Search Results (9,067)

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle loss, affecting 30–60% of patients with advanced renal cell carcinoma (RCC). It significantly impacts treatment tolerance, quality of life, and prognosis, yet its diagnosis and management remain challenging due to fragmented RCC-specific evidence, particularly in the era of immune checkpoint inhibitor (ICI)-based therapy. The pathogenesis involves persistent systemic inflammation, metabolic reprogramming, and tumor–host interactions. The IL-6/STAT3 and TNF-α/NF-κB pathways are central to muscle catabolism, while tumor-derived mediators such as GDF15 and PTHrP, along with mitochondrial dysfunction, further drive cachexia progression. For prognostic assessment, CT-derived skeletal muscle mass evaluation combined with systemic inflammatory and nutritional biomarkers—including neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), and cachexia index (CXI)—has improved risk stratification in advanced RCC. Preclinical and emerging clinical data suggest that targeted therapies may partially attenuate cachexia by modulating inflammatory signaling, while multimodal interventions integrating nutritional support and exercise rehabilitation remain the cornerstone of management. Novel strategies, such as inhibition of the GDF15/GFRAL axis, are under active investigation. Future research should prioritize identification of early biomarkers, standardization of cachexia assessment, and prospective evaluation of cachexia-directed interventions in the immunotherapy era. Integrating cachexia assessment into routine practice may ultimately enable personalized treatment and improve long-term outcomes for patients with advanced RCC. Full article

Background/Objectives: Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in cardiovascular disease, particularly through the transfer of regulatory microRNAs. However, direct evidence of cytosolic microRNA delivery by mesenchymal stem cell (MSC)-derived EVs into cardiomyocytes remains limited. Many prior studies have inferred transfer without fully excluding endogenous microRNA induction or surface-bound artifacts. The objective of this study was to determine whether MSC-derived EV microRNA undergoes functional cytoplasmic delivery into cardiomyocytes and to identify the endocytic pathways involved. Methods: To eliminate background from endogenous microRNA expression, MSC-derived EVs were loaded with the exogenous microRNA cel-miR-39-3p. H9C2 cardiomyocytes were treated with increasing vesicle doses, and intracellular microRNA levels were quantified using real-time polymerase chain reactions. Cytosolic accessibility was assessed indirectly using a cholesterol-modified antagomir targeting cel-miR-39-3p. Pharmacologic inhibitors of macropinocytosis (5-(N-ethyl-N-isopropyl) amiloride (EIPA)) and clathrin-mediated endocytosis (chlorpromazine and ES9-17) were applied to delineate uptake pathways, with transferrin assays confirming clathrin inhibition. Results: EV treatment produced a dose-dependent increase in intracellular cel-miR-39-3p levels. Antagomir administration reduced intracellular microRNA levels by 89%, providing indirect functional evidence that transferred cel-miR-39-3p reached an antagomir-accessible cytosolic compartment. At the highest preparation dose, EIPA and ES9-17 reduced cell-associated cel-miR-39-3p by 71% and 36%, respectively, consistent with contributions from EIPA-sensitive and clathrin-associated uptake processes. Notably, chlorpromazine increased microRNA accumulation despite blocking transferrin uptake, suggesting compensatory or membrane curvature-dependent effects. Conclusions: These findings provide strong functional evidence that exogenous cel-miR-39-3p associated with MSC EV preparations reaches an antagomir-accessible cytoplasmic compartment in H9C2 cardiomyocytes and implicate EIPA-sensitive uptake consistent with macropinocytosis and clathrin-associated uptake. Additional genetic, localization, and pulse-chase studies are required to establish the precise intracellular trafficking mechanisms. This work strengthens the mechanistic foundation for EV-based therapies and informs the rational development of cell-free strategies for cardiovascular disease. Full article

Matrix metalloproteinases (MMPs) have long been recognized as key mediators of tumor invasion and metastasis due to their capacity to degrade extracellular matrix components. However, clinical failure of broad-spectrum MMP inhibitors has revealed a more complex and context-dependent role for these proteases in cancer. Among them, macrophage metalloelastase, MMP-12, has emerged as a particularly intriguing enzyme with both tumor-promoting and tumor-suppressive functions. Predominantly expressed by tumor-associated macrophages, MMP-12 occupies a unique position at the interface of proteolysis, inflammation, and immune regulation within the tumor microenvironment. Accumulating evidence from experimental models and clinical studies demonstrates that MMP-12 can exert potent anti-tumorigenic effects, primarily through inhibition of angiogenesis. Mechanistically, MMP-12 generates angiostatin and other anti-angiogenic fragments, suppresses vascular endothelial growth factor signaling, and reduces tumor vascularization, thereby limiting tumor growth and metastatic expansion. In several cancer types, including lung, colorectal, and hepatocellular carcinoma, elevated MMP-12 expression has been associated with reduced tumor progression and improved patient outcomes. Conversely, MMP-12 can also promote tumor progression through extracellular matrix remodeling, facilitation of invasion, and modulation of inflammatory pathways, particularly in environments characterized by chronic inflammation or immunosuppressive macrophage phenotypes. These seemingly contradictory roles are governed by multiple context-dependent factors, including macrophage polarization, tumor type, disease stage, and microenvironmental cues such as hypoxia and cytokine signaling. In this review, we comprehensively examine the molecular regulation, functional mechanisms, and clinical relevance of MMP-12 in cancer. We highlight the dualistic nature of MMP-12 activity and discuss its implications for therapeutic strategies, emphasizing the need for selective and context-aware targeting approaches rather than broad inhibition of MMP activity. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with lymph node metastasis (LNM) being a key predictor of recurrence and poor prognosis. Preoperative detection of LNM remains challenging due to the limitations of imaging modalities, leading to inadequate surgical resection in 20–30% of patients. While immune checkpoint molecules have been implicated in PTC progression, the heterogeneity of CD8⁺ T cell exhaustion subsets and their specific association with LNM remain poorly defined. In this study, we aimed to perform an exploratory characterization of the distinct immune landscape of PTC prone to LNM, with a focus on terminal immune exhaustion, in order to generate hypotheses for improved risk stratification and therapeutic strategies. Methods: Fresh PTC tissues from 40 patients (22 LNM-positive and 18 LNM-negative) were analyzed via flow cytometry (FCM) to quantify immune cell subsets, inflammatory cytokines, and chemokines. Immunohistochemistry (IHC) validated CD45⁺ immune cell infiltration. Transcriptomic and clinical data from 448 PTC patients in The Cancer Genome Atlas (TCGA-PTC) cohort were used for bioinformatic analysis consistent with the observed phenotype, including Gene Set Variation Analysis (GSVA) of terminal exhaustion gene signatures. Results: LNM-positive PTC exhibited a unique inflammatory milieu with significantly elevated IL-6, IL-1ra, CCL5, and IL-9 levels (all p < 0.05) in tumor interstitial fluid. FCM analysis revealed that LNM-positive PTC had increased infiltration of total CD45⁺ immune cells, CD3⁺ T cells, and CD3⁺CD8⁺ T cells (all p < 0.05). Critically, terminally exhausted PD-1^hiTIM-3⁺ CD8⁺ T cells were significantly enriched in LNM-positive PTC (p = 0.022) and positively correlated with extrathyroidal extension (p = 0.044). Additionally, LNM risk was associated with increased CD4⁺ regulatory T (Treg) cell frequency (p = 0.023) and elevated CTLA-4 expression on CD4⁺ T cells (p = 0.047). In TCGA-PTC validation, the terminal exhaustion gene signature was predominantly enriched in LNM-positive (p < 0.0001) and advanced-stage PTC (p < 0.001) and strongly correlated with BRAF mutation (predominantly V600E) (p < 0.0001)—the most common oncogenic driver in aggressive PTC. Conclusions: Our findings suggest a terminal immune exhaustion phenotype (characterized by PD-1^hiTIM-3⁺ CD8⁺ T cells and Treg enrichment) as a potential key feature associated with LNM-prone PTC. This phenotype shows consistency across clinical samples and TCGA datasets, linking BRAF mutation (predominantly V600E) to immune suppression and metastatic potential. These insights provide a novel exploratory immune-based biomarker for LNM risk stratification and support the potential of combining anti-PD-1/TIM-3 therapy with BRAF inhibitors for high-risk PTC, which should be confirmed in future studies. Full article

Drug resistance in cancer remains a major barrier to durable therapeutic benefits and limits the effectiveness of chemotherapy, targeted therapy, and combination treatment in multiple malignancies. Increasing evidence indicates that specific kinesin superfamily proteins contribute to tumor adaptation and therapeutic response in a context-dependent manner through their roles in mitotic regulation, intracellular transport, and stress-response pathways. Aberrant expression of multiple kinesin family members has been documented across diverse cancers and is frequently associated with aggressive clinicopathological features, poor prognosis, and resistance to treatment. However, expression alterations alone do not establish functional dependency, and mechanistic validation is required to distinguish true resistance drivers from adaptive tumor states. In this review, we summarize the classification, biological functions, and abnormal expression patterns of kinesins in cancer; discuss the major mechanisms through which they contribute to drug resistance; and examine strategies for targeting kinesins, including natural-product-derived direct inhibitors, small-molecule inhibitor development, rational combination approaches, and structure-guided and computational optimization strategies. We also evaluate the biomarker potential of kinesin dysregulation and the value of advanced preclinical models for mechanistic and translational investigations. Finally, we highlight the major challenges that hinder clinical translation, including target specificity, compensatory resistance, insufficient biomarker validation, and tumor heterogeneity. Future progress will require integration of functional genomics, multiomics profiling, and mechanism-guided therapeutic strategies to determine when kinesin inhibition represents a clinically actionable approach for resistant malignancies. Full article

Routine husbandry procedures in sheep induce significant and prolonged pain and inflammation, which often exceeds the duration of action of current commercially available analgesics. Mavacoxib is a selective cyclooxygenase-2 (COX-2) inhibitor approved for canine osteoarthritis treatment. With a half-life exceeding two weeks in dogs, mavacoxib may represent a candidate for investigating whether extended-duration analgesia can be achieved in sheep and more closely aligned with the duration of post-procedural inflammation and pain. This article examines the physiological and behavioural indicators of sheep pain, the limitations of current analgesic strategies, and the pharmacological rationale for mavacoxib as a candidate for pain management in sheep. Further research into its pharmacokinetics, efficacy, and safety in sheep is essential to improve welfare and overcome practical barriers to analgesia in extensive grazing systems. Full article

Cancer immunotherapy has transformed the treatment of multiple malignancies; however, primary and acquired resistance remain major clinical challenges. Because effective immune recognition depends on the repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules, increasing attention has focused on the antigen processing and presentation pathway as a therapeutic target to enhance tumor immunogenicity. Among its key regulators, the endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 shape the MHC-I immunopeptidome by trimming peptide precursors before antigen presentation. Beyond this canonical function, accumulating evidence indicates that ERAP aminopeptidases are multifunctional proteins involved in inflammation, angiogenesis, ER stress responses, cell migration, and tumor-intrinsic signaling. These moonlighting activities suggest that ERAP enzymes influence cancer progression through both immune-dependent and immune-independent mechanisms. Recent advances in medicinal chemistry have enabled the development of selective ERAP1 inhibitors, leading to the first clinical evaluation of this therapeutic strategy and providing early clinical evidence that pharmacological modulation of antigen processing may complement existing immunotherapies. In this review, we summarize the multiple functions of ERAP aminopeptidases in cancer, discuss their role in regulating adaptive and innate immune responses, and highlight emerging therapeutic strategies and future challenges for exploiting ERAP-targeted interventions in precision immuno-oncology. Full article

This review aims to provide a comprehensive overview of the currently available therapies for primary vitreoretinal lymphoma (PVRL) and to evaluate emerging therapeutic strategies that may improve patient outcomes. A comprehensive literature search was conducted in databases including PubMed/MEDLINE, Embase, and Scopus for studies published up to 2026. Search terms included “primary vitreoretinal lymphoma”, “intravitreal methotrexate”, “rituximab”, “radiotherapy”, “targeted therapy”, and “immunotherapy”. Eligible publications included randomized controlled trials, prospective and retrospective studies, observational studies, systematic reviews, relevant clinical guidelines, case series, and case reports. Studies were independently screened and assessed by two reviewers. Current therapeutic strategies include intravitreal chemotherapy, systemic high-dose methotrexate-based regimens, and radiotherapy, either as monotherapy or in combination. While intravitreal approaches provide effective local disease control, they fail to address occult or subsequent central nervous system (CNS) dissemination, necessitating the use of systemic treatments in selected patients. In recent years, significant progress in the understanding of PVRL pathophysiology, including the role of MYD88 mutations and interleukin-10 signaling, has paved the way for the development of targeted and immunomodulatory therapies. Agents such as Bruton’s tyrosine kinase inhibitors, immunomodulatory drugs, and immune checkpoint inhibitors have demonstrated promising results in early clinical studies, particularly in relapsed or refractory disease. Despite advances in diagnostic techniques, the management of PVRL remains challenging due to its heterogeneous presentation, high relapse rates, and frequent progression to CNS involvement. Full article

The Alternative Lengthening of Telomeres (ALT) pathway drives replicative immortality in aggressive malignancies, particularly sarcomas and gliomas. Clinical ALT stratification has relied on screening for structural ATRX and DAXX mutations. However, this genotypic approach fails to capture the dynamic macro-reprogramming required to sustain ALT. Here, we established and validated a 28-gene transcriptomic signature that captures the ALT-associated transcriptomic phenotype of the ALT phenotype. Using multivariate Cox proportional hazards models and time-dependent ROC analyses, we demonstrate that this signature is a robust, independent predictor of poor overall survival in Sarcoma (SARC) and Lower Grade Glioma (LGG) cohorts, outperforming the prognostic value of traditional ATRX/DAXX mutational status. Genomic mapping revealed this transcriptional synchrony is structurally facilitated by non-random focal clustering on Chromosome 8. To deconstruct the machinery driving this lethal phenotype, we employed an integromic approach, synthesizing protein–protein and metabolic flux networks. Topological algorithms prioritized five indispensable hubs: TP53, ATM, ATR, PCNA, and UBE2I. Gene–metabolite profiling identified PCNA as a bottleneck funneling extreme deoxyribonucleotide (dNTP) demand to sustain break-induced telomeric recombination. To translate these vulnerabilities into actionable treatments, we mapped these hubs to a precision pharmacological network. We propose a multi-targeted strategy combining FDA-approved PARP inhibitors to exploit ATR-mediated synthetic lethality, alongside antimetabolites to induce nucleotide starvation. This study redefines ALT risk stratification and provides a data-driven framework to target and treat resistant ALT-positive tumors. Full article

Chloride-induced steel corrosion is one of the major causes of durability degradation in reinforced concrete (RC) structures. Conventional inhibitors have inherent drawbacks in environmental safety, long-term stability, and cement compatibility. Plant extracts, featuring renewability, biodegradability, and abundant bioactive components, have emerged as promising green corrosion inhibitors. This review summarizes the categories, inhibition mechanisms, and evaluation methods of plant-based inhibitors, and discusses multi-scale characterization and computational techniques for mechanism research. A conceptual Ginkgo biloba extract (EGb)-LDH strategy is discussed as a possible future route for plant-based inhibitor delivery, but its chloride-responsive release and corrosion-protection performance remain to be experimentally verified. Full article

Background/Objectives: Conventional clinical and dermoscopic assessment may overestimate treatment response in locally advanced basal cell carcinoma (laBCC) treated with Hedgehog pathway inhibitors due to treatment-induced fibrosis, pigment retention, and stromal remodeling. Reflectance confocal microscopy (RCM) enables noninvasive, near-histologic resolution skin imaging and may improve response evaluation accuracy. This study evaluated the role of RCM in monitoring treatment response and guiding presurgical planning in laBCC patients treated with sonidegib. Methods: In this prospective, single-center, observational pilot study, 15 consecutive patients with laBCC unsuitable for upfront surgery received sonidegib 200 mg daily. Treatment response was assessed using integrated clinical examination and RCM at baseline and follow-up. Study-specific response categories (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) were adapted from RECIST principles. Presurgical RCM mapping was performed in partial responders. Interobserver agreement between two blinded RCM readers was assessed using Cohen’s kappa (κ). Results: The objective response rate was 93.3% (CR: 26.7%; PR: 66.7%; PD: 6.7%). Dose modifications were required in 73.3% of patients; adverse events occurred in 60.0%, most commonly dysgeusia (33.3%) and muscle cramps (20.0%). Clinical–RCM discordance was identified in 13.3% of patients: lesions classified as CR by conventional evaluation were reclassified as PR after RCM detected persistent basaloid tumor nests, prompting treatment continuation (Interobserver agreement: κ = 0.62–0.86). Conclusions: RCM identified residual disease missed by conventional assessment, directly influencing treatment decisions. These findings support integrating RCM into a multimodal, response-adapted management strategy for laBCC. However, the limited sample size warrants cautious interpretation, and larger multicenter studies are required before broad clinical implementation. Full article

Recurrent vulvovaginal candidiasis (RVVC), commonly defined as ≥3 symptomatic episodes per year, affects an estimated 138 million women worldwide. This structured narrative review (PubMed/MEDLINE and open-indexed sources, January 2020–July 2026, as well as selected pre-2020 landmark studies) synthesizes epidemiological and metabolic risk factors (including SGLT2-inhibitor-associated susceptibility), host immunogenetic and vaginal microbiome mechanisms, emerging preventive pharmacotherapies, and patient-reported outcomes within a unified clinical framework. RVVC arises from interacting host, microbial, metabolic, behavioral, and iatrogenic domains—diabetes-related hyperglycemia, innate immune polymorphisms (MBL2, TLR2), altered bacterial–fungal vaginal communities, and non-albicans Candida in difficult-to-treat cases. Fluconazole maintenance remains a guideline-supported suppressive option but relapse after discontinuation is common; oteseconazole and ibrexafungerp expand prevention choices, while probiotics show inconsistent, low-certainty benefit. RVVC consistently impairs health-related quality of life, sexual function, and mental health and imposes substantial economic burden; regional data from Southeastern Europe underscore diagnostic and access gaps. We propose a multifactorial host–pathogen–microbiome model that favors individualized, diagnosis-driven management and routine incorporation of validated patient-reported outcomes. Research priorities include harmonized case definitions, head-to-head trials of new agents, validated quality-of-life instruments, longer post-treatment follow-up, and real-world cost-effectiveness evaluations. Implementation research, equitable access strategies, clinician education, and national health policy are essential to translate evidence into improved patient outcomes globally. Full article

Native Lactic Acid Bacteria (LAB) isolated from fruits and vegetables in Chile’s Maule Region were identified as Lactiplantibacillus plantarum and L. pentosus. Their growth and lactic acid production were evaluated under furan inhibitor stress (furfural and 5-methylfurfural (5-MF)) relevant to agroindustrial waste valorization. In fruit hydrolysates containing natural furans (11–57 mg/L), LAB grew similarly to inhibitor-free controls and produced 17–25 g/L lactic acid. Under controlled conditions, furfural at 12 g/L reduced bacterial growth by over 80% and decreased lactic acid production to only 2 g/L. In contrast, 5-MF at the same concentration allowed substantially higher tolerance, with up to 7 g/L lactic acid. Benchmarked directly against the commercial reference strain Lactiplantibacillus plantarum PL8014 under identical conditions, the native isolate B1 matched or exceeded PL8014’s lactic acid output in most furfural and 5-MF concentrations tested, including the two most severe 5-MF conditions. Logistic growth and Luedeking–Piret models accurately described both bacterial growth dynamics and lactic acid production kinetics under all inhibitory conditions (R² > 0.96). Inhibitor concentration proved more critical than inhibitor type, although furfural consistently showed stronger potency. These findings confirm the biotechnological potential of native Maule LAB and provide quantitative kinetic parameters for optimizing lactic acid production from lignocellulosic waste, supporting circular economy strategies. Full article

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA. Full article

Clear cell renal cell carcinoma (ccRCC) is a highly immune-evasive malignancy that exhibits limited and often transient responses to immune checkpoint inhibitors (ICIs) and remains a major challenge for emerging cellular immunotherapies, including chimeric antigen receptor (CAR)-T cells. A defining feature of ccRCC, largely driven by von Hippel–Lindau (VHL) deficiency, is persistent activation of the transforming growth factor-β1 (TGF-β1) and hypoxia-inducible factor (HIF) signaling network. Acting as a central immunometabolic regulatory axis, TGF-β1/HIF promotes angiogenesis, metabolic reprogramming, epigenetic dysregulation, and immune escape through coordinated induction of immunosuppressive mediators, including PD-L1, VEGF, and CTLA-4, resulting in impaired T-cell infiltration, functional exhaustion, and resistance to immunotherapy. Preclinical studies have demonstrated that pharmacologic-dose Seleno-L-methionine (SLM) and its active metabolite, methylseleninic acid (MSA), suppress TGF-β1 and both HIF-1α and HIF-2α, leading to downregulation of multiple downstream immunosuppressive pathways at pharmacologically achievable, non-toxic concentrations. In addition to enhancing the antitumor activity of chemotherapy and VEGF-targeted agents, accumulating evidence suggests that SLM exerts broad immunologic, metabolic, and epigenetic effects that may overcome key mechanisms of therapeutic resistance. This review synthesizes current mechanistic and translational evidence supporting the repurposing of SLM as a first-in-class pleiotropic immunomodulatory agent. Using ccRCC as a model of TGF-β1/HIF-driven immune resistance, we discuss how simultaneous targeting of this central regulatory axis may restore immune surveillance, improve T-cell fitness and trafficking, enhance responses to ICIs and CAR-T cell therapy, and provide a mechanistically rational strategy for the treatment of advanced solid tumors. Full article