Search Results (1,637)

Background: Melanoma of unknown primary (MUP) is a rare and distinct clinical subtype of metastatic melanoma, in which no identifiable primary tumor is found. The prognosis of MUP compared to melanoma with known primary (MKP) remains unclear, especially in the era of novel therapies like immune checkpoint inhibitors (ICIs) and targeted therapies. This meta-analysis aims to compare the overall survival (OS) of MUP and MKP patients under these therapies. Methods: This systematic review was conducted in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). A systematic search of major databases was conducted, yielding six eligible studies (nine study arms) that assessed the survival outcomes of MUP and MKP patients treated with immunotherapies and targeted therapies. We pooled the hazard ratios (HRs) for OS using both fixed and random effects models. Heterogeneity was assessed with the I² statistic followed by a Baujat plot, and publication bias was evaluated using funnel plots and Egger’s test. Results: Our analysis revealed a borderline significant HR of 0.90 (95% CI: [0.81, 1.00], p = 0.04) under the fixed effect model, suggesting a potential survival benefit for MUP patients. However, the random effects model, accounting for study heterogeneity, showed no significant difference in OS between MUP and MKP (HR = 0.87, 95% CI: [0.73, 1.05], p = 0.15). Significant heterogeneity (I² = 66.9%, p = 0.0022) was observed across studies. No substantial publication bias was detected. Conclusion: While the trend observed in the fixed effect model suggests a potential benefit for MUP patients, the random effects analysis indicates no significant difference between MUP and MKP in terms of OS. These findings underscore the importance of accounting for study heterogeneity and highlight the need for further prospective studies to better understand the impact of novel therapies on MUP. Full article

Primary cutaneous lymphomas (PCLs), including cutaneous T-cell lymphomas (CTCL) and primary cutaneous B-cell lymphomas (PCBCL), are a diverse group of non-Hodgkin lymphomas that primarily affect the skin. Radiotherapy (RT) plays a pivotal role in the treatment of these lymphomas, particularly for localized disease, due to its ability to deliver precise, skin-directed treatment. Mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of CTCL, often require skin-directed therapies such as electron beam therapy and superficial brachytherapy to manage localized lesions. Electron beam therapy, including total skin electron beam therapy (TSEBT), has been utilized for decades, offering high response rates but with the risk of cumulative skin toxicity. Recently, low-dose radiotherapy (LDRT) has gained attention as an effective alternative that reduces toxicity while maintaining durable responses. Superficial brachytherapy is another modality that delivers radiation through custom molds, allowing for homogeneous dosing over complex anatomical areas like the face. Both teleradiotherapy and brachytherapy have demonstrated high complete response rates, with low recurrence rates observed when higher doses are used. In the context of primary cutaneous B-cell lymphomas, such as primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL), radiotherapy also offers excellent local control, particularly for indolent subtypes. However, more aggressive subtypes, such as diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), may require systemic therapies in addition to radiation. Overall, teleradiotherapy and brachytherapy are essential components of the therapeutic arsenal for primary cutaneous lymphomas, offering effective disease control with manageable toxicity, while ongoing research focuses on optimizing treatment strategies and exploring novel combinations with systemic therapies. Full article

Studies of HIV-1 molecular epidemiology describe significant differences in HIV infection spread across geographical areas. We examined 80 HIV-1 samples from the Jewish Autonomous Region of Russia in 2024. HIV-1 genome sequences for 12 samples revealed a novel HIV-1 called CRF173_63A6. HIV-1 CRF173_63A6 was found to have arisen through recombination between a specific Russian A6 subtype and the recombinant virus CRF63_02A6, which is responsible for the PWID-associated HIV outbreak in the Siberian region of Russia. Phylogenetic analysis of pol sequences previously deposited in Genbank showed that the CRF173_63A6 samples we described are grouped into a common phylogenetic cluster that includes 54 HIV-1 samples isolated in the JAR and other areas of the Russian Far East, indicating a wide distribution of this virus genovariant. This study once again proves the significant contribution of the key PWID group not only to the development of local Russian HIV epidemics, but also to the change in the characteristics of the circulating virus population. Full article

This study aims to investigate the molecular mechanisms underlying germ cell tumors (GCTs), focusing specifically on seminomas and teratomas. By analyzing gene expression profiles and miRNA interactions, the goal is to identify key regulatory miRNAs and signaling pathways that differentiate these tumor types and could serve as important regulators for therapy development. Raw data for seminomas and teratomas were extracted from the GEO database, and gene hubs were identified using STRING and Gephi. Signaling pathways and functional annotations were analyzed using miRPathDB, while miRNA–gene interactions were explored via miRWalk. Hub miRNAs were filtered and confirmed using miRDB. This study highlights significant changes in gene expression diversity between tumor and normal gonadal tissues, providing insights into the molecular dynamics of seminomas and teratomas. Distinctions between seminomas and teratomas were identified, shifting the focus toward miRNAs to discover more precise and novel therapeutic approaches. The hub genes of seminomas and teratomas were identified separately. MiRNAs targeting these hub genes were also determined and confirmed. These miRNAs collectively influence essential oncogenic pathways—confirming hsa-miR-138-5p as a regulator of pathways such as Hippo signaling, transcriptional misregulation in cancer, and microRNA cancer signaling in seminomas, and hsa-miR-200b-3p as a regulator of p53 signaling, T cell receptor signaling, and pathways including PI3K/AKT, MAPK/ERK, and Wnt/β-catenin in teratomas—confirming their potential as promising candidates for subtype-specific therapeutic intervention. MiRNAs identified through bioinformatics analyses, and their predicted regulatory roles in key oncogenic pathways, represent potential therapeutic targets or regulators of biological processes. However, further experimental validation is needed to confirm these findings. Full article

Background: Breast cancer continues to pose a significant global health challenge despite advances in early detection and targeted therapies. The development of novel chemotherapeutic agents remains crucial, particularly those with selective cytotoxicity toward specific breast cancer subtypes. Methods: A series of ten hybrid indolyl-methylidene phenylsulfonylhydrazones and one bis-indole derivative were designed, synthesized, and structurally characterized using NMR and high-resolution mass spectrometry (HRMS). Prior to synthesis, in silico screening was performed to assess drug likeness and ADME-related properties. Single-crystal X-ray diffraction was conducted for compound 3e. The cytotoxic potential of the synthesized compounds was evaluated using the MTT assay against MCF-7 (ER-α⁺) and MDA-MB-231 (triple-negative) breast cancer cell lines. Additionally, quantitative structure–activity relationship (QSAR) analysis was conducted to identify key structural features contributing to activity. Results: Most compounds exhibited selective cytotoxicity against MCF-7 cells. Notably, compound 3b demonstrated the highest potency with an IC₅₀ of 4.0 μM and a selectivity index (SI) of 20.975. Compound 3f showed strong activity against MDA-MB-231 cells (IC₅₀ = 4.7 μM). QSAR analysis revealed that the presence of a non-substituted phenyl ring and specific indolyl substituents (5-methoxy, 1-acetyl, 5-chloro) significantly contributed to enhanced cytotoxic activity and ligand efficiency. Conclusion: The synthesized phenylsulfonylhydrazone hybrids exhibit promising and selective cytotoxicity, particularly against ER-α⁺ breast cancer cells. Structural insights from QSAR analysis provide a valuable foundation for the further optimization of this scaffold as a potential source of selective anticancer agents. Full article

Background/Objectives: Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene—particularly those associated with the SPG4 subtype—represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs). Methods: We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired. Results: The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. Conclusions: These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity. Full article

Benzene, a well-established human carcinogen and major industrial pollutant, poses significant health risks through occupational exposure due to its no-threshold effect, leading to multi-system damage involving the hematopoietic, nervous, and immune systems. This makes the investigation of its toxic mechanisms crucial for precise prevention and control of its health impacts. Programmed cell death (PCD), an orderly and regulated form of cellular demise controlled by specific intracellular genes in response to various stimuli, has emerged as a key pathway where dysfunction may underlie benzene-induced toxicity. This review systematically integrates evidence linking benzene toxicity to PCD dysregulation, revealing that benzene and its metabolites induce abnormal subtypes of PCD (apoptosis, autophagy, ferroptosis) in hematopoietic cells. This occurs through mechanisms including activation of Caspase pathways, regulation of long non-coding RNAs, and epigenetic modifications, with recent research highlighting the IRP1-DHODH-ALOX12 ferroptosis axis and oxidative stress–epigenetic interactions as pivotal. Additionally, this review describes a comprehensive monitoring system for early toxic effects comprising benzene exposure biomarkers (urinary t,t-muconic acid (t,t-MA), S-phenylmercapturic acid (S-PMA)), PCD-related molecules (Caspase-3, let-7e-5p, ACSL1), oxidative stress indicators (8-OHdG), and genetic damage markers (micronuclei, p14ARF methylation), with correlative analyses between PCD mechanisms and benzene toxicity elaborated to underscore their integrative roles in risk assessment. Furthermore, the review details analytical techniques for these biomarkers, including direct benzene detection methods—direct headspace gas chromatography with flame ionization detection (DHGC-FID), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and portable headspace sampling (Portable HS)—alongside molecular imprinting and fluorescence probe technologies, as well as methodologies for toxic effect markers such as live-cell imaging, electrochemical techniques, methylation-specific PCR (MSP), and Western blotting, providing technical frameworks for mechanistic studies and translational applications. By synthesizing current evidence and mechanistic insights, this work offers novel perspectives on benzene toxicity through the PCD lens, identifies potential therapeutic targets associated with PCD dysregulation, and ultimately establishes a theoretical foundation for developing interventional strategies against benzene-induced toxicity while emphasizing the translational value of mechanistic research in occupational and environmental health. Full article

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by high intratumoral heterogeneity, therapy resistance, and poor prognosis. Nuclear factor-κB (NF-κB) signaling plays a pivotal role in GBM pathogenesis by promoting proliferation, invasion, inflammation, immune evasion, and treatment resistance. This review provides a comprehensive overview of canonical and non-canonical NF-κB signaling pathways and their molecular mechanisms in GBM, with a focus on their regulation in glioma stem-like cells (GSCs), interactions with key oncogenic factors (including STAT3, FOSL1, and TRPM7), and roles in maintaining tumor stemness, metabolic adaptation, and angiogenesis. We further discuss the reciprocal regulatory dynamics between NF-κB and non-coding RNAs (ncRNAs), particularly microRNAs, highlighting novel ncRNA-mediated epigenetic switches that shape GBM cell plasticity and subtype specification. Additionally, we examine the influence of NF-κB in modulating the tumor microenvironment (TME), where it orchestrates pro-tumorigenic cytokine production, immune cell reprogramming, and stromal remodeling. Finally, we review current NF-κB-targeting therapeutic strategies in GBM, including clinical trial data on small-molecule inhibitors and combinatorial approaches. Understanding the multifaceted roles of NF-κB in GBM offers new insights into targeted therapies aimed at disrupting tumor-promoting circuits within both cancer cells and the TME. Full article

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought to light unexpected complications beyond respiratory illness, including effects on kidney function and a potential link to kidney stone disease (KSD). This review proposes a novel framework connecting COVID-19-induced epigenetic reprogramming to disruptions in mitochondrial sulfur metabolism and the pathogenesis of kidney stones. We examine how SARS-CoV-2 interferes with host methylation processes, leading to elevated homocysteine (Hcy) levels and impairment of the trans-sulfuration pathway mechanisms particularly relevant in metabolic disorders such as homocystinuria. These epigenetic and metabolic alterations may promote specific kidney stone subtypes through disrupted sulfur and oxalate handling. Additionally, we explore the role of COVID-19-associated gut dysbiosis in increasing oxalate production and driving calcium oxalate stone formation. Together, these pathways may accelerate the transition from acute kidney injury (AKI) to chronic KSD, linking viral methylation interference, sulfur amino acid imbalance, mitochondrial dysfunction, and microbiota changes. Unlike earlier reviews that address these mechanisms separately, this work offers an integrated hypothesis to explain post-viral renal lithogenesis and highlights the potential of targeting sulfur metabolism and redox pathways as therapeutic strategies for KSD triggered or aggravated by viral infections such as COVID-19. Full article

Introduction: Previous studies have reported sex differences in stroke. There are few Asian studies. This study was performed to investigate sex differences in stroke risk factors and mechanisms in a multi-ethnic Asian population. Methods: Data on patients admitted to Raffles Hospital for stroke were analysed. Data were extracted on sex, age, hypertension, diabetes mellitus (DM), hyperlipidaemia, smoking, heart disease, and prior cerebrovascular events (pCeVD). Stroke was subtyped into haemorrhagic stroke (HS) or ischaemic stroke (IS) based on brain scan. IS mechanism was categorised using Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, while the clinical syndrome by Oxfordshire Community Stroke Project (OCSP) classification. Results: Data were collected on 1165 patients, mean age 65.6 ± 12.9 yr; 47.4% female, 83.0% Chinese, with hypertension (63.5%) and hyperlipidaemia (60.3%) being the most common risk factors. HS comprised 23.5%. On regression analysis, compared to males, females had older age (OR 1.03, 95%CI 1.02–10.4) and DM (OR 1.60, 95%CI 1.11–2.30), but less smoking (OR 0.09, 95%CI 0.07–0.13), pCeVD (OR 0.67, 95%CI 0.49–0.93), and HS (OR 0.71, 95%CI 0.51–0.98). There were no differences in HS mechanisms, or IS mechanisms or syndromes. Sex–ethnic differences were found (p < 0.001), with more Chinese and fewer Indians among females compared to males. Conclusions: This study corroborates previous studies of significantly older age and more diabetes mellitus, but less smoking and haemorrhagic stroke among female stroke patients compared to males; differences in HS and IS mechanisms were not found. Novel in this study is that sex–ethnicity differences were found. Future studies should prospectively validate these sex/ethnic differences. Full article

Cancer-associated fibroblasts (CAFs) constitute a heterogeneous population of cells within the tumor microenvironment and are associated with cancer development and drug resistance. The absence of a universal classification for CAFs hinders their research and therapeutic targeting. To define CAF phenotypes, we developed patient-derived cell cultures of breast cancer (BC) and validated and characterized four distinct CAF subtypes (S1–S4) by Costa’s classification. Three out of five primary cell cultures of BC demonstrated different functional features rather than fixed cellular states due to the plasticity of the CAF phenotype. CAF crosstalk with cancer cells supported their survival in the presence of anticancer drugs. Based on the analysis of the cytotoxic effect of doxorubicin, cisplatin and tamoxifen, it was demonstrated that CAF-S4 and CAF-S1 cells were sensitive to the action of all drugs investigated, despite the fact that they possessed different mechanisms of action. CAF-S2 cells exhibited the highest level of resistance to the antitumour agents. Homotypic and heterotypic spheroids with CAFs could be used to model the fibrotic area of BC in vitro. The patient-derived cell cultures of CAFs formed spheroids. Hypoxia-activated CAF-S4 have been shown to stimulate the metastatic potential of triple-negative BC cells in a heterotypic spheroid model. Consequently, this study could be a starting point for the development of novel therapeutic strategies that target CAFs and their interactions with cancer cells. Full article

Migraine is a complex neurological disorder characterized by recurrent headaches and sensory disturbances. Emerging evidence highlights a critical role for mitochondrial dysfunction in migraine pathophysiology, including impairments in oxidative phosphorylation, disruptions in mitochondrial dynamics, and altered biogenesis. Experimental migraine models—ranging from nitroglycerin-induced attacks to inflammatory stimuli—consistently demonstrate mitochondrial swelling, cristae disruption, decreased ATP production, and increased oxidative stress. These findings are accompanied by the altered expression of key mitochondrial regulators such as PGC-1α, Drp1, and Mfn1. Recent studies have further identified distinct metabolic subtypes of mitochondria, including P5CS-containing subsets, which exhibit unique structural and functional profiles, including cristae loss and reduced ATP synthase expression. Notably, the mitochondrial alterations observed in migraine models show remarkable parallels to those described in P5CS-related mitochondrial subsets. These similarities suggest a potential mechanistic link between metabolic reprogramming within mitochondria and migraine pathogenesis. Understanding the contribution of these newly defined mitochondrial populations could offer novel insights into migraine biology and open new avenues for targeted therapeutic strategies. Full article

Background: Esophageal cancer (EC), including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), remains a lethal malignancy with limited molecularly tailored treatment options. Due to substantial histologic and transcriptomic differences between subtypes, therapeutic responses often vary, underscoring the need for subtype-stratified analysis and precision drug discovery. Methods: We integrated transcriptomic data from GEO and TCGA to identify differentially expressed genes (DEGs) specific to EAC, ESCC, and their shared profiles. Functional enrichment (GO, KEGG) and protein–protein interaction (PPI) network analyses were conducted to extract hub genes using DAVID, STRING, and Cytoscape. Survival associations were evaluated using TCGA-ESCA and UALCAN. Drug repurposing was performed using L1000FWD, L1000CDS2, and SigCom LINCS. Results: We identified 79, 59, and 17 hub genes in the DEG-EAC, DEG-ESCC, and DEG-EAC&ESCC datasets, respectively. In EAC, 16 novel hub genes including SCARB1, SERPINH1, and DSC2 were discovered, which had not been previously implicated in this subtype. These genes were significantly enriched in pathways related to extracellular matrix (ECM) remodeling and epithelial structure. In addition, shared hub genes across EAC and ESCC—such as COL1A1, SPARC, and MMP1—were enriched in ECM organization and cell adhesion processes, highlighting convergent tumor–stroma interactions. Drug repositioning analysis consistently prioritized MEK inhibitors, trametinib and selumetinib, as potential therapeutic candidates across all DEG datasets. Conclusions: This study presents a comprehensive, subtype-stratified transcriptomic framework for EC, identifying both unique and shared hub genes with potential functional relevance to ECM dynamics. Our findings suggest that ECM remodelers may serve as therapeutic targets, and highlight MEK inhibition as a promising, yet exploratory, repurposing strategy. While these results offer a molecular foundation for future precision oncology efforts in EC, further validation through proteomic analysis, functional studies, and clinical evaluation is warranted. Full article

Mucinous ovarian carcinoma (MOC) represents a rare and biologically distinct subtype of ovarian cancer, characterized by poor response to standard platinum-based chemotherapy and a unique molecular profile, including frequent KRAS mutations and HER2 amplifications. Recent advancements in targeted therapy, such as HER2 inhibitors and KRAS^G12C inhibitors, offer promising avenues for personalized treatment. Immunotherapy, particularly checkpoint inhibitors, shows potential in tumors with high PD-L1 expression or tumor mutational burden. Novel strategies, including antibody–drug conjugates, synthetic lethality approaches, and Wnt/β-catenin pathway inhibitors, are reshaping the therapeutic landscape. Despite these developments, challenges such as intratumoral heterogeneity and therapy resistance persist, underscoring the need for innovative clinical trial designs and combination regimens. This review synthesizes the latest advancements in MOC therapies, highlighting opportunities for improved outcomes in this challenging malignancy. Full article

Background: Breast cancer, one of the most researched cancers in oncology, remains the primary cause of cancer-related mortality in women. Its biological complexity, which includes phenotypic, genetic, and microenvironmental aspects, makes modeling and treatment quite difficult. The need for more physiologically realistic models is highlighted by the comparison of two-dimensional (2D) cell cultures with 3D breast-cancer-derived spheroids, which discloses how important pathways such as epidermal growth factor receptor (EGFR) and insulin-like growth factor I receptor (IGF-IR) influence cell behavior and extracellular matrix (ECM) macromolecular expression. Methods: The purpose of this study was to utilize novel 3D cell platforms to assess the effect of inhibiting the EGFR and IGF-IR pathways, alone or in combination, on the functional properties and the expression levels of certain matrix metalloproteinases (MMPs) which are implicated in breast cancer progression (i.e., triple-negative and luminal A breast cancer subtypes) and related with the EGFR and IGF-ΙR molecular network, as also demonstrated through STRING analysis. Results: Our results demonstrated potential crosstalk between EGFR and IGF-IR signaling, which influences cell proliferation and spheroid growth, dissemination, and migration. Significant phenotypic changes proposed between 2D and 3D cell cultures, and alterations in the expression of MMPs, were also recorded. Conclusions: Both breast cancer cell lines retained acknowledged characteristics across the tested models while also exhibiting new, condition-dependent properties. Overall, our findings enhance our understanding on the interplay between the EGFR and IGF-IR pathways and underscore the value of 3D models in revealing key biological processes underlying distinct breast cancer phenotypes. Full article