Fibrosis is a maladaptive tissue-remodeling process characterized by persistent fibroblast activation, excessive extracellular matrix deposition, and progressive tissue stiffening. Beyond non-neoplastic disorders, fibrosis is also a hallmark of several solid tumors, where it promotes immune evasion, impaired drug delivery, and therapeutic resistance, particularly in pancreatic, hepatocellular, colorectal, and triple-negative breast cancers. In this review, we comparatively analyze fibrosis across non-neoplastic and neoplastic conditions, using idiopathic pulmonary fibrosis as a reference model and comparing it with highly fibrotic tumors. We focus on conserved biological pathways, including TGF-β signaling, ECM remodeling, mechanotransduction, and fibroblast-to-myofibroblast activation, as well as on stromal heterogeneity and the role of cancer-associated fibroblast subsets in tumor progression and immune modulation. We also critically discuss current antifibrotic therapeutic strategies targeting ECM components, fibroblast activation, stromal signaling, and tumor-stroma interactions, highlighting both preclinical rationale and translational limitations. Finally, we examine emerging approaches such as mesenchymal stromal cell-based platforms and drug repurposing strategies bridging oncology and fibrotic diseases. Overall, this review underscores how comparative analysis of cancerous and non-cancerous fibrosis may help identify shared therapeutic vulnerabilities, while supporting the development of context-specific antifibrotic interventions.

Due to accumulation of many genetic changes in cancer oncogenes and tumor suppressor genes can generate an immune response by presenting antigenic peptides on the cell surface. On the other hand, in many cases immune response is muted and unable to effectively fight tumors. Recent studies have shown that T-cell responses are dependent on cytotoxic T cells, these responses can be inhibited by the interaction receptors on the surface of immune cells such as PD-1 with the molecules expressed in the surface of tumors, such as PD-L1. Thus, immune therapies were developed to block this interaction thereby triggering the cytotoxic activity of these activated T cells. In this short article we summarize the role of microRNAs, in particularly miR-155 in avoidance of immune mediated tumor rejection by malignant cells.

Genomic testing is now embedded in contemporary prostate cancer care, yet the clinical meaning of different genomic platforms varies substantially by disease state and clinical context. In localized disease, tissue-based genomic classifiers primarily serve prognostic functions by refining risk estimates beyond clinicopathologic variables, whereas in advanced disease, germline and somatic testing identify predictive biomarkers linked to therapy selection. This distinction is clinically consequential because the supporting evidence, endpoints, and implementation challenges differ across assays and across points on the disease continuum. In this review, we position tissue-based assays, germline testing, somatic sequencing, circulating tumor DNA (ctDNA), and artificial intelligence-enabled biomarkers within a unified clinical framework spanning localized disease, biochemical recurrence, and metastatic progression. We critically compare commercially available genomic assays with respect to methodology, specimen type, intended use, validation cohorts, and clinically relevant outcomes. We distinguish prognostic classifiers from predictive biomarkers such as homologous recombination repair deficiency and mismatch repair deficiency, and we evaluate emerging approaches, including liquid biopsy, multimodal integration with imaging, and digital pathology-based algorithms. We further address implementation barriers that may limit real-world impact, including reimbursement uncertainty, disparities in access to next-generation sequencing, limited provider familiarity with genomic interpretation, and the need for patient-centered communication and navigation in genomics-informed care. A clinically useful framework for prostate cancer genomics must therefore move beyond cataloging tests and instead clarify when genomic results change management, where evidence remains immature, and how implementation strategies can improve equity and actionability.

Hyperhomocysteinemia (HHcy) is an independent risk factor for thrombotic cardiovascular events. We previously demonstrated that homocysteine (Hcy) amplifies platelet activation by promoting membrane remodeling and enhancing signaling through surface platforms such as integrin αIIbβ3 and G protein-coupled receptors. However, the mechanisms by which Hcy remodels platelet membrane lipid metabolism remain poorly understood. Here, using an integrated proteomic and lipidomic approach, we showed that Hcy disrupted platelet lipid homeostasis by impairing fatty acid β-oxidation (FAO), a metabolic pathway that depends on the coordinated action of peroxisomes and mitochondria. Proteomic profiling showed that Hcy downregulated peroxisome proliferator-activated receptor α (PPARα) and its downstream targets carnitine palmitoyltransferase 1 and 2 (CPT1/2), while lipidomic analysis confirmed the accumulation of medium and long-chain fatty acids, which promoted platelet reactive oxygen species production and mitochondrial dysfunction. Notably, pharmacological activation of PPARα with fenofibrate, a PPARα agonist, restored FAO in a CPT1/2-dependent manner, remodeled the platelet lipid membrane, and attenuated Hcy-potentiated platelet hyperactivation and thrombus formation. Collectively, these findings suggest a previously unrecognized Hcy-PPARα-FAO axis in platelet function and thrombosis, linking impaired peroxisomal and mitochondrial FAO to platelet hyperactivation, and support restoring membrane phospholipid dysregulation as a potential therapeutic strategy for HHcy-promoted thrombotic diseases.

BACKGROUND: Non‑small cell lung cancer (NSCLC) remains a leading cause of cancer‑related mortality worldwide. Baicalein, a natural flavonoid, has shown anti‑cancer activity but its molecular targets and cell‑type‑specific effects in the tumor microenvironment (TME) are incompletely understood. METHODS: We integrated network pharmacology, single‑cell RNA‑seq, bulk transcriptomics, spatial transcriptomics, machine learning, and in vitro experiments to identify baicalein‑responsive genes in NSCLC. RESULTS: Single‑cell analysis resolved 21 cell populations, revealing that baicalein targets were enriched in a 32‑gene core set. Consensus clustering defined three molecular subtypes (cluster 1-cluster 3) with distinct immune infiltration; cluster 1 showed an immune‑cold phenotype with upregulation of cell cycle and metabolic pathways, while cluster 3 was immune‑hot. Machine learning selected a 10‑gene signature (TOP2A, CDH1, CCNB1, SATB2, CA9, HMGB2, MB, NQO1, AURKB, CCNB2) with high diagnostic accuracy. SHAP analysis identified TOP2A as the most influential contributor. Spatial transcriptomics confirmed significantly elevated expression of all ten genes in tumor versus adjacent/normal tissues. Cell‑cell communication analysis highlighted enhanced MIF pathway signaling in the TME, with epithelial cells and SPP1+ TAMs acting as key senders. Molecular docking showed strong binding affinities (ΔG ≤ -8.5 kcal/mol) between baicalein and AURKB, MB, TOP2A, and CCNB2, and molecular dynamics simulations further confirmed the stability of these complexes. In vitro, baicalein (30 μM, 24 h) differentially modulated signature gene expression in PC‑9 and A549 cells and suppressed viability in a dose‑ and time‑dependent manner. CONCLUSIONS: This integrative study provides a comprehensive single‑cell and spatial atlas of baicalein‑responsive genes in NSCLC, identifies a robust diagnostic signature, and offers mechanistic insights for developing baicalein as a potential therapeutic agent.

BACKGROUND: Clomiphene citrate (CC) is an established treatment for men with low testosterone, but predictors of treatment response remain poorly defined. AIM: To identify factors associated with clinically meaningful increases in serum testosterone levels during CC therapy. METHODS: This retrospective study analyzed men diagnosed with low testosterone and treated with CC. Inclusion criteria were (1) a diagnosis of low testosterone (total testosterone (TT) ≤300 ng/dL with symptoms) or borderline low testosterone (TT 300-400 ng/dL with objective signs of low testosterone (low bone density or elevated HbA1c)), (2) laboratory follow-up within 12-weeks of initiation, and (4) no prior testosterone therapy. Initial CC dosing was 25 mg every other day (QOD), with escalation to 50 mg QOD if TT remained <400 ng/dL. Labs were redrawn every 4-weeks following dose changes until TT was at goal or until CC discontinuation. Discontinuation within 12-weeks without documented response constituted treatment failure. TT was assessed using liquid chromatography-mass spectrometry. Multivariable models were used to identify predictors of treatment response. OUTCOMES: The primary outcome was achievement of treatment response, defined as TT ≥400 ng/dL on treatment plus an increase in TT ≥200 ng/dL from baseline. RESULTS: The study included 292 men with median age of 60 (IQR 50, 66) years, median baseline TT (219, 314) 264 ng/dL, and median baseline luteinizing hormone (LH) of 3.5 (2.6, 5.1) mIU/mL. Comorbidities included diabetes (18%), hyperlipidemia (46%), hypertension (44%), prior radical prostatectomy (41%), prostate radiotherapy (12%), and androgen deprivation therapy (ADT) (4.5%). Treatment response was achieved in 136 of 292 (47%) patients; 156 (53%) failed to meet response criteria within 12-weeks. Multivariable analysis identified baseline LH (increase per mIU/mL) (OR 0.82, CI = 0.71-0.95, P = .008) as a significant negative predictor for achieving treatment response. Likewise, prior ADT was predictive for poor response (OR 0.11, CI = 0.01-0.6, P = .039). Baseline TT and age at start of CC treatment were not predictive. The study included 292 men with median age of 60 (IQR 50, 66) years, median baseline TT (219, 314) 264 ng/dL, and median baseline LH of 3.5 (2.6, 5.1) mIU/mL. Comorbidities included diabetes (18%), hyperlipidemia (46%), hypertension (44%), prior radical prostatectomy (41%), prostate radiotherapy (12%), and ADT (4.5%). Treatment response was achieved in 136 of 292 (47%) patients; 156 (53%) failed to meet response criteria within 12-weeks. Multivariable analysis identified baseline LH (increase per mIU/mL) (OR 0.82, CI = 0.71-0.95, P = .008) as a significant negative predictor for achieving treatment response. Likewise, prior ADT was predictive for poor response (OR 0.11, CI = 0.01-0.6, P = .039). Baseline TT and age at start of CC treatment were not predictive. CLINICAL IMPLICATIONS: Identification of predictors for CC treatment response enables individualized counseling, leading to better informed treatment decisions and avoidance of treatment failure. STRENGTHS AND LIMITATIONS: Strengths include cohort size, utilization of the gold-standard lab assessment for TT (LCMS), and standardized reproducible clinical pathways. Limitations include having a study population that is skewed older and less healthy than average, lack of long-term follow-up, and lack of quantifiable data on symptoms. CONCLUSION: In men with low testosterone, this study found that higher baseline LH and history of prior ADT predicted worse response to CC therapy.

Dose intensity is critical in diffuse large B-cell lymphoma (DLBCL) but can be limited by toxicity risk. The influence of treatment intensity, illness burden, and socioeconomic status (SES) on survival in DLBCL has not been evaluated on a patient-level analysis. We performed a retrospective study of 344 patients with DLBCL from an urban academic cancer center; 55% received lower intensity treatment (average relative dose intensity [ARDI] of cyclophosphamide and doxorubicin <0.9). ARDI, performance status (PS), Charlson comorbidity index (CCI), and double expressor lymphoma (DEL) were associated with progression-free (PFS) and overall survival (OS). Lower ARDI was linked to worse illness burden, treatment intolerance, and higher-risk disease features. Lower ARDI was associated with worse PFS (HR 2.59,  < 0.001) and OS (HR 4.26,  < 0.001) as well as DLBCL progression (sHR 1.86  = 0.004) and non-relapse mortality (NRM) (sHR 5.45  = 0.001) in competing risks analysis. Comprehensive multidisciplinary care is needed to reduce the risks associated with undertreatment in DLBCL.

In a patient with chronic lymphocytic leukemia (CLL) involving the central nervous system, and concurrent multiple sclerosis (MS), CD19-directed CAR T-cell therapy led to complete remission of CLL and marked improvement in MS disease burden.

Primary ovarian lymphoma (POL) is rare and often presents as an adnexal mass, creating diagnostic and management challenges. We performed a retrospective cohort study of 13 women diagnosed with POL between January 2018 and December 2023. Median age was 44 years (range 13-69), with 69.2% being premenopausal. LDH was elevated in 9/13 (69.2%) and CA-125 in 8/10 (80.0%) while CEA and CA19-9 were negative. Histology was heterogeneous: diffuse large B-cell lymphoma (DLBCL, 46.2%), extranodal NK/T-cell lymphoma (23.1%), Burkitt lymphoma (15.4%), marginal zone lymphoma (7.7%), and follicular lymphoma (7.7%). Median follow-up was 28 months (range 0.5-84). Three deaths occurred, all in patients without timely systemic therapy. Estimated 5-year OS was approximately 76.9% (95% CI, 57.1%-100%). In this contemporary POL series, clinicopathologic heterogeneity was prominent, and laboratory profiles frequently overlapped with ovarian malignancy work-up. Outcomes may be favorable among patients receiving timely, subtype-appropriate systemic treatment.

Menin inhibitors (MI) are promising targeted therapies for acute myeloid leukemia (AML), particularly in NPM1-mutated and KMT2A-rearranged disease. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of MI-based therapy in adults with relapsed/refractory AML. A search of six databases through January 2026 identified 14 studies including 784 treated patients. Among response-evaluable cohorts ( = 22;  = 579), the pooled overall response rate (ORR) was 54.6% (95% CI 46.4-62.6; I=63.5%). The pooled complete response (CR) rate was 29.3%, and CR+CRh was 28.5%. Combination therapy with MI plus hypomethylating agent and venetoclax produced higher CR (43.3% vs 19.5%;  = 0.002) and CR+CRh rates (48.6% vs 25.8%;  = 0.007) than monotherapy. Common adverse events included LFT elevation (38.7%), febrile neutropenia (33.6%), and diarrhea (28.8%). Differentiation syndrome occurred in 14.6%, and treatment-related mortality in 5.0%. MI-based therapy demonstrates meaningful activity in heavily pretreated AML, with deeper responses observed using combination strategies.

Targeting oncogene promoter G-quadruplexes (G4s) is a compelling therapeutic strategy against human malignancies. However, clinical progress has been hindered by the lack of potent and structurally diverse G4-targeting ligands. Herein, using parallel KRAS proximal promoter G4 (KRAS-G4) as a model system, we screened an in-house natural product library and identified dehydroevodiamine (DEE) as a novel G4 stabilizer. Although DEE showed only modest anticancer activity, structural analyses determined its predominant binding mode to KRAS-G4. Leveraging these structural insights, we rationally designed and synthesized 15 DEE analogues. Among them, compound 7i emerged as the lead candidate, demonstrating a 9-fold higher binding affinity and up to 20-fold improvement in antiproliferative activity over DEE. We further determined the high-resolution NMR structure of the KRAS-G4-7i complex, uncovering a distinct dual-binding mode, featuring extensive π-π stacking interactions with outer G-tetrads and specific hydrogen bonding within groove regions. Functional analysis showed 7i effectively suppressed transcription of several G4-containing oncogenes, induced genome-wide G4 formation, and triggered DNA damage in colorectal cancer cells. Moreover, 7i significantly inhibited the growth of patient-derived colorectal tumor organoids. Overall, our findings establish a structural framework for rational design of parallel G4-targeting ligands and emphasize an alternative G4-based therapeutic strategy for KRAS-driven cancers.

Targeting MALAT1 in cancer treatment is an attractive strategy due to the undebatable role of this lncRNA in the disease. Small molecules toward this noncoding RNA have, in fact, entered preclinical trials, without resulting in a robust demonstration in favor of their use in therapy. To test the robustness of this method, we asked how aspects of carcinogenesis get affected when knocking down MALAT1 in different cell lines. Using two such cell lines in this study to compare side-by-side, we observed that small molecule quercetin (and its subsequent reduction of MALAT1 lncRNA levels) showed heterogenic effects on carcinogenesis, which is similarly indicated by previous literature. Further, using a combination of cell biology (including the use of 3D tumor spheroids) and bioinformatics, this study is able to pinpoint the probable function of the SREBP1 protein (which showed a significant reduction of around 50%) in affecting carcinogenesis via MALAT1, corroborating earlier reports that link MALAT1 to the sterol regulation axis. This study, in summary, notes that using MALAT1 reduction (using quercetin or otherwise) needs to be very specific in the targeting of cancer cells in order to avoid paradoxical results.

BACKGROUND: Melanoma brain metastases treated with Gamma Knife radiosurgery show heterogeneous local control trajectories. Accurate prediction of time to local control loss could support risk stratification and follow-up planning using routinely available clinical and treatment variables. METHODS: A retrospective dataset was constructed from a melanoma brain metastasis radiosurgery cohort. The endpoint was time to local control loss with right censoring for lesions maintaining local control at last follow-up. Clinical, demographic, and treatment features were included, focusing on age, sex, race, pre-treatment KPS, systemic therapy, number of metastases, lesion location, eloquence, tumor volume, and margin dose. A Random Survival Forest model was trained using one-hot encoding for categorical variables. Performance was assessed with five-fold stratified cross-validation at the lesion-level using Harrell C index. Feature importance was estimated with permutation importance. RESULTS: A total of 884 lesions were analyzed, including 198 local control loss events. The Random Survival Forest achieved high discrimination with a mean C index of 0.919 ± 0.020 across folds. The most influential predictors were age at treatment, margin dose, pre-treatment KPS, tumor volume, and isodose line. Additional contributions were observed from anatomic location and therapy category. CONCLUSIONS: A Random Survival Forest survival model accurately predicted time to local control loss in melanoma brain metastases using routinely collected variables, with strong discrimination and transparent feature importance. This approach enables individualized risk estimation and time-based predictions that can be integrated into clinical decision support and follow-up strategies.

PURPOSE: In patients with endometrial cancer (EC) with metastases at diagnosis, palliative treatment is the only therapy considered and to our knowledge there is no literature on the evolution of these patients following external-beam-irradiation (EBRT) and image-guided brachytherapy (IGBT). We present the clinical outcomes of 11 FIGO 2009 stage-IVB EC patients treated with IGBT ± EBRT. METHODS/PATIENTS: From July 2009 to February 2018, 11 stage IVB patients were treated with IGBT ± EBRT in 4 European centres. The treatments and the outcomes of these patients were analysed. STATISTICS: Kaplan-Meier and descriptive analysis were used for analysing overall survival (OS). RESULTS: The median age was 63 years (46-79) and the median follow-up was 39 months (8-128). The sites of metastases were reported in 8/11 patients: the lung in 4 patients, peritoneal and liver metastasis in one, pleural metastasis in one, bone in one and inguinal lymph nodes in one. Seven patients underwent chemotherapy (5 achieving complete response (CR)). Two patients received IGBT alone and 9 EBRT + IGBT. Three developed uterine relapse, 3 lymph node relapse and all died. Four had distant metastases and only one was alive after treatment. The OS was 69.3% at 2 and 3 years and 41.6% at 5 and 10 years. CONCLUSION: In this series, patients with stage IVB EC with CR after chemotherapy and treated with IGBT ± EBRT achieved an OS of 41.6% at 5 and 10 years. Local treatment with EBRT ± IGBT should be considered mainly in good responders to chemotherapy and should be validated in prospective trials including biological markers.

BACKGROUND: Sex-related disparities in non-small cell lung cancer (NSCLC) remain incompletely characterized, particularly in low- and middle-income countries. We aimed to evaluate sex-based differences across the entire lung cancer care continuum, from smoking exposure and diagnostic pathways to treatment access and survival outcomes, distinguishing biological susceptibility from healthcare system inequities. METHODS: We conducted a retrospective cohort study of 1031 consecutive patients with histologically confirmed NSCLC managed at two tertiary oncology centers in Tunisia between 2013 and 2023. Smoking exposure, body mass index, age and stage at diagnosis, diagnostic and treatment intervals, access to molecular testing, treatment patterns, and overall survival were compared between women and men. Multivariable regression and interaction analyses were performed. RESULTS: Women represented 20.7% of the cohort and were younger at diagnosis (median 54 vs. 62 years; p = 0.02) with lower cumulative smoking exposure. After adjustment for smoking intensity and age, sex was not independently associated with stage at diagnosis. Women experienced longer patient intervals (156 vs. 125 days; p = 0.025) and diagnostic intervals (42 vs. 31 days; p = 0.02), whereas treatment intervals were similar. Women were more likely to undergo molecular biomarker testing and to receive targeted therapy. Median overall survival was longer in women (20 vs. 14 months; log-rank p < 0.01), but no sex-by-stage or sex-by-smoking interaction was identified for survival. CONCLUSIONS: Sex-related differences in NSCLC are heterogeneous: biological susceptibility drives earlier onset at lower smoking exposure, while prolonged diagnostic delays and under-representation in screening programs reflect addressable healthcare inequities. Targeted interventions are warranted to improve early detection and diagnostic equity in women.

PURPOSE: Ovarian cancer is one of the most lethal cancers in women worldwide. To be able to offer successful treatment and improve the prognosis, knowledge of factors influencing the tumor microenvironment is indispensable. In this context, the influence of the extracellular matrix on tumor progression is increasingly recognized. Of note, preclinical data in cell line and animal models have suggested that several members of the small leucine-rich proteoglycan (SLRP) family are mechanistically involved in the regulation of tumor progression. We hypothesized that dysregulation of SLRP expression may have a prognostic value in ovarian cancer. METHODS: To distinguish whether this expression is altered in the cells themselves or in the extracellular matrix, quantitative Real-Time PCR was performed on ovarian cancer cell lines and complemented by analysis of CCLE datasets. We used Kaplan-Meier survival curves to investigate whether a high or low mRNA expression influences the survival of ovarian cancer patients. Finally, the interactions of the SLRPs were investigated using a STRING analysis. RESULTS: We demonstrated the potential beneficial effect of a low mRNA expression of most SLRPs on the prognosis of serous ovarian cancer. STRING analysis revealed interactions with other proteins already known to influence tumor behavior and metastasis of various carcinomas. CONCLUSION: These findings suggest that SLRPs may be involved in ovarian cancer biology and could represent candidates for further mechanistic investigation. However, their potential relevance for therapeutic strategies, including treatment response, requires additional functional validation.

Stimuli-responsive nanogels have been utilized as perfect nanocarriers for anticancer drug delivery because of their on-demand, controlled, and site-specific drug-releasing chemistry. These HNP are cross-linked hydrophilic polymer nanoparticles with a high-water content, biocompatibility, and adjustable reactivity to chemical or physical stimuli (such as pH, temperature, and redox potential, which are among the most extensively studied triggers in cancer-targeted nanogel systems). Because of their structural flexibility, these nanocarriers can react intelligently and passively to the tumor microenvironment's high glutathione content, acid pH, and overexpressed enzymes, ensuring increased intracellular release and reduced systemic toxicity. Cross-linking strategies, top-down and bottom-up production processes, and core characterization methods concerning size, charge, morphology, and release kinetics are the main topics of this article. Anticancer medications like doxorubicin, paclitaxel, camptothecin, and docetaxel have been shown to be well accommodated in a variety of nanogels, including pH-responsive, thermo-responsive, redox-responsive, magnetic-based, and multi-responsive ones for increased bioavailability and anti-tumor activity. In addition, receptor-mediated endocytosis mediated by targeting ligands such as folic acid, hyaluronic acid, aptamers and monoclonal antibodies improves the cellular uptake and uptake in tumor of drug-loaded nanogels. Collectively, intelligence-triggered nanogels stated above possess outstanding benefits in combination therapy, controlled drug release, and theranostic application and so illustrate these as state-of-the-art intelligent delivery systems for tumor treatment. Future goals include optimizing biocompatibility, removing tumor penetration obstacles using techniques including surface charge modification, PEGylation, and enzyme-sensitive cross-linkers, and guaranteeing scalability and therapeutically transferable formulations.

BACKGROUND: To explore the correlation between cerebrospinal fluid (CSF) and peripheral blood cytokines and survival in patients with Leptomeningeal metastases (LM) of glioblastoma. METHODS: The study retrospectively included 35 patients with glioblastoma LM diagnosed from September 2022 to August 2024 at Beijing Tiantan Hospital. CSF and peripheral blood cytokines were collected from patients and associated with other characteristics with overall survival (OS) using univariate and multivariate analyses. The optimal cutoff values for cytokines were derived using the surv_cutpoint function in the R software. RESULTS: The median OS for LM patients was 11.8 months (95% confidence intervals (CI) 6.1-17.5 months). After univariate and multivariate analyses, CSF IL-6 (95% CI 0.072-0.683; P = 0.009) and Karnofsky Physical Status (KPS) (95% CI, 0.136-0.876; P = 0.025) remained significantly associated with OS. We further combined CSF interleukin-6 (IL-6) with KPS to construct nomogram to predict survival and demonstrated good predictive performance. CONCLUSION: Both CSF IL-6 and KPS are meaningful prognostic biomarkers for patients with LM from glioblastoma.

DNA hypomethylation represents the most prevalent epigenetic alteration in human cancer, yet its cellular origins remain incompletely understood. In lung adenocarcinoma (LUAD), DNA hypomethylation is associated with upregulation of distinct gene groups, including: cancer-germline (CG) genes normally restricted to testicular germ cells, and stratified epithelium (SE) genes typically expressed in multilayered epithelia. Among the latter, FAM83A has emerged as a pro-tumoral gene implicated in cancer progression and therapy resistance. Here, we asked whether FAM83A activation in LUAD represents an epigenetic abnormality or if it reflects redirection of malignant cells towards an existing epithelial program. By analyzing single-cell RNA sequencing data from normal lung we found that, while FAM83A is undetectable in whole lung tissue homogenates, it is expressed in subsets of airway epithelial cells corresponding to basal/suprabasal and goblet cell populations. In contrast, CG gene MAGEA1 is silent in all lung cell types. Consistently, RT-qPCR detected FAM83A, but not MAGEA1, in primary and immortalized human lung basal cells. Bisulfite sequencing showed that the promoter of FAM83A, but not MAGEA1, is unmethylated in these cells. Analyses of transcriptomic datasets from LUAD cell lines and tissues demonstrated that FAM83A expression is correlated with markers of suprabasal and goblet lineages in malignant cells. They further revealed co-expression of FAM83A with NAPSA, a marker of alveolar AT2 cells, from which LUAD originates. Together, these findings indicate that, whereas MAGEA1 activation in LUAD results from an aberrant process of DNA demethylation, FAM83A upregulation in LUAD reflects redirection of alveolar cells towards an airway differentiation program.

BACKGROUND: Bladder urothelial carcinoma (BLCA) exhibits heterogeneous outcomes, creating an urgent need for reliable prognostic biomarkers. Glycosylation modifications are crucial in cancer but understudied for BLCA stratification. METHODS: Using clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) and glycosylation-related genes from the Gene Set Enrichment Analysis (GSEA) database, we constructed a prognostic signature via LASSO regression. It was validated using receiver operating characteristic (ROC) curve and stratified survival analyses. The key gene, alpha-1,3-mannosyltransferase (ALG3), was experimentally validated. RESULTS: A novel 9-glycosylation-mRNA signature effectively stratified BLCA patients into distinct risk groups with significant overall survival differences. The model showed robust predictive accuracy (AUC) and remained independent of common clinicopathological factors. We identified ALG3 as central to the signature, confirming its elevated tumor expression and critical role in promoting cancer cell proliferation. CONCLUSION: We established a potent, glycosylation-based prognostic model for BLCA. Functional validation of ALG3 underscores glycosylation's biological importance in tumor progression and highlights its therapeutic potential.

Cancer cells show increased glucose uptake and lactate secretion due to mitochondrial respiratory dysfunction and hypoxia, leading to extracellular acidification of the tumor microenvironment (TME) and intracellular alkalinization. This metabolic reprogramming promotes malignant phenotypes, including enhanced invasion, metastasis, multidrug resistance, and immune evasion. Therefore, real-time monitoring of intra- and extracellular pH dynamics is essential to understand tumor progression and to evaluate therapeutic strategies. Here, we report the use of a pH-sensitive bioluminescent color-tuning biosensor, derived from the firefly luciferase (AmyLuc), to ratiometrically estimate intracellular and extracellular pH changes associated with metabolic alterations consistent with the Warburg effect in human colorectal adenocarcinoma cells (Caco-2). The ratio of bioluminescence emission intensities at 593 nm (pH 6.0) and 548 nm (pH 8.0) was used to establish a calibration curve for accurate pH determination. Analysis of the green/red emission ratios showed that the treatments with the mitochondrial uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, 50 μM) and the respiratory chain inhibitor antimycin A (50 μM) induced a sustained intracellular acidification (pH ∼6.3), whereas the extracellular environment showed a gradual alkalinization toward near-physiological pH (∼7.1), consistent with buffering effects of the medium. This intracellular acidification is consistent with metabolic alterations and intracellular proton accumulation caused by the transition from mitochondrial respiration to cytoplasmic anaerobic glycolysis. The results highlight the suitability of AmyLuc as a sensitive color-tuning bioluminescent pH biosensor for real-time monitoring of pH dynamics in cancer cells under metabolic stress and therapeutic interventions.

Bacterial wound infections are often complicated by biofilm formation, which leads to persistent inflammation and multidrug resistance, severely impeding the healing process. Conventional antibiotic therapies are challenged by both overuse and rising antimicrobial resistance. To address this, we designed and fabricated a dual-mode responsive delivery system (COC@MN) based on chitosan (CS) and oleanolic acid (OA) composite microneedles for synergistic sono-photodynamic therapy (SPDT). This system employs chlorin e6 (Ce6), which exhibits both photodynamic and sonodynamic activities, as the core antibacterial component. It utilizes the self-assembly properties of OA to form nanoparticles for Ce6 encapsulation, and reinforces the microneedle mechanical strength through composite formation with CS, enabling efficient transdermal delivery. In vitro experiments demonstrated that under combined laser and ultrasound irradiation, the system exhibited strong antibacterial activity against both standard strains (Staphylococcus aureus and Escherichia coli) and a clinically relevant drug-resistant strain and effectively disrupted pre-formed biofilms. The antibacterial effect is attributed to the reactive oxygen species generated during synergistic SPDT. Cytocompatibility assays confirmed good biocompatibility with normal fibroblast cells at effective antibacterial concentrations. This study presents an integrated strategy combining transdermal microneedles with SPDT to combat biofilm-associated infections, showing promising potential for clinical translation.

INTRODUCTION: Lung (LCs) and thymic carcinoids (ThCs) belong to thoracic well-differentiated neuroendocrine tumors (NETs), whose therapeutic options for advanced stages are limited. In the era of precision medicine, tyrosine kinase inhibitors (TKIs) remain a key focus of clinical investigation. This review evaluates the evolving role of TKIs in this setting. AREAS COVERED: This critical review analyzes the clinical evidence from pivotal trials regarding FDA/EMA-approved TKIs and those in advanced phases of clinical investigation for thoracic NETs, including combination strategies and tumor microenvironment modulators. EXPERT OPINION: Despite regulatory approvals (. cabozantinib in 2025), TKI development faces ongoing challenges in balancing incremental efficacy with significant toxicity concerns. While some agents significantly improve progression-free survival, these gains are often overshadowed by high rates of grade 3-4 adverse events and treatment-related mortality. Consequently, alternative strategies with more manageable safety profiles are emerging. While an unfavorable benefit-to-toxicity ratio has hindered late-phase clinical trials, the persistent discrepancy in TKI performance across different malignancies suggests a developmental plateau in the NEN setting. Future research must shift toward multiomic profiling and the identification of novel actionable targets to prioritize personalized, better-tolerated therapies that balance clinical outcomes with quality of life.