No abstract

Fatigue and diarrhea are the most frequent adverse effects of pelvic radiotherapy, while their etiologies are largely unknown. The aim of this study is to investigate the correlations between fatigue, diarrhea, and alterations in gut microbiota induced by pelvic radiotherapy. During the 5-week treatment of pelvic radiotherapy in 11 cancer patients, the general fatigue score significantly increased and was more prominent in the patients with diarrhea. The fatigue score was closely correlated with the decrease of serum citrulline (an indicator of the functional enterocyte mass) and the increases of systemic inflammatory proteins, including haptoglobin, orosomuoid, α1-antitrypsin and TNF-α. Serum level of lipopolysaccharide (LPS) was also elevated, especially in the patients with diarrhea indicating epithelial barrier breach and endotoxemia. Pyrosequencing analysis of 16S rRNA gene revealed that microbial diversity, richness, and the Firmicutes/Bacteroidetes ratio were significantly altered prior to radiotherapy in patients who later developed diarrhea. Pelvic radiotherapy induced further changes in fecal microbial ecology, some of which were specific to the patients with or without diarrhea. Our results indicate that gut microbial dysbiosis prior to radiation therapy may be exploited to predict development of diarrhea and to guide preventive treatment options. Radiation-induced dysbiosis may contribute to pelvic radiation disease, including mucositis, diarrhea, systemic inflammatory response, and pelvic radiotherapy-associated fatigue in cancer patients.

LADG may be a technically feasible alternative for EGC when it is performed in experienced surgical centers in which patients undergoing LADG may benefit from the faster postoperative recovery. However, the currently available evidence cannot exclude the potential clinical benefits or harms, especially in the node-positive cases. Methodologically high-quality comparative studies are needed for further evaluation.

BackgroundHyperlipidemia plays a crucial role in the development and progression of coronary artery disease (CAD). Recent studies have identified that microRNAs (miRNAs) are important regulators of lipid metabolism, but little is known about the circulating levels of lipometabolism-related miRNAs and their relationship with the presence of CAD in patients with hyperlipidemia.MethodsIn the present study, we enrolled a total of 255 hyperlipidemia patients with or without CAD and 100 controls with normal blood lipids. The plasma levels of four known lipometabolism-related miRNAs, miR-122, miR-370, miR-33a, and miR-33b were quantified by real-time quantitative PCR. Blood levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol were determined. Furthermore, the severity of CAD was assessed with the Gensini score system based on the degree of luminal narrowing and its geographic importance.ResultsOur results revealed for the first time that plasma levels of miR-122 and miR-370 were significantly increased in hyperlipidemia patients compared with controls, and the levels of miR-122 and miR-370 were positively correlated with TC, TG, and LDL-C levels in both hyperlipidemia patients and controls. Multiple logistic regression analysis demonstrated that the increased levels of miR-122 and miR-370 were associated with CAD presence, even after adjustment for other cardiovascular risk factors. Furthermore, miR-122 and miR-370 levels were positively correlated with the severity of CAD quantified by the Gensini score. However, both miR-33a and miR-33b were undetectable in plasma.ConclusionsOur results suggest that increased plasma levels of miR-122 and miR-370 might be associated with the presence as well as the severity of CAD in hyperlipidemia patients.

Exercise has been proved to promote the number and activity of circulating endothelial progenitor cells (EPCs) in humans, which contributes to improvement in endothelial function and maintenance of cardiovascular homoeostasis. However, the mechanism underlying the effect of exercise on circulating EPCs in healthy subjects is not completely understood. Here, we investigated whether the regulation of acute exercise on circulating EPCs is associated with nitric oxide (NO), vascular endothelial growth factors (VEGF) and granulocyte macrophage colony stimulating factor (GM-CSF) known to modulate circulating EPCs in healthy subjects. A total of 16 healthy male volunteers underwent a modified Bruce treadmill acute exercise protocol. The number and activity of circulating EPCs, as well as the levels of NO-VEGF and GM-CSF in plasma and culture medium before and after exercise in healthy subjects were measured. The number and activity of circulating EPCs after acute exercise were significantly higher than those before exercise in healthy subjects. In parallel, acute exercise significantly enhanced plasma NO level in healthy subjects. There is a significant linear regression relationship between the enhanced plasma NO level and increased number or activity of circulating EPCs. However, no change of plasma VEGF and GM-CSF level was observed after acute exercise. The secretion of NO-VEGF and GM-CSF by cultured EPCs remained unchanged in response to acute exercise. The present study demonstrates for the first time that acute exercise-induced NO production contributes to upregulation of circulating EPCs in healthy subjects, which suggests that NO plays an important role in the regulation of exercise on circulating EPCs.

The transition from cellular quiescence (G0) into S phase is regulated by the mitogenic-activation of D-type cyclins and cyclin-dependent kinases (Cdks), the sequestration of the Cdk inhibitors (CDKIs), p21 and p27, and the hyperphosphorylation of Rb with release of E2F transcription factors. However, fibroblasts that lack all D-type cyclins can still undergo serum-induced proliferation and key E2F targets are expressed at stable levels despite cyclical Rb-E2F activity. Here, we show that serum induces expression of the Ets transcription factor, Gabpalpha, and that its ectopic expression induces quiescent cells to re-enter the cell cycle. Genetic disruption of Gabpalpha prevents entry into S phase, and selectively reduces expression of genes that are required for DNA synthesis and degradation of CDKIs, yet does not alter expression of D-type cyclins, Cdks, Rb or E2Fs. Thus, GABP is necessary and sufficient for re-entry into the cell cycle and it regulates a pathway that is distinct from that of D-type cyclins and CDKs.

VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

During the preparation of Figure 1 for the above article, the wrong control CD8 T cell flow data was inserted in two panels depicting the time points ''day 3 HIV-1'' and ''day 0 No Virus.'' A revised figure is now provided. The conclusions of the experiment and the interpretation of the data remain entirely unchanged. We regret this production error.