Honghe Zhang

Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis

Objective The objective of this meta-analysis was to systematically assess the survival benefit of aspirin use before or after diagnosis for patients with colorectal cancer (CRC). Design Relevant studies were identified through searching PubMed, Embase and Cochrane databases before May 2014. Two investigators extracted data independently for baseline characteristics and outcomes from the included studies. Either a fixed-effects or a random-effects model was derived to composite the pooled HR for overall mortality and CRC-specific mortality of CRC. Results Seven studies on postdiagnosis aspirin therapy and seven studies on prediagnosis aspirin use were finally included in this meta-analysis. The overall survival benefit associated with postdiagnosis aspirin use represented an HR of 0.84 (95% CI 0.75 to 0.94). This effect was observed both in colon cancer (HR=0.78, 95% CI 0.64 to 0.96) and in rectal cancer (HR=0.90, 95% CI 0.83 to 0.98). Besides, the survival benefit of postdiagnosis aspirin use appeared to be confined to those patients with positive prostaglandin endoperoxide synthase 2 (PTGS2, also known as cyclooxygenase-2, COX-2) expression (HR=0.65, 95% CI 0.50 to 0.85) and with mutated PIK3CA tumours (HR=0.58, 95% CI 0.37 to 0.90). Aspirin use postdiagnosis was not associated with CRC-specific mortality (HR=0.77, 95% CI 0.52 to 1.14). We observed no evidence of an association between prediagnosis aspirin use and CRC overall mortality (HR=1.01, 95% CI 0.96 to 1.06) or CRC-specific mortality (HR=0.93, 95% CI 0.82 to 1.05). Conclusions These findings provide further indication that postdiagnosis aspirin therapy improved CRC overall survival, especially for patients with positive PTGS2 (COX-2) expression and mutated PIK3CA tumours.

In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: an 18F-fluorodeoxyglucose–small animal positron emission tomography study

Cerebral glucose hypometabolism is common in temporal lobe epilepsy (TLE). The temporospatial evolution of these metabolic changes during epileptogenesis remains to be determined. We measured the regional normalized cerebral metabolic rate for glucose (nCMRglc) with (18)F-fluorodeoxyglucose (FDG)-small animal positron emission tomography (microPET) in animals receiving systemic pilocarpine application. The microPET scan was performed on day 2 (early), day 7 (latent) and 42 days (chronic phase) after the initial status epilepticus. We found specific temporospatial changes in glucose utilization in rats during the course of epileptogenesis. In the early phase, the limbic structures underwent the largest decrease in glucose utilization. Most brain structures were still hypometabolic in the latent phase and recovered in the chronic phase. Conversely, the hippocampus and thalamus presented with persistent hypometabolism during epileptogenesis. The cerebellum and pons maintained normal glucose utilization during this process. We also found that severe glucose hypometabolism in the entorhinal cortex during the early phase was correlated with epileptogenesis, indicating the critical role of the entorhinal cortex in the early stages of TLE.

MiR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells

Autophagy has become one of the most important mechanisms of chemotherapy resistance by supporting the survival of tumor cells under metabolic and therapeutic stress. Here, we showed that miR-22 inhibited autophagy and promoted apoptosis to increase the sensitivity of colorectal cancer (CRC) cells to 5-fluorouracil (5-FU) treatment both in vitro and in vivo. B-cell translocation gene 1 (BTG1) was identified as a new target of miR-22, which could reverse the inhibition of autophagy induced by miR-22. Thus, miR-22 may function as an important switch between autophagy and apoptosis to regulate 5-FU sensitivity through post-transcriptional silencing of BTG1. Promisingly, miR-22 could be considered as both a predictor of 5-FU sensitivity for personalized treatment and a therapeutic target for colorectal cancer.

Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients

In the recent years, fluorine 18 fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET)/computed tomography (CT) has emerged as a new modality for staging non–small‐cell lung cancer (NSCLC) patients. The aim of this meta‐analysis was to assess the diagnostic value of 18F‐FDG PET/CT in detecting metastatic lesions in NSCLC patients. Meta‐analysis methods were used to pool sensitivity, specificity, positive and negative likehood ratios, diagnostic odd ratios and to construct a summary receiver‐operating characteristic curve. Data from included studies were pooled to compare the diagnostic accuracy between PET/CT and PET or CT alone in nodal staging. Totally, 56 studies involving 8,699 patients met the inclusion criteria. The pooled sensitivities and specificities of 18F‐FDG PET/CT were 0.72 [95% confidence interval (CI): 0.65–0.78] and 0.91 (95% CI: 0.86–0.94) in determining mediastinal nodal staging; 0.71 (95% CI: 0.60–0.80) and 0.83 (95% CI: 0.77–0.88) in intrathoracic staging; 0.78 (95% CI: 0.64–0.87) and 0.90 (95% CI: 0.84–0.94) in intrathoracic staging on a per‐node basis. For detecting extrathoracic metastases, the pooled sensitivities and specificities of 18F‐FDG PET/CT were 0.77 (95% CI: 0.47–0.93) and 0.95 (95% CI: 0.92–0.97) for all extrathoracic metastases; 0.91 (95% CI: 0.80–0.97) and 0.98 (95% CI: 0.94–0.99) for bone metastases. 18F‐FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases although PET/CT showed low sensitivity in detecting brain metastases. 18F‐FDG PET/CT confers significantly higher sensitivity and specificity than contrast‐enhanced CT (both p < 0.01) and higher sensitivity than 18F‐FDG PET in staging NSCLC (p < 0.05).

Behavioral and [F-18] fluorodeoxyglucose micro positron emission tomography imaging study in a rat chronic mild stress model of depression.

We investigated changes in behavior and brain glucose metabolism in a rat chronic mild stress (CMS) model of depression. The CMS model has been used to mimic depression in humans by using various chronic mild stressors in a 4 weeks period. In the present study, we have developed a combination of tests examining behavior (open field test) and hedonic measure (sucrose preference test) after exposure to CMS, and compared this to control non-stressed rats. We found that CMS induced behavioral changes, including decreased central and rearing activity, increased grooming and defecation, reduced body weight, and reduced relative sucrose intake. Moreover, our study suggests that CMS administered for 4 weeks activated left auditory cortex, while left piriform cortex, left inferior colliculus, septal nuclei and periaqueductal gray were deactivated. These changes in region of interest are left-right asymmetrical and lateralized in the left hemisphere. And activity deficits of depression are related with changes of brain activity in all brain regions showing significant changes by CMS in glucose metabolism. There are significant correlations for relative sucrose intake in left piriform cortex, left inferior colliculus and left auditory cortex, and for anxiety-related behavioral measures in septal nuclei and periaqueductal gray. There are lack of significant effects in the mean glucose metabolism of both hemispheres in hippocampus and amygdala induced by CMS possibly because of various reasons. Changes in glucose metabolism support the view that these significant brain regions are involved in chronic stress and depressive mood regulation. The results of this study might contribute to the awareness of changes in behavior and brain activity of depression induced by CMS.

Long non-coding RNA LINC01133 inhibits epithelial–mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6

Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. Here we reported a novel lncRNA, LINC01133 that was downregulated by TGF-β, which could inhibit epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC) cells. An alternative splicing factor SRSF6 was identified to directly interact with LINC01133, and SRSF6 promoted EMT and metastasis in CRC cells independent of LINC01133 And we confirmed that the EMT process was regulated by LINC01133 in CRC cells dependent on the presence of SRSF6. The observation for LINC01133 to inhibit metastasis was also verified in vivo. Moreover clinical data showed that the LINC01133 expression was positively correlated with E-cadherin, and negatively correlated with Vimentin, and there was a robust association of low LIINC01133 expression in tumors with poor survival in CRC samples. These data suggest that LINC01133 inhibits the EMT and metastasis by directly binding to SRSF6 as a target mimic, and may serve as a prognostic biomarker and an effective target for anti-metastasis therapies for CRC.

GDF15 promotes EMT and metastasis in colorectal cancer

Metastasis is the major cause of cancer deaths, and the epithelial–mesenchymal transition (EMT) has been considered to be a fundamental event in cancer metastasis. However, the role of growth differentiation factor 15 (GDF15) in colorectal cancer (CRC) metastasis and EMT remains poorly understood. Here, we showed that GDF15 promoted CRC cell metastasis both in vitro and in vivo. In addition, the EMT process was enhanced by GDF15 through binding to TGF-β receptor to activate Smad2 and Smad3 pathways. Clinical data showed GDF15 level in tumor tissues, and the serum was significantly increased, in which high GDF15 level correlated with a reduced overall survival in CRC. Thus, GDF15 may promote colorectal cancer metastasis through activating EMT. Promisingly, GDF15 could be considered as a novel prognostic marker for CRC in the clinic.

Molecular mechanisms of microRNAs in regulating epithelial-mesenchymal transitions in human cancers.

The epithelial-mesenchymal transition (EMT) provides a strong driving force in the progression of various human cancers and the development of chemoresistance. Recently, numbers of studies have demonstrated that microRNAs (miRNAs), by post-transcriptionally silencing EMT-related molecules, can promote or inhibit the EMT process and play pivotal roles in effectively manipulating the occurrence, development, invasion, and metastasis of cancers. MiRNAs can also control the EMT or be controlled by genetic modification and mutual regulation, especially negative feedback. Therefore, miRNAs can be viewed as either oncogenes or tumor suppressor genes to facilitate or retard the EMT, resulting in far-reaching impact on tumor metastasis and effective diagnosis, treatment, and prognosis.

Association between dietary antioxidant vitamins intake/blood level and risk of gastric cancer.

We aimed to systematically evaluate the association between dietary intake/blood levels of antioxidant vitamins (vitamin C, vitamin E, β‐carotene, and α‐carotene) and gastric cancer risk. Systematic literature searches were conducted until April 2013 in Pubmed and Embase to identify relevant studies. Either a fixed‐ or a random‐effects model was adopted to estimate overall odds ratios (ORs). Dose–response, meta‐regression, subgroup, and publication bias analyses were applied. Forty articles were finally included in the present study. Higher dietary intake of vitamin C, vitamin E, β‐carotene, and α‐carotene was inversely associated with gastric cancer risk (for vitamin C, pooled OR = 0.58, 95% CI 0.51–0.65; for vitamin E, pooled OR = 0.65, 95% CI 0.57–0.74; for β‐carotene, pooled OR = 0.59, 95% CI 0.49–0.70; for α‐carotene, pooled OR = 0.69, 95% CI 0.52–0.93). Subgroup analyses suggested the effects of these antioxidant vitamins were different in gastric cancer subtypes. As indicated by dose–response analysis, a 100 mg/day increment of vitamin C intake conferred an OR of 0.78 (95% CI 0.67–0.90); a 15 mg/day increment of vitamin E intake conferred an OR of 0.79 (95% CI 0.66–0.94); and a 5 mg/day increment in β‐carotene intake conferred an OR of 0.80 (95% CI 0.60–1.04). No significant association was observed between blood vitamin C, α‐tocopherol, γ‐ tocopherol, β‐carotene and α‐carotene levels and gastric cancer risk. In conclusion, dietary intake of vitamin C, vitamin E, β‐carotene and α‐carotene was inversely associated with gastric cancer risk while no such association was observed for blood levels of these antioxidant vitamins, thus the results should be interpreted cautiously.

HIPPOCAMPAL SPINE-ASSOCIATED Rap-SPECIFIC GTPase-ACTIVATING PROTEIN INDUCES ENHANCEMENT OF LEARNING AND MEMORY IN POSTNATALLY HYPOXIA-EXPOSED MICE

Spine-associated Rap-specific GTPase-activating protein (SPAR) is a postsynaptic protein that forms a complex with postsynaptic density (PSD)-95 and N-methyl-d-aspartate receptors (NMDARs), and morphologically regulates dendritic spines. Mild intermittent hypoxia (IH, 16.0% O(2), 4 h/day for 4 weeks) is known to markedly enhance spatial learning and memory in postnatal developing mice. Here, we report that this effect is correlated with persistent increases in SPAR expression as well as long-term potentiation (LTP) in the hippocampus of IH-exposed mice. Furthermore, an infusion of SPAR antisense oligonucleotides into the dorsal hippocampus disrupted elevation of SPAR expression, preventing enhanced hippocampal LTP in IH-exposed developing mice and also reducing LTP in normoxic mice, without altering basal synaptic transmission. In SPAR antisense-treated mice, acquisition of the Morris water maze spatial learning task was impaired, as was memory retention in probe trails following training. This study provides the first evidence that SPAR is functionally required for synaptic plasticity and contributes to the IH-induced enhancement of spatial learning and memory in postnatal developing mice.