Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia.

BACKGROUND: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. RESULTS: Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. CONCLUSION: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

High-frequency chest wall oscillation multiple times daily can better reduce the loss of pulmonary surfactant and improve lung compliance in mechanically ventilated patients.

BACKGROUND: High-frequency chest wall oscillation (HFCWO) has been widely recognized for its airway secretion clearance effectiveness in critically ill ICU patients. OBJECTIVES: The purpose of this randomized controlled trial is to validate and compare the effects of different frequencies of HFCWO on oxygenation, lung compliance, and pulmonary surfactant proteins (SPs) in critically ill patients admitted to the intensive care unit (ICU). METHODS: Sixty patients with severe craniocerebral injury treated with a tracheostomy and mechanical ventilation were randomized into three groups (20 patients in each group): a single group (treated with 30 minutes of HFCWO once daily) and a double group (treated with 30 minutes of HFCWO twice daily), and a blank group (treated without HFCWO). Primary outcome measures included results on several specific proteins (SP-A, SP-B, SP-C, and SP-D) in serum and alveolar lavage fluid. Secondary outcome measures were lung static compliance test and oxygenation. RESULTS: Patients in both the single and double groups exhibited significant oxygenation and static compliance improvement. Similar results were observed in changes in SPs concentrations in the alveolar lavage fluid. However, a significant reduction of SPs levels was observed in the serum. In the group comparison analysis for the same variables between the single and double group, twice daily HFCWO treatments showed a significantly better result. CONCLUSION: Compared with HFCWO once daily, HFCWO twice daily is advantageous in patients with tracheostomy and prolonged ventilation, which demonstrated significantly greater effectiveness in improving oxygenation and lung static compliance linked to the increase of and SPs contents in the airways as well as a reduction of SPs shift from airways to the blood.

Metallothionein 1M (MT1M) inhibits lung adenocarcinoma cell viability, migration, and expression of cell mobility-related proteins through MDM2/p53/MT1M signaling.

BACKGROUND: Metallothionein 1M (MT1M) functions to regulate cell proliferation and cancer metastasis. This study assessed the effects of MT1M overexpression and mouse double minute 2 homolog (MDM2) knockdown on the regulation of non-small cell lung cancer A549 cell viability, migration, and protein expression in vitro and explored the underlying molecular events. METHODS: A549 cells were stably infected with lentivirus carrying MT1M cDNA or transiently transfected MDM2 siRNA and/or treated with the p53 inhibitor for the assessment of changes in cell viability, wound healing, Transwell migration, and qRT-PCR and Western blot assays. Luciferase reporter assay was performed to investigate p53 binding to the MT1M promoter. RESULTS: The data showed that MT1M overexpression inhibited A549 cell viability and migration capacity in vitro, whereas the p53 inhibitor reversed the inhibition of A549 cell viability and migration caused by MT1M overexpression as well as the expression of MMP2, MMP9, and MMP14. Furthermore, knockdown of MDM2, an upstream inhibitor of p53 activity, was able to reduce A549 cell viability, migration, and protein expression. Thus, MDM2 knockdown had synergistic effects with MT1M overexpression on the suppression of A549 cell viability, migration, and protein expression. CONCLUSIONS: In conclusion, MDM2 can bind to and phosphorylate p53 protein to inactivate the protein, thereby reducing MT1M expression and leading to tumor cell proliferation and migration.

Pancreatic cancer biomarker detection by two support vector strategies for recursive feature elimination.

AIM: Pancreatic cancer is one of the worst malignant tumors in prognosis. Therefore, to reduce the mortality rate of pancreatic cancer, early diagnosis and prompt treatment are particularly important. RESULTS: We put forward a new feature-selection method that was used to find clinical markers for pancreatic cancer by combination of Support Vector Machine Recursive Feature Elimination (SVM-RFE) and Large Margin Distribution Machine Recursive Feature Elimination (LDM-RFE) algorithms. As a result, seven differentially expressed genes were predicted as specific biomarkers for pancreatic cancer because of their highest accuracy of classification on cancer and normal samples. CONCLUSION: Three (MMP7, FOS and A2M) out of the seven predicted gene markers were found to encode proteins secreted into urine, providing potential diagnostic evidences for pancreatic cancer.

Association of Antioxidative Enzymes Polymorphisms with Efficacy of Platin and Fluorouracil-Based Adjuvant Therapy in Gastric Cancer.

BACKGROUND/AIMS: Imbalance of oxidative/antioxidative enzymes in cells is associated with carcinogenesis and cancer cell chemoresistance. The aim of this study was to examine the clinical significance of potentially functional single nucleotides polymorphisms (SNPs) in antioxidative enzymes, GPxs and CAT, in stages II and III gastric cancer patients. METHODS: A total of 591 gastric cancer patients who had radical gastrectomy were recruited. 207 patients received platinum and fluorouracil-based (PF-based) adjuvant chemotherapy and 384 patients were untreated. GPx1 rs1050450, GPx2 rs4902346, GPx3 rs736775, rs3828599 and CAT rs769218 were genotyped in the DNA samples extracted from paraffin-embedded tumor tissue. RESULTS: CAT rs769218 was significantly correlated with the overall survival (OS) in the dominant model (P = 0.014). Multivariate analysis revealed that CAT rs769218 GA/AA (HR, 0.715; 95%CI, 0.562-0.910, P = 0.006) was an independent prognostic marker indicating improved survival. After adjustments, GPx3 rs736775 TC/CC was significantly associated with improved OS (HR, 0.621; 95%CI, 0.399-0.965; P=0.034) in patients treated with PF-based adjuvant chemotherapy, and CAT rs769218 GA/AA was significantly associated with improved OS (HR, 0.646; 95% CI, 0.482-0.864; P = 0.003) in the untreated patients. PF-based chemotherapy significantly decreased risk of death for patients carrying GPx3 rs736775 TC/CC and age ≤ 60 years or with diffused type adenocarcinoma compared to surgery alone. CONCLUSION: our findings suggested CAT rs769218 and GPx3 rs736775 may be considered as prognostic markers in gastric cancer. Patient stratification by GPx3 rs736775 and conventional pathological parameters may provide additional predictive information in treatment decision-making.

Downregulation of microRNA-370 in esophageal squamous-cell carcinoma is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1.

PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that controls cell fate by regulating multiple signal transduction pathways and is found to be overexpressed in a variety of malignant tumors. Herein, we found the expression of PIN1 is up-regulated while miRNA-370 (miR-370) down-regulated in both esophageal squamous-cell carcinoma (ESCC) tissues and cells. Transfection of miR-370 can significantly decrease PIN1 expression in targeting ESCC cells. Overexpression of miR-370 can induce decreased cell proliferation and cell cycle arrest, as well as increased apoptosis in ESCC cells, while this function can be significantly prevented by co-transfection of PIN1. Further experimental results demonstrated that ß-catenin, cyclin D1, and caspase activation might be involved in miR-370/PIN1 induced growth inhibition and apoptosis. Besides, low miR-370 and high PIN1 expression significantly correlated with tumor diameter, poor differentiation, tumor invasion and lymph node metastasis in patients diagnosed with ESCC. In conclusion, downregulation of miR-370 in ESCC is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1, which might be a potential therapeutic target and adverse prognostic factor in the clinic.

Neutrophil CD64 as a diagnostic marker for neonatal sepsis: Meta-analysis.

BACKGROUND: Neutrophil CD64 (nCD64) is a promising marker for diagnosing bacterial infections. Several studies have investigated the performance of nCD64 for diagnosing neonatal sepsis and the results are variable. Interest in nCD64 for detecting serious bacterial infections is increasing rapidly. OBJECTIVES: The aim of the present study was to carry out a meta-analysis to systematically evaluate the diagnostic accuracy of nCD64 in neonatal sepsis. As far as the authors know, no previous studies have undertaken this. MATERIAL AND METHODS: A review of studies from Pubmed, Embase and the Cochrane Library, from inception through June 2015, found 7 studies (involving 2213 neonates) fulfilling the inclusion criteria. These 7 studies were subjected to a bivariate meta-analysis of sensitivity and specificity and a summary receiveroperating characteristic (SROC) curve; I2 was used to test heterogeneity, and the source of heterogeneity was investigated by influence analysis and meta-regression. RESULTS: The pooled sensitivity and specificity were 80% (95%CI, 69-88%) and 83% (95%CI, 71-90%), respectively. The area under the SROC curve (AUC) was 0.88 (95%CI, 0.85-0.91). The studies had substantial heterogeneity (I2 = 87.1%). CONCLUSIONS: The results showed that nCD64 is a reliable biomarker for diagnosing neonatal sepsis (AUC = 0.88).

L-carnitine treatment of insulin resistance: A systematic review and meta-analysis.

BACKGROUND: L-carnitine has been used for several years as an adjuvant therapy in oxidative stress, blood sugar, high-sensitivity C-reactive protein (CRP), anemia, etc. However, the efficacy of L-carnitine treating insulin resistance (IR) remains controversial. Homeostasis model assessment of Insulin Resistance (HOMA-IR) is widely used in the clinical evaluation of patients with IR. OBJECTIVES: A meta-analysis, including randomized controlled trials (RCTs), was performed to assess the effect of L-carnitine on HOMA-IR patients. MATERIAL AND METHODS: The Cochrane Library, PubMed, and EMBASE databases were systematically searched to identify RCTs which evaluated the effects of L-carnitine on HOMA-IR patients. We screened relevant studies according to predefined inclusion and exclusion criteria. In the selected articles, we extracted the data: study design, sample size, age, L-carnitine dose and regimen, body mass index (BMI) of patients, mode of administration, study duration and study outcomes. RESULTS: A total of 5 studies were included for the meta-analysis. The result showed L-carnitine was useful in the treatment of IR (WMD -0.724, CI -0.959 -0.488, p < 0.0001). Evaluation at 3, 6, 9, 12 months, the p-values were 0.875, 0.165, 0.031, 0, 007, respectively. CONCLUSIONS: L-carnitine was useful in treating patients with IR. L-carnitine can treat IR more effectively with prolonging the medication time. However, more RCTs with long-term L-carnitine treatment of IR are needed to confirm the viewpoint.

Synergistic role of Cul1 and c-Myc: Prognostic and predictive biomarkers in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors, and its high rates of recurrence and metastasis are the important causes of treatment failure in CRC. Therefore, the development of valuable molecular markers to accurately predict the prognosis of CRC patients is vital. In the present study, we determined the expression of Cullin1 (Cul1) and c-Myc in a CRC tissue microarray containing 470 cancer and corresponding normal tissues by immunohistochemistry. We found that Cul1 and c-Myc expression was significantly upregulated in the CRC cancer tissues compared with that noted in the adjacent non-cancer tissues. High Cul1 expression in cancer tissues was associated with depth of invasion (P=0.005), lymph node metastasis (P=0.001) and TNM stage (P=0.015). High c-Myc expression in cancer tissues was significantly positively association with age (P=0.004), depth of invasion (P<0.001), lymph node metastasis (P<0.001) and TNM stage (P<0.001). Multivariate Cox regression analysis revealed that Cul1 or c-Myc expression was an independent and unfavorable prognostic factor for CRC patients [hazard ratio (HR), 0.749, 95% confidence interval (CI), 0.563-0.996, P<0.05; and HR, 0.384, 95% CI, 0.257-0.472, P<0.001, respectively]. Furthermore, Cul1 and c-Myc exhibited synergistic potential for the prediction of CRC prognosis, and the patients with low expression of both Cul1 and c-Myc had a favorable survival outcome (P<0.001).

Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α.

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

Upregulation and biological function of transmembrane protein 119 in osteosarcoma.

Osteosarcoma is suggested to be caused by genetic and molecular alterations that disrupt osteoblast differentiation. Recent studies have reported that transmembrane protein 119 (TMEM119) contributes to osteoblast differentiation and bone development. However, the level of TMEM119 expression and its roles in osteosarcoma have not yet been elucidated. In the present study, TMEM119 mRNA and protein expression was found to be up-regulated in osteosarcoma compared with normal bone cyst tissues. The level of TMEM119 protein expression was strongly associated with tumor size, clinical stage, distant metastasis and overall survival time. Moreover, gene set enrichment analysis (GSEA) of the Gene Expression Omnibus (GEO) GSE42352 dataset revealed TMEM119 expression in osteosarcoma tissues to be positively correlated with cell cycle, apoptosis, metastasis and TGF-ß signaling. We then knocked down TMEM119 expression in U2OS and MG63 cells using small interfering RNA, which revealed that downregulation of TMEM119 could inhibit the proliferation of osteosarcoma cells by inducing cell cycle arrest in G0/G1 phase and apoptosis. We also found that TMEM119 knockdown significantly inhibited cell migration and invasion, and decreased the expression of TGF-ß pathway-related factors (BMP2, BMP7 and TGF-ß). TGF-ß application rescued the inhibitory effects of TMEM119 knockdown on osteosarcoma cell migration and invasion. Further in vitro experiments with a TGF-ß inhibitor (SB431542) or BMP inhibitor (dorsomorphin) suggested that TMEM119 significantly promotes cell migration and invasion, partly through TGF-ß/BMP signaling. In conclusion, our data support the notion that TMEM119 contributes to the proliferation, migration and invasion of osteosarcoma cells, and functions as an oncogene in osteosarcoma.

Sleep disturbance in mild cognitive impairment: a systematic review of objective measures.

Sleep disturbance frequently occurs in patients with mild cognitive impairment (MCI) and appears to be involved in the cellular and molecular mechanisms of cognitive decline. The aim of this systematic review is to clarify whether patients with MCI demonstrate alterations in certain sleep parameters: total sleep time (TST), sleep efficiency (SE), sleep latency (SL), rapid eye movement latency (REML), percent of rapid eye movement (REM%), arousal index (AI), wake after sleep onset (WASO), slow-wave sleep (SWS), periodic leg movement in sleep (PLMS), and cyclic alternating pattern (CAP) through polysomnography (PSG) and actigraphy. Databases including PubMed, Web of Science, Embase, ScienceDirect, Cochrane, CBM, CNKI, Wanfang Data, and VIP were searched up to January 2016 to collect literature on the correlation between sleep disturbance and MCI as assessed by objective measures. Meta-analysis was conducted using the Review Manager 5.3 software. A total of ten case-control studies involving 225 MCI patients and 235 healthy elders (HE) were deemed eligible and included in our meta-analysis. Every type of sleep disturbance was present in our studies with significant differences in the MCI subtypes. Compared with HE, overall MCI patients as a group expressed more SL and less SE; MCI patients showed less TST and SE and more SL and CAP; patients with amnestic mild cognitive impairment (aMCI) had less AI; patients with non-amnestic mild cognitive impairment (naMCI) had more TST and less AI. Patients with naMCI expressed more AI than those with aMCI. The results indicate that MCI patients might experience more serious sleep disturbance and that different MCI subtypes have different patterns of sleep disturbance.

A systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy for patients with diabetes and depression.

OBJECTIVE: The aim of this meta-analysis was to systematically examine the efficacy of cognitive behavior therapy (CBT) for diabetic patients who have comorbid depression and to identify which aspects can be improved through intervention. METHODS: A systematic literature review was performed using multiple databases. The inclusion criteria included randomized controlled trials (RCTs) of CBT that were conducted with diabetes patients with clinically relevant depression. Review Manager version 5.3 was used to obtain pooled results. RESULTS: Ten RCTs, with a total sample size of 998 participants, met the inclusion criteria. Compared with control groups, the CBT groups had statistically significant, long-term improvements in depression (standardized mean differences [SMD]=-0.65, 95% confidence interval [CI] (-0.98 to -0.31), P=0.0002), quality of life (SMD=0.29, 95%CI (0.08 to 0.51), P=0.007), fasting glucose (SMD=0.21, 95%CI (0.04 to 0.37), P=0.01) and anxiety (SMD=-0.49, 95%CI (-0.88 to -0.10), P=0.01). No improvements were found in glycemic control or in diabetes-related distress. CONCLUSIONS: The results of this meta-analysis showed that CBT can be effective in reducing depression symptoms and fasting glucose in diabetes patients with comorbid depression as well as in improving quality of life and anxiety in the long-term. The results showed that CBT can serve as a promising treatment alternative for diabetes patients with comorbid depression.

Pleural MAC30 as a prognostic marker in NSCLC with malignant pleural effusion.

Over-expressed meningioma-associate protein (MAC30) in tissues was associated with malignant tumor differentiation, metastasis and poor prognosis. However, the attention of MAC30 in pleural effusion from lung tumor is insufficient. Our retrospective study was prepared to explore the clinical values on diagnosis and prognosis of MAC30 from malignant pleural effusion (MPE) in non-small cell lung cancer (NSCLC). Levels of MAC30 were confirmed in MPE from 48 NSCLC patients and in benign pleural effusion (BPE) from 45 controls via enzyme-linked immunosorbent assay (ELISA). The association of MAC30 in MPE with clinical significance was further determined. We found that the levels of MAC30 in MPE were obviously higher than those in BPE (p < 0.05). Moreover, with a cutoff point (17.5 ng/ml), we confirmed the sensitivity and specificity of MAC30 for MPE were 82.7% and 85.3% using ROC curve analysis. Indeed, longer overall survival (OS) was present in NSCLC patients with low MAC30 expression in MPE. Multivariate analysis explicated that elevated MAC30 in MPE was an independent prognostic factor for shorter OS of NSCLC. Our data suggests that MAC30 in pleural effusion could be a potential prognostic marker in NSCLC with MPE.

The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution.

Although the aspect ratio (AR) play a crucial role in determining biological effects of homogeneous nanomaterials, studies available concerning how the shape contributes to biological effect of heterogeneous nanomaterials is limited. To systematically clarify the shape influence on the endocytosis, biocompatibility and biodistribution of magnetic mesoporous silica nanoparticles (M-MSNPs), three FITC-labeled M-MSNPs with different aspect ratio (AR=1, 2, and 4) were specifically designed and constructed through altering the ratios of CTAB/TEOS in a modified so-gel method. We have demonstrated that long-rod M-MSNP2 possessed higher intracellular internalization amount than the short-rod M-MSNP1 and the sphere-like M-MSNP0 in both cancer cells and normal cells due to the difference in the endocytosis pathways. However, there are no significant shape effects on biocompatibility including cytotoxicity and hemolytic rate. Moreover, biodistribution in HepG2 tumor-bearing mice showed that M-MSNPs administrated intravenously were mainly presented in reticuloendothelial system (RES) organs including liver, spleen and kidney. In particular, sphere-like M-MSNP0 were easily trapped in the liver, while long-rod M-MSP2 exhibited more retention in the spleen. It is worth noting that rod-like M-MSNPs are preferentially accumulated in tumor sites than sphere-like M-MSNPs, indicating an improved drug delivery efficacy in cancer therapy. Our findings may provide useful data for deeply understanding the interaction between the different shapes and biological behavior of M-MSNPs, which is expected to give rise to a new generation of heterogeneous M-MSNPs with significantly enhanced efficacy and safety for the cancer theranostics. STATEMENT OF SIGNIFICANCE: In this work, we systematically clarified the shape influence on the endocytosis, biocompatibility and biodistribution of homogeneous nanomaterials. We have demonstrated that rod-like magnetic mesoporous silica nanoparticles (M-MSNPs) were capable of higher intracellular internalization and tumor accumulation than sphere-like M-MSNPs, which was expected to give rise to a new generation of heterogeneous M-MSNPs with significantly enhanced efficacy and safety for the cancer theranostics.

A comparison of the effects of midazolam, propofol and dexmedetomidine on the antioxidant system: A randomized trial.

Previous studies on the antioxidant activity of sedatives have predominantly been in vitro investigations that are lacking clinical data, resulting in conclusion without cogency. The aim of the present prospective, randomized study was to use single sedative drugs for anesthesia induction to compare their antioxidant properties. The effects on the antioxidant system of midazolam, propofol and dexmedetomidine were assessed using oxidative stress indicators and micronuclei (MN). Forty-nine patients undergoing esophageal cancer radical prostatectomy were selected. Midazolam, propofol and dexmedetomidine were used to induce anesthesia. Venous blood samples were obtained prior to and at 2 and at 24 h after surgery, and oxidative stress indicators were detected using the appropriate kits. The cytokinesis-block micronucleus cytome assay was executed and the frequencies of MN, nucleoplasmic bridges and nuclear buds were examined. It was found that the use of the three sedatives, respectively, led to a marked increase in the levels of free radical indicators at 2 h after surgery, which then decreased at 24 h after surgery. Furthermore, lower levels of oxidative stress were found following the use of propofol and dexmedetomidine compared with those following midazolam administration, and similar results were obtained regarding the level of MN. It is suggested that propofol and dexmedetomidine exhibit a superior antioxidant function to midazolam.

Role of SB203580 in the regulation of human esophageal cancer cells under the effection of Diosgenin.

In order to investigate the mechanism of human esophageal Eca109 cells induced by Diosgenin (Dio), the p38 specific inhibitor SB203580 was used to inhibit the expression of p38 and Western blot was employed to detect the effect of SB203580 in Eca109 cells. MTT experiments were executed to detect the proliferation of the cells. Western blot was also applied to find the expression of phosphorylated p38 (p-p38). It is found that SB203580 can inhibit the expression of p38 in human esophageal cell Eca109. After treated with 50 µg/mL of Dio and 10 µg/mL of SB203580, the proliferation of cells showed significantly increase and the apoptosis of cells showed significantly decrease compared with the proliferation in the cells treated with Dio only. Moreover, p-p38 protein level was significantly decreased after treated by the two drugs. It is concluded that Dio may regulate esophageal Eca109 cells through p-p38 pathway.

SOD2 rs4880 CT/CC genotype predicts poor survival for Chinese gastric cancer patients received platinum and fluorouracil based adjuvant chemotherapy.

Adjuvant chemotherapy is a standard therapy for gastric cancer patients, however, treatment response is quite heterogeneous. Molecular biomarkers will be highly valuable to guide the therapy and predict the response and prognosis in these patients. The antioxidant enzymes superoxide dismutase 2 (SOD2) and glutathione S-transferase pi 1 (GSTP1) are involved in oxidative stress and drug detoxification, which modulate the efficacy of anticancer drugs. Here, we investigated the clinical associations of two functional single nucleotide polymorphisms of SOD2 and GSTP1 in stage II-III postoperative gastric cancer patients. SOD2 rs4880 and GSTP1 rs1695 were genotyped in 207 patients received postoperative platinum and fluorouracil based chemotherapy and 304 patients who did not. SOD2 rs4880 CT/CC significantly associated with decreased median overall survival time of 23 months when compared to the TT genotype (mean overall survival time of 65.2 months, P=0.002) only for patients received adjuvant chemotherapy. Stratification analysis showed SOD2 rs4880 CT/CC affected most significantly the clinical outcome for patients with tumor arising at gastric body (HR, 5.707, P=0.002), well to moderately differentiated adenocarcinoma (HR, 4.900, P<0.001), tumor of intestinal type (HR, 4.398, P<0.001), or tumor size less or equal to 5 cm (HR, 2.490, P=0.004); while GSTP1 rs1695 GA/GG was significant decreased overall survival time among patients with tumor arising at fundus or cardia (HR, 3.001, P=0.004), or mucinous or signet-ring cell carcinoma (HR, 4.750, P=0.042). The present study suggested the two polymorphisms would affect the adjuvant chemotherapy outcome in specific subtype of gastric cancer. SOD2 rs4880 could be used as a biomarker to predict the prognosis and response to therapy.

Cullin1 is a novel prognostic marker and regulates the cell proliferation and metastasis in colorectal cancer.

PURPOSE: To investigate the precise function of Cullin1 (CUL1) in colorectal cancer (CRC). METHODS: Immunohistochemistry was performed to test the expression of CUL1 on a CRC tissue microarray containing the tumor and corresponding normal tissues. Simultaneously, the correlation of CUL1 expression with clinicopathological parameters and survival was evaluated. CUL1 was over-expressed or knocked down in HCT116 and SW480 cells, then the cell proliferation, migration and invasion assays in vitro and in vivo were performed. RESULTS: In this study, we found that CUL1 expression was significantly up-regulated in CRC compared with normal colon tissues. High CUL1 expression was positively associated with lymph node metastasis (P = 0.007) and tumor diameter (P = 0.052). Multivariate Cox regression analysis revealed that high CUL1 expression was an independent unfavorable prognostic factor for CRC patients (HR = 13.9, 95% confidence interval = 5.89-32.6, P < 0.001). Moreover, we found that CUL1 over-expression induced CRC cell proliferation and the growth of xenografts in nude mice via the changing of cell-cycle proteins. In addition, increased CUL1 expression in CRC cells significantly promoted cell migration and invasion abilities in vitro and peritoneal metastasis in vivo through inducing high expression of MMPs. CONCLUSION: Our findings imply that CUL1 may serve as promising prognostic markers in CRC patients.

Ternary copper(II) complexes with amino acid chains and heterocyclic bases: DNA binding, cytotoxic and cell apoptosis induction properties.

Nowadays, chemotherapy is a common means of oncology. However, it is difficult to find excellent chemotherapy drugs. Here we reported three new ternary copper(II) complexes which have potential chemotherapy characteristics with reduced Schiff base ligand and heterocyclic bases (TBHP), [Cu(phen)(TBHP)]H2O (1), [Cu(dpz)(TBHP)]H2O (2) and [Cu(dppz)(TBHP)]H2O (3) (phen=1,10-phenanthroline, dpz=dipyrido [3,2:2',3'-f]quinoxaline, dppz=dipyrido [3,2-a:2',3'-c]phenazine, H2TBHP=2-(3,5-di-tert-butyl-2-hydroxybenzylamino)-2-benzyl-acetic acid). The DNA-binding properties of the complexes were investigated by spectrometric titrations, ethidium bromide displacement experiments and viscosity measurements. The results indicated that the three complexes, especially the complex 13, can strongly bind to calf-thymus DNA (CT-DNA). The intrinsic binding constants Kb of the ternary copper(II) complexes with CT-DNA were 1.37×10(5), 1.81×10(5) and 3.21×10(5) for 1, 2 and 3 respectively. Comparative cytotoxic activities of the copper(II) complexes were also determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed that the ternary copper(II) complexes had significant cytotoxic activity against the human lung cancer (A549), human esophageal cancer (Eca109) and human gastric cancer (SGC7901) cell lines. Cell apoptosis were detected by AnnexinV/PI flow cytometry and by Western blotting with the protein expression of p53, Bax and Bcl-2. All the three copper complexes can effectively induce apoptosis of the three human tumor cells.