The role of alternative polyadenylation in epithelial-mesenchymal transition of non-small cell lung cancer.

The metastatic non-small cell lung cancer (NSCLC) is one of the cancers with high incidence, poor survival, and limited treatment. Epithelial-mesenchymal transition (EMT) is the first step by which an early tumor converts to an invasive one. Studying the underlying mechanisms of EMT can help the understanding of cancer metastasis and improve the treatment. In this study, 1013 NSCLC patients and 123 NSCLC cell lines are deeply analyzed for the potential roles of alternative polyadenylation (APA) in the EMT process. A trend of shorter 3'-UTRs (three prime untranslated region) is discovered in the mesenchymal samples. The identification of EMT-related APA events highlights the proximal poly(A) selection of CARM1. It is a pathological biomarker of mesenchymal tumor and cancer metastasis through losing miRNA binding to upregulate the EMT inducer of CARM1 and releasing miRNAs to downregulate the EMT inhibitor of RBM47. The crucial role of this APA event in EMT also guides its effect on drug responses. The patients with shorter 3'-UTR of CARM1 are more benefit from chemotherapy drugs, especially cisplatin. A stratification of NSCLC patients based on this APA event is useful for chemotherapy design in future clinics.

A vicinal oxygen chelate protein facilitates viral infection by triggering the unfolded protein response in Nicotiana benthamiana.

Vicinal oxygen chelate (VOC) proteins are members of an enzyme superfamily with dioxygenase or non-dioxygenase activities. However, the biological functions of VOC proteins in plants are poorly understood. Here, we show that a VOC in Nicotiana benthamiana (NbVOC1) facilitates viral infection. NbVOC1 was significantly induced by infection by beet necrotic yellow vein virus (BNYVV). Transient overexpression of NbVOC1 or its homolog from Beta vulgaris (BvVOC1) enhanced BNYVV infection in N. benthamiana, which required the nuclear localization of VOC1. Consistent with this result, overexpressing NbVOC1 facilitated BNYVV infection, whereas, knockdown and knockout of NbVOC1 inhibited BNYVV infection in transgenic N. benthamiana plants. NbVOC1 interacts with the basic leucine zipper transcription factors bZIP17/28, which enhances their self-interaction and DNA binding to the promoters of unfolded protein response (UPR)-related genes. We propose that bZIP17/28 directly binds to the NbVOC1 promoter and induces its transcription, forming a positive feedback loop to induce the UPR and facilitating BNYVV infection. Collectively, our results demonstrate that NbVOC1 positively regulates the UPR that enhances viral infection in plants.

Comparative Transcriptome Analysis Reveals the Effect of the DHN Melanin Biosynthesis Pathway on the Appressorium Turgor Pressure of the Poplar Anthracnose-Causing Fungus Colletotrichum gloeosporioides.

Anthracnose of poplar caused by Colletotrichum gloeosporioides is a leaf disease that seriously affects poplar growth. The pathogen invades the host in the form of adherent cells, which generate turgor pressure through the metabolism of intracellular substances prior to penetrating the epidermis of poplar leaves. In this study, the expansion-related pressure of the mature appressorium of the wild-type C. gloeosporioides was approximately 13.02 ± 1.54 MPa at 12 h, whereas it was 7.34 ± 1.23 MPa and 9.34 ± 2.22 MPa in the melanin synthesis-related gene knockout mutants ΔCgCmr1 and ΔCgPks1, respectively. The CgCmr1 and CgPks1 genes were highly expressed at 12 h in the wild-type control, implying that the DHN melanin biosynthesis pathway may play an important role in the mature appressorium stage. The transcriptome sequencing analysis indicated that the upregulated melanin biosynthesis genes in C. gloeosporioides, such as CgScd1, CgAyg1, CgThr1, CgThr2, and CgLac1, are involved in specific KEGG pathways (i.e., fatty acid biosynthesis, fatty acid metabolism, and biotin metabolism). Therefore, we speculate that the melanin synthesis-related genes and fatty acid metabolism pathway genes contribute to the regulation of the turgor pressure in the mature C. gloeosporioides appressorium, ultimately leading to the formation of infection pegs that enter plant tissues. These observations may reflect the co-evolution of C. gloeosporioides and its host.

The long non-coding RNA DKFZp434J0226 regulates the alternative splicing process through phosphorylation of SF3B6 in PDAC.

BACKGROUND: Long noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC. METHODS: Aberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo. RESULTS: In our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage, and decreased overall survival and time to progression. Functional assays demonstrated that DKFZp434J0226 promoted PDAC cell migration, invasion, and growth in vitro and accelerated tumor proliferation in vivo. Mechanistically, DKFZp434J0226 interacted with the splicing factor SF3B6 and promoted its phosphorylation, which further regulated the alternative splicing of pre-mRNA. CONCLUSIONS: This study indicates that DKFZp434J0226 regulates alternative splicing through phosphorylation of SF3B6 in PDAC and leads to an oncogenic phenotype in PDAC.

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00643877.

Pattern of No. 12a lymph node metastasis in gastric cancer.

OBJECTIVE: The current standard D2 lymphadenectomy for gastric cancer (GC) includes dissection of lymph nodes (LNs) along the proper hepatic artery (No. 12a), however, the survival benefit remains controversial. The purpose of this study was to evaluate the pattern of No. 12a LN metastasis (LNM) in GC and explore the indications for No. 12a LN dissection. METHODS: Medical records of 413 consecutive GC patients who underwent curative surgery in Zhongshan Hospital, Fudan University between January 2015 and December 2018 were enrolled and reviewed retrospectively. The correlation between No. 12a LNM and clinicopathologic characteristics of patients was analyzed. RESULTS: The overall incidence of No. 12a LNM was 2.67% (11/413). Tumor location (P=0.012), depth of tumor infiltration (P<0.01) and N stage (P=0.018) were significant factors associated with No. 12a LNM. All the tumors with No. 12a LNM involved the lower third of the stomach and were in T3-4 stages. Patients with No. 12a LNM had extensive LNM than those without (20.91±4.25vs. 5.0±0.54, P<0.001). For advanced GC patients (stage III/IV) with tumors involving the lower third of the stomach, the incidence of No. 12a LNM increased to 10.7% (11/103). Patients with No. 12a LNM had a significantly poorer recurrence-free survival (RFS) (P=0.005) and overall survival (OS) (P=0.017). According to the result of multivariable Cox regression, No. 12a LNM was not an independent impact factor on RFS and OS. CONCLUSIONS: The overall incidence of No. 12a LNM was low but it was much higher in GC patients who had very advanced tumors involving the lower third of the stomach. No. 12a LN dissection should be considered for these patients to improve the survival outcomes.

Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer.

OBJECTIVE: This study was aimed to investigate the prognostic value of tumor-infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. BACKGROUND: TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. METHODS: The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. RESULTS: TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. CONCLUSIONS: TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.

High expression of tumor necrosis factor receptor-associated factor 2 promotes tumor metastasis and is associated with unfavorable prognosis in gastric cancer.

BACKGROUND: Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a key effector in the activation of nuclear factor kappa B (NF-κB). Nevertheless, the role of TRAF2 in gastric tumorigenesis remains little defined. METHODS: Immunohistochemistry was used to find the relationship between TRAF2 expression and clinicopathological characteristics of gastric cancer patients, and nomogram was applied to predict the overall survival of patients. Besides, we performed transwell assays to detect the function of TRAF2 in promoting metastasis and explored the correlations between TRAF2, NF-κB, and interleukin-8 (IL-8) in vitro. In addition, we examined the correlation between TRAF2 and tumor microenvironment by immunohistochemistry staining. RESULTS: In our study, we found that TRAF2 expression was markedly increased in gastric cancer tissues. High intratumoral TRAF2 staining, which was associated with tumor invasion and metastasis, was also an independent poor prognosticator for gastric cancer patients. In vitro studies revealed that TRAF2 enhanced NF-κB activation and subsequent IL-8 expression in gastric cancer cells. Inhibition of NF-κB or IL-8 signaling attenuated TRAF2-induced migration and invasion abilities. High TRAF2 expression was confirmed to be associated with both high intratumoral and serum levels of IL-8. In addition, TRAF2 expression was positively correlated with neutrophil and macrophage infiltration as well as microvessels formation in gastric cancer samples. CONCLUSIONS: These results suggest that TRAF2 functions as an important modulator in tumor metastasis and tumor microenvironment formation and is a novel independent prognostic factor of gastric cancer.

Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration.

The effects of paracrine action from early activated hepatic stellate cells (HSCs) on resident liver epithelium cells are not clear. Here, we investigated whether a systemic infusion of early activated HSC-derived paracrine factors (HSC-CM) would evoke an enhanced liver protective response in acetaminophen (APAP)-induced acute liver injury (ALI) in mice and explored the possible underlying mechanisms. The survival rate, liver injury, and liver regeneration were analyzed in mice with or without HSC-CM treatment in vivo. A systemic infusion of HSC-CM provided a significant survival benefit in APAP-induced ALI. HSC-CM therapy resulted in a reduction of hepatocellular death and increased numbers of both proliferating hepatocytes and adult hepatic progenitor cells (AHPCs) with up-regulation of liver regeneration relevant genes. The HSC-CM treatment reduced leukocyte infiltration and down-regulated systemic inflammation with decreases in IFN-γ, IL-1ra, IL-1ß, TNF-α, and increases in IL-10. The direct anti-death and pro-regeneration effects of HSC-CM on AHPCs were demonstrated using in vitro assays. Treatment with HSC-CM promoted AHPCs proliferation and resulted in increased pAkt expression in vitro, and this effect was abolished by the PI3K/Akt inhibitor LY294002. These data provide evidence that early activated HSC-CM therapy offered trophic support to the acutely injured liver by inhibiting liver cell death and stimulating regeneration, potentially creating a new method for the treatment of ALI.

The IGCA staging system is more accurate than AJCC7 system in stratifying survival of patients with gastric cancer in stage III.

BACKGROUND: A new staging system recently proposed by the IGCA has demonstrated a better capacity of stratifying different prognoses for gastric cancer than the 7th edition AJCC staging system (AJCC7). The aim of this study was to evaluate the efficacy of the IGCA system in Chinese patients. METHODS: Medical records of patients with gastric cancer who received curative surgery in our center from January 2003 to December 2011 were reviewed retrospectively. All the lesions were staged according to both AJCC7 and IGCA staging systems. Overall survival (OS) of the patients was used as the observation endpoint. RESULTS: One thousand five hundred twenty-six cases were included in this study. By comparing the AJCC7 system with the IGCA systems, 395 cases were stratified into different stages, most of which were in stage III. The IGCA system could better stratify stage IIIB and IIIC patients (5-year OS, 38.1% vs. 29.0%; P = 0.005) than the AJCC7 system (5-year OS, 38.2% vs. 35.9%; P = 0.148). T3N3bM0, T4aN2M0 and T4aN3bM0 made up 97.5% (385/395) of the stage shift. T3N3bM0, which was stratified to stage IIIB in the AJCC7 system, showed a significant poorer prognosis than T4aN2M0 and T4aN3aM0, which were staged to IIIB and IIIC in the same system. The improper staging was revised in the IGCA staging system. CONCLUSIONS: The IGCA staging system can stratify stage III gastric cancer patients more properly than the AJCC7 system.

Incorporation of NLR into NIH stratification system increases predictive accuracy for surgically resected gastrointestinal stromal tumors.

Previous studies have reported that preoperative neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios were prognostic for various types of cancers. The aim of this study was to investigate the predictive utilities of preoperative peripheral blood counts in patients with gastrointestinal stromal tumors (GISTs). We enrolled 510 consecutive, previously untreated patients who underwent surgery for primary, localized GISTs. The relationship between recurrence-free survival and outcome variables was assessed by univariate and multivariate analyses, while the clinicopathologic relevance of NLR was determined using the Chi-square test. A preoperative NLR ≥2 was associated with poor prognosis in patients undergoing surgeries for primary, localized GISTs. It was an independent predictor only in patients classified as National Institutes of Health high risk but not in the entire population. Preoperative NLR is a feasible and reproducible peripheral biomarker that helps identify patients for intensive adjuvant therapy and frequent surveillance.

Randomized Controlled Trial of Intraportal Chemotherapy Combined With Adjuvant Chemotherapy (mFOLFOX6) for Stage II and III Colon Cancer.

OBJECTIVES: The optimal time to initiate adjuvant chemotherapy after surgery in patients with colon cancer is not clear. We investigated the benefit of combined intraportal chemotherapy administered during radical surgery with adjuvant chemotherapy for treating stage II and III colon cancer. METHODS: Patients were randomly assigned to OCTREE arm (intraportal chemotherapy plus mFOLFOX6) or a standard adjuvant chemotherapy arm (mFOLFOX6). The primary study endpoint was disease-free survival. The secondary endpoints included metastasis-free survival, overall survival, and safety. RESULTS: The intent-to-treat population comprised 237 patients. With a median follow-up of 44 months, the hazard ratio (OCTREE vs mFOLFOX6) was 0.66 (95% confidence interval, 0.43-0.90), a 34% risk reduction in favor of OCTREE (P = 0.016). The 3-year disease-free survival rate was 85.2% for OCTREE and 75.6% for mFOLFOX6 alone (P = 0.030). The 3-year metastasis-free survival rates were 87.6% for OCTREE and 78.0% for mFOLFOX6 (P = 0.035). Patients had lower distant metastatic rate in the OCTREE arm (12.7% vs 22.7%; P = 0.044), when compared with the mFOLFOX6 arm. The 3-year overall survival was no significant difference between 2 arms (P = 0.178). Neutropenia occurred in 12.7% of the patients receiving OCTREE and in 2.5% of the patients receiving mFOLFOX6 (P = 0.003) within 2 weeks of surgery, and grade 3 or 4 toxicity event was no difference between 2 regimens. CONCLUSIONS: Combination of intraoperative intraportal chemotherapy with mFOLFOX6 reduced the occurrence of distant metastases and improved disease-free survival in patients with stage II and stage III colon cancer.

Low intratumoral regulatory T cells and high peritumoral CD8(+) T cells relate to long-term survival in patients with pancreatic ductal adenocarcinoma after pancreatectomy.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Recent studies have focused on the role of lymphocytes in the PDAC microenvironment. Using immunohistochemistry, our study explored the clinical significance of intratumoral or peritumoral CD4(+)Foxp3(+) regulatory T cells (Tregs) and CD8(+) T cells in the tumor microenvironment and analyzed their relation to the prognosis of PDAC in a consecutive series of 92 patients after resection. CD8(+) T cells were more frequently seen within peritumoral sites, while CD4(+)Foxp3(+) Tregs were more frequent within intratumoral areas. Neither exhibited any relationship with other clinicopathologic factors. Patients with low levels of intratumoral Tregs had longer disease-free survival than those with higher levels (DFS 22.2 vs. 11.2 months, p < 0.001), and patients with higher levels of peritumoral CD8(+) T cells had longer overall survival than those with lower levels (OS 31.0 vs. 14.2 months, p < 0.001). Multivariate analysis demonstrated that intratumoral Tregs (hazard ratio, HR 3.39, p = 0.010) and peritumoral CD8(+) T cells (HR 0.10, p < 0.001) are related to DFS and OS, respectively. These results indicate that intratumoral Tregs are a negative predictor of DFS, while peritumoral CD8(+) T cells are a positive predictor of OS for PDAC patients with pancreatectomy.

Immature Colon Carcinoma Transcript-1 (ICT1) Expression Correlates with Unfavorable Prognosis and Survival in Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of death from cancer worldwide. Immature colon carcinoma transcript-1 (ICT1) has been reported to be correlated with lung cancer; however, whether ICT1 is a functional gene in CRC, as well as the molecular mechanism underlying ICT1 mediation of colorectal-tumor formation, remains unknown. METHODS: The expression of ICT1 was firstly determined by using immunohistochemistry in 861 CRC specimens. The correlation of ICT1 expression with clinicopathological parameters and the survival rate was analyzed. Furthermore, we investigated the effect of ICT1 silencing on CRC cell proliferation and migration by MTT, colony formation, flow cytometry, and transwell in vitro. RESULTS: ICT1 is highly expressed in a cohort of human CRCs, and that higher ICT1 expression may lead to reduced overall survival rate of CRC. Likewise, ICT1 silencing lowered the cell viability through cell-cycle arrest, inhibited cell migration, and induced apoptosis in CRC. We further revealed a novel mechanism in which ICT1 promoted CRC growth via the intracellular AMPK, SAPK/JNK, and PARP signaling pathways. CONCLUSIONS: Our data showed that ICT1 could be an important target for CRC diagnosis and treatment.

Increased expression of C-C motif ligand 2 associates with poor prognosis in patients with gastric cancer after gastrectomy.

Previous studies have demonstrated the clinical significance of polarized tumor-associated macrophages (TAMs) in gastric cancer whereas the cytokines orchestrating TAM polarization remain elusive. This study aims to evaluate the prognostic value of C-C motif ligand 2 (CCL2) expression in gastric cancer patients after surgery. We examined CCL2 expression in tumor tissues by immunohistochemical staining in retrospectively enrolled 414 gastric cancer patients receiving gastrectomy at Zhongshan Hospital during 2008. We used Kaplan-Meier analysis and Cox regression models to assess the prognostic value of CCL2 expression. We generated a predictive nomogram from integrating CCL2 expression with the TNM staging system to evaluate 3- and 5-year overall survival. High intratumor CCL2 expression associated with adverse clinical outcome. Intratumor CCL2 expression provided additional prognostic value in gastric cancer patients. CCL2 expression, as well as well-established TNM staging parameters, was identified as independent prognostic factor for overall survival. The generated nomogram corresponded well with the ideal model in predicting the 3- and 5-year overall survival of gastric cancer patients. CCL2, an identified potential independent adverse prognosticator, could be integrated with TNM staging system to improve the predictive accuracy for overall survival in gastric cancer patients especially with advanced stages.

Survival benefit of greater number of lymph nodes dissection for advanced node-negative gastric cancer patients following radical gastrectomy.

OBJECTIVE: A common clinicopathological factor except for T stage that could significantly influence the clinical outcome of advanced node-negative gastric cancer patients following radical gastrectomy was unknown. This study was designed to investigate the clinicopathological characteristics of these patients, and to evaluate the outcome indicators and improve the risk stratification. METHODS: A total of 195 patients harboring advanced gastric adenocarcinoma with no lymph node and distant metastases and following radical gastrectomy were retrospectively analyzed from the prospectively collected database of Zhongshan Hospital of Fudan University between 2006 and 2010. RESULTS: The 3-year and 5-year overall survival rates of this study population were 85.0 and 69.6%. Factors influencing the overall survival were the degree of tumor differentiation, the depth of invasion and the number of lymph nodes resected (LN, cutoff = 18). Lymph node was recognized as an independent prognostic factor for overall survival of advanced node-negative gastric cancer patients, and the prognosis of the patients with greater number of lymph nodes resected (LN ≥ 18) was significantly better than those with lymph node < 18, and only the patients with T3/T4 stage could be significantly stratified by lymph node. Based on this condition, a new staging system named tumor-node-metastasis staging system for T3/T4 node-negative gastric cancer was constructed, which could have statistically different overall survival between subgroups. CONCLUSIONS: Lymph node was an independent prognostic factor of patients with advanced node-negative gastric cancer, and retrieval of more than 18 lymph nodes should be warranted. In addition, these patients with lesser number of lymph nodes resected might need aggressive postoperative treatment and closer follow-up.

Expanded endoscopic therapy criteria should be cautiously used in intramucosal gastric cancer.

OBJECTIVE: Accurate estimation of lymph node metastasis (LNM) in intramucosal gastric cancer is essential to select less invasive treatment options and even avoid surgery. The aim of this study was to evaluate combined clinicopathological features to predict the presence of LNM. METHODS: A retrospective review of data from 386 intramucosal gastric cancer patients who underwent gastrectomy with extended lymphadenectomy from 2003 to 2010 was conducted. The mutual relation between clinicopathological characteristics and LNM was analyzed. RESULTS: LNM was detected in 40 (10.4%) of the 386 patients. Histological type and vascular or lymphatic invasion presence showed a positive correlation with LNM occurrence by univariate analysis. Multivariate analysis revealed that histological type was the only factor associated with LNM. Combined clinicopathologic characteristics would be more predictable for LNM. We found no LNM when we used combined clinicopathological characteristics conforming to Japanese absolute indications for endoscopic therapy. The LNM rate was as high as 8.7% when Japanese expanded criteria were used. Univariate analysis in cancer conformity to expand endoscopic submucosal dissection (ESD) indication also revealed that the undifferential type was the only significant factor for LNM. CONCLUSIONS: It was possible to predict intramucosal gastric cancer cases without LNM using combined clinicopathological characteristic analysis. Extended indication for ESD should be cautiously used for intramucosal gastric cancer patients.

The prognostic value of CXC-chemokine receptor 2 (CXCR2) in gastric cancer patients.

BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells. The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection. METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center. CXCR2 expression levels were correlated to clinicopathological variables and OS. RESULTS: CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells. High CXCR2 expression was associated with poor tumor differentiation (p = 0.021), increased tumor depth (p < 0.001), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001) and short OS (p = 0.001). CXCR2 expression was an independent prognostic factor for OS (p = 0.001) in multivariate analysis, and could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with gastric cancer. CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients. CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment.

Short-term quality of life in patients undergoing colonic surgery using enhanced recovery after surgery program versus conventional perioperative management.

OBJECTIVE: Enhanced recovery after surgery (ERAS) integrates evidence-based interventions to reduce surgical stress and accelerate rehabilitation. Our study was to compare the short-term quality of life (QOL) in patients undergoing open colonic surgery using ERAS program or conventional management. METHODS: A prospective study of 57 patients using ERAS program and 60 patients using conventional management was conducted. The clinical characteristics of all patients were recorded. QOL was evaluated longitudinally using the questionnaires (EORTC QLQ-C30 and QLQ-CR29) pre- and postoperatively. Generalized estimating equation was used to do the analysis in order to determine the effective impact of correlative factors on the postoperative QOL, including age, sex, BMI, ASA grade, tumor location, tumor size, pTNM stage, recovery program and length of time after surgery. RESULTS: The morbidity in ERAS and control group was 17.5 versus 26.7 % (p = 0.235). The patients in ERAS group had much faster rehabilitation and less hospital stay. In the primary statistical analysis, the scores of global QOL (on POD3, POD6, POD10, POD14, POD21), physical functioning (on POD3, POD6, POD10, POD14, POD21), role functioning (on POD6, POD10, POD14, POD21), emotional functioning (on POD3, POD6, POD10, POD14, POD21), cognitive functioning (on POD3, POD6) and social functioning (on POD3, POD6, POD10, POD14, POD21, POD28) were higher in ERAS group than in control group, which suggested that the patients in ERAS group had a better life status. However, the scores of pain (on POD10, POD14, POD21), appetite loss (on POD3, POD6), constipation (on POD3, POD6, POD10), diarrhea (on POD3, POD10), financial difficulties (on POD10, POD14, POD21), perspective of future health (on POD6, POD10, POD14), gastrointestinal tract problems (on POD3, POD6, POD10) and defecation problems (on POD6, POD10, POD14) were lower in ERAS group than in control group, which revealed that the patients in ERAS group suffered less symptoms. In the further generalized estimating equation analysis, the result showed that recovery program and length of time after surgery had independently positive impact on the patient's postoperative QOL. CONCLUSION: Short-term QOL in patients undergoing colonic cancer using ERAS program was better than that using conventional management.

Advances in the cellular immunological pathogenesis of type 1 diabetes.

Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic ß cells. In recent years, the incidence of type 1 diabetes continues to increase. It is supposed that genetic, environmental and immune factors participate in the damage of pancreatic ß cells. Both the immune regulation and the immune response are involved in the pathogenesis of type 1 diabetes, in which cellular immunity plays a significant role. For the infiltration of CD4(+) and CD8(+) T lymphocyte, B lymphocytes, natural killer cells, dendritic cells and other immune cells take part in the damage of pancreatic ß cells, which ultimately lead to type 1 diabetes. This review outlines the cellular immunological mechanism of type 1 diabetes, with a particular emphasis to T lymphocyte and natural killer cells, and provides the effective immune therapy in T1D, which is approached at three stages. However, future studies will be directed at searching for an effective, safe and long-lasting strategy to enhance the regulation of a diabetogenic immune system with limited toxicity and without global immunosuppression.