Search Results (15,494)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC₅₀ values of 26.7 ± 1.07 µM (Jurkat) and 30.5 ± 1.54 µM (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC₅₀ of 197.9 ± 1.29 µM, corresponding to a 6.5–7.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy. Full article

Approximately half of Japanese patients with lung adenocarcinoma (LUAD) have epi-dermal growth factor receptor (EGFR) gene mutations. Therefore, EGFR is the most critical therapeutic target in treating LUAD. This study’s purpose is to explore novel therapeutic targets for LUAD and further improve EGFR inhibitor combination therapy. We created microRNA (miRNA) expression signatures from clinical specimens of LUAD patients harboring EGFR gene mutations using RNA sequencing. Based on the miRNA signature, we focused on miR-206, which had the most downregulated expression. We searched for its target gene in LUAD cells by facilitating transfection of miR-206 into the EGFR mutant cell line PC9 and searching for genes with suppressed expression. A total of 821 genes were downregulated in PC9 cells. Through molecular classification of these genes, we revealed that 18 genes were closely related to the cell cycle. Among these genes, we focused on cyclin-dependent kinase 4 (CDK4) and investigated the synergistic effects of a CDK4/6 inhibitor (abemaciclib or palbociclib) and osimertinib, an EGFR inhibitor in LUAD cells. In vitro and three-dimensional culture analyses showed that combination therapy with a CDK4/6 inhibitor and an EGFR inhibitor synergistically suppressed proliferation of LUAD cells with EGFR mutations. Our miRNA-based analysis is an excellent strategy for identifying therapeutic targets for LUAD. Continued analysis will reveal target molecules that enhance the therapeutic effects of EGFR inhibitors. Full article

Acute myeloid leukemia (AML) pathogenesis is deeply rooted in the concept of clonal evolution, in which hematopoietic stem cells experience an initial genetic insult, followed by the sequential acquisition of mutations leading to various disease phenotypes. Through natural selection, a malignant clone can diversify and propagate with time. Aside from clonal evolution, a number of time-honored principles of molecular oncology account for the initiation and maintenance of AML. These principles include loss of heterozygosity, genomic instability, epigenomic disruption, deregulation of signaling pathways, anti-apoptotic mechanisms, and oncogene addiction. Such tenets of cancer biology not only explain AML cellular behavior but also may inform target validation in AML. Herein, we highlight the current state of targeted therapeutics, including the 14 novel agents (beyond 7+3 chemotherapy) approved by the Food and Drug Administration, in the context of these tenets and discuss future prospects by leveraging current knowledge of AML genomics. Such therapeutic concepts, including synthetic lethality, are especially relevant to TP53-mutant AML, as there are no unique therapies that have received regulatory approval for this subset to date. We emphasize the emerging role of single-cell genomics and multi-omics toward better understanding of AML biology and development of future successful AML therapies. Full article

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known. Full article

The extracellular matrix (ECM) is a key determinant of melanoma progression, regulating tumor cell behavior through biochemical and biomechanical cues. MicroRNAs (miRNAs) have emerged as critical post-transcriptional regulators of gene expression and are increasingly recognized as important modulators of ECM remodeling in cancer. This review summarizes current evidence on miRNA-mediated regulation of ECM components and ECM-associated pathways in melanoma (matrix-miRNAs). We examine studies reporting miRNAs that directly target structural ECM molecules such as collagens, laminins, fibronectin, hyaluronan-related enzymes, and proteoglycans, as well as miRNAs that indirectly regulate ECM dynamics through modulation of matrix metalloproteinases, signaling pathways, and transcription factors. The collected evidence indicates that miRNAs form complex regulatory networks that influence tumor proliferation, invasion, metastasis, angiogenesis, immune evasion, and therapy resistance by reshaping the tumor microenvironment. Tumor-suppressive miRNAs generally inhibit ECM remodeling and metastatic behavior, whereas oncogenic miRNAs promote matrix degradation and a pro-invasive microenvironment. Importantly, many miRNAs exert pleiotropic effects by targeting multiple components of interconnected signaling pathways, resulting in context-dependent outcomes during melanoma progression. Overall, miRNA-dependent regulation of the ECM represents a crucial layer of control in melanoma biology. Understanding these regulatory circuits may provide novel opportunities for biomarker development and therapeutic intervention targeting both tumor cells and their surrounding microenvironment. Full article

Cancer is a leading health issue worldwide, affecting approximately 20 million people annually. Developing efficient chemotherapy agents for cancer treatment is a challenging, costly, and time-consuming process. Drug repurposing for cancer treatment provides an optimal alternative, as the pharmacokinetic properties and the safety of these drugs have been previously tested. It also offers a faster and more cost-effective path to novel cancer therapies, which is especially valuable when conventional treatments face resistance or toxicity limitations. Antipsychotic drugs, which are primarily used for treating psychiatric disorders, including schizophrenia and bipolar disorder, have recently been investigated for their potential anticancer effects through drug repurposing strategies. While covering preliminary data and providing an overview of their mechanisms of action, this review highlights the latest research on antipsychotic medications’ emerging potential in oncology in experimental models, emphasizing their observed anticancer effects in preclinical studies, safety profile and capacity to enhance the effectiveness of conventional therapies. Despite growing interest, a research gap remains in translating these findings to clinical oncology, an issue this review addresses by proposing future investigative directions. Full article

The gut microbiome has emerged as a critical determinant of health and disease across virtually all organ systems. In the context of chronic kidney disease (CKD) and renal transplantation, mounting evidence reveals a complex bidirectional relationship between the intestinal microbiota and kidney function—commonly referred to as the gut–kidney axis. Patients with CKD harbor a profoundly altered gut microbial ecosystem characterized by reduced diversity, depletion of beneficial commensal organisms, and expansion of pathobiont taxa capable of generating uremic toxins and pro-inflammatory mediators. These perturbations are further compounded by the uremic milieu itself, dietary restrictions, frequent antibiotic exposure, and the use of immunosuppressive agents following transplantation. The gut–liver–kidney axis adds an additional layer of complexity, linking hepatic metabolism, bile acid signaling, endotoxemia, and systemic immune activation to the progression of renal disease. Gut-derived metabolites—including short-chain fatty acids (SCFAs), bile acids, trimethylamine N-oxide (TMAO), and tryptophan-derived uremic solutes such as indoxyl sulfate and p-cresyl sulfate—serve as molecular mediators of inter-organ crosstalk and have been identified as both biomarkers and therapeutic targets. A growing body of literature supports the diagnostic and prognostic utility of microbiome composition and its metabolic signatures in patients with CKD and those undergoing renal replacement therapy. Therapeutic strategies aimed at restoring microbial homeostasis—encompassing dietary interventions, prebiotics, probiotics, synbiotics, fecal microbiota transplantation (FMT), bile acid–based therapies, and novel pharmacological approaches—hold considerable promise for improving outcomes in CKD and transplant recipients. Importantly, the bidirectional relationship between immunosuppressive drugs and the gut microbiota has emerged as a clinically significant determinant of both microbial ecology and drug pharmacokinetics: each major immunosuppressive agent class—corticosteroids, calcineurin inhibitors, mycophenolate mofetil, and mTOR inhibitors—induces characteristic dysbiotic patterns, while in turn, the microbiota modulates drug bioavailability through enzymatic biotransformation (notably bacterial beta-glucuronidase activity affecting mycophenolic acid enterohepatic recirculation) and modulation of host drug-metabolizing enzymes. This narrative review provides a comprehensive overview of the current understanding of microbiome dysbiosis in the setting of renal disease and transplantation, examines the mechanistic underpinnings of the gut–liver–kidney axis, details the multifaceted impact of dysbiosis on transplant outcomes—including allograft function and rejection, infection, post-transplant diabetes, and cardiovascular complications—and critically appraises the translational potential of microbiome-targeted interventions. We conclude by highlighting ongoing challenges and future directions toward personalized, microbiome-informed clinical care. Full article

Traditional speech therapy for children often faces challenges such as fear, a lack of patient motivation, unattractive supportive tools, and a critical shortage of specialized technological tools for under-resourced languages like Slovak. This paper presents a novel conceptual digital speech therapy ecosystem and core technological approaches developed within the 3PoCube project. To address the engagement gap, the proposed framework leverages gamification across five interconnected pillars which are integrating interactive, game-like environments for home practice with asynchronous offline telemedicine to support the parent–child–clinician dynamic. The technological core utilizes state-of-the-art Self-Supervised Learning (SSL) and Transformer-based Automatic Speech Recognition (ASR) models fine-tuned on a newly compiled Slovak children’s speech corpus, consisting of approximately 5 h of annotated speech from 303 speakers. In our experiments, the best-performing Wav2Vec 2.0 MMS architecture achieved a Word Error Rate (WER) of 15.10%, while the adapted Whisper Turbo achieved 16.33% on spontaneous pediatric speech. Several functional prototypes implementing these models are presented, including Neslovkáčik (a telemedicine portal), Hláskové superhrdinstvo (an articulation app), and LogoHra (a highly customizable virtual board game platform). Preliminary formative feedback from parents and speech-language pathologists indicates perceived acceptability during early prototype testing and suggests the potential to support engagement with the proposed solutions. However, while this study establishes a technical and conceptual foundation for home rehabilitation, rigorous clinical validation is required before definitive therapeutic efficacy can be claimed. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC. Full article

Hemophilia is an X-linked inherited bleeding disorder, classified as type A or type B. Therapeutic advances offer new treatment options that improve disease control and reduce associated complications, including inhibitor development and hemophilic arthropathy. This document aims to update the Mexican hemophilia consensus, reviewing current evidence on diagnosis and management, and addressing gaps in the treatment and follow-up of patients in Mexico, aligning local needs with international recommendations. A PubMed literature search covering the last five years (up to September 2025) was conducted, prioritizing consensus statements, guidelines, and systematic reviews. Using the Delphi methodology, a structured questionnaire was submitted electronically to forty-four experts. Aspects without initial agreement were discussed at an in-person meeting. Consensus was defined as at least 80% of votes in favor. Recommendations were issued across six domains: laboratory diagnosis, genetic testing, management of hemophilia A and B without and with inhibitors, adjuvant treatments, and gene therapy. The recommendations address prophylaxis with coagulation factor concentrates, non-factor therapies, immune tolerance induction, perioperative management, pain management, and eligibility criteria and follow-up protocols for gene therapy with adeno-associated viral vectors. This consensus provides updated, evidence-based recommendations adapted to the Mexican healthcare context, identifying priority areas, including timely access to non-factor therapies and gene therapy, development of a national referral network for complex cases, and inclusion of novel therapeutic agents in the institutional essential medicines list, with the aim of improving the quality of life of people with hemophilia in Mexico. Full article

Among cardiovascular diseases, myocardial infarction (MI) has become one of the leading causes of mortality worldwide, and the prevalence is anticipated to rise considerably in the coming years. Within non-surgical procedures, chemical drugs, including diuretics, vasodilators, calcium channel blockers, ꞵ blockers, angiotensin converting enzyme inhibitors, are now a well-established option to treat MI progression. However, these drugs are not developed to mitigate oxidative stress directly, which has been recently proven to contribute to MI advancement. Naturally occurring antioxidant compounds possess promising cardioprotective properties and have the potential to be used both as lead compounds for finding novel drugs and complementary therapy to manage MI. While some of them, namely quercetin, puerarin, α-lipoic acid, and curcumin, have already made their way up to clinical trials, numerous compounds have not been sufficiently investigated clinically. To develop and formulate natural antioxidant compounds as drugs against MI, it is crucial to comprehend their underlying mechanisms of cardio-protective activities and structure–activity relationships (SARs). This comprehensive review sheds light on the contribution of oxidative stress in the pathogenesis and progression of Myocardial Infarction, and highlights the cardio-protective roles of 51 natural antioxidant compounds along with their mechanistic insights and SAR. Full article

The emergence of swine acute diarrhea syndrome coronavirus (SADS-CoV), an alpha-coronavirus that causes fatal enteric disease in neonatal piglets with mortality rates up to 90%, demonstrates that bat-origin coronavirus has expanded its host range to pigs. Although SADS-CoV exhibits significant pandemic potential and capacity for cross-species transmission, the replication mechanisms of SADS-CoV remain largely unexplored. Identifying host factors responsible for SADS-CoV replication and elucidating its underlying mechanisms is essential for advancing fundamental knowledge of coronavirus biology and developing antiviral therapies. Here, we identified PABPC1 as a novel interactor of the SADS-CoV nucleocapsid (N) protein. Overexpression of PABPC1 restricted SADS-CoV infection, whereas knockdown of PABPC1 enhanced viral replication. Further study indicated PABPC1 as a host restriction factor of SADS-CoV in a manner dependent on its PABC domain. Mechanistically, PABPC1 enhances the ubiquitination of the N protein, therefore facilitating its recognition by the cargo receptor TOLLIP for selective autophagic degradation. This study systematically analyzes the interaction of host factors and the SADS-CoV N protein and identifies PABPC1 as a host restriction factor that limits viral replication via TOLLIP-mediated selective autophagy degradation of the N protein. These findings expand our knowledge of the SADS-CoV replication mechanism and provide additional antiviral strategies for controlling SADS-CoV. Full article

Background: Novel Sézary syndrome (SS) biomarker genes identified previously through transcription profiling were examined for changes in expression after mogamulizumab treatment. Incorporating new biomarkers for measuring response to disease would improve clinical care. Objective: To assess novel SS biomarker and cytokine genes in patients treated with mogamulizumab with clinical response, blood response, and immunologic parameters. Methods: We performed a real-world case–control and case–case study analyzing the expression of SS biomarker genes in peripheral blood mononuclear cells (PBMCs) from six SS patients treated with mogamulizumab using qRT-PCR. Results: We demonstrated a reduced expression of SS biomarker genes in PBMCs of SS patients following mogamulizumab therapy. In our cohort, five of the SS biomarker genes (PLS3, TWIST1, KCNK1, DNM3 and TOX) showed statistically consistent high expression compared to normal PBMCs at baseline. After treatment with mogamalizumab, these five SS biomarkers showed significant correlations with skin response (p < 0.05) and three (TOX, TCRL3 and DNM3) with blood response (p < 0.05). A decrease in GATA3 expression correlated to an improvement in skin severity, and STAT4 inversely correlated to Sézary cell decrease (p < 0.05). Two cytokine genes, IL4 and IFNG, reflective of an immune response that is abnormal in SS, showed a trend to normalized expression with IL-4 decreasing and IFNG increasing after treatment. Limitations: This was a real-world study of patients who failed prior treatments, with a small sample size and variable timing between patient sample collection. Conclusions: Unique SS biomarker, cytokine and T cell transcription factor genes are valuable in assessing molecular and immune responses following treatment. Full article

First-line (1L) therapy for mantle cell lymphoma (MCL) continues to evolve rapidly, with several recent phase II and phase III trials consistently showing the activity of novel covalent Bruton’s tyrosine kinase inhibitor (cBTKi) combinations. Historical treatment selection criteria such as patient age, fitness, and eligibility for autologous stem cell transplantation generally remain applicable for some, but not all, of these novel regimens. This potential for flexibility necessitates the consideration of additional factors during decision-making, such as MCL biology, patient risk tolerance, logistical and resource implications, and the impact on use of later-line options. This paper presents three illustrative patient cases to explore 1L therapy selection among these new and emerging cBTKi options. The realized and anticipated benefits, limitations, and challenges and persisting evidence gaps associated with these regimens are discussed. Full article

Background: Metronomic chemo-endocrine therapy combining fulvestrant with metronomic VEC (vinorelbine, cyclophosphamide, and capecitabine)—the FulVEC regimen—demonstrated promising activity in an initial cohort of 38 patients with advanced ER+/HER2− breast cancer (JCM 2023). Here, we present an extended analysis of 72 consecutive patients, with a focus on a novel hypothesis: that treatment-emergent adverse events (AEs) requiring dose modification serve as a surrogate for sufficient pharmacological exposure in metronomic combination chemotherapy. Methods: Retrospective analysis of 72 consecutive patients with metastatic ER+/HER2− breast cancer treated with FulVEC at Jagiellonian University Hospital between 2018 and 2024. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and biochemical response, as assessed by CA15-3 dynamics. Patients were stratified by AE severity requiring intervention (grade 0: no modification; grade 1: dose reduction; and grade 2: treatment delay). The association between AE grade and efficacy outcomes was assessed using Spearman’s correlation, the log-rank test, and the chi-square test. Results: The median PFS was 8.5 months, and the median OS was 18.0 months. The biochemical benefit rate (any CA15-3 decline) was 81.6%. No statistically significant differences in efficacy were observed according to prior exposure to CDK4/6 inhibitors, fulvestrant, or cytotoxic components of the FulVEC regimen. A monotonic dose–response relationship was observed across AE grade categories: non-progression rates increased from 73.2% (grade 0) to 84.2% (grade 1) and 91.7% (grade 2); biochemical benefit rates from 68.4% to 90.9% and 100.0%; and median CA15-3 reduction deepened from −34% to −44% and −52%, respectively (Spearman r = 0.258 and p = 0.043 for AE grade vs. treatment duration). Formal log-rank comparisons of PFS and OS across the three AE-grade categories did not reach statistical significance (p = 0.583 and p = 0.743, respectively), reflecting the limited size of the treatment-delay subgroup (n = 12); the dose–response signal should, therefore, be regarded as exploratory. No patient required permanent treatment discontinuation due to toxicity. Conclusions: The extended FulVEC cohort confirms durable activity and a reproducible, manageable safety profile in a heavily pretreated population, including CDK4/6i-refractory patients. The exploratory, hypothesis-generating observation of a dose–response gradient between AE severity and clinical outcomes raises the possibility that treatment-emergent AEs may, in some patients, reflect adequate pharmacological exposure to the metronomic regimen. Given confounding by treatment duration and survivor bias, and the absence of pharmacokinetic data, this hypothesis requires prospective validation and does not, at this stage, support any change to current treatment practice. Full article