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Background: The electromechanical activation time (EMAT) normalized by cardiac cycle length (%EMAT) and the third heart sound (S3) strength, as measured by automated acoustic cardiography, are predictive of postdischarge adverse events in patients with acute heart failure (AHF). The aim of this study was to evaluate whether the acoustic cardiography-guided management improves outcomes in patients with AHF when it is compared with the conventional therapy.Methods and Results: This prospective single-blind study randomized 225 patients with AHF (74.1 ± 14.5 years of age, 26.2% women, and left ventricular ejection fraction 38.4 ± 14.4%) before discharge to the EMAT-guided group (n = 114) with the postdischarge treatment goals to reduce %EMAT to < 15% and S3 < 5, and the symptom-guided group (n = 111) to adjust medications without knowledge of the results of acoustic cardiography. The primary endpoints were rehospitalization for heart failure and total mortality during 1-year follow-up. The 2 groups were well matched in age and predischarge %EMAT and S3 strength. After a mean follow-up period of 238.1 ± 140.8 days, a significant reduction in the primary endpoints was seen in the EMAT-guided group compared with the symptom-guided group (43 events vs 61 events, P = 0.0095). Kaplan-Meier curves demonstrated significant differences in the time to first event, favoring the EMAT-guided group in the total study population (n = 225, hazard ratio and 95% confidence interval: 0.61, 0.42-0.91, log-rank P = 0.0129), as well as in the prespecified subgroup of patients with predischarge %EMAT > 15% (n = 85; 0.32, 0.16-0.65, P = 0.0008).Conclusions: In patients hospitalized due to AHF, EMAT-guided postdischarge management was superior to the conventional symptoms-driven therapy in terms of 1-year outcomes (ClinicalTrials.gov number NCT01298232). [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common life-threatening malignances worldwide. CRC relapse markedly decreases the 5-year survival of patients following surgery. Aberrant expression of genes involved in pathways regulating the cell cycle, cell proliferation, or cell death are frequently reported in CRC tumorigenesis. We hypothesized that genes involved in CRC relapse might serve as prognostic indicators. We first evaluated the significance of gene sequences in the feces of patients with CRC relapse by consulting a public database. Tumorigenesis of target tissues was tested through tumor cell growth, cell cycle regulation, and chemotherapeutic efficacy. We found a highly significant correlation between CRC relapse and growth arrest-specific 2 (GAS2) gene expression. Based on cell models, the overexpressed GAS2 was associated with cellular growth rate, cell cycle regulation, and with chemotherapeutic sensitivity. Cell division was impaired by treating cells with 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), even when the cells were overexpressing GAS2. Thus, downregulation of GAS2 expression might control CRC relapse after curative resection. GAS2 could serve as a noninvasive marker from the feces of patients with prediagnosed CRC. Our findings suggest that GAS2 could have potential clinical applications for predicting early CRC relapse after radical resection, and that XK469 might impair tumor cell division by reducing GAS2 expression or blocking its cellular translocation. This will help in selecting the best therapeutic option, 5-fluorouracil in combination with XK469, for patients overexpressing GAS2 in CRC cells. Thus, GAS2 might act as a prognostic biomolecule and potential therapeutic target in patients with CRC relapse. [ABSTRACT FROM AUTHOR]

Abstract: Small ubiquitin-related modifier (SUMO) is a protein moiety that is ligated to lysine residues in a variety of target proteins. The SUMO E2 enzyme ubiquitin-conjugating enzyme 9 (Ubc9) is sufficient for substrate recognition and lysine modification of known SUMO targets. Previous studies have demonstrated that mutated Ubc9 that has lost its SUMO-ligating activity retains its enhancement on transactivation mediated by androgen receptor (AR). In contrast to the binding ability to Ubc9, the sumoylation of AR via the association of SUMO-1 and PIAS1 is able to repress AR-dependent transcription. In the present study, we present several lines of evidence to explain the role of over-expressed Ubc9 as a cofactor in the nuclear receptor and coactivator functions, including (i) activity that is independent of its ability to catalyze SUMO-1 conjugation, (ii) an insight into the protein–protein interaction motif in its eight C-terminal residues, (iii) selective coactivator function in nuclear receptor-relevant transactivation activities, and (iv) a non-trichostatin A-sensitive autonomous transcription repression domain in its far C-terminal region. Taken together, our data suggest that the both the protein–protein interaction through the Ubc9 C-terminus and its sumoylation-modifying activity provide the mechanism for regulating nuclear receptor functions. [Copyright &y& Elsevier]

Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and constitutes a major medical and economic burden worldwide. A thorough understanding of the oncogenes or genes related to tumorigenesis is the key to developing successful therapeutic strategies. Molecular analysis of feces constitutes a potentially potent and noninvasive method for detection of CRC. Using nested reverse transcription-polymerase chain reaction (RT-PCR) and amplified restriction fragment length polymorphism analysis, sloughed cells from the entire length of the colon and rectum were analyzed for expression of activating K-ras codon 12 mutants, which are becoming attractive targets for antisense treatment. K-ras codon 12 mutant sequences were detected in feces of 5% (1/20) of healthy controls, in feces of 41% (12/29) of CRC patients, in 10% (3/29) of isolates of tissue complementary DNA (cDNA), and in 14% (4/29) of isolates of genomic DNA. Age of patient was significantly associated with K-ras codon 12 sequences in feces: Patients with wild-type K-ras codon 12 sequences were significantly younger than those with mutated forms of K-ras codon 12. Fecal ribonucleic acid (RNA) analysis was demonstrated to be a useful for diagnosis of CRC. This technique may be suitable for screening and determinatign the clinical significance of active mutations of the K-ras gene in feces and would possibly be useful for identificating patients that would benefit from antisense therapy. [Copyright &y& Elsevier]

Abstract: Kleine-Levin syndrome (KLS) is a rare disorder characterized by recurrent episodes of hypersomnia, cognitive or behavior disturbances, compulsive eating behavior, and hypersexuality. The etiology of KLS remains unknown even though its clinical symptoms suggest an underlying autoimmune process. In this study, we analyzed the human leukocyte antigen (HLA) typing alleles in Taiwanese patients with KLS using the polymerase chain reaction sequence-specific priming technique. We report that an immunoresponsive HLA-DQB1, DQB1∗0602, was detected in significant quantities in patients with KLS (three of 12, p =0.046) and could elevate the risk of KLS (odds ratio, 1.143; 95% confidence interval, 0.0982–1.329). In conclusion, an identification of genomic susceptibility to KLS will be helpful in determining the immunospecific targeted therapies for patients with KLS. [Copyright &y& Elsevier]

Abstract: Naphtho[1,2-b] furan-4,5-dione (NFD) was investigated for its anti-proliferation effect on human hepatocellular carcinoma (HCC), Hep3B, HepG2, and Huh-7 cells. The effect of NFD on inhibiting proliferation and apoptosis was correlated with up-regulation of pro-apoptotic protein and down-regulation of pro-survival proteins. Remarkably, we found that NFD inhibited the nuclear translocation of NF-κB, likely accounting for the down-regulation of pro-survival Bcl-2 family. Furthermore, suppression of p38 MAPK activity by a specific inhibitor significantly rescued the cell proliferation inhibited by NFD. These findings suggest that signaling imbalance between p38 MAPK and NF-κB by NFD results in the proliferative inhibition and apoptosis of HCC tumor cells. [Copyright &y& Elsevier]

Abstract: Early diagnosis for colorectal cancer (CRC) by monitoring of gastrointestinal epithelial cells is a possible direct approach. Although human faeces form a heterogeneous mixture of gastrointestinal mucosal epithelial cells and other materials, we have developed a method to purify total RNA from human stool samples. The gene for faecal cytokeratin 19 (CK19) was highly expressed in stools from patients with metastatic CRC, but not from patients with non-metastatic CRC or from normal individuals. Thus, purified faecal RNA can be used for the detection of differentially expressed genes. This technique may help identifying meaningful faecal RNA markers for the non-invasive screening of patients with CRC. [Copyright &y& Elsevier]

Abstract: Objectives: Urothelial carcinoma (UC) of the bladder is the second most common cancer of the genitourinary system. Clinical UC treatment usually involves transurethral resection of the bladder tumor followed by adjuvant intravesical immunotherapy or chemotherapy to prevent recurrence. Intravesical chemotherapy induces fewer side effects than immunotherapy but is less effective at preventing tumor recurrence. Improvement to intravesical chemotherapy is, therefore, needed. Methods and Materials: Cellular effects of mitomycin C (MMC) and hydrostatic pressure on UC BFTC905 cells were assessed. The viability of the UC cells was determined using cellular proliferation assay. Changes in apoptotic function were evaluated by caspase 3/7 activities, expression of FasL, and loss of mitochondrial membrane potential. Results: Reduced cell viability was associated with increasing hydrostatic pressure. Caspase 3/7 activities were increased following treatment of the UC cells with MMC or hydrostatic pressure. In combination with 10kPa hydrostatic pressure, MMC treatment induced increasing FasL expression. The mitochondria of UC cells displayed increasingly impaired membrane potentials following a combined treatment with 10μg/ml MMC and 10kPa hydrostatic pressure. Conclusions: Both MMC and hydrostatic pressure can induce apoptosis in UC cells through an extrinsic pathway. Hydrostatic pressure specifically increases MMC-induced apoptosis and might minimize the side effects of the chemotherapy by reducing the concentration of the chemical agent. This study provides a new and alternative approach for treatment of patients with UC following transurethral resection of the bladder tumor. [Copyright &y& Elsevier]