diagnosed with endometriosis. WES was conducted on the three sisters and their mother. We used the enGenome-Evai and Varelect software to perform our analysis, which mainly focused on rare, missense, frameshift, and stop variants. Results: Bioinformatic analysis identified 36 co-segregating rare variants. Six missense variants in genes associated with cancer growth were prioritized. The top candidates were c.3319G>A (p.Gly1107Arg) in the LAMB4 gene and c.1414G>A (p.Gly472Arg) in the EGFL6 gene. Variants in NAV3, ADAMTS18, SLIT1, and MLH1 may also contribute to disease onset through a synergistic and additive model. Conclusions: We identified novel candidate genes for endometriosis in a multigenerational affected family, supporting a polygenic model of the disease. Our study is an exploratory family-based WES study, and replication and functional studies are warranted to confirm these preliminary findings. Full article

Background/Objectives: Non-coding microRNA-34a (miR-34a) regulates the expression of key factors involved in several cellular processes, such as differentiation, apoptosis, proliferation, cell cycle, and senescence. Deregulation of the expression of these factors is implicated in the onset and progression of several human diseases, including cancer, neurodegenerative disorders, and pathologies associated with viral infections and inflammation. Despite numerous studies, the molecular mechanisms regulated by miR-34a remain to be fully understood. The present study aimed to generate miR-34a knockout cell lines to identify novel genes potentially regulated by its expression. Methods: We employed the CRISPR-Cas9 gene editing system to knock out the hsa-miR-34a gene in HeLa and 293T cell lines, two widely used models for studying molecular and cellular mechanisms. We compared proliferation rates and gene expression profiles via RNA-seq and qPCR analyses between the wild-type and miR-34a KO cell lines. Results: Knockout of miR-34a resulted in a decreased proliferation rate in both cell lines. Noteworthy, the ablation of miR-34a resulted in increased expression of the long non-coding RNA MALAT1. Additionally, miR-34a-5p silencing in the A375 melanoma cell line led to MALAT1 overexpression. Conclusions: Our findings support the role of the miR-34a/MALAT1 axis in regulating proliferation processes. Full article

Gastric cancer traditionally affects older adults, and its precursor lesions and risk factors are well-documented in this population. Helicobacter pylori (H. pylori) infection remains highly prevalent in Saudi Arabia and contributes to gastric pathology. However, early-onset gastric cancer (EOGC), diagnosed in individuals aged ≤ 45 years, presents unique challenges and remains poorly understood in young populations. Therefore, we conducted an observational cohort study using a prospective longitudinal design (2021–2024) involving 1823 Saudi nationals aged 18–45 years who underwent zoom high-definition chromoendoscopy to evaluate the prevalence of premalignant gastric lesions (PGLs) and EOGC. We found a high H. pylori prevalence (78.0%) with PGLs in 1.9% of participants and EOGC-adenocarcinoma in 0.7% of patients. All EOGC cases arose from dysplasia, with most PGLs being classified as OLGA/OLGIM stage II/III. Multiple risk factorswere significantly associated with PGLs and EOGC, including H. pylori infection (p = 0.022), increasing age (p < 0.001), a family history of gastric cancer (p < 0.001), poor dietary habits (p < 0.001), obesity (p < 0.001), and smoking (p < 0.001). Additional EOGC risk factors include dage of 36–45 years (p = 0.018), EBV infection (p = 0.016), and diabetes mellitus (p = 0.001). These findings demonstrate the notable presence of PGLs and EOGC in young Saudi adults and emphasize the importance of early detection and risk factor management in this vulnerable population. Full article

Background/Objectives: Chronic inflammation and Western-style diets elevate colorectal cancer (CRC) risk, particularly in individuals with colitis, a feature of inflammatory bowel disease (IBD). Diets rich in polyphenol-containing functional foods, such as cocoa, may reduce gut inflammation and modulate the gut microbiome. This study investigated the impact of cocoa polyphenol (CP) supplementation on inflammation and microbiome composition in mice with colitis, fed either a healthy or Western diet, before, during, and after the onset of disease. We hypothesized that CPs would attenuate inflammation and promote distinct shifts in the microbiome, especially in the context of a Western diet. Methods: A 2 × 2 factorial design tested the effects of the basal diet (AIN93G vs. total Western diet [TWD]) and CP supplementation (2.6% w/w CocoaVia™ Cardio Health Powder). Inflammation was induced using the AOM/DSS model of colitis. Results: CP supplementation did not reduce the severity of colitis, as measured by disease activity index or histopathology. CPs did not alter gene expression in healthy tissue or suppress the colitis-associated pro-inflammatory transcriptional profile in either of the two diet groups. However, fecal microbiome composition shifted significantly with CPs before colitis induction, with persistent effects on several rare taxa during colitis and recovery. Conclusions: CP supplementation did not mitigate inflammation or mucosal injury at the tissue level, nor did it affect the expression of immune-related genes. While CPs altered microbiome composition, most notably in healthy mice before colitis, these shifts did not correspond to changes in inflammatory signaling. Basal diet remained the primary determinant of inflammation, mucosal damage, and colitis severity in this model. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Background/Objectives: Erysipelas is an acute bacterial skin infection, particularly affecting the lower limbs, with a tendency to recur. Despite its clinical importance, data on demographic and epidemiological risk factors, as well as factors influencing hospitalization, remain limited. This study aimed to analyze the epidemiological and clinical characteristics of patients hospitalized with primary and recurrent erysipelas, focusing on risk factors contributing to disease onset, recurrence, and prolonged hospitalization. Methods: A retrospective single-center analysis was conducted on 239 patients hospitalized for erysipelas at the Department of Dermatology, Pediatric Dermatology, and Oncology at the Medical University of Lodz. Data collected included demographics, lesion location, laboratory markers, comorbidities, and hospitalization outcomes. Statistical analyses were performed to assess associations between risk factors, disease recurrence, and hospitalization duration. Results: The majority of erysipelas cases (85.4%) involved the lower limbs, with a higher prevalence in men. Upper extremities were mostly affected in women, especially those who had undergone breast cancer surgery. Recurrent erysipelas accounted for 75.7% of cases. Most patients (89.1%) had at least one comorbidity, with hypertension, diabetes type 2 (DM2), and obesity being the most common. Higher white blood cell (WBC) count, obesity, atrial fibrillation (AF), and the need for enoxaparin administration were independently associated with prolonged hospitalization. Dyslipidemia was significantly associated with erysipelas recurrence (p < 0.05). Conclusions: Both primary and recurrent erysipelas are associated with specific risk factors. Recurrent erysipelas may be linked to components of metabolic syndrome, particularly obesity and dyslipidemia, which emerged as a significant risk factor in this study. Hospitalization length may be prolonged by inflammation markers (WBC and CRP) and comorbidities such as AF, obesity, or the need for enoxaparin in patients with elevated thrombosis risk. Further multicenter studies with larger cohorts are needed to assess the impact of demographics, biomarkers, metabolic disorders, and treatment strategies on erysipelas recurrence and outcomes. Awareness of these risk factors is essential for effective prevention, management, and recurrence reduction. Full article

Background/Objectives: Mutations in the BRCA1 and BRCA2 genes are well-known risk factors for ovarian cancer. They are also associated with response to platinum-based chemotherapy; however, their definitive impact on patient prognosis remains not fully understood. This study aimed to investigate the influence of BRCA mutation status on the age of ovarian cancer onset and on treatment outcomes in patients with high-grade serous ovarian cancer. Methods: This single-center retrospective analysis included newly diagnosed FIGO stage III and IV HGSOC patients treated between June 2018 and April 2023. Patients’ age, tumor histology, CA125 levels, BRCA mutation status, type of treatment (neoadjuvant or adjuvant chemotherapy), and surgical outcomes were collected and analyzed. Survival analyses were performed using the Kaplan–Meier method and log-rank test. Results: Pathogenic mutations were identified in 25 patients (15 in BRCA1, 10 in BRCA2). Patients with a BRCA mutation were diagnosed at a significantly younger age (median 58.78 years) compared to non-carriers (66.81 years; p < 0.001), with BRCA1 carriers being diagnosed the youngest (median 46.52 years). The study found no statistically significant difference in progression-free survival (PFS) between BRCA carriers and non-carriers. However, a significant improvement in overall survival (OS) was observed for patients with a BRCA1 mutation (p = 0.036). No significant OS difference was found for BRCA2 carriers. Conclusions: BRCA mutations, particularly in the BRCA1 gene, are associated with an earlier onset ovarian cancer. BRCA1 mutation appears to be a favorable prognostic factor for overall survival in patients with HGSOC. Our findings demonstrate the clinical implications of different BRCA mutations and support the need for further research in larger cohorts to confirm their influence on prognostic effects. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

About 10% of all forms of melanoma occur in a familial context and may be due to germline predisposing mutations transmitted as autosomal dominant traits within the affected families. CDKN2A is a highly penetrant gene associated to familial melanomas, being responsible of up to 40% of the cases. Other high, moderate, and low penetrance genes are being discovered, even if their own contribution to melanoma risk is still under debate. Indeed, next generation sequencing-based strategies enable large genomic regions to be analyzed, thus identifying novel candidate genes. These strategies, in diagnostic settings, may also improve the identification of the hereditary cases between all melanomas. The identification of the at-risk subjects gives an important opportunity for cancer surveillance in order to reduce the risk of onset and/or make early diagnosis. In addition, the identification of molecular biomarkers may drive the future development of specific targeted therapies, as already done for other inherited cancer syndromes. Here, we summarize the state of the art regarding the molecular basis of the hereditary susceptibility to develop melanoma. Full article

Background and Objectives: COVID-19 may have long-term adverse effects on bone health, particularly in individuals aged ≥50 years with obesity or diabetes, who are predisposed to impaired bone quality. Materials and Methods: This retrospective cohort study used TriNetX data from 141 healthcare organizations across North America and Western Europe. Patients aged ≥50 years with overweight (body mass index 25–30 kg/m²), obesity (body mass index ≥ 30 kg/m²), or type 2 diabetes (T2DM) and COVID-19 (2019–2024) were propensity score-matched to non-COVID-19 controls. Exclusion criteria included prior overweight, obesity, diabetes, osteoporosis, T-score ≤ −2.5, Z score ≤ −2.0, fractures, pneumonia, tuberculosis, and cancer. Outcomes included new-onset osteoporosis, fragility fractures, and low T-scores (≤−2.5). Cox regression estimated hazard ratios (HRs); sensitivity analyses assessed lag effects (1–4 years). Results: Among 327,933 matched pairs, COVID-19 was linked to increased osteoporosis risk at 3 years (HR, 1.039; 95% CI, 1.003–1.077) and 6 years (HR, 1.095; 95% CI, 1.059–1.133). Sensitivity analysis showed rising risk with longer lag times: HRs were 1.212, 1.379, 1.563, and 1.884 at 1 to 4 years, respectively. Subgroup analyses confirmed consistent trends. Conclusions: COVID-19 is independently associated with elevated long-term osteoporosis risk in older adults with new-onset overweight, obesity, or T2DM, peaking at 4 years post-infection and persisting through 6 years. Full article

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Background/Objectives: Obstetrical monitoring following radical trachelectomy (RT) for cervical cancer is marked by the lack of a standardized protocol, which may lead to delays in the intervention for cervical shortening. In light of the typical cervical remodeling process that occurs at the onset of labor, we hypothesized that the onset of premature cervical shortening in patients who have undergone radiotherapy commences at the internal ostium. Methods: We introduced the concepts of internal distance (distance between internal cervical ostium and cerclage thread) and the latent shortening of internal distance, which is characterized as a painless reduction in the internal distance, serving as an early marker of preterm contractions, thus enabling timely tocolytic intervention. Results: Three patients spontaneously conceived after RT. They were obstetrically followed-up after RT, using a combined approach of transvaginal ultrasound cervical markers and cardiotocography. Active tocolysis was used if internal distance shortening was observed. All patients delivered term healthy babies. Conclusions: The consistent ultrasound evaluation of both internal and external distances permits the proactive diagnosis of premature contractions and enables swift therapeutic measures. Full article

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI-HOPE-JAK-STAT, a novel conversational artificial intelligence platform built to enable the real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis-generating analyses for precision oncology. Methods: AI-HOPE-JAK-STAT combines large language models (LLMs), a natural language-to-code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age < 50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with significantly more favorable trends (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusions: AI-HOPE-JAK-STAT establishes a new standard for pathway-level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports the scalable, real-time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts. Full article

Background: Around one-quarter of all people in the developed world die of cancer, with primary care being the main setting in which the disease is first suspected because the majority of patients consult a general practitioner (GP) when they present with symptoms. Diagnostic delay may thus be attributable to the patient, the GP, or the healthcare system. While some findings suggest that as much as half of the total delay consists of patient delay, more research is nonetheless needed into how GPs can facilitate access to diagnostic evaluation when patients experience symptoms. Methods: A retrospective observational study will be conducted to evaluate a cohort of patients diagnosed with cancer, with data being obtained from both primary and specialised care settings. Different time intervals will be analysed, dating from onset of first symptoms to diagnosis or initiation of treatment, and will be classified as: patient interval; primary-care interval; healthcare-system interval; diagnostic interval; treatment interval; and total interval. Study variables will include patient characteristics (socio-demographic, risk factors, morbidity, etc.), tumour characteristics (tumour stage, symptom onset, alarm symptoms, etc.), and healthcare characteristics (place of initial consultation, referral to specialised care, etc.). Discussion: The study will describe diagnostic delays in patients with cancer in primary care, considering the time elapsed between symptom onset and initial consultation, request for tests and/or patient referral, first evaluation in the hospital setting, and date of diagnostic confirmation and treatment initiation. Additionally, the study will make it possible to identify the patient-, healthcare-, and disease-related variables that intervene in the duration of such delays. Full article

The advantages of extra virgin olive oil (EVOO) intake as part of a varied, healthy and balanced diet were demonstrated by many epidemiological studies. In particular, several components present in EVOO, such as tocopherols, carotenoids and phenolic compounds, play an important protective role in mitigating inflammatory diseases, atherosclerosis, neurodegenerative diseases and cancer. The protective effect exerted by EVOO was proposed to be accounted for by its antioxidant, anti-inflammatory or anti-proliferative properties. The present review will focus on the interactions among EVOO’s components and pro-inflammatory cytokines, aiming to reveal the mechanisms potentially involved in the anticancer action of EVOO. Cancer patients very frequently develop a devastating syndrome known as cachexia, which negatively impinges on their outcome. The main features of cachexia include progressive body weight loss, fat and muscle wasting, and dysmetabolism, all of which partially result from the onset of systemic inflammation. In this regard, the possibility that EVOO could be beneficial to cancer patients by mitigating cachexia will be reviewed, focusing on the skeletal muscle. Full article