Importance Patients with prostate cancer have a high burden of cardiovascular risk factors, often suboptimally controlled, and adverse cardiovascular outcomes. Objective To determine whether the routine referral of patients with prostate cancer to a cardiovascular specialist to implement a systematic risk factor strategy is more likely to reduce adverse cardiovascular outcomes and improve risk factor control than usual care. Design, Settings, and Participants This randomized clinical trial included patients with prostate cancer from 55 sites in 8 countries between 2015 and 2025. Eligible patients were diagnosed with prostate cancer during the past 12 months; had received treatment with androgen deprivation therapy (ADT) for the first time within the past 6 months; or planned to start ADT in the next month. Patients taking a statin with a systolic blood pressure of 130 mm Hg or lower were ineligible. Data were analyzed from May 25 to August 7, 2026. Intervention Patients were allocated in a 1:1 ratio to receive usual care alone or usual care plus routine referral to an internist or cardiologist. The specialists provided a systematic intervention, including a target of systolic blood pressure of 130 mm Hg or lower and a statin medication, irrespective of the patient’s cholesterol levels (even if not usual or guideline-driven practice); encourage smoking cessation; and provide guidance on diet and exercise. Main Outcomes and Measures Hierarchical composite of cardiovascular death, myocardial infarction, stroke, heart failure, suboptimal cholesterol (total cholesterol, >155 mg/dL [to convert to mmol/L, multiply by 0.0259]) and suboptimal blood pressure (systolic blood pressure, >130 mm Hg) as evaluated by the win ratio. Results The analysis included 2487 patients with prostate cancer (mean [SD] age, 68 [8] years). During median (IQR) follow-up of 5.8 (2.7-8.2) years, the win ratio in favor of the intervention was 1.60 (95% CI, 1.42-1.81), mostly attributable to lower cholesterol in the intervention group (mean difference, 12 mg/dL; 95% CI, 9-15 mg/dL) as a consequence of greater protocol-mandated statin use. Mean (SD) close-out systolic blood pressure values were 131.1 (16.9) mm Hg in the intervention group and 132.9 (18.3) mm Hg in the control group. There was no difference in time to cardiovascular death, myocardial infarction, stroke, or heart failure between groups (subdistribution hazard ratio, 1.08; 95% CI, 0.79-1.49). Conclusions and Relevance In this randomized clinical trial, routine referral of patients with prostate cancer to a cardiovascular specialist lead to improved outcomes, specifically through better cholesterol control. However, it is uncertain whether this reduced clinical cardiovascular events. Trial Registration ClinicalTrials.gov Identifier: NCT03127631

Clear cell renal cell carcinoma (ccRCC) is characterized by a complex tumor microenvironment, in which stromal components such as collagen and cancer-associated fibroblasts (CAF) play a pivotal role in therapeutic resistance. To investigate the contribution of fibrosis to interpatient variability in treatment response, we developed a patient-derived xenograft (PDX) model using the chick chorioallantoic membrane (CAM) ex ovo assay. This model preserves key stromal features of the original tumors, including collagen types I, III and VII, fibronectin, lysyl oxidases (LOX), and CAF markers such as fibroblast activation protein (FAP) and alpha-smooth muscle actin (alpha-SMA). Transcriptomic analyses confirm the conservation of gene expression profiles related to stromal architecture, extracellular matrix composition, and cellular metabolism within the xenografts. In vivo assays across multiple PDXs reveal heterogeneous responses to antifibrotic agents, which correlate with the collagen content of the original tumors. Notably, antifibrotic pretreatment enhances therapeutic efficacy in xenografts derived from tumors with collagen levels ranging from 5 to 25%. This model provides a physiologically relevant platform to assess fibrosis-driven therapeutic responses in ccRCC and supports the integration of stromal profiling into personalized treatment strategies.

Background/Objectives: This study explores the potential of the inducible G protein-coupled kinin B1 receptor (B1R) as a target for the diagnosis and treatment of prostate cancer (PCa) and aims to develop the first theranostic agent targeting hB1R for both molecular imaging and radionuclide therapy. Methods: B1R expression was analyzed via qPCR and immunohistochemistry in human PCa cells and tissues specimens. A novel 64Cu/NOTA-conjugated peptide analog of the potent B1R antagonist R954 was synthetized and evaluated in vitro and in vivo. Results: B1R was confirmed to be expressed (RNA, protein) by varying degrees in all PCa cell lines and tissues investigated, with protein level significantly correlating with tumor grades. This finding was supported by similar analyses from the TCGA and MSKCC databases. In vitro, the 64Cu/NOTA-βAla-R954 conjugate showed nanomolar affinity/potency at hB1R, complete plasma stability over 24 h, significant cellular uptake (up to 33% of ID at 24 h), and dose-dependent anti-clonal growth effects. In vivo, the radioconjugate remained stable in circulation for up to 90 min and was primarily excreted intact via the kidneys following IV administration. Intravenous 64Cu/NOTA-βAla-R954 (7.5 MBq) effectively detected subcutaneous PCa xenografts via µPET imaging in male athymic nude mice. At a single higher dose (65 MBq; 50 µg/kg), it significantly reduced tumor growth without observable toxicity. This antitumor effect was associated with increased apoptosis (active caspase-3) and reduced proliferation (Ki67), as shown by immunohistochemistry. In contrast, the nonradioactive NatCu/NOTA-βAla-R954 had no therapeutic effect at the same dose. Conclusions: Our findings provide proof-of-concept for the potential theranostic use of 64Cu/NOTA-R954 in PCa, and potentially other types of B1R-positive solid cancers.

80 Background: As a disease of older individuals, prostate cancer (PC) may feature physical frailty. Most related studies are retrospective and focus on short-term surgical outcomes. Methods: We conductedan analysis of a prospective study of PC patients either diagnosed within the past year, treated with androgen deprivation therapy (ADT) for the first time within the past six months, or scheduled to initiate ADT within a month . Frailty was assessed using Fried's criteria which includes five domains [Handgrip strength, gait speed, physical activity, unintentional weight loss (>4 kg/year) and exhaustion (≥3 days/week)]. Patients were classified as frail (≥3 criteria), pre-frail (1-2 criteria), or robust (0 criteria). Participants were followed annually to ascertain the occurrence of mortality, new metastases, major adverse cardiovascular events (MACE: myocardial infarction, stroke, cardiovascular death, stroke, heart failure, peripheral arterial disease, venous thromboembolism or arterial revascularization) and hospitalization. The relationship between frailty and these events was evaluated by Cox proportional hazards models adjusted for age at enrolment, education, race, tobacco and alcohol use, diabetes, past history of cardiovascular disease, estimated glomerular filtration rate, PC risk, metastatic disease and ADT exposure. Results: We studied 4304 participants (mean age 69±8 years) from 9 countries: 1429 (33%) were robust, 2394 (56%) pre-frail and 481 (11%), frail. During a median 2.4 years, 336 (8%) died, 161 (4%) died from PC or developed new metastases, 506 (12%) were hospitalized and 262 (6%) experienced MACE. Being prefrail or frail was associated with a higher risk of death, hospitalization and MACE but not PC death or new metastases (Table). Conclusions: Pre-frailty and frailty are common among patients with PC. Frailty is associated with approximately a two-fold increase in mortality, hospitalization or MACE in PC patients independent of a wide range of prognostic factors. Relationship between frailty and clinical outcomes. Characteristic Death Hospitalization PC death or new metastases MACE Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Frailty Robust Pre-frail Frail Ref1.54(1.13-2.00)2.90(2.00-4.21) 0.007<0.001 Ref1.39(1.10-1.74)2.29(1.70-3.09) 0.005<0.001 Ref1.05(0.70-1.57)1.47(0.85-2.52) 0.830.17 Ref1.44(1.05-1.97)2.21(1.46-3.34) 0.023<0.001 Estimates are from Cox proportional hazards models adjusted for age at enrolment, education, race, tobacco and alcohol use, diabetes, past history of cardiovascular disease, estimated glomerular filtration rate, PC risk, metastatic disease and ADT exposure.

BACKGROUND There are limited data on the physical effects of androgen deprivation therapy (ADT) for prostate cancer (PC), and on the relationships of such measures of adiposity and strength to cardiovascular outcomes. OBJECTIVES The primary objective of this study was to evaluate the relationships of measures of adiposity and strength to cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, heart failure, arterial revascularization, peripheral arterial disease, and venous thromboembolism) in patients with PC. A secondary objective was to characterize the relationships between ADT use and 12-month changes in these physical measures. METHODS This international, prospective cohort study included 3,967 patients with PC diagnosed in the prior 12 months or being treated with ADT for the first time. Median follow-up duration was 2.3 years. RESULTS Participants' mean age was 68.5 years, and 1,731 (43.6%) were exposed to ADT. ADT was associated with a 1.6% increase in weight, a 2.2% increase in waist circumference, a 1.6% increase in hip circumference, a 0.1% increase in waist-to-hip ratio, a 27.4% reduction in handgrip strength, and a 0.1% decrease in gait speed. High waist circumference and low handgrip strength were associated with adverse cardiovascular outcomes. Adjusting for age, education, race, tobacco and alcohol use, physical activity, cardiovascular disease, glomerular filtration rate, and ADT use, waist circumference above the highest quartile (110 cm) and handgrip strength below the lowest quartile (29.5 kg) were associated with higher likelihoods of a future cardiovascular event, with respective HRs of 1.40 (95% CI: 1.03-1.90; = 0.029) and 1.59 (95% CI: 1.14-2.22; P = 0.006). CONCLUSIONS ADT was associated with increased adiposity and reduced strength over 12-month follow-up. High waist circumference and low baseline strength were associated with future adverse cardiovascular outcomes. (JACC CardioOncol. 2024;6:761-771) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

<p>miRNA alignment results</p>

Supplementary data and material regarding the alternative splicing detailed analysis by PCR and IHC, decitabine efficacy, supplementary cell line testing by overexpression and silencing and substrate screening by western blots

DOI of original article: https://doi.org/10.1016/j.kint.2023.06.038 It was discovered that the XML version of the above article contained errors in the graphical abstract that were not the fault of the authors. The Publisher decided to “resupply” (repost and replace) the XML version of the article. Elsevier regrets and apologizes for any inconvenience caused by posting a new version of this article online but hopes that the reader will understand the reasons for doing so. Deletion of protein tyrosine phosphatase SHP-1 restores SUMOylation of podocin and reverses the progression of diabetic kidney diseaseKidney InternationalVol. 104Issue 4PreviewBoth clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss are not completely understood, critical structural proteins such as podocin play a major role in podocyte survival and function. We have reported that the protein tyrosine phosphatase SHP-1 expression increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the in vivo contribution of SHP-1 in podocytes is unknown. Full-Text PDF Open Access

<p>SILAC secretome data</p>

Antibody validation panel and distinct intracellular localization by IHC

<p>Primer sequences and antibodies specifications</p>

<p>Primer sequences and antibodies specifications</p>

Both clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss are not completely understood, critical structural proteins such as podocin play a major role in podocyte survival and function. We have reported that the protein tyrosine phosphatase SHP-1 expression increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the in vivo contribution of SHP-1 in podocytes is unknown. Conditional podocyte-specific SHP-1-deficient mice (Podo-SHP-1-/-) were generated to evaluate the impact of SHP-1 deletion at four weeks of age (early) prior to the onset of diabetes and after 20 weeks (late) of diabetes (DM; Ins2D/C96Y) on kidney function (albuminuria and glomerular filtration rate) and kidney pathology. Ablation of the SHP-1 gene specifically in podocytes prevented and even reversed the elevated albumin/creatinine ratio, glomerular filtration rate progression, mesangial cell expansion, glomerular hypertrophy, glomerular basement membrane thickening and podocyte foot process effacement induced by diabetes. Moreover, podocyte-specific deletion of SHP-1 at an early and late stage prevented diabetes-induced expression of collagen IV, fibronectin, transforming growth factor -fi, transforming protein RhoA, and serine/threonine kinase ROCK1, whereas it restored nephrin, podocin and cation channel TRPC6 expression. Mass spectrometry analysis revealed that SHP-1 reduced SUMO2 post-translational modification of podocin while podocyte-specific deletion of SHP-1 preserved slit diaphragm protein complexes in the diabetic context. Thus, our data uncovered a new role of SHP-1 in the regulation of cytoskeleton dynamics and slit diaphragm protein expression/stability, and its inhibition preserved podocyte function preventing DKD progression.

Abstract Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation–sensitive alternative splicing of its terminal exon 3′ untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863–79. ©2017 AACR.

PACE4 mRNA splicing analysis and primer design

Supplementary material and methods relating to cell culture, cell treatments and transfections, proliferation assays, Western blot analysis etc. and Supplementary Figure Legends for Supplementary Figures 1-8

Background:Cardiovascular disease (CVD) incidence is higher in men with prostate cancer (PC) than without. Objectives:We describe the rate and correlates of poor cardiovascular risk factor control among men with PC. Methods:We prospectively characterized 2,811 consecutive men (mean age 68 ± 8 years) with PC from 24 sites in Canada, Israel, Brazil, and Australia. We defined poor overall risk factor control as ≥3 of the following: suboptimal low-density lipoprotein cholesterol (>2 mmol/L if Framingham Risk Score [FRS] ≥15 and ≥3.5 mmol/L if FRS <15), current smoker, physical inactivity (<600 MET min/wk), suboptimal blood pressure (BP) (≥140/90 mm Hg if no other risk factors, systolic BP ≥120 mm Hg if known CVD or FRS ≥15, and ≥130/80 mm Hg if diabetic), and waist:hip ratio >0.9. Results:Among participants (9% with metastatic PC and 23% with pre-existing CVD), 99% had ≥1 uncontrolled cardiovascular risk factor, and 51% had poor overall risk factor control. Not taking a statin (odds ratio [OR]: 2.55; 95% CI: 2.00-3.26), physical frailty (OR: 2.37; 95% CI: 1.51-3.71), need for BP drugs (OR: 2.36; 95% CI: 1.84-3.03), and age (OR per 10-year increase: 1.34; 95% CI: 1.14-1.59) were associated with poor overall risk factor control after adjustment for education, PC characteristics, androgen deprivation therapy, depression, and Eastern Cooperative Oncology Group functional status. Conclusions:Poor control of modifiable cardiovascular risk factors is common in men with PC, highlighting the large gap in care and the need for improved interventions to optimize cardiovascular risk management in this population.

Background Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. Methods In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. Results A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. Conclusions Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.