Search Results (632)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes. Full article

Mimivirus, a giant double-stranded DNA virus ($1.2$ Mbp), possesses unique bacteria-like features, including a Gram-positive staining reaction due to peptidoglycan-containing surface fibers. While detected in the respiratory secretions of pneumonia patients since 2005, its clinical role remains controversial due to high genetic variability and detection challenges. This study aims to clarify the pathological significance of Mimivirus by investigating its presence and replication potential in human lung tissue, specifically exploring its association with fatal respiratory outcomes. A comparative post-mortem analysis was conducted on lung tissue samples from two cohorts: patients who succumbed to lethal viral pneumonia and a control group with no history of pulmonary pathology. Mimivirus is known to productively infect alveolar macrophages, suggesting they may serve as a reservoir for lung inflammation and tissue damage. Current evidence suggests it may act as an opportunistic or commensal agent, particularly in immunocompromised or critically ill patients. By systematically screening autopsy samples, this research seeks to establish whether Mimivirus is a primary causative agent of fatal pneumonia or an incidental inhabitant of the human respiratory tract. Full article

Background: Pancreatic cancer is a highly lethal malignancy, with a 5-year survival rate of approximately 8%. Roughly 10% of cases occur in individuals with familial pancreatic cancer or identified high-risk germline mutations, including STK11, CDKN2A, BRCA1/2, MLH1, and MSH2. Aim: We aimed to evaluate the risk of pancreatic cancer associated with inherited genetic mutations and to characterize these genetic syndromes. Methods: A systematic search of the PubMed database up to 2024 identified 1500 articles, of which 90 met the criteria for inclusion in this review. Results: High-risk individuals were defined as those with at least a 10-fold increased risk, moderate risk as 5–10-fold and low risk as under 5-fold. High-risk individuals included those with Peutz–Jeghers syndrome (132–140-fold risk), hereditary pancreatitis (50–87-fold risk), Familial Atypical Multiple Mole Melanoma syndrome (up to 48-fold risk), hereditary breast and ovarian cancer with BRCA2 mutation (up to 22-fold risk), and familial pancreatic cancer with at least three affected relatives (up to 32-fold risk). Moderate-risk patients had BRCA1, MLH1, MSH2, MSH6, p53, and ATM mutations, as well as familial pancreatic cancer with 1–2 affected kindred. Low-risk patients had familial adenomatous polyposis. Conclusions: Identifying high-risk individuals is crucial for effective genetic counseling, testing, and potential screening programs to facilitate early diagnosis and improve outcomes. Future research should prioritize large prospective cohorts, screening programs, and the integration of emerging technologies, such as AI-assisted imaging. Full article

Hepatocellular carcinoma remains one of the most common and lethal cancers worldwide, and many patients are diagnosed at stages where curative therapy is not possible. Recent progress in systemic therapies and refinements in locoregional treatment have shifted how clinicians approach this disease. As evidence has accumulated from trials such as KEYNOTE-937, IMbrave050, and CheckMate 9DX, it has become clear that pairing immunotherapy with ablation or transarterial interventions can deepen and extend treatment responses compared with using either approach alone. This review summarizes the current landscape of these combination strategies, explains the biological and clinical principles that support their use, and highlights ongoing trials that aim to clarify optimal sequencing and patient selection. It also considers future directions for integrating locoregional and systemic therapies to expand curative opportunities and improve long-term outcomes for a broader range of patients. Full article

Currently, there are very few efficient treatment options for hepatobiliary pancreatic cancer (HPC), which comprises pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), and hepatocellular carcinoma (HCC). The HPC tumors are the most lethal malignant tumors in the world. Traditional chemotherapy offers little survival benefit and is associated with notable systemic toxicity, which has made antibody–drug conjugates (ADCs) a hopeful treatment option. Strong cytotoxic drugs combine with monoclonal antibodies to attack tumor-associated antigens. This review discusses the benefits and current developments of Antibody–Drug Conjugates (ADCs) in treating HPC. It also covers their mechanisms of action, ongoing clinical trials, and the challenges of targeting specific antigens like B7-H3, c-MET, and Trop-2. ADCs deliver chemotherapy directly to cancer cells while protecting healthy tissues. It also addresses the favorable outcomes of several preclinical and clinical studies and highlights future paths to enhance ADC efficacy, including addressing tumor heterogeneity, overcoming resistance, and optimizing drug-delivery techniques. This approach has the possibility to further increase patient survival and minimize side effects in HPC patients. To the best of our knowledge and based on the available literature, we have made every effort to include all relevant publications; any inadvertent omissions are entirely unintentional. Full article

Prostate cancer frequently progresses to lethal, drug-resistant castration-resistant prostate cancer (CRPC), where conventional therapies often fail due to intrinsic and acquired resistance mechanisms. This resistance creates a critical therapeutic impasse, leaving patients with limited options and poor prognoses. Immunotherapy has emerged as a promising strategy to harness the immune system against these treatment-refractory tumors, offering a potential avenue to overcome the immunosuppressive barriers that underlie CRPC drug resistance. This review synthesizes findings from a structured search of PubMed, Web of Science, and Embase (2020–2025), revealing significant clinical progress: 4 vaccine trials, 5 immune checkpoint inhibitor trials, 18 combination therapy trials (≥2 agents), and 6 targeted drug trials have been conducted. Preliminary efficacy was observed in novel approaches like bispecific antibodies (e.g., Xaluritamig achieving 59% PSA50 response), PSMA-CAR-T (P-PSMA-101), and oncolytic viruses (Ad5 PSA/MUC-1/brachyury). Basic research identified four targeted resistance mechanisms (e.g., AR-LLT1, Pygo2, and HnRNP L) and one nanoparticle-mediated triple-combination therapy (CM-AMS@AD NPs integrating photothermal, chemotherapy, and immunotherapy), which enhanced cytotoxic T-cell infiltration and suppressed CRPC growth preclinically. These collective findings suggest the potential of immunotherapy for CRPC in overcoming resistance barriers and improving patient outcomes, with bispecific T cell engagers (Xaluritamig, 59% PSA50) and PSMA-directed CAR-T therapy (P-PSMA-101, >50% PSA reduction) emerging as the most promising near-term candidates and biomarker-stratified combinations (nivolumab plus rucaparib, 84.6% PSA50, in HRR-deficient patients) illustrating the transformative power of precision patient selection; however, these findings require validation in larger, biomarker-stratified trials before definitive conclusions can be drawn. Translating this potential into clinical reality requires optimized patient selection through predictive biomarkers and rigorously validated Phase III trials to confirm durable clinical responses and long-term survival benefits. Full article

Targeted therapies and chemoimmunotherapy have transformed outcomes for non–small cell lung cancer (NSCLC), yet relapse remains common. Resistance is increasingly recognized to include an early, largely reversible phase in which a minor subpopulation survives lethal therapy through non-genetic adaptation. These drug-tolerant persister (DTP) cells may be quiescent or cycling, and provide a reservoir from which stable, genetically resistant clones can later emerge. In parallel, late recurrence may reflect tumor dormancy, in which disseminated or residual cells persist for prolonged periods under microenvironmental constraint and/or immune surveillance. This review integrates DTP and dormancy frameworks in NSCLC, summarizes mechanisms that sustain persistence (chromatin and transcriptional plasticity, stress signaling, metabolic rewiring, and stromal/immune protection), and highlights experimental models and translational readouts, including circulating tumor DNA (ctDNA)–based minimal residual disease (MRD) monitoring. We also discuss potential therapeutic concepts to prevent DTP formation, exploit persister liabilities, or enforce dormancy in minimal-disease settings. A mechanistically grounded understanding of these survival programs is essential for rational combinations and biomarker-guided trials aimed at durable remission. Full article

Objective: The aim of this retrospective study was to evaluate clinical and laboratory characteristics in adult patients with neuroinvasive West Nile virus (WNDD). We also studied the phylogeny and molecular characteristics of some of the WNV strains. Methods: A retrospective analysis was conducted at “Annunziata” Hub Hospital, a secondary referral facility in Calabria region, in Southern Italy. Sample pre-processing, sequencing and bioinformatic analyses were carried out at IRCCS Sacro Cuore Don Calabria Hospital in Negrar di Valpolicella, Verona, Veneto region in North-East Italy. Results: Nine cases of WNDD were analyzed, involving eight males and one female, with a mean age of 70.33 years (range 60–85). The overall average hospital stay was 20.6 days (range 6–46). Six patients made a full recovery after a mean of 35.3 days of acute care. Thirty-day mortality rate was 23%. VNDD in some of our patients manifested itself in the form of cerebral hemorrhage (ICH) in three patients, causing lethality in two patients and other unusual manifestations, such as Guillain–Barré syndrome with fatal outcome and severe facial palsy. Phylogenetic analysis shows that our sequences are closely related to other southern-Italian and cluster with Central–Southern–Eastern European sequences, while being evidently separated from northern Italian and Central–Western European ones, belonging to the sub-lineage 2a of the WNV-2, clustering with sequences from the Central–South–Eastern clade, mainly to Hungary. Conclusions: Cerebrovascular complications of WNE may be an important clinical manifestation of WNV neuroinvasive infection. Preliminary data do not allow us to determine whether our strains, closely related to other southern-Italian and cluster with Central–Southern–Eastern European sequences, really presented an increased neurovirulence. Full article

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains highly lethal, with median overall survival rarely exceeding 15 months despite maximal surgical resection, radiotherapy, and temozolomide-based chemotherapy. Therapeutic resistance in GBM is driven by intrinsic tumor cell adaptations, extensive inter- and intratumoral heterogeneity, and microenvironmental constraints. Key mechanisms include enhanced DNA repair, disrupted apoptosis, pathway redundancy, altered drug metabolism, oxidative stress tolerance, and glioblastoma stem cell–mediated plasticity. In vivo, resistance is reinforced by the blood–brain barrier, hypoxia, stromal and immune interactions, and selective expansion of therapy-resistant clones. Current strategies to overcome resistance target DNA repair, oxidative stress, autophagy, and metabolic vulnerabilities; however, their efficacy is limited by tumor heterogeneity and delivery barriers. Precision oncology approaches are hampered by a paucity of validated predictive biomarkers, leaving many patients without actionable targets. Ex vivo functional drug sensitivity testing of patient-derived tumor cells offers a complementary strategy, directly assessing individual tumor responses and guiding rational combination therapies. This review highlights the molecular and cellular mechanisms underlying chemoresistance in GBM, examines emerging therapeutic strategies, and explores the potential of integrating personalized, functionally guided approaches into clinical management. Addressing GBM’s profound heterogeneity and adaptive plasticity is essential to improving outcomes in this aggressive and refractory malignancy. Full article

Ovarian cancer remains a leading cause of gynecologic cancer–related mortality worldwide, and long-term outcomes with conventional cytotoxic chemotherapy remain limited. The integration of targeted therapies has substantially reshaped treatment paradigms by exploiting key molecular pathways involved in angiogenesis, DNA damage repair, and folate receptor signaling. This review synthesizes evidence from pivotal phase II and III clinical trials, translational studies, and meta-analyses evaluating inhibition of the VEGF, PARP, and folate receptor-alpha (FRα) pathways, with a focus on bevacizumab, rucaparib, and mirvetuximab soravtansine. Across disease settings, these agents have demonstrated clinically meaningful improvements in progression-free survival, durability of response, and tolerability when deployed in biomarker-selected populations. Bevacizumab has shown consistent benefit when combined with platinum-based chemotherapy and as maintenance therapy in advanced disease. PARP inhibitors, including rucaparib, exploit homologous recombination deficiency (HRD) to induce synthetic lethality and are now central to frontline and recurrent treatment strategies for BRCA-mutated and HRD-positive tumors. Mirvetuximab soravtansine has emerged as an effective and well-tolerated option for patients with FRα-high, platinum-resistant ovarian cancer, addressing a longstanding unmet clinical need. Collectively, VEGF-, PARP-, and FRα-targeted therapies have enabled more rational treatment sequencing, informed combination strategies, and personalized clinical decision-making in ovarian cancer. Ongoing efforts to define optimal sequencing, overcome acquired resistance, and refine predictive biomarkers are expected to further enhance the durability and breadth of benefit from targeted therapies and advance precision oncology in gynecologic malignancies. Full article

Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear and mitochondrial genome instability have been shown to drive aging in the hematopoietic system, which then propagates to non-lymphoid tissues, enhancing morbidity and mortality. The loss of TFAM, a key regulator of mitochondrial DNA replication and nucleoid stability, in T cells has been shown to cause mitochondrial dysfunction, leading to premature immune aging and eventual systemic aging. We sought to investigate whether the loss of TFAM in all immune cells would have a comparable or stronger effect on both the immune system and parenchyma. To address this, we attempted to generate Vav-iCre^+/−; Tfam^fl/fl mice, which are deficient in TFAM in all immune cells. However, this genotype was unrecoverable as no mutant pups were born, suggesting embryonic lethality. Conversely, we generated mice lacking SIRT6, a nuclear DNA repair enzyme that also regulates mitochondrial homeostasis, in all immune cells and found them to be viable and born at expected Mendelian frequencies. Our findings demonstrate the necessity of mitochondrial genome maintenance and homeostasis repair in immunity. Full article

Melanoma is the most lethal form of skin cancer, and early detection is critical for improving patient outcomes. Although dermoscopy combined with deep learning has advanced automated skin-lesion analysis, progress is hindered by limited access to large, well-annotated datasets and by severe class imbalance, where melanoma images are substantially underrepresented. To address these challenges, we present the first systematic benchmarking study comparing four GAN architectures—DCGAN, StyleGAN2, and two StyleGAN3 variants (T and R)—for high-resolution ($512\times 512$) melanoma-specific synthesis. We train and optimize all models on two expert-annotated benchmarks (ISIC 2018 and ISIC 2020) under unified preprocessing and hyperparameter exploration, with particular attention to R1 regularization tuning. Image quality is assessed through a multi-faceted protocol combining distribution-level metrics (FID), sample-level representativeness (FMD), qualitative dermoscopic inspection, downstream classification with a frozen EfficientNet-based melanoma detector, and independent evaluation by two board-certified dermatologists. StyleGAN2 achieves the best balance of quantitative performance and perceptual quality, attaining FID scores of 24.8 (ISIC 2018) and 7.96 (ISIC 2020) at $\gamma =0.8$. The frozen classifier recognizes 83% of StyleGAN2-generated images as melanoma, while dermatologists distinguish synthetic from real images at only 66.5% accuracy (chance = 50%), with low inter-rater agreement ($\kappa =0.17$). In a controlled augmentation experiment, adding synthetic melanoma images to address class imbalance improved melanoma detection AUC from 0.925 to 0.945 on a held-out real-image test set. These findings demonstrate that StyleGAN2-generated melanoma images preserve diagnostically relevant features and can provide a measurable benefit for mitigating class imbalance in melanoma-focused machine learning pipelines. Full article

Glioblastoma (GBM) remains one of the most lethal brain tumors, largely due to the resilience and plasticity of glioblastoma stem cells (GSCs), which drive tumor growth, recurrence, and resistance to conventional therapies. A key mechanism underlying their aggressiveness is transdifferentiation, whereby GSCs acquire endothelial- and pericyte-like phenotypes, promoting neovascularization and remodeling the tumor microenvironment to sustain malignancy. Conventional treatments often fail to eliminate these resilient populations, highlighting the need for innovative targeted strategies. Chimeric antigen receptor (CAR)-based immunotherapies offer a targeted strategy to specifically eliminate GSCs and interfere with their role in promoting tumor vascularization and suppressing immune responses. This review aims to provide a comprehensive overview of the molecular mechanisms driving GSC transdifferentiation and to summarize the current landscape of CAR-T therapies developed to target these cells. By integrating knowledge of GSC biology with advances in CAR-T-based interventions, this work highlights the potential of next-generation immunotherapies to overcome therapeutic resistance, limit tumor recurrence, and improve clinical outcomes in GBM. 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

Influenza virus infection remains a major global health burden, with severe disease outcomes driven not only by viral replication but also by excessive host inflammatory responses. Current antiviral therapies predominantly target viral components and fail to adequately control virus-induced hyperinflammation. In this study, we report a dual-target therapeutic strategy integrating direct antiviral activity with host-directed immunomodulation. Using a molecular hybridization approach, we designed and synthesized several dual-target inhibitors simultaneously targeting the influenza virus PB2 cap-binding subunit and host JAK2 kinase. Among them, PB05 emerged as the most promising candidate and was systematically evaluated in vitro and in vivo. PB05 exhibited potent broad-spectrum antiviral activity against influenza A viruses, with nanomolar EC₅₀ values. Mechanistic studies demonstrated that PB05 directly binds to the PB2 cap-binding domain, thereby disrupting viral cap-snatching and RNA synthesis. In parallel, PB05 inhibited JAK–STAT signaling by suppressing STAT2 phosphorylation and downstream ISRE-mediated transcription, leading to a marked reduction in pro-inflammatory cytokine production, including IL-6, IL-1β, and IFN-β, in infected or stimulated immune cells. In a lethal influenza A/PR/8/34 (H1N1) mouse model, oral administration of PB05 at 100 mg/kg (twice daily) markedly decreased lung viral titers, attenuated pulmonary tissue damage and edema, and moderated excessive inflammatory responses. Collectively, these findings identify PB05 as a dual PB2/JAK2 inhibitor that effectively couples antiviral efficacy with immunomodulatory activity, promoting a therapeutic strategy for the treatment of severe influenza and other viral diseases associated with excessive inflammation. Full article