Surgical treatment of patients with aortic valve disease complicated with moderate functional mitral regurgitation and heart failure with midrange ejection fraction: a cohort study.

Background: Controversies exist on the treatment of moderate functional mitral regurgitation (FMR) in patients with severe aortic valve disease undergoing the aortic valve replacement (AVR). While a substantial proportion of these patients can be complicated with heart failure with midrange ejection fraction (HFmrEF), established studies show that the latter might compromise the patient outcome. This study was aimed to evaluate the prognostic value of concomitant mitral valve surgery during AVR in patients with severe aortic valve disease followed by moderate FMR and HFmrEF. Methods: A total of 78 consecutive patients were retrospectively recruited. Patients were divided into control (isolated AVR) and treatment (AVR + mitral valve surgery) groups. Follow-up outcomes were compared by Kaplan-Meier method, followed by multiple adjustment with inverse probability treatment weighting (IPTW) analysis. The primary outcome was the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE). Results: Thirty-six patients received isolated AVR, while 42 received AVR with mitral valve repair or replacement. The median follow-up time was 28.7 months. Unadjusted analysis showed that there was no significant difference in the rate of MACCE between the two groups [hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.48-2.69, Plogrank=0.770], which was sustained in IPTW analysis (HR: 1.64, 95% CI: 0.59-4.55, Plogrank=0.342). In addition, while concomitant mitral valve surgery improved follow-up FMR more completely (P=0.026) in the IPTW analysis, the ejection fraction was comparable between the two groups (P=0.276). Furthermore, IPTW analysis also showed that mitral valve surgery was associated with the increased risk of postoperative acute kidney injury (P=0.007). Conclusions: In patients with aortic valve disease followed by moderate FMR and HFmrEF, mitral valve surgery concomitant to AVR may not bring extra benefit in the MACCE-free survival and the improvement of HFmrEF. However, while concomitant mitral valve surgery has priority on the complete improvement of FMR, it might increase the risk of postoperative acute kidney injury.

AZD3463, an IGF-1R inhibitor, suppresses breast cancer metastasis to bone via modulation of the PI3K-Akt pathway.

BACKGROUND: The bone-derived insulin-like growth factor I (IGF-1) and its receptor IGF-1R play a crucial role in promoting the survival and proliferation of cancer cells, and have thus been considered as prime targets for the development of novel antitumor therapeutics. METHODS: By using the MDA-MB-231BO cell line, which is the osteotropic metastatic variant of the human breast adenocarcinoma cell line MDA-MB-231, and an in vivo model of breast cancer metastasis to bone, the current study evaluated the effect of AZD3463, an IGF-1R inhibitor, used alone or in combination with zoledronic acid (ZA), on the regulation of IGF-1R associated signal pathway and treatment of bone metastases (BM). Cell proliferation and invasion were measured by methyl thiazolyl tetrazolium (MTT) and Transwell assay respectively. Apoptotic cell number was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). RESULTS: AZD3463 was shown to alleviate IGF-1R phosphorylation promoted by IGF-1 treatment in MDA-MB-231BO cells in a dose-dependent manner. In both the cells and the mouse model, 5 nM of AZD3463 stimulated cell apoptosis and suppressed proliferation on a level similar to that of 100 µM of ZA. Remarkably, the combined use of AZD3463 and ZA exhibited a synergistic effect and greater antitumor activity compared to when they were employed individually. Mechanistic investigations indicated that the apoptosis-inducing activity of AZD3463 could be associated to its role in the activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. CONCLUSIONS: These findings suggested that AZD3463 could serve as a promising therapeutic molecule for treating BM in breast cancer patients, particularly when applied in conjunction with ZA or other antitumor agents.

MORC4 is a novel breast cancer oncogene regulated by miR-193b-3p.

A better understanding of breast cancer pathogenesis would contribute to improved diagnosis and therapy and potentially decreased mortality rates. Here, we found that the MORC family CW-type zinc finger 4 (MORC4) overexpression in breast cancer tissues is associated with poor survival, and the short-interfering RNA knockdown of MORC4 suppresses the growth of breast cancer cells by promoting apoptosis. To investigate the mechanisms associated with MORC4 upregulation, microRNAs potentially targeting MORC4 were analyzed, with miR-193b-3p identified as the regulator and a negative correlation between miR-193b-3p and MORC4 expression determined in both breast cancer cell lines and tissues. Further analysis verified that MORC4 silencing did not affect miR-193b-3p expression, although altered miR-193b-3p expression attenuated MORC4 protein levels. Moreover, dual-luciferase reporter assays verified miR-193b-3p binding to the 3' untranslated region of MORC4. Furthermore, restoration of miR-193b-3p expression in breast cancer cells led to decreased growth and activation of apoptosis, which was consistent with results associated with MORC4 silencing in breast cancer cells. These results identified MORC4 as differentially expressed in breast cancer cells and tissues and its downregulation by miR-193b-3p, as well as its roles in regulating the growth of breast cancer cells via regulation of apoptosis. Our findings offer novel insights into potential mechanisms associated with breast cancer pathogenesis.

Role of beta1-adrenoceptor in increased lipolysis in cancer cachexia.

Increased production of hormone-sensitive lipase (HSL) protein has been demonstrated to be the major cause behind enhanced lipolysis in cancer cachexia. The mechanism governing this alteration is unknown and was presently investigated. This study was conducted to detect the expression of relevant receptors in the adipocytes of cancer cachexia patients, and to elucidate their implication in the increased lipolysis. Gene expressions of beta1-adrenoceptor (ADRB1), beta2-adrenoceptor (ADRB2), beta3-adrenoceptor (ADRB3), alpha2C-adrenoceptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose tissues of 34 patients by real-time PCR. Protein levels of ADRB1 and HSL were determined by western blot analysis. beta1-Adrenoceptor (ADRB1) was also detected by immunofluorescence staining. mRNA expressions of both ADRB1 and HSL were approximately 50% elevated selectively in the cachexia group, whereas mRNA levels of the other receptors were unchanged. beta1-Adrenoceptor (ADRB1) protein expression was 1.5-fold increased in cachexia as compared with the cancer controls, and 3-fold increased as compared with nonmalignant controls, and was confirmed as a membrane protein in adipocytes by immunofluorescence. Hormone-sensitive lipase (HSL) protein expression was 2-2.5-fold increased selectively in cachectic patients. There was a positive correlation between the protein expressions of ADRB1 and HSL. As much as approximately 50% of the variations in HSL protein expression could be explained by variations in ADRB1 protein expression. There was a link between ADRB1 protein level and lipolytic rate. Increased ADRB1 expression may account for some of the functional changes of HSL in patients with cancer cachexia.

Diagnostic methods for initial evaluation of primary gastrointestinal stromal tumors.

OBJECTIVE: To describe the imaging features of gastrointestinal stromal tumors (GISTs) at initial presentation with clinical, surgical, and pathologic correlation, and to evaluate values of various techniques in GISTs. METHODS: This retrospective study recruited 70 patients with histologically proved GISTs between December 2004, and May 2009 in the Department of General Surgery, Zhongshan Hospital, Fudan Univeristy, Shanghai, China. Each patient underwent CT scanning, 39 patients underwent simultaneous endoscopy, 12 patients underwent endoscopic ultrasound (EUS), and 36 patients underwent transabdominal ultrasonography (TAUS) simultaneously. Features of GISTs were assessed. RESULTS: Computerized tomography findings showed an eccentric mass in 44 patients, an intraluminal component in 24, and a transmural distribution in 2. Forty-two tumors were dumbbell-shaped, 2 were round, while 26 were irregular. Forty-three tumors presented with well-defined masses, while 27 with unclear borders. The arterial phase attenuation showed the continuous enhancement. The portal-venous phase attenuation was heterogeneous in 26 and homogeneous in the other 44. There was a significant correlation between certain CT features and tumor risk stratification. Gastrointestinal stromal tumors were characterized by a smooth shape and normal overlying mucosa in endoscopy, hypoechoic, and solid in TAUS. CONCLUSION: Imaging examinations are pivotal in the management of GISTs. The CT scan is valuable in the diagnosis, staging, and treatment planning of GISTs. Endoscopy and EUS contribute to the detection of mucosal lesions. Other methods including TAUS, fluorodeoxyglucose positron emission tomography, CT gastrography, and MRI help in specific cases.

Resting energy expenditure and body composition in patients with newly detected cancer.

BACKGROUND & AIMS: Elevated resting energy expenditure (REE) may be a major determinant in the development of cancer cachexia. The aim of the study was to evaluate REE and body composition in cancer patients and find out the relationship between energy expenditure and substrate utilization. METHODS: Measured resting energy expenditure (mREE), carbohydrate oxidation (C-O), and fat oxidation (F-O) were measured by indirect calorimetry in 714 cancer patients and 642 controls. Extracellular fluid (ECF), intracellular fluid (ICF), and total water (TW) were measured by bioelectrical impedance appliance; fat mass (FM), fat free mass (FFM), and body cell mass (BCM) were further determined. RESULTS: Compared with the controls, cancer patients showed no significant difference in mREE, but had higher mREE/FFM and mREE/pREE. 46.7% (n=333) of cancer patients were hypermetabolic, 43.5% (n=310) normometabolic, and 9.8% (n=71) hypometabolic; whereas 25.2% (n=162) of control subjects were hypermetabolic, 56.5% (n=363) normometabolic, and 18.3% (n=117) hypometabolic. Cancer patients showed an increase in F-O, ECF, TW/BW and ECF/BW; and a decrease in C-O, npRQ, ICF, ICF/BW. REE was correlated to substrate oxidation rate. Cancer patients exhibited an elevation in FM, FM/BW, FFM, and BCM, and a decrease in FFM/BW. CONCLUSIONS: 1. Cancer patients had elevated REE. Cancer type, pathological stage and duration of disease influenced REE. 2. Aberrations in substrate utilization may contribute to the elevated REE in cancer patients. 3. FM, FFM, and BCM diminished in cancer patients, which may be related to the elevated REE.