Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in G(alpha)q-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation.

BackgroundRecently, the preoperative immune-nutritional status has been reported to correlate with the survival rate in patients with colorectal cancer (CRC). However, there have been no reports on the relationship between the controlling nutritional status (CONUT) score and the clinical outcome after curative surgery for CRC. We herein evaluated the prognostic significance of the CONUT score in patients with CRC, and then compared the accuracy of the CONUT score and the prognostic nutritional index (PNI) as a predictor of survival.MethodsWe retrospectively reviewed a database of 204 patients who underwent curative surgery for Stage II/III CRC. Patients were divided into two groups according to the CONUT score and the PNI.ResultsThe five-year cancer-specific survival (CSS) rate was significantly higher at 92.7% in the low CONUT group, compared to a rate of 81.0% in the high CONUT group (p=0.0016). The five-year CSS was 71.2% in the low PNI group and 92.3% in the high PNI group, which showed a significant difference (p=0.0155). A multivariate analysis showed that lymph node metastasis and the CONUT score were independent risk factors for CSS.ConclusionThis study suggested that the CONUT score is a strong independent predictor of the survival among CRC patients.

BackgroundThe purpose of this study was to investigate the impact of the Controlling Nutritional Status (CONUT) score on survival compared with the platelet to lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), and the Glasgow Prognostic Score (GPS) in patients with resectable thoracic esophageal squamous cell carcinoma (ESCC).MethodsOne hundred eighty-five consecutive patients who underwent subtotal esophagectomy with curative intent for resectable thoracic ESCC were retrospectively reviewed. Time-dependent receiver operating characteristic curve analyses for 3-year overall survival (OS) as the endpoint were performed, and the maximal Youden indices were calculated to assess discrimination ability and to determine the appropriate cut-off values of CONUT, PLR, and NLR. The patients were then classified into high and low groups based on these cut-off values. Correlations between CONUT and other clinicopathological characteristics were analyzed. Prognostic factors predicting overall survival (OS) and relapse-free survival (RFS) were analyzed using Cox proportional hazards models.ResultsThe areas under the curve predicting 3-year OS were 0.603 for CONUT, 0.561 for PLR, 0.564 for NLR, and 0.563 for GPS. The optimal cut-off values were two for the CONUT score, 193 for PLR, and 3.612 for NLR. The high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2 groups. On univariate analysis, high-CONUT, high-PLR, high-NLR, and GPS 1/2 groups were significantly associated with poorer OS and RFS. Of these factors, multivariate analysis revealed that only the CONUT score was an independent prognostic factor for OS (HR 2.303, 95 % CI 1.191–4.455; p = 0.013) and RFS (HR 2.163, 95 % CI 1.139–4.109; p = 0.018).ConclusionsThe CONUT score was an independent predictor of OS and RFS before treatment and was superior to PLR, NLR, and GPS in terms of predictive ability for prognosis in patients with resectable thoracic ESCC.

To define molecular mechanisms of cardiac hypertrophy, genes whose expression was perturbed by any of four different transgenic mouse hypertrophy models [protein kinase C-epsilon activation peptide (PsiepsilonRACK), calsequestrin (CSQ), calcineurin (CN), and Galpha(q)] were compared by DNA microarray analyses using the approximately 8,800 genes present on the Incyte mouse GEM1. The total numbers of regulated genes (tens to hundreds) correlated with phenotypic severity of the model (Galpha(q) > CN > CSQ > PsiepsilonRACK), but demonstrated that no single gene was consistently upregulated. Of the three models exhibiting pathological hypertrophy, only atrial natriuretic peptide was consistently upregulated, suggesting that transcriptional alterations are highly specific to individual genetic causes of hypertrophy. However, hierarchical-tree and K-means clustering analyses revealed that subsets of the upregulated genes did exhibit coordinate regulatory patterns that were unique or overlapping across the different hypertrophy models. One striking set consisted of apoptotic genes uniquely regulated in the apoptosis-prone Galpha(q) model. Thus, rather than identifying a single common hypertrophic cardiomyopathy gene program, these data suggest that extensive groups of genes may be useful for the prediction of specific underlying genetic determinants and condition-specific therapeutic approaches.