[Hydrogen Sulfide Ameliorates Myocardial Injury Caused by Sepsis Through Suppressing ROS-Mediated Endoplasmic Reticulum Stress].

Objective: To investigate the effect of hydrogen sulfide (H 2S) on reactive oxygen species (ROS)-mediated endoplasmic reticulum stress in myocardial injury caused by sepsis. Methods: A sepsis model was induced in Sprague-Dawley (SD) rats by cecal ligation and puncture (CLP). The rats were randomly divided into sham operation (sham) group, sepsis (CLP) group, and sepsis+sodium hydrosulfide (NaHS) (CLP+NaHS) group. The left ventricular function of the rats was observed with echocardiography and their plasma H 2S levels were measured. Lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH) levels were measured and HE staining was done to evaluate the level of myocardial oxidative stress in rats. HE staining was done to observe the morphological changes of rat myocardium, and transmission electron microscope was used to observe the ultrastructure of myocardial mitochondria. Western blot was done to examine changes in the expression of two endogenous hydrogen sulfide synthases, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), and changes in the expression of endoplasmic reticulum stress (ERS) marker proteins, including phosphorylated (p) protein kinase R-like endoplasmic reticulum kinase (p-PERK), p-eukaryotic translation initiation factor 2α (p-eIF2α), p-inositol requires enzyme 1α (IRE1α), recombinant activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). TUNEL staining was performed to observe the changes of cardiomyocyte apoptosis in rats. Results: Left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS) and plasma H 2S decreased in septic rats ( P<0.05). Plasma H 2S exhibited linear correlation with LVEF and LVFS ( r 2=0.62 and r 2=0.64, all P<0.05). The ROS levels were significantly elevated in rats of the CLP group. In addition, these rats showed increased level of LDH ( P<0.05), increased expression of MDA ( P<0.05), and decreased expression of GSH ( P<0.05). Inflammatory cell infiltration and cardiomyocyte edema were observed in HE staining. Transmission electron microscopic observation revealed significant mitochondrial damage, observable mitochondrial edema, and cristae structure dissolution. The Western blot results showed that the expression levels of CSE and 3-MST decreased ( P<0.05), while the ERS marker proteins, including p-PERK, p-eIF2, IRE1α, ATF4, and CHOP, were expressed at increased levels ( P<0.05). TUNEL staining showed significant increase of apoptosis in cardiomyocytes ( P<0.05). After NaHS treatment, LVEF and LVFS increased ( P<0.05) and plasma H 2S increased in septic rats ( P<0.05). Myocardial oxidative stress levels decreased. HE staining and transmission electron microscopy showed improved myocardial morphology. Mitochondrial damage was reduced and CSE and 3-MST levels were significantly increased ( P<0.05). The expression of p-PERK, p-eIF2α, p-IRE1α, and CHOP proteins decreased ( P<0.05). A decrease in cardiomyocyte apoptosis levels was observed by TUNEL staining ( P<0.05). Conclusion: H 2S reduces septic cardiomyocyte apoptosis by inhibiting ROS-mediated ERS, thereby improving myocardial dysfunction in sepsis.

The Oncolytic Virus in Cancer Diagnosis and Treatment.

Cancer has always been an enormous threat to human health and survival. Surgery, radiotherapy, and chemotherapy could improve the survival of cancer patients, but most patients with advanced cancer usually have a poor survival or could not afford the high cost of chemotherapy. The emergence of oncolytic viruses provided a new strategy for us to alleviate or even cure malignant tumors. An oncolytic virus can be described as a genetically engineered or naturally existing virus that can selectively replicate in cancer cells and then kill them without damaging the healthy cells. There have been many kinds of oncolytic viruses, such as herpes simplex virus, adenovirus, and Coxsackievirus. Moreover, they have different clinical applications in cancer treatment. This review focused on the clinical application of oncolytic virus and predicted the prospect by analyzing the advantages and disadvantages of oncolytic virotherapy.

Pancreatic cancer-derived exosomes promoted pancreatic stellate cells recruitment by pancreatic cancer.

Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been identified in the blood circulation of patients with cancer metastasis, and metastatic cancer cells can recruit circulating CAFs. However, primary carcinoma sites usually regulate the behavior of metastatic cancer cells through exosomes. Here, we hypothesized that cancer-derived exosomes could enhance CAF recruitment. Exosomes secreted by pancreatic cancer cells (PANC-1 and MIA PaCa-2) were isolated and characterized. The ability of pancreatic cancer to recruit pancreatic stellate cells (PSCs) was assessed with Transwell assays in vitro and bioluminescent imaging in a mouse model in vivo, and the underlying molecular mechanism was also investigated. The results showed that pancreatic cancer cell-derived exosomes (Exo-Pan and Exo-Mia) promoted the pancreatic cancer recruitment of PSCs. This effect was mediated partially by the transfer of the exosomal protein Lin28B to the recipient cells to activate the Lin28B/let-7/HMGA2/PDGFB signaling pathway. These results suggested that exosomes derived from local cancer could promote the formation of distant metastases through transferring the exosomal protein Lin28B to the metastatic cancer cells.

MEPO promotes neurogenesis and angiogenesis but suppresses gliogenesis in mice with acute ischemic stroke.

Previously study has proved the non-erythropoietic mutant erythropoietin (MEPO) exerted neuroprotective effects against ischemic cerebral injury, with an efficacy similar to that of wild-type EPO. This study investigates its effects on neurogenesis, angiogenesis, and gliogenesis in cerebral ischemic mice. Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and reperfusion. EPO (5000 U/kg), MEPO (5000 U/kg) or equal volume of normal saline was injected intraperitoneally. Neurological function was evaluated by Rota-rod test, Neurological severity scores (NSS) and Adhesive removal test. After ischemia and reperfusion (I/R), the survival rate, brain tissue loss, neurogenesis, angiogenesis and gliogenesis were detected by Nissl staining, Immunofluorescence and Western blot, respectively. The results shown that MEPO significantly increased survival rate, reduced brain tissue loss, and improved neurological function after MCAO (P < 0.05). Furthermore, MEPO obviously enhanced the proliferation of neuronal precursors (DCX) and promoted its differentiation into mature neurons (NeuN) (P < 0.05). In addition, compared to normal saline treatment mice, MEPO increased the number of BrdU-positive cells in the cerebral vasculature (P < 0.05). Whereas, MEPO treatment also reduced the numbers of newly generated astrocytes (GFAP) and microglia (Iba1) (P < 0.05). Among all the tests in this study, there was no significant difference between EPO group and MEPO group. Taken together, MEPO promoted the regeneration of neurons and blood vessels in peripheral area of infarction, and suppressed the gliogenesis, thus promoting neurogenesis, improving neurological function and survival rate. Our findings suggest that the MEPO may be a therapeutic drug for ischemic stroke intervention.

Positive prognostic value of HER2-HER3 co-expression and p-mTOR in gastric cancer patients.

BACKGROUND: The HER2-HER3 heterodimer significantly decreases survival in breast cancer patients. However, the prognostic value of HER2-HER3 overexpression remains unknown in gastric cancer (GC). METHODS: The expression levels of HER2, HER3, Akt, p-Akt, mTOR and p-mTOR were examined in specimens from 120 GC patients by immunohistochemistry and quantitative reverse transcription-PCR. The associations of HER proteins, PI3K/Akt/mTOR pathway-related proteins, clinicopathological features of GC, and overall survival (OS) were assessed. To comprehensively evaluate the prognostic values of pathway-related proteins, meta-analyses were conducted with STATA 11.0. RESULTS: HER2 overexpression was significantly associated with HER3 levels (P = 0.02). HER3 was highly expressed in gastric cancer tissues. High HER2 and HER3 levels were associated with elevated p-Akt and p-mTOR amounts (P < 0.05). Furthermore, HER2-HER3 co-expression was associated with high p-Akt and p-mTOR (P < 0.05) levels. Meanwhile, p-mTOR overexpression was tightly associated with differentiation, depth of invasion, lymph node metastasis, TNM stage and OS (P < 0.05). By meta-analyses, Akt, p-Akt, and mTOR levels were unrelated to clinicopathological characters. HER3 overexpression was associated with depth of invasion (OR = 2.39, 95%CI 1.62-3.54, P < 0.001) and lymph node metastasis (OR = 2.35, 95%CI 1.34-4.11, P = 0.003). Further, p-mTOR overexpression was associated with patient age, tumor location, depth of invasion (OR = 1.63, 95%CI 1.08-2.45, P = 0.02) and TNM stage (OR = 1.73, 95%CI 1.29-2.32, P < 0.001). In addition, HER2-HER3 overexpression corresponded to gradually shortened 5-year OS (P < 0.05), and significant relationships were shown among HER3, p-mTOR overexpression, and 1-, 3-, 5-year OS (P < 0.05). CONCLUSIONS: HER2-HER3 co-expression may potentially enhance mTOR phosphorylation. HER2-HER3 co-expression and p-mTOR are both related to the prognosis of GC patients.

High-order mode conversion based on adiabatical mode evolution for mode division multiplexing applications.

Mode conversion based on adiabatical mode evolution in a two-core configuration is investigated. The configuration can convert all the launching modes to higher-order modes from one port and convert all the launching modes to lower-order modes from another port. Mode conversion between the two degenerated high-order modes is also demonstrated numerically. The mode conversion feature is only dependent on the relationship between the effective mode indices of the two cores in the configuration, which shows the characteristics of high flexibility and large fabrication tolerance.

Role of metastasis-associated protein 1 in prognosis of patients with digestive tract cancers: A meta-analysis.

OBJECTIVES: Metastasis-associated protein 1 (MTA1) is a transcriptional regulator and significantly associated with prognosis of patients with cancer. However, its role as a potential prognostic marker in digestive tract cancer (DTC) is controversial. In this study, a meta-analysis was conducted to evaluate the MTA1 expression as a predictor of clinicopathology and survival of patients with DTC. METHODS: We searched PubMed, Ovid, Web of Science and Cochrane databases using multiple search strategies for eligible studies. STATA 11.0 software was used to pool the data and analyze the association, odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the strength of the association. Furthermore, the Newcastle-Ottawa scale was used to evaluate the quality of eligible studies. RESULTS: MTA1 overexpression was strongly associated with depth of invasion (OR = 1.88, 95%CI: 1.05-3.37, P = 0.03), lymph node metastasis (OR = 2.30, 95%CI: 1.76-3.01, P<0.001), vascular invasion (OR = 2.02, 95%CI: 1.40-2.91, P<0.001) and TNM stage (OR = 2.78, 95%CI: 1.63-4.74, P<0.001), and was related to 1- (RR = 1.84, 95%CI: 1.18-2.89, P = 0.008), 3- (RR = 1.74, 95%CI: 1.32-2.30, P<0.001) and 5-year (RR = 1.64, 95%CI: 1.18-2.27, P = 0.003) OS. Further, MTA1 was associated with 1- (RR = 4.16, 95%CI: 1.35-12.81, P = 0.01), 3- (RR = 1.90, 95%CI: 1.02-3.53, P = 0.04) and 5- (RR = 2.17, 95%CI: 1.41-3.32, P<0.001) year DFS. In subgroup analyses based on study quality and tumor type, MTA1 overexpression was obviously related to clinical parameters, such as lymph node metastasis and TNM stage, and was also associated with prognosis of patients with gastrointestinal or esophageal cancer. CONCLUSIONS: MTA1 expression is strongly correlated with metastasis-related variables, and represents a promising prognostic factor in DTC.

Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer.

AIMS: The mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) occurring downstream in the PI3K/Akt/mTOR pathway, are regarded as potential prognostic markers for gastric cancer (GC). However, the prognostic value of mTOR/p-mTOR expression remains controversial. In this study, we determined the expression of mTOR, p-mTOR, p70S6k, and p-p70S6K in GC, and investigated the correlation between their overexpression, clinicopathological parameters, and overall survival (OS). METHODS: The expression of mTOR, p-mTOR, p70S6k, and p-p70S6K was examined in 120 GC patients by immunohistochemistry (IHC). The association of protein expression with clinicopathological features and OS was explored. The p-mTOR expression was detected in normal, adjacent, and GC tissues using Western blot. Eligible studies retrieved from PubMed, Ovid, Web of Science and Cochrane databases, were reviewed in this meta-analysis. RESULTS: IHC showed that the rates of expression of the signal transduction molecules mTOR, p-mTOR, p70S6k and p-p70S6K in GC were 60.8%, 54.2%, 53.3% and 53.3%, respectively. Overexpression of mTOR and p70S6K showed no significant association with clinical variables. Expression of p-mTOR was significantly associated with differentiation (P < 0.01), depth of invasion (P < 0.01), lymph node metastasis (P = 0.04) and TNM stage (P = 0.02). Expression of p-p70S6K was associated with differentiation (P = 0.006), depth of invasion (P < 0.001), and TNM stage (P = 0.02). In survival analysis, differentiation, depth of invasion, lymph node metastasis and TNM stage were not related to OS (all P > 0.05). Furthermore, p-mTOR and p-p70S6K expression, but not mTOR and p70S6K, were tightly associated with OS of GC patients (P = 0.006 and P < 0.001, respectively). In Western blot, p-mTOR was significantly higher in GC tissues than in normal and adjacent tissues. In the present meta-analysis, mTOR overexpression showed no relationship with any clinicopathological variables. However, p-mTOR was correlated with depth of invasion, and TNM stage (all P < 0.05), and its overexpression was associated with a shorter survival time (P < 0.001). CONCLUSION: The results suggest that p-mTOR is a more valuable prognostic factor than mTOR in GC.

HER3, but Not HER4, Plays an Essential Role in the Clinicopathology and Prognosis of Gastric Cancer: A Meta-Analysis.

BACKGROUND AND AIM: Human epidermal growth factor receptor (HER) family plays an important role in gastric cancer (GC), especially HER2. Too much attention has been paid to HER2; however, the functions of HER3 and HER4 overexpression in GC are always ignored. The clinicopathological and prognostic roles of HER3 and HER4 in GC are controversial. In this study, a systematic review and meta-analysis was conducted to evaluate the use of HER3 or HER4 as a predictor of clinicopathology and survival time in GC patients. METHODS: Eligible studies were searched on PubMed, Ovid, Web of Science, and Cochrane databases through multiple search strategies. Data collection and statistical analysis were carried out by the Revman 5.3 software. The Newcastle-Ottawa scale was used to assess the quality of included studies. RESULTS: A total of 448 studies about HER3 overexpression and GC, and 398 studies about HER4 overexpression and GC were searched. Of these, 5 eligible studies about HER3 including 1016 GC patients and 3 eligible studies about HER4 including 793 GC patients met the inclusion criteria. The results showed that HER3 and HER4 overexpression were significantly associated with depth of tumor invasion (OR = 0.44, 95%CI 0.29-0.67, P = 0.0002 and OR = 0.50, 95%CI 0.38-0.86, P = 0.007) and lymph node metastasis (OR = 0.40, 95%CI 0.20-0.77, P = 0.007 and OR = 0.57, 95%CI 0.38-0.86, P = 0.007), and HER3 overexpression reveals a tendency of later tumor node metastases (TNM) stage (OR = 0.50, 95%CI 0.22-1.15, P = 0.10) and predicts a worse survival time (RR = 0.71, 95%CI 0.61-0.84, P<0.00001), while HER4 overexpression had no correlation with TNM stage (OR = 0.60, 95%CI 0.20-1.78) and survival time (RR = 1.09, 95%CI 0.91-1.30). CONCLUSIONS: This meta-analysis indicated that HER3 plays an essential role in the clinicopathology and prognosis of GC. However, HER4 may not be an ideal prognostic factor for GC.