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MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115−/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115−/− cells compared to the wild-type counterparts. Consequently, the Rnf115−/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling., MAVS and MITA are adapter proteins that play distinct roles in the context of the host response to RNA and DNA viruses, respectively. Here the authors implicate RNF115 in dual temporal and spatial mechanisms of interacting and catalyzing distinct ubiquitination of MAVS and MITA to modulate RNA and DNA antiviral immune responses.

STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity., The cGAS-STING pathway is a DNA sensing mechanism that enables response to viral infection by inducing type 1 interferon expression. Here the authors show a mechanism by which the deubiquitinating enzyme USP13 prevents STING from enabling response to virus.

The purpose of this study was to investigate the efficacy and mechanism of oxaliplatin in combination with capecitabine (XELOX) regimen as neoadjuvant chemotherapy in the treatment of patients with advanced gastric cancer.Eighty-five patients with advanced gastric cancer (stage IIB and IIIC) were randomly divided into two groups: neoadjuvant chemotherapy group (40 cases) and surgery alone group (45 cases). In the neoadjuvant chemotherapy group, patients received oral administration of Xeloda 1000 mg/m(2) twice a day on days 1-14 and intravenous infusion of oxaliplatin 130 mg/m(2) on day 1 (XELOX regimen). The regimen was repeated every 21 days. In the surgery alone group, patients directly received radical resection of gastric cancer. The R0 resection rate, overall survival and disease free survival (DFS) were observed in all cases. The cycles and apoptosis rate of the gastric cancer cells were detected by flow cytometry. The expression of proliferating cell nuclear antigen (PCNA), p21, p53 and survivin was detected by Western blot.In the neoadjuvant chemotherapy group, the total effective rate was 32.5% (13/40), and the tumor control rate was 90% (36/40), with few side effects. Compared with the surgery alone group, R0 resection rate was significantly higher in the neoadjuvant chemotherapy group (P0.05). The survival analysis indicated that both the overall survival and DFS were longer in the neoadjuvant chemotherapy group in comparison with those in the surgery alone group, but no significant differences were found (P0.05). In the neoadjuvant chemotherapy group, both the apoptosis rate and the ratio of cells in stage G0 and G1 were significantly higher than those in the surgery alone group (P0.05). The expression of PCNA and survivin was lower in the neoadjuvant chemotherapy group, while the expression of p21 and p53 was higher.XELOX regimen as neoadjuvant chemotherapy in the treatment of patients with advanced gastric cancer can effectively improve the R0 resection rate and prolong the survival time of the patients. Its mechanism is probably that the neoadjuvant chemotherapy can markedly enhance apoptosis in gastric cancer cells and inhibit their proliferation.

Different differentiations of cancer have resulted in its unique biological characteristics. We screen and appraise differentially expressed proteins in different differentiated gastric adenocarcinoma with comparative proteomics technology in order to find regulatory factors of tumor differentiation related and finally reach the purpose of tumor differentiation reversal.With two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) and liquid chromatography in conjunction with tandem mass spectrometry (LC–MS/MS), the differentially expressed proteins from 8 patients with different differentiated gastric adenocarcinoma were identified and some factors identified were verified with application of QPCR and Western blot techniques.Significant differences in 35 protein spots were found and 48 kinds of proteins were identified. Other than structural proteins and non-specific protein, six possible proteins associated with tumor differentiation were determined - the serine protease inhibitor B1 (serine protease inhibitor, clade B, member 1, SERPINB1), calcium-phospholipid binding protein III (annexin A3), transcription factor Nm23-H1, adenine phosphoribosyl-transferase enzyme APRT (Adenine Phosphoribosyltransferase in APO and AMP), glutathione S-transferase P1-1 (GST-π-1), antimicrobial peptides Dermcidin-lL. The identified SERPINB1, annexin A3, Nm23-H1 and APRT were verified, confirming the expression of these factors was in line with proteomics identification.Protein expression in different differentiated gastric adenocarcinoma was varied.

We report on a case of a 65-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with capecitabine and oxaliplatin (XELOX) regimen. He underwent esophagogastroduodenoscopy, which revealed a 6x5cm gastric ulcer. Biopsy of gastric ulcer revealed adenocarcinoma. Further workups with abdominal enhancement computed tomography (CT) staged his cancer as T4N2M0. He received 2 cycles of neoadjuvant chemotherapy with XELOX without severe toxicity. Afterwards, he underwent curative surgery consisting of total gastrectomy with extended D2 lymph node dissections and a Roux-en-Y esophagojejunostomy. On microscopic examination, no tumor cells were detected in the ulcer scar of the resected stomach and in the regional lymph nodes. The benefit of XELOX regimen as neoadjuvant chemotherapy in gastric cancer is worth further investigation.

The purpose of comprehensive treatment for early gastric cancer (EGC) is curing tumor, prevention of recurrence or metastasis. The aim of the present study was to analyze the clinical pathological characteristics of EGC, and to find out factors which influence lymph node metastasis.Records of 417 patients with EGC who underwent surgery from January 1996 to December 2006 were collected. The information including general characteristics, tumor relevant factors, surgical complications, clinical manifestations and pathological features, were evaluated.EGC accounted for 6.03% of total gastric cancer (GC) cases. In EGC subjects, mucosal cancer and sub-mucosal cancer accounted for 55.2% and 44.8%, respectively; 11.5% (48/417) of patients were found with positive lymph nodes metastasis, the incidence of lymph node metastasis was 5.64% (168/2979); 6 cases were found with liver metastasis; 96.64% of patients undertook radical surgical treatment; 5 cases with positive upper incisal margin (1.2%). Logistic regression analysis showed that multiple original tumors, lesions of over 2cm, tumor invasion to the submucosa, poor differentiation, and vascular tumor thrombus, were independent risk factors for lymph node metastasis in EGC.The risk factors of lymph node metastasis should be noticed and evaluated in EGC treatment.

To evaluate the synergistic effects of tetrandrine (TET) on the antifungal activity of topical ketoconazole (KCZ) in the treatment of dermatophytoses.The minimum inhibitory concentrations (MICs) for KCZ and combined KCZ and TET were compared in vitro. A randomized, double-blind trial was conducted among 97 patients with dermatophytoses who were assigned to 3 groups and received: treatment with combination of 2% KZC and 2% TET cream (KCZ + TET group), or only 2% KZC cream (KCZ group), or 2% TET cream (TET group). Patients with tinea corporis and/or tinea cruris were treated for 2 weeks, separately. The patients with tinea pedis and/or tinea manuum were treated for 4 weeks.Compared with KZC alone, combined use of KZC and TET showed lower MICs against clinical isolates of dermatophytes (P0.05 for all). In the patients with tinea corporis and/or tinea cruris, the rates of overall cure (clinical cure plus mycologic clearance) were 81.25% vs. 33.33% for combined treatment and KZC monotherapy, respectively, after 4 weeks. All clinical indices were significantly different between the combination therapy and only KCZ therapy groups (P0.05). Among the patients with tinea pedis and/or tinea manuum after 4 weeks treatment, the overall cure rates in the KCZ + TET group and KCZ group were 75.00% vs. 40.00%, respectively. In the KCZ + TET group, all the clinical indices were significantly better than those in the KCZ group and TET group (P0.05). The rates of overall efficacy in the TET group were all zero. No local skin redness or itching was observed during TET treatment. No clinically significant changes were found in post-treatment routine blood, urine, or stool tests, ECG, or tests for liver and kidney function; no serious adverse events occurred.TET synergistically enhanced the clinical efficacy of topical KZC cream in the treatment of dermatophytoses.

To study the effects of local application of allicin via gastroscopy on progressive gastric carcinoma, and to investigate its possible mechanisms.Eighty patients with progressive gastric adenocarcinoma, whose diagnosis was confirmed by gastroscopy and pathological examination, were assigned to 2 groups, 40 in each group. Forty-eight hours before operation, allicin was infused via gastroscopy to the lesion region of patients in the allicin group, and normal saline was infused instead to those in the control group. The gastric carcinoma tissue gotten from gastrectomy was taken to determine the percentage of cells in various cell cycle phases ( G0/ G1, S and G2/M), the cell apoptosis rate, proliferation index value and apoptosis related gene protein such as Fas, Bax and Bcl-2 by flow cytometry.In the allicin group, the cell apoptosis rate was 9.60 +/- 1.52%, the percentage of cell in G0/G1 phase was 72.12 +/- 8.35%, in G2/M phase 9.54 +/- 3.20%, and PI 27.80 +/- 8.35, while in the control group, the corresponding data was 2.20 +/- 0.58%, 69.56 +/- 5.15%, 13.20 +/- 3.05%, and 30.40 +/- 5.15, respectively, and significant difference in all the 4 indexes could be found between the two groups (P0.05, P0.01). Moreover, allicin showed effects in up-regulating the protein expressions of apoptosis promoting gene Bax and apoptosis initiating gene Fas (P0.05, P0.01), and down-regulating that of anti-apoptosis gene Bcl-2 (P0.05).Local application of allicin via gastroscopy can inhibit the cell growth and proliferation of progressive gastric carcinoma, and can also promote gastric carcinoma cell apoptosis.

To examine the distribution of fluorouracil in gastric cancer (CA), lymph node (LN), normal gastric mucosa (NG), peritoneum (PE), greater omentum (GO) and lesser omentum (LO) by preoperative intraperitoneal chemotherapy with Co-fluorouracil liposome (Co 5-Fu), and offer an experimental basis for clinic practice.Ninety-six gastric cancer patients were divided into four groups: Co 5-Fu i.v. injection group (Co 5-Fu i.v.), Co 5-Fu intraperitoneal perfusion group (Co 5-Fu i.p.), 5-Fu i.v. injection group (5-Fu i.v.) and intraperitoneal perfusion group (5-Fu i.p.) given on day-2, day-1 and 60 minutes before operation. Fluorouracil concentration in all tissues collected during operation were examined by high performance liquid chromatography (HPLC).The fluorouracil concentration in the tissues in Co 5-Fu i.p. group was significantly higher than that in Co 5-Fu i.v. or 5-Fu i.p. group (P0.05 or P0.01), and that in 5-Fu i.p. group was greatly higher than that at 5-Fu i.v. group (P0.01). In Co 5-Fu i.p. group, the concentration of drug in LN, CA, PE, NG, GO and LO decreased gradually with the former 3 tissues significantly higher than the latter 3 tissues (P0.01), and adjacent lymph node was the highest. In Co 5-Fu i.v. group, the ranking was LN, CA, NG, PE, GO and LO with the former 3 tissues significantly higher than the latter 3 tissues (P0.01) and showing tumor tissues higher than the other tissues (P0.01). In 5-Fu i.p. group, the ranking was PE, LN, CA, NG, GO and LO with the former 2 tissues significantly higher than the latter tissues (P0.01).Co 5-Fu possesses drug targeting, slow release and long effect in gastric cancer tissues and adjacent lymph nodes. Preoperative chemotherapy with Co 5-Fu i.p. is more advantageous than 5-Fu given i.v. or 5-Fu i.p.

The invasion depth and lymph node metastasis result from the polygenes and their protein expression in gastric carcinoma. The key of the basic and clinical research of the gastric carcinoma is to find out the related molecular biology marker. This study was designed to investigate the relationship between the expression of MUC1, CD44v6, nm23 in gastric carcinomas and regional lymph node tissues and invasion, metastasis, and prognosis of the tumor.The expression of MUC1, CD44v6, and nm23 in 110 advanced gastric carcinomas and 613 regional lymph node specimens were examined by immunohistochemical technique. The results was judged by the criterion of the positive or the negative expression.(1) The expression of MUC1 (84.6%, 88.1%, 87.3%, 91.7%, 94.4%, and 95.5%, respectively) and CD44v6 (79.5%, 74.6%, 79.4%, 81.7%, 87.0%, and 87.9%, respectively) in gastric carcinoma tissues in the groups of low differentiated adenocarcinoma, infiltrated type, T3+T4, lymph node metastasis, stage III-IV, and survival5 years were significantly higher than those in the groups of high-middle differentiated adenocarcinoma, limited type, T1+T2, no lymph node metastasis, stage I-II, and survivalor= 5 years (P0.01 or P0.05); while the expression of nm23 was contrary (P0.01 or P0.05) except for the groups of differentiation and Borrmann type. (2) The expression of MUC1 and CD44v6 in the lymph node metastasis group of the gastric carcinoma (94.7% and 89.4%, respectively)were remarkably higher than those in the no lymph node metastasis group (19.6% and 19.6%, respectively) (P0.01); while the expression of nm23 was contrary (16.8% versus 74.9%, P0.01). (3) The 5-year survival rates of the patients in MUC1 and CD44v6 positive expression group (13.0% and 15.4%, respectively) in the regional lymph nodes of gastric carcinoma were significantly lower than those in the negative expression group (100% and 62.1%) (P0.01); while the 5-year survival rate of the patients in nm23 positive expression group was contrary (70.0% versus 4.0%, P0.01).The high expression of MUC1, CD44v6 and low expression of nm23 were related to the invasion, metastasis, and prognosis of the gastric carcinoma. The detection of MUC1, CD44v6, and nm23 can be useful for the diagnosis and treatment of advanced gastric carcinoma.