Anthracycline chemicals with anthracyclinone structure exert antitumor effects by inhibiting angiogenesis and lymphangiogenesis in a xenografted gastric tumor model.

BACKGROUND: It is vital to screen or develop alternative therapeutic drugs with higher curative characteristics and fewer side effects for the clinical treatment of gastric cancer. METHODS: Gastric cancer cells were exposed to different auramycin G doses while determining the impact on cell viability, migration, and invasion. Then the antitumor effects of auramycin G, 5-fluorouracil (5-Fu) and their combination were evaluated. Furthermore, the molecular mechanisms of angiogenesis and lymphangiogenesis regulated by auramycin G and its analogs were investigated. RESULTS: Auramycin G inhibited cell viability in a dose-dependent manner, with a 50% inhibitory concentration of 23.72 ± 6.36 mg/L and 32.54 ± 5.91 mg/L for AGS and MGC803 cells, respectively. The migration and invasion of gastric cancer cells were significantly inhibited by 10 mg/L auramycin G, which was consistent with the down-regulation of the VEGFR2-VEGFA-pPI3K-pAkt-pErk1 and VEGFR3-VEGFC-pPI3K-pAkt-pmTOR proteins. Notably, the average tumor weights were significantly reduced in both the auramycin G (2.21 ± 0.45 g) of 50 mg/kg body weight and auramycin G + 5-fluorouracil (5-Fu) groups (1.33 ± 0.28 g), compared with the control (3.73 ± 0.56 g). Considering that auramycin G decreased the growth of blood and lymphatic vessels while reducing the degree of tumor malignancy, it effectively suppressed tumors by regulating the angiogenic and lymphangiogenic pathways. CONCLUSION: The present study confirmed that auramycin G displayed a prominent antitumor activity in gastric tumor models, both in vitro and in vivo. Moreover, it was confirmed that auramycin G played a specific role in certain gastric cancer cell types, while the mechanism was validated to be associated with angiogenesis- and lymphangiogenesis-related pathway suppression.

Pathologic complete response to chemoimmunotherapy of an advanced gastric cancer patient with high PD-L1 expression, dMMR, and unique gut microbiota composition: A case report.

Background: Advanced gastric cancer (AGC) is a malignant disease with limited therapeutic options and a poor prognosis. Recently, immune checkpoint inhibitors (ICIs), represented by inhibitors of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), have emerged as a potential gastric cancer (GC) therapy. Case presentation: This case study aimed to reveal the tumor response to neoadjuvant chemotherapy combined with camrelizumab in a patient with AGC based on the characteristics of the clinical pathology, genomics variation, and gut microbiome. Samples from a 59-year-old male patient diagnosed with locally advanced unresectable GC (cT4bN2M0, high grade) presenting PD-L1-positive, deficient mismatch repair (dMMR), and highly specific gut microbiota enrichment were subjected to target region sequencing, metagenomic sequencing, and immunohistochemistry staining. The patient received neoadjuvant therapy, including camrelizumab, apatinib, S-1, and abraxane, which eventually promoted dramatic tumor shrinkage without serious adverse effects and allowed subsequent radical gastrectomy and lymphadenectomy. Finally, the patient achieved pathologic complete response (pCR), and the recurrence-free survival time was 19 months at the last follow-up in April 2021. Conclusions: The patient with PD-L1-positive, dMMR, and a highly specific gut microbiota enrichment exhibited a pCR to neoadjuvant chemoimmunotherapy.

Lactoferrin suppresses the progression of colon cancer under hyperglycemia by targeting WTAP/m6A/NT5DC3/HKDC1 axis.

BACKGROUND: Although the relationship between type 2 diabetes (T2D) and the increased risk of colorectal carcinogenesis is widely defined in clinical studies, the therapeutic methods and molecular mechanism of T2D-induced colon cancer and how does hyperglycemia affect the progression is still unknown. Here, we studied the function of lactoferrin (LF) in suppressing the progression of colon cancer in T2D mice, and uncovered the related molecular mechanisms in DNA 5mC and RNA m6A levels. METHODS: We examined the effects of LF (50% iron saturation) on the migration and invasion of colon tumor cells under high concentration of glucose. Then, transcriptomics and DNA methylation profilings of colon tumor cells was co-analyzed to screen out the special gene (NT5DC3), and the expression level of NT5DC3 in 75 clinical blood samples was detected by q-PCR and western blot, to investigate whether NT5DC3 was a biomarker to distinguish T2D patients and T2D-induced colon cancer patients from healthy volunteers. Futhermore, in T2D mouse with xenografted colon tumor models, the inhibitory effects of LF and NT5DC3 protein on colon tumors were investigated. In addition, epigenetic alterations were measured to examine the 5mC/m6A modification sites of NT5DC3 regulated by LF. Utilizing siRNA fragments of eight m6A-related genes, the special gene (WTAP) regulating m6A of NT5DC was proved, and the effect of LF on WTAP/NT5DC3/HKDC1 axis was finally evaluated. RESULTS: A special gene NT5DC3 was screened out through co-analysis of transcriptomics and DNA methylation profiling, and HKDC1 might be a downstream sensor of NT5DC3. Mechanistically, LF-dependent cellular DNA 5mC and RNA m6A profiling remodeling transcriptionally regulate NT5DC3 expression. WTAP plays a key role in regulating NT5DC3 m6A modification and subsequently controls NT5DC3 downstream target HKDC1 expression. Moreover, co-treatment of lactoferrin and NT5DC3 protein restrains the growth of colon tumors by altering the aberrant epigenetic markers. Strikingly, clinical blood samples analysis demonstrates NT5DC3 protein expression is required to direct the distinction of T2D or T2D-induced colon cancer with healthy humans. CONCLUSIONS: Together, this study reveals that lactoferrin acts as a major factor to repress the progression of colon cancer under hyperglycemia, thus, significantly expanding the landscape of natural dietary mediated tumor suppression.

Dynamic regulation of eEF1A1 acetylation affects colorectal carcinogenesis.

The dysregulation of the translation elongation factor families which are responsible for reprogramming of mRNA translation has been shown to contribute to tumor progression. Here, we report that the acetylation of eukaryotic Elongation Factor 1 Alpha 1 (eEF1A1/EF1A1) is required for genotoxic stress response and maintaining the malignancy of colorectal cancer (CRC) cells. The evolutionarily conserved site K439 is identified as the key acetylation site. Tissue expression analysis demonstrates that the acetylation level of eEF1A1 K439 is higher than paired normal tissues. Most importantly, hyperacetylation of eEF1A1 at K439 negatively correlates with CRC patient survival. Mechanistically, CBP and SIRT1 are the major acetyltransferase and deacetylase of eEF1A1. Hyperacetylation of eEF1A1 at K439 shows a significant tumor-promoting effect by increasing the capacity of proliferation, migration, and invasion of CRC cells. Our findings identify the altered post-translational modification at the translation machines as a critical factor in stress response and susceptibility to colorectal carcinogenesis.

Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment.

BACKGROUND: The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized. RESULTS: We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival. CONCLUSIONS: Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.

Baicalin suppresses the progression of Type 2 diabetes-induced liver tumor through regulating METTL3/m6A/HKDC1 axis and downstream p-JAK2/STAT1/clevaged Capase3 pathway.

BACKGROUND: Epidemiological and clinical evidence suggests that diabetes increases the risk of liver cancer. Although the co-occurrence of type 2 diabetes (T2D) and liver cancer is becoming more frequent, the underlying mechanisms remain unclear. Even though baicalin, extensively used in traditional Chinese medicine (TCM), can control T2D and inhibit liver cancer separately, minimal research is available regarding its possible effect on T2D-induced liver cancer. Thus, in the present study, we aimed to investigate the role of baicalin in T2D-induced hepatocellular cancer, and for the first time, we particularly emphasized the regulation of baicalin in genes RNA m6A in hepatocellular cancer. METHODS: Here, we constructed a cell culture model under a high concentration of glucose and a T2D-induced liver tumor model to evaluate the in vitro and in vivo role of baicalin in T2D-induced liver cancer progression. After confirming the suppressive effect of baicalin and the HKDC1 antibody on T2D-induced liver tumors, the epigenetic alterations (DNA 5mC and RNA m6A) of the baicalin-regulated HKDC1 gene were detected using MS and q-PCR. Next, the METTL3 gene-regulated m6A (2854 site) was investigated using SELECT PCR. Finally, the impact of the other three baicalin analogs (baicalein, wogonoside, and wogonin) on tumor inhibition was tested in vivo while verifying the related RNA m6A mechanism. RESULTS: The results showed that baicalin and the HKDC1 antibody suppressed T2D-induced liver tumor progression in vitro and in vivo. Furthermore, baicalin significantly inhibited the epigenetic modification (DNA 5mC and RNA m6A) of HKDC1 in HepG2 tumors, mainly targeting the RNA m6A site (2854). The m6A-related gene, METTL3, regulated the RNA m6A site (2854) of HKDC1, which was also restricted by baicalin. Moreover, the study verified that baicalin regulated the METTL3/HKDC1/JAK2/STAT1/caspase-3 pathway in liver cancer cells when exposed to a high glucose concentration. In addition, the three baicalin analogs were proven to regulate the m6A (2854 site) of HKDC1 and suppress T2D-induced liver tumors. CONCLUSIONS: The findings of this study revealed that baicalin suppressed T2D-induced liver tumor progression by regulating the METTL3/m6A/HKDC1 axis, which might support its potential application for preventing and treating T2D-induced liver cancer.

Apatinib plus S-1 for previously treated, advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study.

BACKGROUND: The current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma. METHODS: In this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40-60 mg twice daily on days 1-14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, NCT04338438. RESULTS: Between April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50-4.90) months and 8.2 (95% CI: 4.69-11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc. CONCLUSIONS: The combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status. TRIAL REGISTRATION: NCT04338438.

Deformation Behavior and Microstructural Evolution of T-Shape Upsetting Test in Ultrafine-Grained Pure Copper.

Ultrafine-grained (UFG) materials can effectively solve the problem of size effects and improve the mechanical properties due to its ultra-high strength. This paper is dedicated to analyzing the deformation behavior and microstructural evolution of UFG pure copper based on T-shape upsetting test. Experimental results demonstrate that: the edge radius and V-groove angle have significant effects on the rib height and aspect ratio λ during T-shape upsetting; while the surface roughness has little effect on the forming load in the first stage, but in the second stage the influence becomes significant. The dynamic recrystallization temperature of UFG pure copper is between 200 °C and 250 °C.

SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases.

Protein lysine acetylation affects colorectal cancer (CRC) distant metastasis through multiple pathways. In a previous proteomics screen, we found that isocitrate dehydrogenase 1 (IDH1) is hyperacetylated in CRC primary tumors and liver metastases. Here, we further investigate the function of IDH1 hyperacetylation at lysine 224 in CRC progression. We find that IDH1 K224 deacetylation promotes its enzymatic activity and the production of α-KG, and we identify sirtuin-2 (SIRT2) as a major deacetylase for IDH1. SIRT2 overexpression significantly inhibits CRC cell proliferation, migration, and invasion. IDH1 acetylation is modulated in response to intracellular metabolite concentration and regulates cellular redox hemostasis. Moreover, IDH1 acetylation reversely regulates HIF1α-dependent SRC transcription which in turn controls CRC progression. Physiologically, our data indicate that IDH1 deacetylation represses CRC cell invasion and migration in vitro and in vivo, while the hyperacetylation of IDH1 on K224 is significantly correlated to distant metastasis and poor survival of colorectal cancer patients. In summary, our study uncovers a novel mechanism through which SIRT2-dependent IDH1 deacetylation regulates cellular metabolism and inhibits liver metastasis of colorectal cancer.

Cancer IgG, a potential prognostic marker, promotes colorectal cancer progression.

OBJECTIVE: Currently, no satisfactory targets for colorectal cancer or markers for immunotherapy and diagnosis and prognosis are available. Immunoglobulin G (IgG) is widely expressed in many cancers, and it promotes cancer progression. This study explored the role of cancer-derived IgG (CIgG) in colorectal cancer. METHODS: First, using a monoclonal antibody to CIgG, we examined the expression levels of CIgG in colorectal cancer cell lines by western blot and immunofluorescence analyses and in tissue specimens by immunohistochemistry. Second, the variable region gene was amplified by nested polymerase chain reaction (PCR), and PCR products were sequenced and analyzed. Third, we investigated the effect of CIgG on colorectal cancer cells by cell proliferation, wound healing, migration and invasion assays, and colony formation assay. Fourth, we performed in vivo tumorigenicity experiments to explore the effect of CIgG on tumorigenicity. Finally, we used RNA-seq analysis and co-immunoprecipitation experiments to further clarify possible mechanisms of CIgG. RESULTS: We found that CIgG is widely expressed in colorectal cancer cells, and the overexpression of CIgG indicates significantly poor colorectal cancer prognosis. Furthermore, CIgG knockdown significantly inhibits the proliferation, migration and invasion ability of cells, and tumor growth in vivo. RNA-seq analysis indicated that CIgG knockdown results primarily in changes in expression of apical junction and epithelial-mesenchymal transition-related genes. CIgG may be involved in colorectal cancer invasion and metastasis through interacting with E-cadherin. CONCLUSIONS: CIgG is a potential human oncogene in colorectal cancer and that it has potential for application as a novel target in targeted therapy and a marker for prognostic evaluation.

Acetylation of PHF5A Modulates Stress Responses and Colorectal Carcinogenesis through Alternative Splicing-Mediated Upregulation of KDM3A.

Alternative pre-mRNA-splicing-induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. Here, we uncover a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHF5A, a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses, which is dependent on p300. PHF5A acetylation strengthens the interaction among U2 snRNPs and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation-induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer. Our findings uncover a mechanism of an anti-stress pathway through which acetylation on PHF5A promotes the cancer cells' capacity for stress resistance and consequently contributes to colon carcinogenesis.

Human colorectal cancer cells frequently express IgG and display unique Ig repertoire.

BACKGROUND: There is growing evidence proving that many human carcinomas, including colon cancer, can overexpress immunoglobulin (Ig); the non B cancer cell-derived Ig usually displayed unique V(D)J rearrangement pattern that are distinct from B cell-derived Ig. Especially, the cancer-derived Ig plays important roles in cancer initiation, progression, and metastasis. However, it still remains unclear if the colon cancer-derived Ig can display unique V(D)J pattern and sequencing, which can be used as novel target for colon cancer therapy. AIM: To investigate the Ig repertoire features expressed in human colon cancer cells. METHODS: Seven cancerous tissue samples of colon adenocarcinoma and corresponding noncancerous tissue samples were sorted by fluorescence-activated cell sorting using epithelial cell adhesion molecule as a marker for epithelial cells. Ig repertoire sequencing was used to analyze the expression profiles of all 5 classes of Ig heavy chains (IgH) and the Ig repertoire in colon cancer cells and corresponding normal epithelial cells. RESULTS: We found that all 5 IgH classes can be expressed in both colon cancer cells and normal epithelial cells. Surprisingly, unlike the normal colonic epithelial cells that expressed 5 Ig classes, our results suggested that cancer cells most prominently express IgG. Next, we found that the usage of Ig in cancer cells caused the expression of some unique Ig repertoires compared to normal cells. Some VH segments, such as VH3-7, have been used in cancer cells, and VH3-74 was frequently present in normal epithelial cells. Moreover, compared to the normal cell-derived Ig, most cancer cell-derived Ig showed unique VHDJH patterns. Importantly, even if the same VHDJH pattern was seen in cancer cells and normal cells, cancer cell-derived IgH always displayed distinct hypermutation hot points. CONCLUSION: We found that colon cancer cells could frequently express IgG and unique IgH repertoires, which may be involved in carcinogenesis of colon cancer. The unique IgH repertoire has the potential to be used as a novel target in immune therapy for colon cancer.

Decreased expression of miR­490­3p in colorectal cancer predicts poor prognosis and promotes cell proliferation and invasion by targeting RAB14.

Growing evidence indicates a potential role for miR­490­3p in tumorigenesis. However, its function in colorectal carcinoma (CRC) remains undefined. In this study, miR­490­3p was markedly downregulated in fifty colorectal cancer tissue samples compared with the corresponding adjacent non­cancerous specimens, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of miR­490­3p were closely associated with tumor differentiation and distant metastasis. In addition, both Kaplan-Meier and multivariate analyses indicated CRC patients with elevated miR­490­3p amounts had prolonged overall survival. Overexpression of miR­490­3p markedly reduced proliferation, colony formation and invasion in CRC cells by enhancing apoptosis and promoting G2/M phase arrest. Furthermore, ectopic expression of miR­490­3p resulted in decreased expression of RAB14, which was directly targeted by miR­490­3p, as shown by the dual-luciferase reporter gene assay. Finally, in a nude mouse model, miR­490­3p overexpression significantly suppressed the growth of CRC cells. The above results indicated that miR­490­3p might constitute a prognostic indicator and a novel molecular target for miRNA-based CRC therapy.

[Meta-analysis for high-risk factor of anastomotic leakage after anal-preserving surgery for rectal cancer].

OBJECTIVE: To systematically evaluate the effect of defunctioning stoma, preoperative radiotherapy, and level of inferior mesenteric artery (IMA) ligation on the postoperative anastomotic leakage in rectal cancer by meta-analysis. METHODS: Randomized controlled trials (RCT) published before December 2017 regarding the effects of defunctioning stoma, preoperative radiotherapy, and level of inferior mesenteric artery ligation on the postoperative anastomotic leakage in rectal cancer were searched from PubMed, Embase, Scopus, Cochrane Library, CNKI, Wanfang database, meanwhile open data in unpublished trials from clinicaltrials.gov were retrieved. Associated data were screened according to standard and their quality was evaluated strictly. Review manager 5.3 software was used to perform meta-analysis with data. Random effect model based on DerSimonian and Laird method was applied. Heterogenicity among trials was estimated with Chi-square test. RESULTS: Twenty articles were included in the meta-analysis. The overall incidence of anastomotic leakage was 7.0%(488/7004). The incidence of anastomotic leakage in the defunctioning stoma group and non-defunctioning stoma group was 5.2%(24/459) and 17.3%(77/445) respectively. The incidence of anastomotic leakage in the radiotherapy group and non-radiotherapy group was 6.5%(188/2900) and 6.1%(179/2946) respectively. The incidences of anastomotic leakage in the low and high IMA ligation groups was 4.7%(6/129) and 11.2%(14/125) respectively. Meta-analysis showed that the incidence in defunctioning stoma group was significantly lower than that in non-defunctioning stoma group (RR:0.33, 95%CI:0.21-0.50, P<0.00001); the incidences between radiotherapy group and non-radiotherapy (RR:1.05, 95%CI: 0.80-1.38, P=0.72), and between low IMA ligation group and high IMA ligation group (RR:0.50, 95%CI:0.20-1.23, P=0.13) were not significantly different. Funnel figure drawn with RCTs about defunctioning stoma and preoperative radiotherapy revealed no significant publication bias existed within included studies. CONCLUSION: Defunctioning stoma can effectively prevent the occurrence of postoperative anastomotic leakage, whereas the preoperative radiotherapy and high IMA ligation may not increase the risk of anastomotic leakage.

MicroRNA­4284 promotes gastric cancer tumorigenicity by targeting ten-eleven translocation 1.

Increasing evidence has shown that abnormal expression of miR-4284 participates in the progression of several types of cancer. However, the expression and the role of miR­4284 in gastric cancer remain largely unknown. Therefore, in the present study the miR­4284 expression levels in gastric cancer tissues and cell lines, was examined using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and found that miR­4284 was significantly upregulated in 40 pairs of gastric cancer tissues and five gastric cancer cell lines compared to the corresponding normal tissues and GES­1 cell line. In addition, increased miR­4284 expression was positively associated with TNM stage (P=0.035), distal metastasis (P=0.022) and poor prognosis in gastric cancer patients. Furthermore, the overexpression of miR­4284 expression was shown to promote cell proliferation, clone formation, invasion and migration, while the suppression of miR­4284 expression induced opposite effects. Additionally, luciferase reporter assay was conducted and showed that ten-eleven translocation 1 (TET1), a tumor suppressor gene that regulating cell survival and metastasis, was a direct target of miR­4284. Upregulated miR­4284 decreased the mRNA and protein levels of TET1 in SGC­7901 cells and downregulated miR­4284 increased the mRNA and protein levels of TET1 in AGS cells. In addition, miR­4284 expression was negatively correlated with the TET1 expression in gastric cancer tissues. Moreover, inhibition of TET1 suppressed the effect of miR­4284 inhibitors on cell proliferation in AGS cells. Therefore, data demonstrated that miR­4284 could promote tumor cell growth, migration and invasion by directly targeting TET1 in gastric cancer, which may provide a potential therapeutic target for gastric cancer treatment.

Pathological outcomes of transanal versus laparoscopic total mesorectal excision for rectal cancer: a systematic review with meta-analysis.

BACKGROUND: Since 2010, comparative studies on transanal and laparoscopic total mesorectal excision (TME) have been published and it remains unclear about the oncological benefit from transanal total mesorectal excision (taTME). METHODS: We have searched English databases to identify all taTME studies published between January 2010 and August 2017. Pathological outcomes included circumferential resection margin (CRM), positive CRM (< 1 M), length of distal resection margin (DRM), positive DRM, quality of mesorectum (complete mesorectum), harvested lymph node, and length of the specimen. Odds ratios (ORs) were calculated for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes. RESULTS: We have included ten studies comprising of 762 patients. Compared with laparoscopic TME, taTME had a longer CRM (WMD, 0.833; 95% CI 0.366-1.299; P < 0.001), a lower positive rate of CRM (OR, 0.505; 95% CI 0.258-0.991; P = 0.047), and a longer DRM (WMD, 6.261; 95% CI 1.049-11.472; P = 0.019). There were no significant differences in other pathological outcomes. Both cumulative meta-analysis and sensitivity analysis were unable to detect potential sources of the heterogeneity in DRM. There was no evidence of publication bias. CONCLUSIONS: This meta-analysis revealed that taTME had more advantages on positive CRM, CRM, and DRM compared with laparoscopic TME. Compared with laparoscopic TME, more benefits of taTME on pathological outcomes remained undetected. The current findings are all based on observational studies, RCTs with adequate power are required.

Long non-coding RNA GPR65-1 is up-regulated in gastric cancer and promotes tumor growth through the PTEN-AKT-slug signaling pathway.

Increasing evidence has shown that abnormal expression of lncRNAs is involved in various biological behaviors and major cellular pathways of human cancers. However, the role of lncRNAs in the progression of gastric cancer has not been adequately investigated. Therefore, in this study, we investigated the expression levels of linc-GPR65-1 using Quantitative real-time PCR (qRT-PCR) and found that linc-GPR65-1 was significantly up-regulated in 50 gastric cancer tissues compared to the corresponding normal tissues. In addition, increased linc-GPR65-1 expression was associated with TNM stage (P = 0.037), tumor size (P = 0.024), distal metastasis (P = 0.023), and poor prognosis of gastric cancer patients. Moreover, functional assays indicated that decreased linc-GPR65-1 expression inhibited the aggressive phenotypes of gastric cancer cells, and enhanced linc-GPR65-1 expression resulted in the opposite phenomenon. Then, a cancer signaling phosphoantibody microarray was conducted to explore the potential mechanisms of linc-GPR65-1 in regulating gastric cancer progression and observed that linc-GPR65-1 could regulate the PTEN-AKT-slug signaling pathway. These data showed that linc-GPR65-1, regulating the PTEN-AKT-slug signaling pathway, might act as a tumor promoter and serve as a novel target for gastric cancer prevention and therapy.

Ultrasonic versus electrosurgical device for laparoscopic cholecystectomy: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Ultrasonic and electrosurgical energy dissectors are main dissecting devices widely used for the laparoscopic cholecystectomy. Trial sequential analyses can establish whether firm evidence favoring a specific device has been reached from accumulated literature. To explore this, we performed a meta-analysis and trial sequential analyses. METHODS: PubMed, Embase, and the Cochrane Library were searched from inception to October 2016. The primary outcome was operative time. The secondary outcomes included adverse events during operation, postoperative complications, intra-abdominal collection, hospital stay, hospital costs, and sick leave or time to full recovery. Relative risks (RRs) were calculated for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Finally, we calculated numbers needed to treat to examine benefits of the ultrasonic device. RESULTS: We identified 19 studies. Compared with the electrosurgical device, the ultrasonic device led to shorter operative time (MD, -14.86; 95% confidence interval (CI), -21.45 to -8.27; P < 0.00001), less blood loss (MD, -47.24; 95% CI, -79.57 to -14.90; P = 0.004), fewer gallbladder perforations (RR, 0.45; 95% CI, 0.35 to 0.57; P < 0.00001), shorter hospital stay (MD, -0.37; 95% CI, -0.61 to -0.14; P = 0.002), and fewer abdominal pains (MD, -0.95; 95% CI, -1.40 to -0.50; P < 0.0001). The trial sequential analysis demonstrated that the cumulative z-curve crossed the trial sequential monitoring and reached the required information size of the operative time. The numbers needed to treat to avoid one gallbladder perforation and postoperative nausea, respectively, were 7 and 15. CONCLUSIONS: Compared with the electrosurgery device, the ultrasonic device could be superior with more clinical effectiveness. The trial sequential analysis demonstrated that further studies about the operative time were not needed.

Marginal vitamin A deficiency facilitates Alzheimer's pathogenesis.

Deposition of amyloid ß protein (Aß) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer's disease (AD). Aß is derived from amyloid ß precursor protein (APP) by ß- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aß production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.

Meta-analysis of hand-sewn versus mechanical gastrojejunal anastomosis during laparoscopic Roux-en-Y gastric bypass for morbid obesity.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most performed bariatric procedures in treating morbid obesity. There is no consensus on which technique used for gastrojejunal anastomosis is optimal. The meta-analysis aimed to solve the issue by comparing hand-sewn with mechanical gastrojejunostomy during LRYGB for morbid obesity. METHODS: PubMed, Embase, Cochrane Library, Scopus, Google Scholar and Research Gate were searched (from inception to April 2016). Primary outcome was operation time. Secondary outcomes were postoperative complications (anastomotic leak, stricture, bleeding, marginal ulcer and wound infection), percent excess weight loss during one-year follow-up, reoperation, and postoperative hospital stay. Odds ratios (OR) were calculated for dichotomous outcomes and mean differences (MD) for continuous outcomes. RESULTS: Twelve trials were included comprising 13,626 patients (3309 hand-sewn vs. 6791 circular vs. 3526 linear). There was no difference in operation time when hand-sewn anastomosis was compared with mechanical gastrojejunostomy (MD, -6.00; 95% confidence interval (CI), -34.85 to 22.85; P = 0.68), circular stapled anastomosis (MD, -5.24; 95% CI, -32.71 to 22.24; P = 0.71) or linear stapled anastomosis (MD, - 3.75; 95% CI, -64.81 to 57.31; P = 0.90). Hand-sewn anastomosis had significantly lower incidence rate of postoperative bleeding (OR, 0.48; 95% CI, 0.31-0.74; P = 0.001) and wound infection (OR, 0.19; 95% CI, 0.08-0.45; P = 0.0002) than circular stapled anastomosis; there were no significant differences in the other secondary outcome. And there were no significant differences in all the comparable outcomes between hand-sewn anastomosis and linear stapled anastomosis. CONCLUSIONS: This meta-analysis revealed no significant differences between mechanical and hand-sewn anastomosis except for greater incidence rates of postoperative bleeding and wound infection with the use of circular staplers. Besides, more trials with adequate power are required and a cost analysis also worth trying. REGISTRATION NO. IN PROSPERO: CRD42015020025.