BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.

BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.

Relative B-Type Natriuretic Peptide Deficiency May Exist in Diastolic Dysfunction in Subclinical Population.

Background: Heart failure patients are deficient in B-type natriuretic peptide (BNP) but the significance of subclinical BNP deficiency is unclear. Methods and Results: A total of 1,398 subjects without cardiovascular disease, with left ventricular ejection fraction (LVEF) ≥50% and BNP level <100 pg/mL, were selected from a 2005-2008 health checkup in Arita-cho, Japan, and divided into 2 groups: with and without LV diastolic dysfunction (DD+ or DD-). We performed propensity score matching on non-cardiac factors affecting BNP levels and analyzed 470 subjects in each group (372/940 men; median age, 66 years). The DD(+) group showed higher lateral E/e', an index of estimated left ventricular filling pressure, and greater prevalence of concentric hypertrophy (CH) despite similar BNP levels, suggesting a relative deficiency of BNP in DD(+) compared with DD(-). Multivariable logistic regression analysis revealed an increase in BNP correlated with decreased odds of CH (adjusted odds ratio [aOR] 0.663, 95% confidence interval (CI) 0.484-0.909, P=0.011), whereas an increase in lateral E/e' was associated with increased odds of CH (aOR, 2.881; 95% CI, 1.390-5.973; P=0.004). Furthermore, CH in combination with diastolic dysfunction independently predicted major adverse cardiovascular events (hazard ratio 3.272, 95% CI 1.215-8.809; P=0.019). Conclusions: Relative BNP deficiency was associated with CH, which had a poor prognosis in patients with diastolic dysfunction.

Candidate Screening for Heart Failure With Preserved Ejection Fraction Clinic by Fib-4 Index From Subclinical Subjects.

Background and Aims: Recognition of heart failure with preserved ejection fraction (HFpEF) at an early stage in mass screening is desirable, but difficult to achieve. We examined whether the fibrosis (Fib)-4 index, a simple index of liver stiffness/fibrosis, could be used as a screening tool to select candidates requiring expert diagnostics. Methods: Individuals who participated in annual health checks between 2006 and 2007 in Arita-cho, Saga, Japan, with no history of cardiovascular disease and EF ≥ 50% were enrolled (total 710; 258 men; median age, 59 years). Results: Participants were divided into 5 groups according to HFpEF risk: 215 (30%), 100 (14%), 171 (24%), 163 (23%), and 61 (9%) with Heart Failure Association (HFA)-PEFF scores of 0, 1, 2, 3, and 4-6 points, respectively. The highest HFpEF risk group (HFA-PEFF score, 4-6 points) showed poor prognosis for the clinical events of all-cause mortality and hospitalization for HF (log-rank test, P = .002). The Fib-4 index was correlated with HFpEF risk stratification (rs = 0.526), and increment in the Fib-4 index was independently linked to high HFpEF risk by multiple logistic regression analysis (adjusted odds ratio, 1.311; 95% confidence interval, 1.078-1.595; P = .007). The Fib-4 index stratified clinical prognosis (log-rank test, P < .001) was an independent predictor of all-cause mortality and hospitalization for HF (hazard ratio, 1.305; 95% confidence interval, 1.139-1.495; P < .001). Conclusion: The Fib-4 index can be used to select appropriate candidates for a detailed examination of HFpEF in a subclinical population.