Reactive oxygen species (ROS)-catalytic artificial enzymes have emerged as a promising way to combat malignant tumors, yet their efficacy remains constrained by tumor hypoxia, oxygen dependence, and robust antioxidant defenses. Herein, we report the de novo design of a bioinspired manganese@gold cluster-coordinated covalent organic frameworks-based artificial metalloenzymes (AuC@SCOF-Mn) with efficient cascade biocatalysis and amplified systemic stimulation to combat malignant tumor metastasis. Experimental and theoretical results demonstrate that the AuC@SCOF-Mn heterojunction architecture accelerates electron transfer and drives oxygen-independent type I photoreactions under low-dose light irradiation, which confer dual-enzyme-like activities to catalyze glucose-to-HO-to-ROS conversion and deplete intracellular glutathione. The multiple functionalities not only disrupt redox homeostasis to amplify ROS accumulation but also elicit potent tumoricidal effects through mitochondrial dysfunction and DNA damage. Beyond direct cytotoxicity, AuC-SCOF-Mn effectively reprograms the tumor microenvironment by enhancing cytokine-cytokine receptor interactions, thereby promoting dendritic cell antigen presentation, CD8T cell activation, and NK cell infiltration. Correspondingly, AuC@SCOF-Mn demonstrates potent tumor suppression and long-term inhibition of tumor recurrence in vivo. When combined with checkpoint therapy, it further amplifies systemic antitumor responses and inhibits malignant tumor lung metastasis. We believe the innovative design of ROS-catalytic, photo-activable artificial enzymes will open a promising avenue for treating malignancies.

Drug resistance is a major barrier to effective hepatocellular carcinoma therapy, and autophagy targeting holds great potential for overcoming this issue. Using binding energy data from molecular docking with TBC1 domain family member 2 (TBC1D2) as the target, we rationally designed compound G2 featuring a piperazine moiety. Target binding was validated via a competitive immunofluorescence assay. The binding affinity of G2 was determined by surface plasmon resonance, yielding a dissociation constant (K) of 0.4 μM. Functional evaluation of G2 determined its aqueous solubility to be 0.3 mg/mL, with a half-maximal inhibitory concentration value of 80 ± 20 nM and a selectivity index of 23.1 in HCCLM3 cells. Subsequent mechanistic investigations revealed that this selectivity arose from the heightened responsiveness of TBC1D2 expression to G2 in HCCLM3 cells, thereby inducing selective autophagic cell death. In HCCLM3 xenograft mouse models, G2 showed excellent hepatic retention. G2 monotherapy (58.2% tumor growth inhibition) and its combination with sorafenib (70.9%) exerted superior antitumor activity versus sorafenib monotherapy (52.8%), with favorable safety. Collectively, our findings establish G2 as a promising therapeutic candidate for surmounting sorafenib resistance, characterized by selective antitumor activity against malignant hepatocellular carcinoma.

Breast cancer treatment can worsen frailty, but the impact of this decline on long-term quality of life (QoL) remains uncertain. We identified women ≥65 years old with non-metastatic breast cancer from the Life and Longevity after Cancer survivorship cohort of the Women's Health Initiative. We examined the association between clinically-significant worsening of frailty, measured by a validated claims-based index one year post-diagnosis, and long-term decline in QoL, assessed on a ten-point scale 4 to 6 years post-diagnosis. Among 1,061 eligible patients, 692 (65.2%) were robust (not living with frailty), 343 (32.3%) were living with pre-frailty, and 26 (2.5%) were living with frailty at cancer diagnosis. Clinically-significant worsening of frailty occurred in 19.5% of patients. In fully adjusted models, worsening frailty was significantly associated with long-term QoL declines (Odds Ratio 1.48; 95% Confidence Interval [1.07 to 2.04]). These findings highlight the need for interventions to prevent worsening frailty during breast cancer treatment.

BACKGROUND: Neural substrates of cancer-related cognitive impairment (CRCI) remain poorly understood, especially in older adults facing aging-related cognitive decline and comorbid chronic conditions. METHODS: Breast cancer survivors aged ≥60 years (n = 64) and non-cancer controls (n = 62) completed structural MRI and neuropsychological testing and self-reported cognition and health information at pretreatment baseline and 12- and 24-month follow-ups. Regional gray matter volume and brain age were evaluated using FreeSurfer and brainageR. Longitudinal linear mixed models tested effects of group, time, and group-by-time interactions on volume. Secondary analyses examined relationships between group, comorbidities, age, gray matter volume, and cognition. RESULTS: Survivors exhibited frontal (p = 0.025, q = 0.058), thalamic (p = 0.008, q = 0.052), and limbic (p = 0.015, q = 0.052) gray matter decline relative to controls over 24 months, with smaller effects in parietal (p = 0.055, q = 0.097) and temporal (p = 0.091, q = 0.127) regions. Survivors showed average yearly frontal and thalamic volume loss at twice the rate of controls (p < 0.05). Survivors with a high comorbidity burden (≥3 comorbidities) exhibited the lowest frontal gray matter volume at all timepoints. A trend-level group-by-time interaction for brain age (p = 0.093) suggested accelerated brain aging in survivors. Survivors failed to show practice effects in the attention, processing speed, and executive functioning neuropsychological domain, whereas controls improved significantly over time (group-by-time interaction p = 0.030). CONCLUSIONS: Older breast cancer survivors tended to demonstrate gray matter decline and accelerated brain aging throughout the first two years of survivorship, with comorbidity burden amplifying frontal vulnerability. Findings highlight the need for longitudinal cognitive monitoring and targeted intervention, particularly for older survivors with high comorbidity burden.

BACKGROUND: Artificial intelligence (AI) holds considerable promise for strengthening sexual, reproductive and maternal health (SRMH) by enhancing diagnosis, optimising service delivery and expanding access to information. In Latin America and the Caribbean (LAC), however, the scope, focus and maturity of AI applications in SRMH remain poorly described. OBJECTIVE: To identify, map and analyse existing applications of AI in SRMH priority services in LAC, characterising thematic areas, target populations, and types of AI tools, whilst highlighting gaps and future research needs. METHODS: We conducted a scoping review guided by the Arksey and O'Malley framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR). Searches were performed in PubMed, SciELO, Cochrane and LILACS up to August 2023, complemented by targeted Google searches and snowballing. We included records reporting AI applications in SRMH services in LAC and extracted data on setting, population, SRMH domain, AI techniques and implementation stage. RESULTS: A total of 1,518 records were identified, of which 143 met the inclusion criteria. Most were published between 2020 and 2023 and originated from Mexico, Colombia, Peru, Brazil and Argentina. Over half were peer-reviewed articles, with additional theses and web-based reports. Applications concentrated on prenatal, childbirth and postnatal care (36%) and reproductive organ cancers (31%), with far fewer initiatives addressing sexual health, contraception, gender-based violence, sexual satisfaction or counselling. Machine learning methods predominated (52%), followed by deep learning (41%). Almost half of initiatives (48%) were exploratory projects, 17% implemented tools without outcome data and 35% reported performance in real-world contexts. CONCLUSIONS: AI applications in SRMH in LAC are expanding but remain thematically narrow, population-selective and predominantly exploratory, highlighting the need for more diverse, rigorously evaluated and equity-oriented tools.

PURPOSE: This study examined psychological distress and financial toxicity among cancer patient-caregiver dyads receiving chemotherapy in Western India, focusing on emotional and financial interdependence. METHODS: In this cross-sectional study of 357 chemotherapy patient-caregiver dyads, psychological distress (NCCN Distress Thermometer), financial toxicity (COST-FACIT), and adverse drug reactions (standard causality and severity scales) were assessed, with patient predictors analyzed by multivariable logistic regression and dyadic effects examined using the Actor-Partner Interdependence Model. RESULTS: Clinically significant distress was reported by 55.74% of patients and 10.92% of caregivers, while nearly 70% of both groups experienced mild-to-moderate financial toxicity. Patient distress was significantly associated with adverse drug reactions (AOR = 2.208), higher patient financial toxicity (AOR = 0.895), caregiver financial toxicity (AOR = 1.056), and caregiver distress (AOR = 1.951). Caregiver distress was significantly associated with caregiver financial toxicity (AOR = 1.19), patient distress (AOR = 0.72), breadwinner status, and marital status. APIM showed strong actor effects for patients (β = 0.446) and caregivers (β = 0.366), and partner effects indicating cross-dyad influence (β = 0.157; β = 0.168). CONCLUSIONS: Psychological distress and financial toxicity are prevalent, and addressing patient-caregiver interdependence-particularly in primary caregivers and patients with treatment toxicities-may improve outcomes.

PURPOSE: Whether de novo organized left atrial tachyarrhythmia (LAT) shows preserved left atrial appendage (LAA) mechanics has not been adequately characterized. We compared LAA peak emptying velocity across atrial fibrillation (AF) phenotypes and de novo LAT. METHODS: Multicenter retrospective cohort of 634 consecutive first-ablation candidates undergoing pre-ablation transesophageal echocardiography (TEE) at five centers: paroxysmal AF (PAF, n = 146), persistent AF (PeAF, n = 310), long-standing persistent AF (LsPeAF, n = 86), and LAT (n = 92). Markedly reduced LAA function was peak emptying velocity <25 cm/s. Multivariable regression adjusted for rhythm during TEE, CHADS-VASc, body mass index (BMI), left ventricular ejection fraction (LVEF), and left atrial (LA) diameter. RESULTS: Mean LAA velocity was 55.7 ± 19.4 (PAF), 44.3 ± 18.5 (PeAF), 31.0 ± 12.5 (LsPeAF), and 36.6 ± 13.5 cm/s (LAT); p < 0.001. LAT lay closer to LsPeAF than to PAF and did not differ from LsPeAF (Tukey p = 0.140). Prevalence of velocity <25 cm/s: 2.7%, 11.9%, 32.6% and 18.5% (p < 0.001). After adjustment, larger LA diameter (β = -0.53/mm, p < 0.001) and higher CHADS-VASc (β = -1.93/point, p < 0.001) were independently associated with lower velocity. Compared with LAT, PAF had lower odds of velocity <25 cm/s (OR 0.19, 95% CI 0.06-0.62). CONCLUSION: De novo organized LAT exhibits LAA mechanical dysfunction comparable to long-standing persistent AF rather than to PAF. Organized rhythm does not imply preserved appendage function. LAA peak emptying velocity may serve as a functional remodeling marker for pre-ablation phenotyping.

BACKGROUND: Learning curves in esophagectomy are often described in terms of procedural volume, but institutional maturation also reflects progressive standardization of reconstruction, operative choreography, and team-based decision-making. Gastric conduit viability remains central to safe esophageal reconstruction, with conduit ischemia, torsion, and tension contributing substantially to leak and necrosis. We examined the institutional learning curve of a high-volume esophageal cancer program, focusing on technical standardization of gastric conduit formation and conduit-related outcomes. METHODS: We retrospectively analyzed 187 consecutive patients who underwent esophagectomy for locally advanced esophageal cancer between 2019 and 2025 at a tertiary cancer center. For descriptive temporal comparisons, the cohort was divided into two pragmatic phases corresponding to institutional practice before and after routine formalization of the conduit protocol: up to 2022 (n = 101) and 2023-2025 (n = 86). During program maturation, a standardized gastric conduit protocol was formalized, emphasizing preservation of conduit vascularity, controlled conduit geometry, minimal omental bulk, cervical-first dissection, torsion-free transposition, and selective pyloric management. The primary outcome was composite major conduit-related morbidity, defined per patient as major anastomotic leak, major conduit necrosis, or conduit-related re-exploration. Secondary outcomes included overall leak, vocal cord palsy, chyle leak, Clavien-Dindo grade, 30-day mortality, R0 resection, and lymph node yield. Outcomes were interpreted within the broader context of institutional maturation rather than as a simple calendar-era comparison. RESULTS: Composite major conduit-related morbidity declined from 8.9% in the earlier phase of the program to 2.3% in the later phase. Within this composite, major conduit necrosis declined from 5% to 0%, while overall leak rates remained stable. Thirty-day mortality was 4.3%, and most complications were minor. Oncologic adequacy was preserved, with R0 resection in 94.7% and a median lymph node yield of 25. Improvements in pathological complete response and recurrence over time paralleled broader changes in neoadjuvant treatment intensity and lymphadenectomy and should not be attributed solely to conduit protocolization. CONCLUSIONS: Institutional maturation in esophagectomy was associated with transition from experience-dependent practice to reproducible technical standardization of gastric conduit formation. This learning curve coincided with disappearance of major conduit necrosis without compromising oncologic adequacy. Standardization of conduit construction may represent an important and exportable quality-improvement step in developing high-volume esophageal cancer programs, especially in resource-variable settings.

The coexistence of extramammary Paget disease and clinically apparent herpes simplex virus (HSV) infection is extremely uncommon, with only two cases previously described in detail. Herein, we present the case of an elderly woman with an extensive vulvar lesion showing concurrent extramammary Paget disease and HSV infection. Triple immunohistochemical staining for cytokeratin 7, cytokeratin 10, and HSV antigen was performed to re-evaluate the hypothesis that HSV-mediated fusion between Paget cells and keratinocytes contributes to multinucleated giant cell formation. HSV antigen was detected in both Paget cells and keratinocytes. HSV-positive multinucleated giant cells displayed a cytoplasmic staining pattern similar to that of keratinocytes, whereas no Paget cell-like cytoplasmic staining pattern was observed. These findings indicate that HSV can directly infect Paget cells and that the multinucleated giant cells in this case were of keratinocytic origin. No definitive evidence of cell fusion-either among Paget cells or between Paget cells and keratinocytes-was observed in the examined sections. However, the possibility of rare fusion events in unexamined tissue cannot be entirely excluded.

INTRODUCTION: The management of rectal adenocarcinoma requires navigation of complex, branching guideline pathways encompassing neoadjuvant sequencing, surgical approach, organ preservation, and surveillance, yet real-world guideline adherence remains as low as 60-70%. The ability of current-generation large language models (LLMs) to accurately navigate these decision points has not been fully characterized. METHODS: In this cross-sectional, vignette-based study, 135 clinical questions were constructed from 45 pages of NCCN Rectal Cancer Guidelines (Version 4.2024). ChatGPT-4o was queried using standardized prompts with up to 3 clarifying questions permitted per query. Responses were independently evaluated by two physician raters on a 5-point Likert scale, with potential discrepancies adjudicated by a board-certified surgical oncologist. Primary outcomes were the proportion of responses rated Correct (score ≥ 3) and Accurate (score ≥ 4). Inter-rater reliability was assessed using Cohen's kappa, and subgroup analysis was performed across clinical domains using the Kruskal-Wallis test. RESULTS: Of 135 questions, 127 (94.1%; 95% CI, 88.7-97.0%) were Correct and 121 (89.6%; 95% CI, 83.3-93.7%) were Accurate. One hundred two responses (75.6%) were completely correct without additional prompting. Performance was consistent across clinical domains (Kruskal-Wallis H = 0.530, p = 0.767). Inter-rater agreement was perfect (κ = 1.0). Eight responses (5.9%) contained partially or wholly incorrect information, with errors concentrated in multi-step conditional treatment decision points. CONCLUSION: ChatGPT-4o demonstrates high concordance with NCCN rectal cancer guidelines across all evaluated clinical domains with notable improvement over prior ChatGPT iterations evaluated by our group. The concentration of errors in complex conditional treatment algorithms suggests that LLMs excel at discrete factual recall but may struggle with multi-step reasoning under clinical uncertainty. Prospective validation using real-world clinical data and comparison with multidisciplinary tumor board recommendations remain necessary prior to clinical integration.

BACKGROUND AND OBJECTIVES: Persistent disparities in breast cancer (BC) care highlight the need to better understand patient experiences across diverse populations. This study examined racial differences in BC treatment, BR decisions, and social media use. METHODS: A web survey of 413 racially diverse breast cancer survivors collected self reported clinical data, BREAST-Q scores, and social media use. Multivariate regression examined BC treatment, BR complications, social media use, and satisfaction by race. RESULTS: Black and Hispanic women were more likely to have mastectomy and chemotherapy than white women (p < 0.01; p < 0.001), even after adjusting for stage (p = 0.368). Asian women were less likely to receive chemotherapy or radiation (p < 0.01). Despite more breast-conserving surgery (p < 0.001 vs. Black; p < 0.05 vs. Hispanic), white women reported lower breast satisfaction (p < 0.05). Black and Hispanic women relied more on social media for information (p < 0.001; p < 0.01). Younger age, tobacco use, radiation, and comorbidities increased BR complication risk. CONCLUSIONS: Women of color in this study experienced more aggressive treatment patterns and were more likely to rely on social media for information, highlighting an opportunity to address inequities in breast cancer care. Leveraging social media to deliver culturally tailored, evidence-based information may enhance understanding of treatment and surgical options, as well as complication risks, thereby promoting more equitable, patient-centered care.

Immunohistochemical negativity of AID and MUM1 identifies a prognostically favorable subgroup of diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit, and a gene set and enrichment analysis showed that genes belonged to PI3K-Akt, matrix remodeling and metastasis, cell adhesion and migration, myeloid compartment, and metabolic stress were up-regulated in the AID-negative/MUM1-negative subgroup.

BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of epithelioid cells that co-express melanocytic and smooth muscle markers. They can arise in various anatomic sites, most commonly the uterus, retroperitoneum, gastrointestinal tract, and liver. While most PEComas are sporadic and associated with TSC1/TSC2 mutations leading to mTOR pathway activation, a distinct molecular subset harbors TFE3 gene rearrangements, often exhibiting more aggressive clinical behavior. Given their rarity, the diagnosis and management of PEComas remain challenging and largely unstandardized. CASE PRESENTATION: We report the case of a 37-year-old woman with no significant medical history who presented with fatigue, unintentional weight loss, and vomiting. Imaging revealed a large hepatic mass and pulmonary nodules. Histopathological and immunohistochemical evaluation confirmed a diagnosis of TFE3-rearranged PEComa involving the liver and left upper lung lobe. The patient underwent right partial hepatectomy with complete resection of the hepatic lesion. Subsequent disease progression was noted in the lung, lymph nodes, and bone despite treatment with an mTOR inhibitor. CONCLUSION: TFE3-rearranged PEComas represent a rare and aggressive molecular subset with limited therapeutic options. This case demonstrates resistance to mTOR inhibition, highlighting the critical importance of molecular subtyping to distinguish TFE3-rearranged from TSC1/TSC2-mutant disease and guide individualized management. Expanded molecular profiling is essential to refine treatment strategies for this uncommon entity.

BACKGROUND: The clinical relevance of concordance between multidisciplinary tumor board (MDT) decisions and artificial intelligence (AI)-based treatment recommendations remains unclear. This study evaluated not only concordance but also the clinical impact of discordance direction on outcomes in endometrial cancer. METHODS: We retrospectively analyzed 150 patients with endometrial cancer discussed at a single-center MDT. AI-based recommendations were generated using a large language model according to ESGO/ESTRO/ESP guidelines, based on standardized clinicopathological inputs without molecular classification. Concordance between MDT and AI recommendations was assessed at the patient level. Discordant cases were classified as relative undertreatment or overtreatment. Agreement beyond chance was evaluated using Cohen's kappa. Recurrence-free survival (RFS) was analyzed using Cox regression and Kaplan-Meier methods. RESULTS: Overall concordance was observed in 76.7% of patients, with fair agreement beyond chance (Cohen's κ = 0.365, 95% CI 0.181-0.549). During follow-up, 68 events (45.3%) occurred. Concordance was not independently associated with RFS in multivariable analysis (adjusted HR 1.26, 95% CI 0.64-2.48, p = 0.50). In contrast, relative undertreatment was associated with worse RFS (HR 1.94, 95% CI 1.03-3.64, p = 0.040), whereas overtreatment was not. Event rates were higher in the undertreatment group compared to concordant patients (67.9% vs 40.0%), despite more favorable baseline characteristics. CONCLUSIONS: Concordance alone may be insufficient to determine the clinical relevance of AI-based recommendations. Discordance direction appears more informative, with treatment de-escalation associated with inferior outcomes. AI-based systems may help identify potential undertreatment and support more consistent implementation of guideline-based care.

Breast cancer remains the most prevalent malignancy among women worldwide, presenting significant clinical challenges due to tumor heterogeneity, multidrug resistance (MDR), and the severe systemic toxicity associated with conventional chemotherapy. In the rapidly evolving field of nanomedicine, Metal-Organic Frameworks (MOFs) have emerged as a superior class of porous nanomaterials with exceptional potential for oncology applications. Distinguished by their ultra-high surface area, tunable porosity, and biodegradable nature, MOFs offer a versatile platform for encapsulating chemotherapeutic agents, genetic materials, and photosensitizers. This review provides a comprehensive overview of the recent advancements in MOF-based nanoplatforms for the diagnosis and treatment of breast cancer. We critically analyze the synthesis and functionalization strategies that enhance the stability and targeting capability of MOFs in the physiological environment. Furthermore, we highlight the development of stimuli-responsive drug delivery systems that utilize the unique tumor microenvironment (pH, redox, and ATP) for controlled release. Finally, the review discusses the dual role of MOFs as theranostic agents integrating bioimaging (MRI, CT, and optical imaging) with therapeutic modalities (chemotherapy, photothermal, and photodynamic therapy) and outlines the future perspectives for their clinical translation.

Patients with myelodysplastic neoplasms (MDS) have a risk of secondary acute myeloid leukemia (sAML) transformation, but previous studies on the paired samples at both MDS and sAML were very rare. This study aimed to investigate the genetic changes during the progression from MDS to sAML by comparing both phases of MDS at diagnosis and sAML in the same individuals. Seventy-nine paired matched samples of MDS at diagnosis and sAML phase were examined for 32 gene mutations commonly occurring in myeloid neoplasms, including epigenetic regulators, cohesin complex, spliceosome complex, signaling pathway, tumor suppressors, and transcription factors by next-generation sequencing. The acquisition of gene mutations involving signaling pathway and transcription factors was significantly more frequent during the progression to sAML compared to other groups of genes. Mutations involving epigenetic regulators, cohesin complex, and spliceosome complex were generally stable or expanded when disease progressed. Loss of gene mutations was rare, and all mutations showed no apparent decline in their variant allele frequencies except STAG2 mutation. RUNX1 mutations were characterized by acquisition or clonal expansion with no loss or decline during disease progression. TP53 mutations exhibit unique mutational complexity and evolutionary patterns. The dynamic distribution pattern of various gene mutations remained similar regardless of BM blast counts at MDS or the rate of disease progression. Our results demonstrated a distinct pattern of clonal changes in different groups of gene mutations during the progression from MDS to sAML.

STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC = 4 nM and of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC = 5-11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.

Tumor vasculature has traditionally been viewed as structurally and functionally abnormal and, therefore, is primarily targeted for inhibition. However, emerging evidence from vascular biology, regenerative medicine, and bioengineering challenges this paradigm, demonstrating that blood vessels actively instruct and shape the tumor microenvironment. Here, we propose that tumor vasculature functions as a dynamic and programmable interface that regulates cancer progression and define vascular reprogramming as a therapeutic strategy to actively redesign vascular structure, function, and signaling to control the tumor ecosystem. By integrating recent advances in endothelial cell heterogeneity, vascular niche biology, and multiscale modeling, we illustrate how tumor vessels govern cancer stemness, immune-cell trafficking, and metabolic adaptation, positioning the vasculature as a central regulatory hub rather than a passive conduit. We further highlight enabling technologies, including vascularized organoids, organ-on-a-chip systems, and iPSC-derived vasculature, that enable the precise reconstruction and manipulation of human vascular microenvironments, providing unprecedented opportunities to experimentally control vascular dynamics. Importantly, we distinguish vascular reprogramming from conventional anti-angiogenic and normalization strategies, emphasizing its potential to achieve sustained and integrative control of the tumor microenvironment. By modulating vascular permeability, perfusion, and immunoregulatory signaling, this approach enhances drug delivery, improves immune infiltration, and increases therapeutic sensitivity. Finally, we discuss the key challenges for clinical translation, including safety, scalability, and model limitations, and highlight future directions driven by spatial omics and artificial intelligence. Collectively, this framework establishes tumor vasculature as a designable therapeutic interface and advances a new paradigm in cancer therapy: not merely targeting the tumor microenvironment but engineering it through vascular control.

BACKGROUND: FMR1, a gene classically linked to Fragile X syndrome, functions as a multifunctional RNA-binding protein regulating RNA metabolism. Emerging evidence indicates its role in modulating cancer progression and tumor immunity, yet a comprehensive pan-cancer analysis to confirm its viability as a biomarker for cancer screening, prognosis, and precision therapy remains lacking. METHODS: We first validated FMR1 expression in renal cell carcinoma cell lines via qRT-PCR and assessed its functional role using colony-formation, wound-healing, and Transwell assays. Subsequently, we performed pan-cancer analyses by mining multi-omic data from public databases including UCSC Xena, TCGA, GTEx, TIMER, and TISIDB, integrating expression, prognosis, immune infiltration, and genetic alteration data. RESULTS: FMR1 was downregulated in renal cancer cell lines, and its overexpression inhibited cell proliferation and migration. Pan-cancer analysis revealed dysregulated FMR1 expression across multiple tumors. Low FMR1 expression correlated with poor prognosis in cancers like KIRC and SKCM. It also correlated with RNA methylation genes, immune/molecular subtypes, immune checkpoint genes, and immune cell infiltration. FMR1 amplification was the most frequent genetic alteration, and it demonstrated possibly improved predictive value compared to some traditional biomarkers. CONCLUSION: FMR1 acts as a tumor suppressor in renal cancer and represents a promising pan-cancer biomarker for screening, prognostic evaluation, and immunotherapy response prediction, providing new insights for precision cancer therapy.

The flow of blood through stenotic arteries is considered one of the most significant areas of investigation in the world of mathematical fluid mechanics. This significance arises from the topic's application to the field of biomedicine. Within an arterial system of blood that has been stenosed, the goal of this research initiative is to investigate the effect that nanoparticles have on the characteristics that define the human circulatory system. The current investigation analyzes blood flow behavior in a controlled, permeable artery employing the Casson hybrid nanofluid model and, additionally, gold, Cu, and silver nanoparticles. The current study examines the investigation of magnetohydrodynamics (MHD) Casson hybrid nanofluid Darcy-Forchheimer flow (DFF) over a stenotic artery with a heat source/sink. By transforming the partial differential equations (PDEs) into ordinary differential equations (ODEs) by utilizing suitable similarity variables. After that, the mathematical solution of these equations used the BVP4c method in the MATLAB solver and analysis for skin and Nusselt number table values for hybrid nanofluid cases. The statistical analysis is used to solve for different physical factors. During a study in which values of both variables are subject to essentially unknown oversights, the task is utilizing statistical techniques to discover the best possible linear equations. In this concept, two different hybrid nanomaterials are used for analyzing heat transfer characteristics. According to these graphical results, the present model concludes that case-2 has better performance than case-1. Rising values of the magnetic parameter improve heat transfer owing to Joule heating impacts and control flow via the Lorentz force, which in turn affects the distribution of shear stresses close to the artery wall. The current work highlights the role of nanoparticles and magnetic fields in enhancing flexibility near arteries' surfaces. This work has substantial repercussions for the treatment of cancer and the treatments that are used to avoid cardiovascular disease, as it suggests that improved heat transfer and shear stress distribution can enhance the effectiveness of therapies targeting tumor cells and improve blood flow in cardiovascular interventions.

infection (CDI) is a major cause of antibiotic-associated diarrhea, with frequent recurrences closely linked to antibiotic-induced dysbiosis of the gut microbiota and bile acid metabolism. , a potential probiotic capable of converting primary to secondary bile acids, has shown therapeutic promise in several metabolic and inflammatory diseases. This study evaluated the preventive and therapeutic effects of against CDI and explored the underlying mechanisms. We characterized the probiotic properties of four strains and investigated the inhibitory activity of strain 1190003 against , as well as its protective and therapeutic efficacy in mouse models. Gut microbiota structure and bile acid metabolic profiles were analyzed by integrating 16S rRNA gene sequencing and metabolomics. The four strains exhibited strong acid and bile salt tolerance as well as auto-aggregation ability. Supernatants from co-cultured with cholic acid (4 mM and 8 mM) significantly inhibited growth, toxin expression and spore formation, with deoxycholic acid identified as the key inhibitory metabolite. Both live and its culture supernatant alleviated disease severity in CDI mouse models and ameliorated gut microbiota dysbiosis. Notably, the relative abundance of was increased following supernatant treatment. Furthermore, intervention with either live or its supernatant elevated the level of hyodeoxycholic acid. In summary, acts as a potential probiotic that alleviates CDI by ameliorating gut microbiota dysbiosis and remodeling bile acid metabolism. These findings provide experimental evidence for its use as a microbiota-based therapeutic strategy.

The pharmaceutical industry's shift toward new drug modalities, including therapeutic peptides, modified oligonucleotides, and antibody-drug conjugates, has exposed fundamental gaps in cheminformatics infrastructure. Unlike small molecules, which benefit from mature representation standards and reliable data exchange, new modalities lack robust and interoperable systems capable of capturing their structural and chemical complexity. Drawing on our experience at AstraZeneca, we examine these challenges across peptides, oligonucleotides, and ADCs, focusing on the limitations of current approaches, particularly HELM. We show that these limitations arise from both technical constraints, as new modalities exceed the scope of purely atomistic or sequence-based representations, and organizational gaps, including unresolved standardization and governance. We argue that local solutions exacerbate fragmentation, and that vendor- and community-driven standards, open implementations, and stronger governance are required to enable standardized and interoperable chemical information systems for next-generation therapeutics.

The phosphoinositide 3-kinase alpha inhibitor alpelisib has been increasingly used in the treatment of venous malformations. In this systematic review of 47 patients with a molecular diagnosis for their venous malformations treated with alpelisib, a partial or complete radiological response was achieved by 77% of evaluable patients and symptomatic improvement in 98%. Adverse effects were predominantly mild, with hyperglycaemia the most frequent, occurring in 58% of patients with available safety data. TRIAL REGISTRATION: PROSPERO Registration: CRD420261339549.

Prostate cancer (PCa) is characterized by significant metabolic heterogeneity, particularly in glutathione (GSH) metabolism. Elevated GSH metabolism is closely linked to PCa progression, therapeutic resistance, and poor clinical outcomes. Recent studies have highlighted the impact of protein butyrylation on cancer biology, although related therapeutic strategies remain limited. Herein, we utilized a cysteine-based, GSH-responsive polymer (Cys8E) to deliver a broad-spectrum antitumor agent CBL0137. Exploiting high GSH levels in PCa cells, the resulting CBL0137-loaded nanoparticles (Cys8E@CBL NPs) achieved targeted and efficient intracellular delivery and enhanced tumor-killing efficacy. Mechanistic investigations revealed that upon internalization by tumor cells, Cys8E NPs perturbed butyrate-associated metabolic homeostasis, as reflected by altered abundance of related metabolic enzymes and increased intracellular protein butyrylation levels. This metabolic remodeling was accompanied by enhanced lysine-95 butyrylation of PGAM5, which promoted necroptosis. Collectively, these findings define Cys8E@CBL NPs as a redox-responsive formulation in which the carrier contributes to therapy not only by improving CBL0137 delivery but also by reshaping butyrate-associated metabolism. This process promotes PGAM5 K95 butyrylation and strengthens necroptotic tumor cell killing. These results extend the design rationale of nanomedicine from passive payload transport toward active regulation of metabolism-dependent post-translational signaling in prostate cancer.

BACKGROUND The coexistence of cardiac myxoma and hypertrophic cardiomyopathy is exceedingly rare and poses diagnostic and therapeutic challenges. While atrial myxomas may cause acute hemodynamic compromise, concomitant left ventricular outflow tract obstruction (LVOTO) due to hypertrophic cardiomyopathy can remain clinically underestimated, raising uncertainty regarding the optimal timing of septal reduction therapy. CASE REPORT A 38-year-old man was admitted with acute dyspnea and hypoxemia. Imaging revealed pulmonary congestion and a large left atrial mass causing functional mitral stenosis. Transthoracic echocardiography demonstrated asymmetric septal hypertrophy (maximum thickness 25 mm) with dynamic LVOTO and a mobile left atrial mass consistent with myxoma. The patient underwent surgical resection of the tumor with concomitant septal myectomy. Histopathology confirmed atrial myxoma and myocardial hyperplasia. Postoperatively, complete atrioventricular block required permanent dual-chamber pacemaker implantation. At short-term follow-up, the patient was asymptomatic with mild residual LVOTO. CONCLUSIONS This case underscores the importance of comprehensive structural and functional assessment in patients with intracardiac tumors. In young patients with favorable prognostic features and significant left atrial dilatation, early septal myectomy performed concomitantly with tumor resection may be justified, even when resting LVOT gradients are below conventional thresholds. This strategy aligns with the latest American and European guidelines on cardiomyopathies and may prevent delayed intervention and disease progression. The case also highlights atrioventricular block as a relevant complication of surgical myectomy, reinforcing the need for careful perioperative planning. Overall, this report provides an instructive example of individualized surgical decision-making in complex cardiomyopathy presentations.