The efficacy of irinotecan supplementation for colorectal cancer: A meta-analysis of randomized controlled studies.

BACKGROUND: The efficacy of irinotecan as the adjunctive therapy to fluorouracil and leucovorin remains controversial in patients with colorectal cancer. We conduct this meta-analysis to explore the efficacy of irinotecan supplementation for colorectal cancer. METHODS: We have searched PubMed, EMBASE, Web of science, EBSCO, and Cochrane library databases through March 19, 2020, and included randomized controlled trials assessing the efficacy of irinotecan plus fluorouracil and leucovorin for colorectal cancer. RESULTS: Five randomized controlled trials were included in the meta-analysis. Compared with fluorouracil and leucovorin for colorectal cancer, irinotecan supplementation could significantly improve progression-free survival rate (hazard ratio = 0.72; 95% confidence interval [CI] = 0.58-0.90; P = .003), median progression-free survival (standard mean difference = -0.30; 95% CI = -0.44 to -0.15; P < .0001), overall survival rate (hazard ratio = 0.77; 95% CI = 0.66-0.90; P = .001), and objective response (risk ratio [RR] = 0.57; 95% CI = 0.49-0.66; P < .00001) and decrease progressive disease (RR = 2.10; 95% CI = 1.40-3.14; P = .0003), but revealed no obvious effect on complete response (RR = 0.88; 95% CI = 0.33-2.29; P = .79). The incidence of grade ≥3 adverse events in irinotecan supplementation group was increased compared to control group (RR = 0.67; 95% CI = 0.57-0.79; P < .00001). CONCLUSIONS: Irinotecan as the adjunctive therapy to fluorouracil and leucovorin can increase the survival and objective response of patients with colorectal cancer, but the incidence of grade ≥3 adverse events is found to be increased after irinotecan supplementation.

New Biotransformation Mode of Zearalenone Identified in Bacillus subtilis Y816 Revealing a Novel ZEN Conjugate.

An increasing number of Bacillus strains have been identified, and the removal capacity of zearalenone (ZEN) was determined; however, they failed to reveal the detoxification mechanism and transformation product. Here, Bacillus subtilis Y816, which could transform 40 mg/L of ZEN within 7 h of fermentation, was identified and studied. First, the biotransformation products of ZEN and 17-ß-estradiol (E2) were identified as ZEN-14-phosphate and E2-3-phosphate by HPLC-TOF-MS and NMR, respectively. An intracellular zearalenone phosphotransferase (ZPH) was found through transcriptome sequencing analysis of B. subtilis Y816. The phosphorylated reaction conditions of ZEN by ZPH were further revealed in this work. Furthermore, the phosphorylated conjugates showed reduced estrogenic toxicity compared with their original substances (ZEN and α/ß-zearalenol) using an engineered yeast biosensor system. The first report on the phosphorylated conjugated mode of ZEN in B. subtilis Y816 will inspire new perspectives on the biotransformation of ZEN in Bacillus strains.

The effect of VNS on the rehabilitation of stroke: A meta-analysis of randomized controlled studies.

INTRODUCTION: The efficacy of vagus nerve stimulation (VNS) for the rehabilitation of stroke remains controversial. We conduct a systematic review and meta-analysis to explore the influence of VNS on the rehabilitation of stroke. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through March 2020 for randomized controlled trials (RCTs) assessing the effect of VNS on the rehabilitation of stroke. This meta-analysis is performed using the random-effect model. RESULTS: Three RCTs are included in the meta-analysis. Overall, compared with control group in stroke, VNS is associated with significantly improved FMA-UE (SMD = 3.86; 95% CI = 1.19 to 6.52; P = 0.005) and Motor Function Test (SMD = 0.33; 95% CI = 0.04 to 0.62; P = 0.03), but has no obvious impact on Box and Block Test (SMD = -0.31; 95% CI = -3.48 to 2.86; P = 0.85), Nine-Hole Peg Test (SMD = 8.35; 95% CI = -40.59 to 57.28; P = 0.74), atrial fibrillation (RR = 3.46; 95% CI = 0.39 to 30.57; P = 0.26) or adverse events (RR = 0.59; 95% CI = 0.21 to 1.61; P = 0.30). CONCLUSIONS: VNS may be beneficial to the rehabilitation of stroke.

Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway.

Recent studies found that irisin, a newly discovered skeletal muscle-derived myokine during exercise, is also synthesized in various tissues of different species and protects against neuronal injury in cerebral ischemia. The NOD-like receptor pyrin 3 (NLRP3) inflammasome play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke. However, it is unclear whether irisin is involved in the regulation of NLRP3 inflammasome activation during ischemic stroke. In the present study, PC12 neuronal cells were exposed to oxygen-glucose deprivation (OGD), exogenous irisin (12.5, 25, 50nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200µmol/L) were used as an intervention reagent, NLRP3 was over-expressed or suppressed by transfection with a NLRP3 expressing vector or NLRP3-specifc siRNA, respectively. Our data showed that both irisin and its precursor protein fibronectin type III domain containing 5 (FNDC5) expression were significantly down-regulated (p<0.05); but oxidative stress and ROS-NLRP3 inflammasome signaling were activated by OGD (p<0.05); treatment with irisin or inhibition of NLRP3 reversed OGD-induced oxidative stress and inflammation (p<0.05). However, these irisin-mediated effects were blunted by over-expression NLRP3 (p<0.05). Taken together, our results firstly revealed that irisin mitigated OGD-induced neuronal injury in part via inhibiting ROS-NLRP3 inflammatory signaling pathway, suggesting a likely mechanism for irisin-induced therapeutic effect in ischemic stroke.

ZEB2 promotes tumor metastasis and correlates with poor prognosis of human colorectal cancer.

Colorectal cancer remains the most common cause of cancer-related deaths worldwide and it continues to lack an effective treatment. Here, we found that zinc finger E-box binding homeobox 2 (ZEB2) was overexpressed in several colorectal cancer cell lines and colorectal cancer specimens relative to adjacent non-cancerous tissues. Although ZEB2 has been reported to be associated with several tumors, its involvement in colorectal cancer progression remains unclear. In this study, we investigated the biological functions and molecular mechanisms of ZEB2 underlying colorectal carcinoma metastasis and angiogenesis. HCT116 colorectal cancer cells were treated with ZEB2 shRNA or recombinant ZEB2, and the expression of ZEB2 was assessed using reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting, respectively. Ectopic expression of ZEB2 induced proliferation and epithelial-mesenchymal transition (EMT), and increased the metastatic capacity of HCT116 cells in vitro and in vivo. Furthermore, endothelial cell tube formation and angiogenesis in chick embryo chorioallantoic membrane (CAM) were accelerated by conditioned medium from ZEB2-overexpressing HCT116 cells. Further, overexpression of ZEB2 accelerated tumor growth and angiogenesis in xenotransplantation models. However, silencing endogenous ZEB2 caused an opposite outcome. Our results provide new evidence that ZEB2 promotes the progression of colon cancer, and thereby might represent a novel therapeutic target for colorectal carcinoma.

Association between CXCR2 and IL-22BP expression indicate a poor outcome for gastric adenocarcinoma progression.

C-X-C motif chemokine receptor type 2 (CXCR2), a key regulatory protein, has been associated with multiple roles in the progression of numerous tumors, including gastric adenocarcinoma (GA). However, the mechanism of CXCR2 in the development of tumors remains controversial and unclear. In a previous study, the expression of CXCR2 and interleukin-22 receptor 2 (IL-22BP) was observed in GA. This promoted the present study, which aimed to explore the association between the two proteins, and to further analyze their roles in GA. CXCR2 and IL-22BP protein expression was analyzed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction assays in gastric cancer (GC) tissue, additionally confirmed via western blotting and immunocytochemical analysis in the MKN-45, BGC-823 and SGC-7901 cell lines. The association between expression levels and clinicopathological characteristics was evaluated by the Mann-Whitney U and Kruskal-Wallis tests. Using Kaplan-Meier plots and Cox proportional hazard models, overall survival (OS) was analyzed. Compared with non-cancerous tissue, CXCR2 and IL-22BP were over expressed (P<0.001 and P<0.001, respectively), and were observed mainly in the cytoplasm (P=0.022 and P=0.014, respectively) in GA. The associated protein and messenger RNA levels were analyzed, and coexpression was identified. Increased expression and more positive cases of CXCR2 and IL-22BP were observed with advanced pathological tumor-node-metastasis (p-TNM) stage in GC (P<0.001 and P<0.001, respectively), as well as the presence and absence of lymph node metastasis (LNM) (P=0.003 and P=0.041, respectively) and deep or superficial muscular invasion (P=0.002 and P=0.004, respectively). In addition, an association between IL-22BP and tumor diameter was indicated (P=0.021). In a Kaplan-Meier analysis, compared with negative expression, the two proteins identified a group of patients with the shortest OS. Cox proportional hazard models revealed that the two proteins, in addition to p-TNM stage, LNM and depth of invasion, predicted a short time to OS. The coexpression of CXCR2 and IL-22BP was demonstrated in GA, which may indicate that CXCR2 is involved in more complex mechanisms and roles, and indicate a poor outcome in GA progression.

Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been identified as having functional roles in cancer biology and are deregulated in many cancers. The present study aimed to determine the expression, roles and functional mechanisms of a long noncoding RNA CCAT1 in the progression of hepatocellular carcinoma (HCC). METHODS: CCAT1 expression levels in 66 pairs of HCC tissues and pair-matched noncancerous hepatic tissues were tested by real-time PCR. The effects of CCAT1 on HCC cells proliferation and migration were assessed using in vitro cell proliferation and migration assays. A computational screen of microRNAs (miRNAs) target sites in CCAT1 was conducted to search for specific miRNAs binding to CCAT1. The specific binding between CCAT1 and miRNAs was confirmed by RNA immunoprecipitation assay combined with luciferase reporter assay. RESULTS: CCAT1 levels are markedly increased in HCC tissues compared with pair-matched noncancerous hepatic tissues. Up-regulation of CCAT1 is correlated with tumor size, microvascular invasion, AFP and poor prognosis. CCAT1 promotes the proliferation and migration of HCC cells. CCAT1 functions as a molecular sponge for let-7, antagonizes its functions, and leads to the de-repression of its endogenous targets HMGA2 and c-Myc. The effect of CCAT1 on HCC cell proliferation and migration is dependent upon its competitively binding to let-7. CONCLUSIONS: These data suggest that CCAT1 plays a pivotal role in HCC progression via functioning as let-7 sponge, and implicate the potential application of CCAT1 for the prognosis and treatment of HCC.

Loss of stromal caveolin-1 expression in colorectal cancer predicts poor survival.

AIM: To investigate the clinicopathological significance and prognostic value of caveolin-1 (CAV-1) in both tumor and stromal cells in colorectal cancer (CRC). METHODS: A total of 178 patients with CRC were included in this study. The correlation between CAV-1 expression and clinicopathologic features and survival was studied. RESULTS: CAV-1 expression was detected in tumor and stromal cells. The expression of stromal CAV-1 was closely associated with histological type (P=0.022), pathologic tumor-node-metastasis stage (P=0.047), pathologic N stage (P=0.035) and recurrence (P=0.000). However, tumor cell CAV-1 did not show any correlation with clinical parameters. Additionally, the loss of stromal CAV-1 expression was associated with shorter disease-free survival (P=0.000) and overall survival (P=0.000). Multivariate analysis revealed that the loss of stromal CAV-1 expression was an independent prognostic factor for both overall survival (P=0.014) and disease-free survival (P=0.006). CONCLUSION: The loss of stromal CAV-1 expression in CRC was associated with poor prognosis and could be a prognostic factor for CRC patients.

Surgical outcomes and prognostic factors of T4 gastric cancer patients without distant metastasis.

OBJECTIVE: To evaluate surgical outcomes and prognostic factors for T4 gastric cancer treated with curative resection. METHODS: Between January 1994 and December 2008, 94 patients diagnosed with histological T4 gastric carcinoma and treated with curative resection were recruited. Patient characteristics, surgical complications, survival, and prognostic factors were analyzed. RESULTS: Postoperative morbidity and mortality were 18.1% and 2.1%, respectively. Multivariate analysis indicated lymph node metastasis (hazard ratio, 2.496; 95% confidence interval, 1.218-5.115; p = 0.012) was independent prognostic factor. CONCLUSIONS: For patients with T4 gastric cancer, lymph node metastasis was associated with poorer survival. Neoadjuvant chemotherapy or aggressive adjuvant chemotherapy after radical resection was strongly recommended for these patients.

[Closed reduction and fixation for the treatment of Gartland type II and III supracondylar fracture of humerus in children].

OBJECTIVE: To evaluate the feasibility and results of closed reduction and fixation for the treatment of Gartland type I and III supracondylar fracture of humerus in children. METHODS: From January 2004 to December 2011,110 children with supracondylar fracture of humerus were treated. Among them, 76 patients were boy and 34 patients were girl, ranging in age from 2 to 13 years old, averaged 7 years old. Ninety-eight patients were extension type and 12 patients were flexion type. There were 32 patients with fracture of Gartland type II and 78 patients with fractures of Gartland type III. Thirty-seven patients had distal rotational displacement. Under anesthesia, the upper arm and forearm of the affected limb were treated with contraction for several minutes. The patients were treated with closed manipulative reduction and plaster external fixation while the satisfactory reduction was confirmed by C-arm X-ray. After the reduction, 1 to 2 Kirschner pins were used through the radial side of the skin and plaster external fixation was carried out. Radiographic examination was conducted within 3 to 4 weeks after surgery,and the plaster and Kirschner pins were then removed, accompanied by rehabilitation training of the patients. RESULTS: All the patients were followed up,and the duration ranged from 3 to 18 months,with a mean of 12 months. All fractures healed within 6 to 8 weeks and the average healing time was 6.9 weeks. No complications such as cubitus varus deformity, neurovascular injury or Volkmann's contracture occurred. According to Flynn evaluation criteria,74 patients got an excellent result, 26 good and 10 fair. CONCLUSION: Through carefully reading X-ray films,Gartland type II and III supracondylar fracture of the humerus in children can be treated with closed reduction, plaster external fixation combined with percutaneous pinning for unstable fracture, which is a simple, less-invasive and satisfactory treatment method.

[Prognostic value of metastatic lymph node ratio in gastric cancer patients undergoing radical gastrectomy].

OBJECTIVE: To assess the prognostic value of metastatic lymph node ratio in gastric cancer patients undergoing radical gastrectomy (D2). METHODS: Prognostic analysis of 1042 gastric cancer patients undergoing radical gastrectomy (D2) was performed based on metastatic lymph node ratio (MLR), the N staging in the 6th and 7th edition of UICC staging system respectively. Homogeneity, discriminatory ability, and gradient monotonicity of these three staging methods were compared using linear trend χ(2), likelihood ratio χ(2) statistics and Akaike information criterion (AIC) calculations, respectively. The area under the ROC curve (AUC) was calculated to compare the prognostic value of these three staging methods. RESULTS: The 5-year survival rate of 1042 patients was 47.5%. The metastatic lymph node ratio (P<0.01) and N staging of the 7th edition UICC (P<0.05) were independent prognostic factors according to univariate and multivariate analyses. The AUC was 0.754 in MLR staging group, higher than that in N staging of the 6th (0.692) and 7th (0.705) edition of UICC group. Compared to the 6th and 7th edition of UICC N staging group, homogeneity and linear curve were better and AIC value was lower in MLR staging group (7240.017 vs. 7364.073 and 7325.731). CONCLUSION: Prognostic value of MLR staging is better than that of UICC N staging for patients undergoing radical gastric cancer resection. The MLR staging can be a new method of lymph node staging for gastric cancer patients.

Meta-analysis of laparoscopic versus open colorectal surgery within fast-track perioperative care.

BACKGROUND: Both laparoscopic surgery and fast-track perioperative care have demonstrated advantages in patients undergoing elective colorectal resections. It is unclear whether there is an additive effect by combining these 2 procedures. OBJECTIVE: The study aimed to conduct a meta-analysis of the randomized evidence to compare laparoscopic with open colorectal surgery within fast-track perioperative care. DATA SOURCES: PubMed, MEDLINE, Embase, and the Cochrane library databases were electronically searched (January 1985 to August 2011). STUDY SELECTION: Randomized clinical trials compared laparoscopic with open colorectal resections within fast-track programs. INTERVENTION: Investigators independently reviewed articles, extracted data, and assessed study quality according to standardized criteria. MAIN OUTCOME MEASURES: The main outcomes measured were postoperative hospital stay, overall hospital stay, readmission rate, morbidity, and mortality. RESULTS: Three trials were considered suitable for meta-analysis. A total of 171 patients underwent laparoscopic surgery, and 142 had open surgery. Meta-analysis showed that laparoscopic colorectal surgery had shorter postoperative hospital stays (weighted mean difference -1.06; 95% CI, -2.06 to -0.06, z = 2.08, p = 0.04) and shorter overall hospital stays (weighted mean difference -2.04; 95% CI, -3.50 to -0.58, z = 2.74, p < 0.01). No significant differences were noted for readmission rate (OR 0.54; 95% CI, 0.26-1.12, z = 1.65, p = 0.10), morbidity (OR 0.68; 95% CI, 0.42-1.10, z =1.58, p = 0.11), and mortality (OR 0.33; 95% CI, 0.09-1.18, z =1.70, p = 0.09). No publication bias and no significant heterogeneity were noted. LIMITATIONS: This study was limited because of its small sample size. CONCLUSIONS: Laparoscopic colorectal surgery has shorter postoperative hospital stays and overall hospital stays than open surgery within fast-track perioperative care. There is no significant difference with respect to readmission rate, morbidity, and mortality. Because the number of patients included in the present trials was small, further studies should be undertaken to confirm these findings.

Electroacupuncture pretreatment prevents cognitive impairment induced by limb ischemia-reperfusion via inhibition of microglial activation and attenuation of oxidative stress in rats.

Limb ischemia-reperfusion (LI/R) is associated with high morbidity and mortality. Furthermore, critical trauma survivors can present cognitive impairment. Cognitive function, survival rate, oxidative stress and neuronal health were examined to elucidate (1) the magnitude of cognitive effects of prolonged reperfusion, (2) potential players in the mechanistic pathway mediating such effects, and (3) possible benefits of electroacupuncture (EA) pretreatment at Baihui (GV20), Yanglingquan (GB34), Taichong (LR3), Zusanli (ST36) and Xuehai (SP10) acupoints. LI/R was induced in rats by placing a rubber tourniquet on each hind limb for 3h, and the animals were evaluated periodically for 7d after LI/R. Rats subjected to LI/R had significantly lower survival rates, and displayed evidence of brain injury and cognitive dysfunction (as determined by the Morris water maze test) 1d and 3d after reperfusion compared to sham-operated controls. LI/R also resulted in higher levels of reactive oxygen species (ROS) and malondialdehyde (MDA), microglial activation, and decreased superoxide dismutase (SOD) activity within Cornu Ammonis area 1 (CA1) of the hippocampus. Depressed survival rates, microglial activation, oxidative damage, and histological changes, as well as cognitive dysfunction were partially or fully attenuated in rats that received 14d of EA prior to LI/R. These findings indicate that LI/R can result in cognitive dysfunction related to activated microglia and elevated oxidative stress, and that EA has neuroprotective potential mediated, at least in part, by inhibition of microglial activation and attenuation of oxidative stress.

Superiority of metastatic lymph node ratio to the 7th edition UICC N staging in gastric cancer.

AIM: To compare and evaluate the appropriate prognostic indicators of lymph node basic staging in gastric cancer patients who underwent radical resection. METHODS: A total of 1042 gastric cancer patients who underwent radical resection and D2 lymphadenectomy were staged using the 6th and 7th edition International Union Against Cancer (UICC) N staging methods and the metastatic lymph node ratio (MLNR) staging. Homogeneity, discriminatory ability, and gradient monotonicity of the various staging methods were compared using linear trend χ(2), likelihood ratio χ(2) statistics, and Akaike information criterion (AIC) calculations. The area under the curve (AUC) was calculated to compare the predictive ability of the aforementioned three staging methods. RESULTS: Optimal cut-points of the MLNR were calculated as MLNR0 (0), MLNR1 (0.01-0.30), MLNR2 (0.31-0.50), and MLNR3 (0.51-1.00). In univariate, multivariate, and stratified analyses, MLNR staging was superior to the 6th and 7th edition UICC N staging methods. MLNR staging had a higher AUC, higher linear trend and likelihood ratio χ(2) scores and lower AIC values than the other two staging methods. CONCLUSION: MLNR staging predicts survival after gastric cancer more precisely than the 6th and 7th edition UICC N classifications and should be considered as an alternative to current pathological N staging.