Artificial intelligence (AI) has revolutionized every field of medicine [...]

Mechanotransduction critically shapes tumor progression by regulating cytoskeletal remodeling, epithelial-to-mesenchymal transition (EMT), invasion, and immune evasion. Polycystin-1 (PC1) and polycystin-2 (PC2), established mechanosensitive proteins in epithelial systems, have recently been implicated in tumor biology; however, their roles across diverse solid malignancies remain insufficiently defined. We assessed PC1 and PC2 expression patterns and their associations with clinicopathological features in human lung, breast, prostate, and brain tumors. PC1 functional modulation was performed in xenograft models using an extracellular mechanosensitivity-blocking antibody, and in cancer cell lines via polycystic kidney disease 1 (PKD1) siRNA. We evaluated consequences on EMT, tumor growth, migration, and the mechanotransduction effector TAZ. PC1 and PC2 exhibited strong positive correlation across multiple tumor types, indicating coordinated mechanobiological regulation in cancer. Their expression associated with clinically aggressive features, including PD-L1 expression in lung cancer, adverse pathological characteristics in prostate cancer, and poorer survival in HER2⁺ breast cancer with elevated PC2 levels. In vivo, inhibition of PC1 mechanosensing consistently attenuated EMT programs across tumor types, accompanied by reductions in tumor growth. In vitro, PKD1 silencing reduced cell migration and induced context-dependent modulation of EMT markers. Notably, PC1 suppression induced TAZ activation in breast cancer and glioma cells, indicating a cell type-specific regulatory interaction between PC1 and Hippo-mechanotransduction signaling. Our data suggest that polycystins, PC1 in particular, exert conserved yet context-dependent mechanoregulatory functions in solid tumors. By influencing EMT, migration, tumor progression, and TAZ-mediated mechanotransduction, PC1 emerges as a potential biomarker and mechanotherapeutic target in mechanically responsive cancers.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder characterized by sterile bone lesions, heterogeneous clinical presentation, and the absence of validated diagnostic or prognostic biomarkers. Traditionally considered a distinct disease entity, emerging genetic, mechanistic, and translational evidence challenges this view. Emerging genetic, mechanistic, and translational evidence suggests that CNO may represent a convergent clinical phenotype of sterile bone inflammation arising from diverse disturbances in innate immunity. Central to its pathogenesis is the inflammasome-interleukin-1 beta (IL-1β) axis, which integrates upstream signals from genetic variants, cytokine imbalance, and environmental factors, ultimately driving osteoclast activation and bone remodeling. Recent advances highlight the role of biomarkers as translational tools linking molecular mechanisms to clinical phenotypes. Although whole-body MRI remains central to disease assessment, integration of imaging with molecular biomarkers may provide more comprehensive disease stratification. Conventional markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) show limited utility, whereas pathway-relevant biomarkers, including cytokine profiles, P2X purinoceptor 7 (P2X7R) signaling, and the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio provide deeper insight into disease biology. These biomarkers may ultimately enable biologically driven patient stratification and inform future targeted therapeutic approaches, although prospective validation remains necessary. Reframing CNO as a convergent phenotype supports a mechanism-based classification and offers a framework for precision medicine approaches, with implications extending beyond pediatric rheumatology to inflammatory bone diseases more broadly.

Pediatric astrocytomas are characterized by increased molecular and clinical heterogeneity with epigenetic alterations contributing to aggressiveness and therapy resistance. The repressive histone mark H4K20 trimethylation (H4K20me3) and the methyltransferase SUV4-20H2 (KMT5C) are critical regulators of chromatin integrity and genome stability, with limited investigation in pediatric astrocytomas. KMT5C mRNA levels were evaluated in a publicly available pediatric gliomas database using bioinformatic analysis. Investigation of SUV4-20H2 and H4K20me3 expression was performed in a cohort of 43 pediatric astrocytoma tissues by immunohistochemistry. Their functional role and mechanism of action was investigated in pediatric glioma cell lines by using the substrate-competitive inhibitor of SUV4-20, A-196. Cell viability, apoptosis and migration were assessed using XTT, cleaved PARP, and wound healing assays, respectively. Effects of treatment on H4K20 methylation, DNA damage, mitotic stress [Polo-like kinase (PLK1) expression], and invasion markers (N-cadherin, β-catenin expression) were examined by western immunoblotting. KMT5C mRNA was significantly enriched in pediatric high-grade astrocytomas compared to low-grade tumors. A significant elevation of SUV4-20H2 and H4K20me3 expression was detected in astrocytoma tissues indicating epigenetic dysregulation contributing to malignancy. Treatment with A-196 reduced cell proliferation of pediatric glioma cell lines and induced apoptosis in a dose-dependent manner. It further impaired cell migration, accompanied by reduced N-cadherin and β-catenin expression. Mechanistically, inhibition of SUV4-20 depleted H4K20me3, inducing chromatin destabilization, replication-associated DNA damage and was associated with increased PLK1 expression, consistent with activation of a mitotic stress response. Our findings indicate that SUV4-20H2-mediated H4K20 activity in pediatric high-grade astrocytomas maintains their growth and migratory potential by regulating chromatin integrity and may serve as potential therapeutic target.

Skeletal safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) remains uncharted, with emerging evidence suggesting a divergence between mono- and dual-agonist therapies. GLP-1RA monotherapy appears bone-neutral, with modest or no adverse effects on bone mineral density (BMD), whilst dual agonists may confer a relatively higher risk of osteoporosis and fractures, plausibly mediated by greater weight loss magnitude and concomitant reductions in lean body mass (LBM) rather than direct osteotoxicity. Intensified surveillance is warranted in susceptible phenotypes, including older adults and postmenopausal women with low baseline BMD under conditions of rapid weight loss. Osteoporosis risk is further amplified by pre-existing osteopenia, nutritional deficiencies, and concomitant exposure to bone-active agents. Given the limitations of serial dual-energy X-ray absorptiometry (DXA), including cumulative radiation exposure and limited sensitivity to early remodeling changes, biochemical markers potentially depict bone turnover more dynamically. Measurement of dynamic bone resorption markers enables early identification of skeletal disturbances, supporting proactive adjustment of therapeutic strategy, dosing, and duration. Specifically, deoxypyridinoline (DPD), a bone-specific collagen crosslink, is a highly sensitive and rapidly responsive urine biomarker of osteoclastic activity. Incorporating DPD urine testing into monitoring frameworks potentially facilitates individualized therapeutic modulation, optimizing the metabolic efficacy of GLP-1RAs while safeguarding skeletal integrity.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal prognosis. Although immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancer, their impact in SCLC has been modest, with only 2-3 months' improvement in median survival. This paradox persists despite SCLC's high tumor mutational burden, suggesting complex, multifactorial resistance mechanisms. Here we critically review the latest advances in understanding immunotherapy resistance in SCLC. We highlight tumor-intrinsic immune escape mechanisms, including genetic drivers, MHC class I downregulation, and epigenetic repression, as well as the profoundly immunosuppressive tumor microenvironment. We also examine the evolving classification of SCLC into molecular subtypes, which reveals distinct immunogenic landscapes with potential predictive value for immunotherapy response. Importantly, we integrate a comprehensive update on ongoing and recently reported clinical trials that aim to restore immune responsiveness, ranging from combination ICI regimens to novel strategies involving epigenetic modulators, antigen presenting pathway agonists, and bispecific T-cell engagers. Finally, we discuss translational strategies to overcome immunotherapy resistance and outline a precision immunotherapy roadmap, arguing for biomarker-guided and subtype-stratified clinical trial design. By synthesizing mechanistic, translational, and clinical perspectives, this review provides a framework for rational therapeutic innovation in SCLC.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal prognosis. Although immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancer, their impact in SCLC has been modest, with only 2–3 months improvement in median survival. This paradox persists despite SCLC’s high tumor mutational burden, suggesting complex, multifactorial resistance mechanisms. Here we critically review the latest advances in understanding immunotherapy resistance in SCLC. We highlight tumor-intrinsic immune escape mechanisms, including genetic drivers, MHC class I downregulation and epigenetic repression, as well as the profoundly immunosuppressive tumor microenvironment. We also examine the evolving classification of SCLC into molecular subtypes, which reveals distinct immunogenic landscapes with potential predictive value for immunotherapy response. Importantly, we integrate a comprehensive update on ongoing and recently reported clinical trials that aim to restore immune responsiveness, ranging from combination ICI regimens to novel strategies involving epigenetic modulators, antigen presenting pathway agonists, and bispecific T-cell engagers. Finally, we discuss translational strategies to overcome immunotherapy resistance and outline a precision immunotherapy roadmap, arguing for biomarker-guided and subtype-stratified clinical trial design. By synthesizing mechanistic, translational, and clinical perspectives, this review provides a framework for rational therapeutic innovation in SCLC.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy with notable high rates of therapeutic failure. Diversity in prognostication reflects the interplay between differential environmental exposures-tobacco, alcohol, human papillomavirus (HPV) infection-and the intrinsic genomic heterogeneity of HNSCC. The present Perspective elaborates upon a multiplex genomic panel targeting key disrupted pathways and clinically relevant genes, including cell-cycle regulators (tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A)), lineage-determining pathways (NOTCH1-3, FAT atypical cadherin 1 (FAT1)), HPV-associated oncogenic drivers (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3), and targetable receptor tyrosine kinase (RTK) alterations. Mapping the multilayered genetic nature enhances stratification by identifying prognostic subtypes and therapeutic vulnerabilities. To advocate the broad adoption of multi-gene panels in diagnostic algorithms, a pre-screening based on HPV-status and anatomic site of carcinoma is merited, to ensure the optimal selection of biomarkers. Nevertheless, the prognostic value of selected genes should be established in wide genomic clinical trials, regarding drug response and overall survival rate (OSR). This article aims to elucidate the clinical utility of several genetic alterations towards a genetically informed prognostication and rationalized combination of novel targeted therapeutic tools.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that establishes lifelong latent infection [...]

The therapeutic interventions for pulmonary arterial hypertension (PAH) have predominantly focused on facilitating pulmonary blood flow by inducing vasodilation to reduce the mechanical resistance against the right ventricle (RV) [...]

Severe eosinophilic asthma remains a major therapeutic challenge despite advances in biologic therapies targeting type 2 inflammation. Depemokimab (Exdensur®), a novel ultra-long-acting anti-interleukin-5 (IL-5) monoclonal antibody, introduces a new treatment paradigm through sustained eosinophil suppression and twice-yearly administration. Engineered with enhanced IL-5 binding affinity and fragment crystallizable (Fc) modifications that prolong systemic persistence, depemokimab achieves durable pharmacodynamic activity and extended dosing intervals. Phase III SWIFT-1 and SWIFT-2 trials demonstrated significant reductions in annualized asthma exacerbations, with efficacy comparable to established anti-IL-5 agents and a favorable safety profile. However, benefits in lung function, symptom control, and quality of life have been less consistent, underscoring the complex relationship between eosinophilic inflammation and broader disease manifestations. The principal advantage of depemokimab lies in its potential to reduce treatment burden, improve adherence, and decrease healthcare utilization. As severe asthma management evolves, depemokimab represents a promising patient-centered option, although optimal patient selection and long-term outcomes require further investigation.

Bilirubin, a metabolite of hemoglobin and a biomarker of liver function, has been considered for quite some time as harmful metabolic waste [...]

Bone is a highly mechanosensitive tissue that adapts its function in response to mechanical cues. These cues are converted into biomechanical signals that regulate osteogenic gene expression through mechanotransduction. Bone homeostasis and the long-term bone adaptation to its mechanical environment depend on the proper integration of mechanical signals with transcriptional programs that regulate osteogenesis. Runt-related transcription factor 2 (RUNX2) is a pioneer transcription factor, a mechanosensitive molecule, which coordinates osteoblast differentiation and bone remodeling. RUNX2 activity in mechanically induced environments is subject to epigenetic regulation. Mechanical cues modulate RUNX2 through epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Proper epigenetic coordination ensures the stability of osteogenic gene expression. Any disruption of this mechanotransduction-epigenetic route leads to bone diseases such as osteoporosis, osteoarthritis, and dysfunctional fracture repair. Moreover, epigenetic reprogramming of RUNX2 is increasingly evident in bone tumors, particularly osteosarcoma, where aberrant RUNX2 activity is associated with cell proliferation, tumor progression, survival, metastasis, and loss of differentiation. This chapter examines current evidence on RUNX2 epigenetic regulation in response to mechanical forces, discusses how its orchestration relates to bone disease and bone tumor development, and underscores potential therapeutic opportunities that arise from targeting specific epigenetic mechanisms.

Background:Progressive loss of pancreatic β-cell function in type 2 diabetes mellitus (T2DM) is linked to endoplasmic reticulum (ER) stress-induced apoptosis. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have glucose-lowering and potential cytoprotective effects. We investigated whether empagliflozin protects β-cells from ER stress-mediated apoptosis and the underlying pathway. Methods:Mouse Beta-TC-6 (BTC-6) and hamster HIT-T15 pancreatic β-cell lines were exposed to tunicamycin (5 or 10 μg/mL) to induce ER stress, with or without empagliflozin (10-8, 10-9, 10-10 M). SGLT-1 and SGLT-2 mRNA were assessed by RT-qPCR. Expression of ER stress markers (GRP-94, BiP, PERK, eIF-2α, IRE-1, ATF-4, CHOP) was measured by RT-qPCR; eIF-2α, phospho-eIF-2α and CHOP protein levels were analyzed by Western blot. Cell proliferation and apoptosis were quantified by XTT and Annexin V-FITC assays. Results:BTC-6 cells expressed SGLT-1 but not SGLT-2. Empagliflozin (10-8 and 10-9 M) increased BTC-6 proliferation (p < 0.01 and p < 0.05 respectively). Tunicamycin caused significant apoptosis after 48h (p < 0.001). Co-treatment with empagliflozin (10-8, 10-9 M) significantly reduced tunicamycin-induced apoptosis, especially at 5 μg/ml tunicamycin (p < 0.01). Empagliflozin co-incubation lowered PERK, eIF-2α, IRE-1α and CHOP mRNA levels versus tunicamycin alone (all p < 0.05), and decreased phospho-eIF-2α (p < 0.01) and CHOP (p < 0.05) protein levels. Similar anti-apoptotic effects were observed in HIT-T15 cells. Conclusions:Empagliflozin enhances β-cell proliferation and attenuates ER stress-induced apoptosis in vitro, primarily via downregulation of the PERK-eIF-2α-CHOP pathway. These findings support further investigation of SGLT-2 inhibitors for preservation of β-cell survival and function.