SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

Immune Checkpoint Inhibitor Myocarditis: Concomitant Coronary Artery Disease and Heart Failure

https://openworks.mdanderson.org/sumexp21/1209/thumbnail.jp

Frequency and Practice-Level Variation in Inappropriate Aspirin Use for the Primary Prevention of Cardiovascular Disease Insights From the National Cardiovascular Disease Registry’s Practice Innovation and Clinical Excellence Registry

AbstractBackgroundAmong patients without cardiovascular disease (CVD) and low 10-year CVD risk, the risks of gastrointestinal bleeding and hemorrhagic strokes associated with aspirin use outweigh any potential atheroprotective benefit. According to the guidelines on primary prevention of CVD, aspirin use is considered appropriate only in patients with 10-year CVD risk ≥6% and inappropriate in patients with 10-year CVD risk <6%.ObjectivesThe goal of this study was to examine the frequency and practice-level variation in inappropriate aspirin use for primary prevention in a large U.S. nationwide registry.MethodsWithin the National Cardiovascular Disease Registry’s Practice Innovation and Clinical Excellence registry, we assessed 68,808 unique patients receiving aspirin for primary prevention from 119 U.S. practices. The frequency of inappropriate aspirin use was determined for primary prevention (aspirin use in those with 10-year CVD risk <6%). Using hierarchical regression models, the extent of practice-level variation using the median rate ratio (MRR) was assessed.ResultsInappropriate aspirin use frequency was 11.6% (7,972 of 68,808) in the overall cohort. There was significant practice-level variation in inappropriate use (range 0% to 71.8%; median 10.1%; interquartile range 6.4%) for practices; adjusted MRR was 1.63 (95% confidence interval [CI]: 1.47 to 1.77). Results remained consistent after excluding 21,052 women age ≥65 years (inappropriate aspirin use 15.2%; median practice-level inappropriate aspirin use 13.8%; interquartile range 8.2%; adjusted MRR 1.61 [95% CI: 1.46 to 1.75]) and after excluding patients with diabetes (inappropriate aspirin use 13.9%; median practice-level inappropriate aspirin use 12.4%; interquartile range 7.6%; adjusted MRR 1.55 [95% CI: 1.41 to 1.67]).ConclusionsMore than 1 in 10 patients in this national registry were receiving inappropriate aspirin therapy for primary prevention, with significant practice-level variations. Our findings suggest that there are important opportunities to improve evidence-based aspirin use for the primary prevention of CVD

Prospective Study Evaluating Management of Hypertension Induced by anti-VEGF Therapy in Patients with Active Cancer: VEGFHTN Trial

https://openworks.mdanderson.org/sumexp23/1027/thumbnail.jp

Possible Molecular Mechanisms Underlying the Development of Atherosclerosis in Cancer Survivors

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors

Quantitative Analysis of Protein Phosphorylations and Interactions by Multi-Colour IP-FCM as an Input for Kinetic Modelling of Signalling Networks

BACKGROUND: To understand complex biological signalling mechanisms, mathematical modelling of signal transduction pathways has been applied successfully in last few years. However, precise quantitative measurements of signal transduction events such as activation-dependent phosphorylation of proteins, remains one bottleneck to this success. METHODOLOGY/PRINCIPAL FINDINGS: We use multi-colour immunoprecipitation measured by flow cytometry (IP-FCM) for studying signal transduction events to unrivalled precision. In this method, antibody-coupled latex beads capture the protein of interest from cellular lysates and are then stained with differently fluorescent-labelled antibodies to quantify the amount of the immunoprecipitated protein, of an interaction partner and of phosphorylation sites. The fluorescence signals are measured by FCM. Combining this procedure with beads containing defined amounts of a fluorophore allows retrieving absolute numbers of stained proteins, and not only relative values. Using IP-FCM we derived multidimensional data on the membrane-proximal T-cell antigen receptor (TCR-CD3) signalling network, including the recruitment of the kinase ZAP70 to the TCR-CD3 and subsequent ZAP70 activation by phosphorylation in the murine T-cell hybridoma and primary murine T cells. Counter-intuitively, these data showed that cell stimulation by pervanadate led to a transient decrease of the phospho-ZAP70/ZAP70 ratio at the TCR. A mechanistic mathematical model of the underlying processes demonstrated that an initial massive recruitment of non-phosphorylated ZAP70 was responsible for this behaviour. Further, the model predicted a temporal order of multisite phosphorylation of ZAP70 (with Y319 phosphorylation preceding phosphorylation at Y493) that we subsequently verified experimentally. CONCLUSIONS/SIGNIFICANCE: The quantitative data sets generated by IP-FCM are one order of magnitude more precise than Western blot data. This accuracy allowed us to gain unequalled insight into the dynamics of the TCR-CD3-ZAP70 signalling network

2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

[Extract] Top 10 Take-Home Messages for the Primary Prevention of Cardiovascular Disease 1. The most important way to prevent atherosclerotic vascular disease, heart failure, and atrial fibrillation is to promote a healthy lifestyle throughout life. 2. A team-based care approach is an effective strategy for the prevention of cardiovascular disease. Clinicians should evaluate the social determinants of health that affect individuals to inform treatment decisions. 3. Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician–patient risk discussion before starting on pharmacological therapy, such as antihypertensive therapy, a statin, or aspirin. In addition, assessing for other risk-enhancing factors can help guide decisions about preventive interventions in select individuals, as can coronary artery calcium scanning. 4. All adults should consume a healthy diet that emphasizes the intake of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish and minimizes the intake of trans fats, red meat and processed red meats, refined carbohydrates, and sweetened beverages. For adults with overweight and obesity, counseling and caloric restriction are recommended for achieving and maintaining weight loss. 5. Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity. 6. For adults with type 2 diabetes mellitus, lifestyle changes, such as improving dietary habits and achieving exercise recommendations, are crucial. If medication is indicated, metformin is first-line therapy, followed by consideration of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide-1 receptor agonist. 7. All adults should be assessed at every healthcare visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit. 8. Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit. 9. Statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated low-density lipoprotein cholesterol levels (≥190 mg/dL), those with diabetes mellitus, who are 40 to 75 years of age, and those determined to be at sufficient ASCVD risk after a clinician–patient risk discussion. 10. Nonpharmacological interventions are recommended for all adults with elevated blood pressure or hypertension. For those requiring pharmacological therapy, the target blood pressure should generally be <130/80 mm Hg

BNP and obesity in acute decompensated heart failure with preserved vs. reduced ejection fraction: The Atherosclerosis Risk in Communities Surveillance Study

Background Levels of B-type natriuretic peptide (BNP), a prognostic marker in patients with heart failure (HF), are lower among HF patients with obesity or preserved Left Ventricular Ejection Fraction (LVEF). We examined the distribution and prognostic value of BNP across BMI categories in acute decompensated heart failure (ADHF) patients with preserved vs. reduced LVEF. Methods We analyzed data from the Atherosclerosis Risk in Communities (ARIC) HF surveillance study which sampled and adjudicated ADHF hospitalizations in patients aged ≥ 55 years from 4 US communities (2005–2009). We examined 5 BMI categories: underweight (< 18.5 kg/m2), normal weight (18.5–<25), overweight (25–<30), obese (30–<40) and morbidly obese (≥ 40) in HF with preserved LVEF (HFpEF) and reduced LVEF (HFrEF). The outcome was 1-year mortality from admission. We used ANCOVA to model log BNP and logistic regression for 1-year mortality, both adjusted for demographics and clinical characteristics. Results The cohort included 9820 weighted ADHF hospitalizations (58% HFrEF; 42% HFpEF). BNP levels were lower in HFpEF compared to HFrEF (p < 0.001) and decreased as BMI increased within the LVEF groups (p < 0.001). After adjustment for covariates, log10 BNP independently predicted 1-year mortality (adjusted OR 1.62 (95% CI 1.17–2.24)) with no significant interaction by BMI or LVEF groups. Conclusions BNP levels correlated inversely with BMI, and were higher in HFrEF compared to HFpEF. Obese patients with HFpEF and ADHF had a significant proportion with BNP levels below clinically accepted thresholds. Nevertheless, BNP was a predictor of mortality in ADHF across groups of BMI in HFpEF and HFrEF

Endothelial Activation and Fibrotic Changes Are Impeded by Laminar Flow-Induced CHK1-SENP2 Activity Through Mechanisms Distinct From Endothelial-To-Mesenchymal Cell Transition

BACKGROUND: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. METHOD: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation. RESULT: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS). SUMMARY: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes

Association of cytokines with endothelium dependent flow mediated vasodilation (FMD) of systemic arteries in patients with non-ischemic cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Aim of this study was to elucidate the relation between localised inflammatory heart disease and endothelial dysfunction in the peripheral circulation, considering circulating cytokines as a potential link.</p> <p>Methods</p> <p>In 38 patients with non-ischemic heart disease, myocardial biopsies were examined for myocardial inflammation (immunohistology) and virus persistence (PCR). Cytokines (sIL-4, IFN-g, IFN-b, IFN-a, sIL-12p7, TNF-a) were measured by ELISA in venous serum. Endothelial function of the radial artery was examined by ultrasound, measuring diameter changes in response to reactive hyperemia (FMD), compared to glyceroltrinitrate (GTN-MD). Patients with EF < 35% were excluded.</p> <p>Results</p> <p>Age 44 ± 14 years, 19 male, 19 female, EF 63.5[16]%. FMD 4.38 [4.82]%. 30 patients had myocardial inflammation (8 not), 23 virus persistence (15 not). FMD correlated significantly with sIL-12p7 (p = 0.024, r = -0.365), but not with other cytokines. sIL-12p7 levels were significantly higher in patients with severely impaired FMD (n = 17), compared with normal FMD (n = 21): 10.70 [10.72] vs. 4.33 [7.81] pg/ml (p = 0.002). Endothelium independent vasodilation (GTN-MD 23.67 [8.21]%) was not impaired.</p> <p>Conclusion</p> <p>Endothelial dysfunction of peripheral arteries in patients with non-ischemic cardiomyopathy is associated with elevated serum concentrations of sIL-12p7, but not of other cytokines. Circulating sIL-12p7 may partly explain, that endothelial dysfunction is not restricted to the coronary circulation, but involves systemic arteries.</p