Citations

Introduction Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in immune signaling and has been implicated in tumor-intrinsic resistance to DNA-damaging therapies. Although SYK activity has been associated with poor outcomes in triple-negative breast cancer (TNBC), its role in resistance to combined radiotherapy and immune checkpoint blockade remains unclear. Methods SYK expression and clinical relevance were assessed across multiple breast cancer cohorts, including radiotherapy-treated datasets. Integrated transcriptomic analyses were used to characterize SYK-associated immune states. The functional effects of pharmacologic SYK inhibition were evaluated using in vitro assays and an immunocompetent bilateral 4T1 tumor model in female BALB/c mice treated with radiotherapy and PD-1 blockade. Treatment-associated immune remodeling was assessed by flow cytometry and transcriptomic profiling. Results Across multiple cohorts, elevated SYK expression, particularly in TNBC, was associated with inferior clinical outcomes and immune dysregulation. Pharmacologic SYK inhibition enhanced tumor responses to radiotherapy and PD-1 blockade at both irradiated and distant tumor sites. These effects were accompanied by coordinated remodeling of the tumor immune microenvironment, including suppression of neutrophil-associated signatures and reductions in immunosuppressive myeloid populations, including M2-like macrophages and myeloid-derived suppressor cells. Discussion Pharmacologic SYK inhibition enhances responses to radiotherapy and PD-1 blockade in preclinical TNBC models and is accompanied by remodeling of the immunosuppressive myeloid compartment. These findings support further investigation of SYK-targeted strategies to improve responses to combined radiotherapy and immune checkpoint blockade.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

Cardiovascular disease causes the largest number of deaths across the world. The weak regenerative ability of adult hearts originates from limited cell proliferation and polyploidization of postnatal cardiomyocytes, which severely hinders tissue repair after myocardial injury. Fetal development represents a critical window during which maternal physiological and metabolic status can shape long-term offspring cardiac structure and function. Maternal exercise represents a safe nonpharmacological prenatal intervention that confers long-term benefits to offspring health. Available evidence indicates that maternal exercise enhances placental apelin secretion and elevates α-ketoglutarate (α-KG) levels in fetal brown adipose tissue, liver, and skeletal muscle. The apelin and α-KG signaling cascade participates in epigenetic regulation and confers protective effects on offspring metabolic health. Independent animal experiments have further validated that supplementation with either apelin or α-KG alleviates myocardial infarction (MI)-induced cardiac injury in adult mice, with α-KG showing direct evidence of reactivating cardiomyocyte proliferation. Nevertheless, it remains poorly elucidated whether maternal exercise could modulate fetal cardiomyocyte proliferative capacity in offspring through apelin- or α-KG-associated signaling. This narrative review integrates current evidence and proposes a testable framework in which maternal exercise influences fetal cardiac growth and regenerative potential through placental, metabolic, and epigenetic signaling. Because direct evidence remains limited, this model should be regarded as a hypothesis that requires further experimental validation.

Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.

Vascular stents are crucial devices in the treatment of cardiovascular diseases, and their structural design and function critically affect therapeutic efficacy and patient prognosis. Conventional stents can effectively restore vascular patency by providing mechanical support to blood vessels. However, they still face significant challenges including restenosis, thrombosis, and limited adaptability to complex patient-specific lesion characteristics. To address these limitations, drug delivery offers an important strategy to modulate the pathological microenvironment, enhance long-term vascular healing, and reduce systemic side effects. Meanwhile, advances in computational simulations have provided powerful tools for optimizing stent design through structural mechanics, hemodynamics, and drug release modeling. Computational approaches enable the rational design of stent architectures with improved mechanical stability, vascular compatibility, and therapeutic regulation. Consequently, the development of vascular stents is evolving toward the synergistic integration of drug delivery, structural optimization, and intelligent design. This review summarizes the latest advances in functional vascular stents, clinical applications and computational design. This work aims to provide valuable insights for the engineering of efficient, precise, and intelligent vascular stents for cardiovascular therapies.

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) and cancer-related myelopathy often cause pain, numbness, and mobility impairment. While treatments such as medications typically target positive sensory symptoms (eg, burning or tingling), negative symptoms such as numbness and proprioceptive loss remain difficult to manage and significantly affect balance and gait. This study evaluated the feasibility of using textured insoles as a noninvasive approach to improve these symptoms. Methods: A prospective feasibility study was conducted with adult patients with cancer experiencing negative sensory symptoms due to CIPN or myelopathy. Participants were provided with textured insoles designed to enhance plantar sensory input and instructed to wear them during daily activities for 1 month. Outcomes were measured pre- and postintervention using the 4-Stage Balance Test, Timed Up and Go test, and patient-reported assessments of balance and mobility. Results: Twenty participants were enrolled: 70% reported numbness, 45% gait impairment, 40% balance impairment, and 35% pain. Objective improvements in balance and gait were observed with the use of insoles, with significant Timed Up and Go gains at both initial ( P < .001) and follow-up ( P = .01) visits, adjusting for additional therapy. Sixteen participants reported improved stability and confidence after 1 month. Adherence was high, and no adverse events occurred. Conclusion: Textured insoles are a feasible, well-tolerated supportive intervention for patients with negative sensory symptoms from CIPN or cancer-related myelopathy. By enhancing sensory feedback, insoles may improve balance, mobility, and quality of life. Larger controlled trials are warranted to confirm efficacy and long-term outcomes.

ABSTRACT Background & Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is highly prevalent and increasingly recognized as a multisystem cardiometabolic disorder. The global burden, incidence and prognostic implications of coexisting chronic kidney disease (CKD) in MASLD remain uncertain. Methods In this meta‐analysis, we searched MEDLINE and EMBASE from inception through September 25, 2025, for observational studies reporting CKD prevalence and/or incidence among adults (≥ 18 years) with MASLD. The primary outcomes were pooled CKD prevalence, estimated using random‐effects models on the logit scale with the Hartung–Knapp adjustment, and pooled CKD incidence (per 1000 person‐years), estimated using random‐effects models with exact Poisson confidence intervals. Secondary outcomes included all‐cause mortality and cardiovascular, renal and cancer outcomes. Results From 2811 records, 36 observational studies met the inclusion criteria. Twenty‐three studies contributed prevalence estimates (575 615 participants; 56 248 CKD cases) and thirteen studies contributed incidence estimates (27 996 new events). The pooled global CKD prevalence among individuals with MASLD was 15.22% (95% CI 9.69–23.12). The pooled CKD incidence was 22.17 per 1000 person‐years (95% CI 11.44–32.89) in the MASLD population. Hypertension (OR 1.49, 95% CI 1.29–1.72), dyslipidaemia (OR 1.22, 95% CI 1.20–1.24) and diabetes (OR 1.94, 95% CI 1.69–2.22) were associated with higher odds of CKD in the MASLD population. All‐cause mortality rates were 18.28 per 1000 person‐years (95% CI 3.45–33.11) in coexistent MASLD and CKD, more than double those in the MASLD‐only population (7.26 per 1000 person‐years (95% CI 2.97–11.56)). Conclusions Coexistent CKD affects one in seven individuals with MASLD worldwide, conferring a more than two‐fold increased risk of all‐cause mortality compared with individuals with MASLD alone.

Background: A diagnosis of cancer creates a stressful situation owing to the uncertainties related to the thought of possible suffering from complications associated with treatment toxicities, the fear of not responding to the prescribed treatment, or death. The prevalence of mental health disorders is relatively higher in cancer patients vis-à-vis the general population. Methods: We performed a retrospective cohort study to evaluate the impact of mental health disorders on outcomes of relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR T-cell) therapy using data from the TriNetX research network. Results: A total of 1587 patients met the inclusion criteria (858 with a mental health diagnosis and 729 without). After propensity score matching for age and gender, 1320 patients were included in the analysis (660 in each group). The 1-year OS was higher in patients without a mental health disorder (76.0% versus 69.4%, P = 0.004). Patients with mental health disorders had a higher incidence of cytokine release syndrome (all grades) compared with those without (35.5% versus 27.6%, P < 0.001) and immune effector cell-associated neurotoxicity syndrome (all grades) (16.8% versus 10.1%, P < 0.001). Conclusions: These findings emphasize the importance of thorough psychiatric evaluation and management in patients receiving CAR T-cell therapy. Patients with mental health disorders may need significant assistance with coordinating medical services to better adhere to required care management. Future studies are needed to help determine whether preventive and real-time mental health interventions can favorably impact outcomes of these patients.