Citations

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and metabolites that confer health benefits—are emerging as promising and safer alternatives to live probiotics in oncology. This review provides a comprehensive mechanistic overview of the potential role of postbiotics against cancer, with a specific focus on breast cancer. Preclinical evidence demonstrates that selected postbiotics exert dose- and time-dependent anticancer effects against multiple breast cancer subtypes by modulating key oncogenic pathways (such as PI3K/AKT and NF-κB) and inducing epigenetic regulation through histone deacetylase inhibition. Beyond direct effects on tumor cell proliferation and apoptosis, postbiotics influence the breast cancer microenvironment by reshaping cytokine networks, suppressing pro-metastatic inflammation, and enhancing antitumor immune responses through the activation of NK cells and T cells. We also provide emerging links between microbiome composition, estrobolome activity, and breast cancer subtype-specific biology. Despite these encouraging findings, the clinical translation of postbiotics in oncology remains limited. Currently, only one registered clinical trial investigates postbiotics in the oncology setting (melanoma), and no clinical trials have specifically evaluated postbiotics in breast cancer patients. This highlights a substantial translational gap between preclinical evidence and clinical application. Accordingly, well-designed, tumor-specific clinical trials are urgently needed to validate the safety, efficacy, and therapeutic potential of postbiotics as novel strategies in personalized breast cancer management.

ABSTRACT Background Higher time in sedentary behavior and insufficient physical activity are very common in bipolar disorder (BD). Whereas physical activity and exercise offer significant benefits across mental health, brain health, and heart health in BD. The International Society for Bipolar Disorders Nutrition and Exercise Task Force (NExT) synthesized evidence to evaluate the impacts of sedentary behavior, physical activity, and exercise on illness course, physical health, and treatment outcomes. Methods A best‐evidence synthesis was conducted using a question‐and‐answer format. We searched PsycINFO, SPORTDiscus, Embase, PubMed, and Web of Science from inception to March 1st, 2026, supplemented by reference lists and existing guidelines. Search terms included combinations of physical activity, exercise, sedentary behavior, and bipolar disorder‐related terms. Results Observational studies show that individuals with BD exhibit significantly higher sedentary behavior and lower physical activity compared to the general population, with notable discrepancies between self‐reported and objective measurements. Evidence on physical activity's protective role against BD onset is mixed, with some prospective and Mendelian randomization studies suggesting reduced risk, while others report bidirectional or null associations. Preliminary findings from clinical trials indicate that exercise improves overall functioning, reduces mood episode frequency and hospitalizations, and alleviates depressive symptoms, with one pilot study showing an 82% antidepressant response rate. Exercise also shows potential to reduce anxiety and improve sleep, though robust data are limited. Conclusions Despite limited high‐quality evidence, physical activity and exercise demonstrate promising physical and mental health benefits for individuals with BD. Future research should prioritize multicenter randomized controlled trials, enhanced assessment tools, and accessible, tailored programs to integrate physical activity into routine BD management.

Abstract Background While the radiation dose to left anterior descending (LAD) artery is associated with overall survival (OS) in NSCLC patients, manual segmentation is labor‐intensive. Several auto‐segmentation models were developed on average 4DCT with promising geometric agreement, yet their feasibility in clinical outcome analysis on lung CT remains unclear. Purpose This study evaluates whether automated LAD segmentation can reproduce, at the group level, the established dose‐survival association in a multi‐institutional clinical trial dataset. Methods Three deep learning‐based auto‐segmentation (DLAS) models for automatic segmentation of the LAD coronary artery were applied to 460 patients from the NRG Oncology/RTOG 0617 dataset. Kaplan–Meier curves and Cox proportional hazard ratio (HR) were calculated using each model's segmentation. The LAD V15 Gy was used to stratify patients into high‐and low‐risk groups, and the cut‐off values were determined by minimizing mean absolute error (MAE) between DLAS‐derived and manual OS curves. Results All three models demonstrated significantly different OS curves between the high risk and low risk groups ( p < 0.05). The HR was 1.40 (95% CI: 1.02–1.93; p = 0.0381; MAE = 7.1%), 1.32 (95% CI: 1.03–1.68; p = 0.0258; MAE = 9.6%), and 1.37 (95% CI: 1.03–1.84; p = 0.0331; MAE = 7.9%) for the three models using a common V15 Gy ≥ 10% cut‐off. After optimizing the cut‐off, one model aligned well with what was derived from manual segmentation (MAE = 4.3%). Conclusion Among the evaluated models, one DL model showed the strongest performance of survival groups separation and achieved group‐level overall survival stratification comparable to that previously reported using manual contours in the multi‐institutional cohort. Further validation with paired manual contours and pre‐specified cutoffs is warranted.

Recent data suggest that sodium–glucose cotransporter 2 inhibitors have cardioprotective benefits. This effect may extend towards cardioprotection in cancer therapy-related cardiac dysfunction, with proposed mechanisms extending beyond glycemic control to include anti-inflammatory effects, oxidative stress reduction, and metabolic reprogramming. This review synthesizes potential mechanisms, observational data, and emerging trial evidence to support sodium–glucose cotransporter 2 inhibitors as a primary prevention strategy for cancer therapy-related cardiac dysfunction, particularly in anthracycline-exposed populations.

Abstract Background Complications such as intermittent pouchitis (IP) and chronic inflammatory disorders of the pouch (CP) are common after ileal pouch-anal anastomosis (IPAA), particularly among patients with both ulcerative colitis and primary sclerosing cholangitis (PSC). There are no standardized approaches for prophylaxis against these complications for patients with PSC undergoing IPAA. We compared outcomes among patients with PSC and IPAA who received antibiotic or immunosuppressive therapies to those who did not. Methods We designed a retrospective cohort study that included patients with ulcerative colitis and PSC from 7 tertiary care centers that underwent IPAA between 1994 and 2023. Patients were categorized on whether they received medications following IPAA that may provide primary prophylactic benefit, such as antibiotics, probiotics, immunomodulators, or biologic medications; and the proportion of patients developing IP and CP was evaluated. Results A total of 172 patients were included in the cohort, and 13 (7.6%) patients received antibiotics or immunosuppressant medications. Antibiotics and probiotics were the most common therapy (5 patients, 2.9%), followed by biologics, small-molecule inhibitors, immunomodulators, or mesalamine (all 1 patient, 0.6%). Compared to patients not receiving antibiotics or immunosuppression, patients receiving antibiotics or immunosuppression were significantly less likely to develop IP (69.2% vs 91.2%; P = .03; odds ratio 0.22; 95% CI, 0.06-0.80) and CP (23.1% vs 56.0%, P = 0.04; OR 0.24, 95% CI, 0.06-0.89). Conclusions In this retrospective cohort of patients with ulcerative colitis and PSC undergoing IPAA, usage of concomitant antibiotics or immunosuppression was low. However, use of concomitant antibiotics or immunosuppression may decrease the burden of inflammatory conditions of the pouch in these high-risk patients.

SUMMARY OBJECTIVE: The aim of this study was to estimate the prevalence of isthmocele using transvaginal ultrasound, magnetic resonance imaging and diagnostic hysteroscopy. METHODS: A cross-sectional study conducted from 2020 to 2022 in tertiary academic hospital with ninety non-pregnant women with a history of cesarean section. Transvaginal ultrasound (n=90), magnetic resonance imaging (n=65) and office diagnostic hysteroscopy (n=81) were performed within a short interval for each patient. RESULTS: The women had a mean age of 34.8±6.3 years, mean number of 2.0±1.1 cesarean sections and mean duration of 40 months since their last cesarean. The prevalence of isthmocele with 95%CIs was 11.3% (5.5–19.7%) on transvaginal ultrasound, 66.1% (53.3–77.4%) on magnetic resonance imaging, and 43.2% (32.2–54.6%) on diagnostic hysteroscopy. When transvaginal ultrasound was considered reference, accuracy for diagnostic hysteroscopy was 57.89% (44.1%; 70.6%) and magnetic resonance imaging, 43.86% (30.9; 57.5%); when magnetic resonance imaging was reference, accuracy for diagnostic hysteroscopy was 54.39% (40.75; 67.43%). Agreement analysis (kappa) among the methods showed low scores between diagnostic hysteroscopy and magnetic resonance imaging regarding transvaginal ultrasound (0.126, p<0.001 and 0.103, p<0.001, respectively) and between diagnostic hysteroscopy and magnetic resonance imaging (0.206, p=0.014). CONCLUSION: The prevalence of isthmocele was lower in transvaginal ultrasound and higher in magnetic resonance imaging. Accuracy varied from 43 to 58% among the three methods and agreement between tests for diagnosing isthmocele was low.

Abstract Background Cardiac papillary fibroelastoma (PFE) is the most common benign primary cardiac tumor. Despite their benign pathology, PFEs pose a significant embolic risk, which can lead to severe neurological sequelae. However, subclinical or silent emboli often go undetected, presenting a diagnostic challenge. This study aims to assess the prevalence of silent emboli in patients with pathology-proven PFEs using brain magnetic resonance imaging (MRI). Methods We conducted a retrospective review of 385 cases of pathology-confirmed PFEs. Inclusion criteria was those with brain MRI performed within 5 years of surgical resection of the PFE and no clinical neurological events. Patients with a history of symptomatic cerebral infarction (stroke or TIA) were excluded. Patient demographics and PFE imaging features were analyzed by two cardiologists experienced in cardiac tumors. Clinical neurological data, and MRI findings were analyzed by two neurologists with expertise in cerebrovascular disease. Results Out of 385 patients, 132 underwent brain MRI. In the entire cohort, 105/385 patients (27%) experienced clinically overt embolic events. After excluding patients with symptomatic cerebral infarctions and MRI scans older than 5 years, 27 patients (mean age: 71±9.6, gender: 66% female) met the inclusion criteria. Of these, 8 patients (30%) showed signs of silent infarctions on MRI, with 4 (15%) displaying findings consistent with cerebral infarction highly suggestive for embolic source. Conclusion This study underscores the substantial risk of silent cerebral embolic events in patients with PFE. The limited availability of MRI data, largely attributable to the absence of standardized neuroimaging protocols, indicates that the true prevalence of silent embolization in this population is likely underestimated. Given the propensity of PFE to generate clinically silent emboli, systematic cerebral MRI should be strongly considered as part of the diagnostic assessment of patients with cardiac masses, irrespective of neurological symptoms. Early identification of subclinical cerebrovascular lesions may facilitate timely therapeutic decision-making and secondary prevention strategies, thereby reducing the risk of future symptomatic and potentially disabling ischemic strokes.

Abstract Background AL amyloidosis and multiple myeloma are plasma cell dyscrasias characterized by excess light-chain production leading to cardiac amyloid deposition and organ dysfunction. While effective, proteasome inhibitor–based therapy and stem cell transplantation are often limited in advanced disease. Daratumumab provides durable and well-tolerated plasma cell suppression and enables assessment of long-term cardiac outcomes. Purpose To evaluate the long-term effects of daratumumab therapy on cardiac biomarkers and myocardial amyloid burden, assessed by artificial intelligence- based electrocardiographic (AI-ECG) and echocardiographic measures, in patients with AL amyloidosis and cardiac involvement. Methods Following IRB approval, we conducted a retrospective review of patients with AL amyloidosis and cardiac involvement treated with daratumumab at Mayo Clinic Rochester since 2015, with a minimum follow-up of 6 months. Demographic, clinical, cardiac biomarker, electrocardiographic, and echocardiographic data were collected at baseline and last follow-up. Paired comparisons were performed using the Wilcoxon signed-rank test. Results Overall, 67 patients with AL amyloidosis were included (mean age at diagnosis 59 ± 10 years; 47 [70%] male; concomitant multiple myeloma 13 (19%) patients, mean left ventricular ejection fraction 61 ± 7%), with a mean follow-up duration of 8.3 ± 5.4 years. At diagnosis, the most common organ involvements were renal and cardiac, affecting 78% and 67% of patients, respectively. Free light-chain isotype was λ in 52 patients (75%) and κ in 17 (25%) and immunoglobulin heavy-chain was identified in 26 patients. Among patients with available baseline staging data, Mayo Clinic revised cardiac staging (2012) classified 32% as stage I, 14% as stage II, 21% as stage III, and 32% as stage IV. Most patients were NYHA class II (62%), with 27% in class III–IV. Baseline creatinine clearance &lt;60 ml/min was observed in 48% of patients. No significant changes were observed in conventional echocardiographic parameters during follow-up. In contrast, cardiac biomarkers improved significantly with high-sensitivity troponin T decreased from a baseline median of 59 [25, 104.5] ng/L to 30.5 [14.5, 58.75] ng/L at follow-up (p = 0.003), and NT-proBNP declined from 1,053 [423.5, 6,211.5] pg/mL to 729 [299, 2,328] pg/mL (p = 0.02). Interestingly, artificial intelligence–based electrocardiographic analysis demonstrated a marked reduction in the predicted likelihood of cardiac amyloidosis, decreasing from 55.8% [5.1, 99.6] at baseline to 19.3% [4.3, 68.4] at follow-up (p &lt; 0.0001). Conclusions Long-term daratumumab therapy was associated with significant reductions in cardiac biomarkers and AI-ECG derived measures of myocardial amyloid burden. These findings support the hypothesis that sustained suppression of pathogenic light-chain production may permit gradual improvement in amyloid cardiomyopathy over time.

Abstract Background Light chain cardiac amyloidosis (AL-CM) is an infiltrative cardiomyopathy associated with significant morbidity and mortality. Early diagnosis and risk stratification is critical for prognostication and management, particularly identifying patients most likely to need heart transplants. The systemic light chain amyloidosis (sAL) score is derived from echocardiographic parameters: relative wall thickness (RWT), E/e' ratio, global longitudinal strain (GLS), and tricuspid annular plane systolic excursion (TAPSE) and is validated in the diagnosis of AL-CM [1]. Its prognostic value for development of atrial fibrillation, progression of heart failure, and hospitalizations remains unclear. This study evaluates the association between the sAL score, arrhythmias, and functional outcomes in patients with confirmed AL-CM. Methods A retrospective review of patients seen at our hospital, with confirmed AL-CM diagnosed between June 2014 and October 2021 was conducted on an IRB-approved protocol. The sAL score was collected at the time of diagnosis. Binary outcomes were evaluated using a weighted Mann-Whitney U test, with effect size calculated as r=Z/sqrt(N). Ordinal and continuous outcomes were analysed using weighted Spearman correlation, with Spearman’s rho reported as the effect size. Results 37 patients with AL-CM were included (51.4% male), with a median age of 70 years [IQR 66–76], a median sAL score of 5 [IQR 3–6], and a median left ventricular ejection fraction (LVEF) of 55% [IQR 50–60] at diagnosis. 24 patients had their AL-CM diagnosed by cardiac MRI and positive Congo red on peripheral biopsy (e.g., fat pad); the other 13 had positive endomyocardial biopsy. 22 patients had sAL scores ≥ 5 with overall survival of 17/22 (77.3%) and median follow-up of 53 months. 15 patients had sAL scores &lt; 5 with overall survival of 14/15 (93.3%) and median follow-up of 57 months. 4 patients had atrial fibrillation or flutter at diagnosis. 6 patients developed atrial fibrillation or flutter with a median onset of 15 months after diagnosis. Higher sAL scores at diagnosis were associated with development of new-onset atrial fibrillation or flutter (median sAL 4.5 vs 5, p = 5.75×10^-10, r = 1.02), heart failure hospitalizations (median sAL 5 vs 5, p = 1.94×10^-6, r = 0.78), and ≥30% eGFR decline at 12 months (median sAL 4.5 vs 6, p=8.69×10^-24, r = 1.65). Higher sAL scores were moderately correlated with NYHA class (rho = 0.44, p = 0.00378) and strongly correlated with diastolic dysfunction grade (rho = 0.549, p = 9.99×10^-6) but not associated with change in LVEF (p = 0.51 and p = 0.62, respectively). Conclusion sAL scores of ≥5 at diagnosis were associated with worse functional and clinical outcomes in patients with proven AL-CM. These findings suggest the sAL score predicts electrophysiological changes, supporting its potential role in early risk stratification and disease monitoring.