Chinese Medicine Prolongs Overall Survival of Chinese Patients with Advanced Gastric Cancer: Treatment Pattern and Survival Analysis of a 20-Year Real-World Study.

OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).

LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop.

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Multivariate prognostic index and triplet regimen efficacy predictive index in locally advanced and metastatic gastric cancer: pooled analysis from three clinical trials using individual patient data.

Background: To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Objectives: Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. Designs: We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Methods: Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Results: Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). Conclusion: The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

A prognostic index in locally advanced and metastatic gastric cancer To date, no recognized systematic prognostic score has been established for advanced gastric cancer (AGC). Our research aims to construct an effective prognostic index to predict overall survival (OS) for AGC patients to aid clinical decision-making and individual risk stratification. In our research, seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic index named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in low-risk group (median OS, 15.5 months vs. 8.0 months, P < 0.001). Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (P = 0.018).

Unraveling the macroevolution of horseshoe bats (Chiroptera: Rhinolophidae: Rhinolophus).

Unraveling the diversification mechanisms of organisms is a fundamental and important macroevolutionary question regarding the diversity, ecological niche, and morphological divergence of life. However, many studies have only explored diversification mechanisms via isolated factors. Here, based on comparative phylogenetic analysis, we performed a macroevolutionary examination of horseshoe bats (Chiroptera: Rhinolophidae: Rhinolophus), to reveal the inter-relationships among diversification, intrinsic/extrinsic factors, and climatic ecological niche characteristics. Results showed a general slowing trajectory during diversification, with two dispersal events from Asia into Southeast Asia and Africa playing key roles in shaping regional heterogeneous diversity. Morphospace expansions of the investigated traits (e.g., body size, echolocation, and climate niche) revealed a decoupled pattern between diversification trajectory and trait divergence, suggesting that other factors (e.g., biotic interactions) potentially played a key role in recent diversification. Based on ancestral traits and pathway analyses, most Rhinolophus lineages belonging to the same region overlapped with each other geographically and were positively associated with the diversification rate, implying a competitive prelude to speciation. Overall, our study showed that multiple approaches need to be integrated to address diversification history. Rather than a single factor, the joint effects of multiple factors (biogeography, environmental drivers, and competition) are responsible for the current diversity patterns in horseshoe bats, and a corresponding multifaceted strategy is recommended to study these patterns in the future.

Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer.

This research found that the clinical outcomes (PFS, ORR, OS) of the non-platinum-based doublet regimen (docetaxel capecitabine combination) were similar to those of the platinum-based (oxaliplatin capecitabine combination) when used as first line therapy for MGC patients. Background: Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes of the docetaxel capecitabine combination and the oxaliplatin capecitabine combination as first-line therapy in MGC patients. Methods: In this phase II trial, MGC patients were randomly assigned and treated with either TX (capecitabine 1000 mg/m2/twice daily/1-14 days and docetaxel 60/75 mg/m2 on the 1st day) (because of toxicity, the dose of docetaxel was reduced to 60 mg/m2) or XELOX (capecitabine the same dose with TX and oxaliplatin 130 mg/m2 on the 1st day) as first-line therapy. After progression, patients were crossover to the other group as second-line treatment. Results: Total 134 MGC patients were randomized (69 in TX, 65 in XELOX). There was no significant difference between the PFS of the two groups (TX vs XELOX, 4.6 months vs 5.1 months, p=0.359), and the SFS (9.3 months vs 7.5 months, p=0.705), OS (13.1 months vs 9.6 months, p=0.261), and ORR (46.4% vs 46.2%) were also similar. Among patients with ascites, the TX group had significantly longer PFS and OS than the XELOX group. A total of 85 patients (48 in TX, 37 in XELOX) received second-line treatment, with overall survival of second-line chemotherapy (OS2) of 8.0 m and 5.3 m (p=0.046), respectively. Grade 3 to 4 treatment-related adverse events of first line treatment occurred more in TX group than that in XELOX group(60.6% vs 55.4%). Conclusion: TX regimen is an alternative choice of first-line treatment for MGC patients. We still need to explore the large number of cohort to confirm this results.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma.

Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.

Three-Tier Prognostic Index in Young Adults With Advanced Gastric Cancer.

PURPOSE: To characterize clinical features and identify baseline prognostic factors for survival in young adults with advanced gastric cancer (YAAGC). MATERIALS AND METHODS: A total of 220 young inpatients (age less than or equal to 40 years) with an initial diagnosis of advanced gastric cancer were retrospectively enrolled in this study. RESULTS: Of a consecutive cohort of 220 patients with YAAGC, the median overall survival (OS) time was 16.3 months. One-year survival rate was 43.6% (95% CI: 36.5 to 50.7). In this cohort, a female (71.4%, n = 157) predominance and a number of patients with poorly differentiated tumors (95.9%, n = 211) were observed. In the univariate analysis, OS was significantly associated with neutrophil-lymphocyte ratio (NLR) (≥3.12), hypoproteinemia (<40 g/L), presence of peritoneal or bone metastases, and previous gastrectomy of primary tumor or radical gastrectomy. In multivariate Cox regression analysis, hypoproteinemia [hazard ratio (HR) 1.522, 95% CI 1.085 to 2.137, p = 0.015] and high NLR level (HR 1.446, 95% CI 1.022 to 2.047, p = 0.021) were two independent poor prognostic factors, while previous radical gastrectomy was associated with a favorable OS (HR 0.345, 95% CI 0.205 to 0.583, p = 0.000). A three-tier prognostic index was constructed dividing patients into good-, intermediate-, or poor-risk groups. Median OS for good-, intermediate-, and poor-risk groups was 36.43, 17.87, and 11.27 months, respectively. CONCLUSIONS: Three prognostic factors were identified, and a three-tier prognostic index was devised. The reported prognostic index may aid clinical decision-making, patient risk stratification, and planning of future clinical studies on YAAGC.

OnclncRNA-626 promotes malignancy of gastric cancer via inactivated the p53 pathway through interacting with SRSF1.

Gastric cancer (GC) is a serious health problem worldwide. The potential involvement of long noncoding RNAs in GC progression remains largely unexplored. Here, we identified a novel long noncoding RNA referred to as onclncRNA-626 (oncogenic lncRNA RP11-626H12.3), which was highly upregulated in GC tissues. The high expression levels of onclncRNA-626 in GC patients predicted poor prognoses. Functional assays indicated that onclncRNA-626 could promote the proliferation and metastasis of GC cells in vitro and in vivo. In exploring the molecular mechanisms guiding these functions, we found that onclncRNA-626 specifically interacted with serine- and arginine-rich splicing factor 1 (SRSF1) and increased its stability. SRSF1 was upregulated in GC tissues and correlated with onclncRNA-626 expression and patient survival. Furthermore, RNA-seq data revealed that onclncRNA-626 affected multiple signaling pathways, including the p53 signaling pathway. Rescue experiments showed that onclncRNA-626 probably performed its biological function through SRSF1 mediation of the p53 pathway. Together, our findings demonstrate that onclncRNA-626 promotes GC progression by binding SRSF1; further, this lncRNA is a potential prognostic biomarker for GC patients.

A revision of Kerivoula hardwickii and occurrence of K. furva (Chiroptera: Vespertilionidae) in China.

Although increased survey efforts using improved capture methods (particularly harp traps) have greatly expanded the quantity of Kerivoula specimens available in China, the understanding of the genus has been long constrained. After the recently published revision of the hardwickii-complex with the description of K. furva and re-evaluation of occurrence of K. titania in Taiwan, the critical overview of the previous data of Chinese Kerivoula (with the exception of K. picta, a strikingly colored and unmistakable species) is imperative. To clarify the taxonomy and distribution of the hardwickii-complex in China, 40 additional specimens collected from South China were studied through detailed morphological comparisons, multivariate statistical methods and phylogenetic inference. Our results evidently classified these specimens as K. furva instead of K. titania or K. hardwickii sensu stricto and together with the critical review of literature data indicate that all previous Chinese records of the two latter species were based on either misidentifications or outdated taxonomy. K. furva have so far been recorded in the Chinese provinces of Chongqing, Fujian, Guangdong, Guangxi, Hainan, Hunan, Jiangxi, Yunnan and Taiwan, but more field surveys are needed to confirm whether it could be found in other nearby provinces.

MiR-616-3p promotes angiogenesis and EMT in gastric cancer via the PTEN/AKT/mTOR pathway.

Dysregulation of microRNAs has been demonstrated to be involved in a variety of biological events related to cancer, including proliferation, metastasis, angiogenesis and immune escape. MiR-616-3p is located on the chromosome region 12q13.3, however, its potential role and clinical implications in gastric cancer remain poorly understood. The current study aimed to investigate the potential role of miR-616-3p in gastric cancer. The results showed that miR-616-3p was up-regulated in cancer tissues. Higher expression of miR-616-3p in tumor tissues also predicted poor prognosis. Furthermore, loss- and gain-of-function in vitro revealed that miR-616-3p promoted angiogenesis and EMT in gastric cancer cells. Mechanistically, further analysis demonstrated that the effects of miR-616-3p on metastasis and angiogenesis occurred through the down-regulation of PTEN, a direct target of miR-616-3p. We propose that the restoration of PTEN expression may block miR-616-3p-induced EMT and angiogenesis. Collectively, our findings suggest that the miR-616-3p-PTEN signaling axis might be a potential therapeutic target for gastric cancer.

CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-κB-miR-21 pathways.

BACKGROUND: Chromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs' constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms. METHODS: Firstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell-like properties of gastric cancer were explored. RESULTS: We found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-κB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics. CONCLUSIONS: CBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF-κB-miR-21 pathway.

Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer.

Mel-18, a polycomb group protein, has been reported to act as a tumor suppressor and be down-regulated in several human cancers including gastric cancer. It was also found that Mel-18 negatively regulates self-renewal of hematopoietic stem cells and breast cancer stem cells (CSCs). This study aimed to clarify its role in gastric CSCs and explore the mechanisms. We found that low-expression of Mel-18 was correlated with poor prognosis and negatively correlated with overexpression of stem cell markers Oct4, Sox2, and Gli1 in 101 gastric cancer tissues. Mel-18 was down-regulated in cultured spheroid cells, which possess CSCs, and overexpression of Mel-18 inhibits cells sphere-forming ability and tumor growth in vivo. Besides, Mel-18 was lower-expressed in ovary metastatic lesions compared with that in primary lesions of gastric cancer, and Mel-18 overexpression inhibited the migration ability of gastric cancer cells. Interestingly, overexpression of Mel-18 resulted in down-regulation of miR-21 in gastric cancer cells and the expression of Mel-18 was negatively correlated with the expression of miR-21 in gastric cancer tissues. Furthermore, miR-21 overexpression partially restored sphere-forming ability, migration potential and chemo-resistance in Mel-18 overexpressing gastric cancer cells. These results suggests Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer cells.

Genetic variant of miR-146a rs2910164 C>G and gastric cancer susceptibility.

The single nucleotide polymorphism (SNP) rs2910164 G>C within miR-146a has been reported that is associated with the increased risk of gastric cancer (GCa). However, the results are inconclusive, espicially among Asian populations, which probably due to small sample size in each single study. To validate this association and get a more precise estimation, we conducted a large GCa study including 1,125 cases and 1,196 controls in an eastern Chinese population. Our results showed that this SNP was not associated with GCa risk in either of the three genetic models [co-dominant model: CG vs. CC, odds ratio (OR) = 0.99, 95% confidence interval (95%CI): 0.83-1.19; GG vs. CC, OR = 1.03, 95%CI: 0.81-1.32; dominant model: (CG+GG) vs. CC, OR = 1.00, 95%CI = 0.84-1.19; recessive model: GG vs. (CG+CC), OR = 1.04, 95%CI = 0.83-1.29]. Stratified analysis by age, gender, smoking status, drinking status, or tumor location confirmed this non-significant association. In summary, these results suggest that the miR-146a SNP rs2910164 may not be a risk factor for GCa in this Chinese population. Larger and well-designed, preferably prospective studies are needed to further confirm our findings.

PSCA polymorphisms and gastric cancer susceptibility in an eastern Chinese population.

The prostate stem cell antigen (PSCA) gene, which encodes a prostate-specific antigen (PSA), was identified as a gene involved in cell adhesion and proliferation. The associations between the PSCA rs2294008 and rs2976392 single nucleotide polymorphisms (SNPs) and gastric cancer (GCa) susceptibility were still controversial. To derive a more precise estimation of the associations, we conducted a case-control study of 1,124 cases and 1,192 controls in an eastern Chinese population. We found that the rs2294008T variant genotypes were associated with an increased GCa risk in this study population (CT vs CC, OR=1.59, 95% CI=1.33-1.89 and CT+TT vs CC, OR=1.38, 95% CI=1.17-1.62). For SNP rs2976392, the variant A genotypes were also associated with an increased GCa risk (AG vs GG, OR=1.61, 95% CI=1.35-1.91 and AG+AA vs GG, OR=1.47, 95% CI=1.25-1.74). The results were further validated by a meta-analysis. In conclusion, the results indicated that the PSCA rs2294008 T and rs2976392 A alleles were low-penetrate risk factors for GCa in this study population. However, large and well-designed studies are warranted to validate our findings.

Genetic variant rs4072037 of MUC1 and gastric cancer risk in an Eastern Chinese population.

Published data on the association between the MUC1 rs4072037A > G polymorphism and gastric cancer (GCa) risk were inconclusive. To derive a more precise estimation of the association, we conducted a large GCa study of 1,124 cases and 1,192 controls to confirm this association in an Eastern Chinese population. Our results showed that the G allele was strongly associated with a decreased GCa risk in the study population [GG vs. AA, odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.31-0.73; AG/GG vs. AA, OR = 0.82, 95% CI = 0.68-0.99; GG vs. AA/AG, OR = 0.48, 95% CI = 0.32-0.74]. These associations remained significant in subgroups of age, tumor site, drinking and smoking status. Moreover, this association was supported by an additional meta-analysis of published studies. In summary, these results suggest that the MUC1 rs4072037G allele may be a low-penetrating protection factor for GCa risk in Chinese populations.

Genetic variant of PRKAA1 and gastric cancer risk in an eastern Chinese population.

Published data on the association between PRKAA1 rs13361707 T > C polymorphism and gastric cancer (GCa) susceptibility were inconclusive. To derive a more precise estimation of the association, we conducted a large-scale GCa study of 1,124 cases and 1,194 controls to confirm this association in an eastern Chinese population. Our results showed that the C allele of PRKAA1 rs13361707 increased the GC risk in the study population [CT vs. TT, odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.40-2.12; CC vs. TT, OR = 2.15, 95%CI = 1.70-2.71; CT/CC vs. TT, OR = 1.86, 95%CI = 1.53-2.26; CC vs.TT/CT, OR = 1.49, 95%CI = 1.24-1.79]. In addition, the association of C allele with an increased GCa risk was still significant in subgroups, when stratified by age, sex, tumor site, drinking and smoking status. Moreover, the findings in the present study were validated by our further meta-analysis. In summary, these results indicated that the C allele of PRKAA1 rs13361707 was a low-penetrate risk factor for GCa.

Expression of CD44 in pancreatic cancer and its significance.

BACKGROUND: CD44 is a potentially interesting prognostic marker and therapeutic target in pancreatic cancer. The expression of CD44 has been reported to correlate with poor prognosis of pancreatic cancer in most literatures. The purpose of this study is to investigate the roles of CD44 in pancreatic caner, and their correlation with the prognosis of pancreatic cancer patients. METHODS: 67 pancreatic cancer samples were collected in Xinhua hospital affiliated to Shanghai Jiaotong University dating from Jan 2010 to Dec 2012. Immunohistochemistry was applied to test the expression of CD44 in pancreatic cancer. The clinical data of the patients were collected including their gender, age, the histology and location, lymph node metastasis and so on. The correlation between the CD44 expression and the clinicopathological factors of patients with pancreatic cancer was analyzed by the software SPSS 13.0. We devise and synthesis of effectively interference of shRNA sequence of CD44, which was transefected to the pancreatic cancer cells PANC-1. Colony formation assay, cell migration assays and western blot were performed. RESULTS: The positive rates of CD44 expression in pancreatic samples were 73.1% (49/67). Univariate analysis showed that there were a significant differences between the CD44 expression and the pancreatic cancer' T staging, TNM staging, lymph node metastasis, the differentiation degree, tumor location (P < 0.05). The Cox proportional hazards model showed that differentiation, CD44 expression and nerve invasion were independent prognostic factors. Knockdown of CD44 expression in pancreatic cancer cells led to decreased cellular proliferation and migration ability, accompanied by downregulation of p-ERK and p-AKT. CONCLUSION: CD44 were related to the distant metastasis and aggressive malignant behaviors of pancreatic cancer. CD44 may regulate tumorigenesis and cancer metastasis partially via PI3K/AKT or MAPK/ERK regulatory pathway.

The roles of IL-2 and IL-10 enhance anti-CD45RBmAb immune inhibition in allograft skin.

As a new type of immune tolerance inducer, anti-CD45RB monoclonal antibodies (anti-CD45RBmAb) can prolong the graft survival time of animal organs or cell transplantation as well as induce stable immune tolerance. Both interleukin (IL)-2 and IL-10 have important roles in the induction and maintenance of immunological tolerance. However, whether these cytokines combined with anti-CD45RBmAb can promote immune tolerance is poorly understood. Therefore, we investigated the effect of IL-2 and IL-10 in vitro and in vivo on the tolerance induction by anti-CD45RBmAb. The changes of Treg and Th17 cells and Th1/Th2 cytokines in anti-CD45RBmAb induced prolongation of skin allograft survival in mice. The finding of a role for IL-2 is novel, of interest, IL-2 promoted anti-CD45RBmAb-induced CD4(+) T cell differentiation into Treg and Th2 cells and suppressed Th17 and Th1 cells. IL-2 enhanced the induction of immune tolerance by anti-CD45RBmAb and significantly prolonged skin graft survival time in vivo. In contrast, this effect should be demonstrated experimentally by neutralizing IL-2 and inhibition of the effect of anti-CD45RBmAb, and neutralizing IL-10 showed no effect for anti-CD45RBmAb-induced tolerance. These data reveal that IL-2 significantly enhances anti-CD45RBmAb-induced immune tolerance via up-regulated T regulatory (Treg) cells and the balance of Th1/Th2 shifts. Conversely, IL-10 showed no effect on anti-CD45RBmAb-induced tolerance.

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop.

The tumour suppressor p53 plays an important role in tumourigenesis. Besides inducing apoptosis, it regulates cellular senescence, which constitutes an important barrier to tumourigenesis. The mechanism of regulation of cellular senescence by p53 and its downstream pathway are poorly understood. Here, we report that the ubiquitin domain-containing 1 (UBTD1) gene, a new downstream target of p53, induces cellular senescence and acts as a novel tumour suppressor by a mechanism that depends on p53. Expression of UBTD1 increased upon cellular senescence induced by serial passageing of cultures, as well as by exposure to DNA-damageing drugs that induce premature senescence. Over-expression of UBTD1 induces senescence in human fibroblasts and cancer cells and attenuation of the transformed phenotype in cancer cells. UBTD1 is down-regulated in gastric and colorectal cancer tissues, and its lower expression correlates with a more aggressive phenotype and worse prognosis. Multivariate analysis revealed that UBTD1 expression was an independent prognostic factor for gastric cancer patients. Furthermore, UBTD1 increased the stability of p53 protein, by promoting the degradation of Mdm2 protein. Importantly, UBTD1 and p53 function mutually depend on each other in regulating cellular senescence and proliferation. Thus, our data suggest that, upon DNA damage, p53 induction by UBTD1 creates a positive feedback mechanism to further increase p53 expression. Our results establish UBTD1 as a regulator of cellular senescence that mediates p53 function, and provide insights into the mechanism of Mdm2 inhibition that impacts p53 dynamics during cellular senescence and tumourigenesis.