Palladium and Iron Cocatalyzed Aerobic Alkene Aminoboration.

Aminoboration of simple alkenes with nitrogen nucleophiles remains an unsolved problem in synthetic chemistry; this transformation can be catalyzed by palladium via aminopalladation followed by transmetalation with a diboron reagent. However, this catalytic process faces inherent challenges with instability of the alkylpalladium(II) intermediate toward ß-hydride elimination. Herein, we report a palladium/iron cocatalyzed aminoboration, which enables this transformation. We demonstrate these conditions on a variety of alkenes and norbornenes with an array of common nitrogen nucleophiles. In the developed strategy, the iron cocatalyst is crucial to achieving the desired reactivity by serving as a halophilic Lewis acid to release the transmetalation-active cationic alkylpalladium intermediate. Furthermore, it serves as a redox shuttle in the regeneration of the Pd(II) catalyst by reactivation of nanoparticulate palladium.

Periostin secreted from podoplanin-positive cancer-associated fibroblasts promotes metastasis of gastric cancer by regulating cancer stem cells via AKT and YAP signaling pathway.

Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells present in the tumor microenvironment (TME), which play a critical role in gastric cancer (GC) progression. Here, we examined a subset of CAFs with high podoplanin (PDPN) expression, which is correlated with tumor metastasis and poor survival in GC patients. Animal models of gastric cancer liver metastasis monitored by micro-PET/CT confirmed that periostin (POSTN) derived from PDPN(+) CAFs regulated CAFs' pro-migratory ability. Mechanistically, PDPN(+) CAFs secreted POSTN to modulate cancer stem cells (CSCs) through FAK/AKT phosphorylation. Furthermore, POSTN could also activate FAK/YAP signaling in GC cells to produce increased amounts of IL-6, which in turn induced phosphorylation of PI3K/AKT in PDPN(+) CAFs. Prolonged PI3K/AKT pathway activation in PDPN(+) CAFs maintains the production of POSTN and the effect on CSC enrichment and GC cell migration. In conclusion, our study demonstrated a positive feedback loop between PDPN(+) CAFs and CSCs during GC progression and suggested a selective target for GC treatment.

A study protocol of a randomized phase II trial of perioperative chemoimmunotherapy verses perioperative chemoimmunotherapy plus preoperative chemoradiation for locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma: the NeoRacing study.

BACKGROUND: Perioperative chemotherapy (ChT) and preoperative chemoradiation (CRT) are both the standard treatments for locally advanced gastric cancer (LAGC). CRT can achieve a higher pathological complete regression (pCR) rate, but whether this higher pCR rate can be transformed into a long-term survival benefit remains inconclusive. Therefore, relevant studies are in progress. On the other hand, immunotherapy has been established for the first-line treatment of advanced gastric cancer (AGC) and has been widely explored in the perioperative setting. The combination of chemotherapy/radiotherapy and immunotherapy may have a synergistic effect, which will lead to a better antitumor effect. The preliminary reports of ongoing studies show promising results, including a further improved pCR rate. However, the preferred treatment combination for LAGC is still not established. To solve this problem, we are carrying out this randomized phase II trial, which aims to evaluate the efficacy and safety of perioperative chemotherapy plus the use of PD-1 antibody with or without preoperative chemoradiation for LAGC. METHODS: Eligible patients with LAGC or gastroesophageal junction (GEJ) adenocarcinoma were randomized to receive perioperative ChT, PD-1 antibody, surgery with (Arm A) or without preoperative CRT (Arm B), and PD-1 antibody maintenance until one year after surgery. The primary endpoint of this study is that the pCR rate of Arm A will be significantly higher than that of Arm B. The secondary endpoints include the pathological partial regression (pPR) rate, R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), safety and surgical complications. Moreover, several explorative endpoints will be evaluated to find and validate the predictive biomarkers of immunotherapy. DISCUSSION: The results of the NeoRacing study will provide important information concerning the application of PD-1 antibody in LAGC patients during the perioperative setting. Meanwhile, the two treatment protocols will be compared in terms of efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05161572 . Registered 17 December 2021 - Retrospectively registered.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer.

Gastric cancer (GC) is one of the major causes of cancer-related deaths and chemoresistance is a key obstacle to the treatment of GC, particularly in advanced GC. As an active component of saffron stigma, crocetin has important therapeutic effects on various diseases including tumors. However, the therapeutic potential of crocetin targeting GC is still unclear and the underlying mechanisms are remained to be further explored. In this study, crocetin significantly inhibited angiogenesis in GC, including tubes of HUVECs and vasculogenic mimicry (VM) formation of GC cells. Crocetin also suppressed cell proliferation, migration and invasion. To explore which signaling pathway involving in crocetin, HIF-1α, Notch1, Sonic hedgehog (SHH) and VEGF were examined with crocetin treatment and we found that SHH significantly decreased. Crocetin suppressed SHH signaling with SHH, PTCH2, Sufu and Gli1 protein level decreased in western blot assay. In addition, crocetin suppressed SHH secretion in GC and HUVEC cells. The promoted effects on cell migration induced by secreted SHH were also inhibited by crocetin in GC and HUVEC cell co-culture system. Furthermore, recombinant SHH promoted angiogenesis as well as cell migration and proliferation. However, these promoted effects were reversed by crocetin treatment. These results revealed that crocetin suppressed GC angiogenesis and metastasis through SHH signaling pathway, indicating that crocetin may function as an effective therapeutic drug against GC.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10-8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10-9) and 4q28.1 (OR=1.14, p=3.33×10-11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.

Analysis of lymph node metastasis in early gastric cancer: a single institutional experience from China.

BACKGROUND: Lymph node metastasis (LNM) has a strong influence on the prognosis of patients with early gastric cancer (EGC). The aim of this study was to reveal the incidence of LNM and evaluate risk factors for LNM to determine the appropriate treatment for EGC in a Chinese population. METHODS: Patients who underwent radical gastrectomy with lymph node dissection for EGC between 2012 and 2017 were retrospectively analyzed. Univariate and multivariate analyses were conducted to identify clinicopathological features that were risk factors for LNM. RESULTS: A total of 1033 patients with EGC were enrolled. Of these patients, 668 (64.7%) were men, and 365 (35.3%) were women, ranging in age from 19 to 82 years (mean 56.9 ± 10.9 years). LNM was detected in 173(16.7%) patients with EGC. Among 508 patients with mucosal cancer, 44 (8.7%) patients had LNM. In 525 patients with submucosal cancer, the incidence of LNM was 24.6% (129/525). The age, gender, tumor size, type of differentiation, Lauren classification, and lymphovascular and perineural invasion showed a significant correlation with the rate of LNM in EGC by univariate and multivariate analyses. Patients with submucosal gastric cancer had an older age, a higher proportion of proximal lesion, larger tumor size, more frequent lymphovascular invasion, perineural invasion, and more LNM than patients with mucosal gastric cancer. CONCLUSIONS: Our study revealed a relatively high incidence of LNM in EGC, compared with Japanese and Korean cohorts. Female sex, large tumor size, undifferentiated-type, and lymphovascular invasion were independent risk factors for LNM in EGC. Radical gastrectomy with lymphadenectomy should be performed in EGC patients with a high risk of LNM.

RPS15A promotes gastric cancer progression via activation of the Akt/IKK-ß/NF-κB signalling pathway.

This study aimed to investigate the clinical significance, potential biological function and underlying mechanism of RPS15A in gastric cancer (GC) progression. RPS15A expression was detected in 40 pairs of GC tissues and matched normal gastric mucosae (MNGM) using qRT-PCR analysis. Immunohistochemistry assay was conducted using a tissue microarray including 186 primary GC samples to characterize the clinical significance of RPS15A. A series of in vitro and in vivo assays were performed to elucidate the biological function of RPS15A in GC development and underlying molecular mechanisms. The expression of RPS15A was significantly up-regulated in GC samples compared to MNGM, and its expression was closely related to TNM stage, tumour size, differentiation, lymph node metastasis and poor patient survival. Ectopic expression of RPS15A markedly enhanced the proliferation and metastasis of GC cells both in vitro and in vivo. RPS15A overexpression also promoted the epithelial-mesenchymal transition (EMT) phenotype formation of GC cells. Investigations of underlying mechanisms found that RPS15A activated the NF-κB signalling pathway by inducing the nuclear translocation and phosphorylation of the p65 NF-κB subunit, transactivation of NF-κB reporter and up-regulating target genes of this pathway. In addition, RPS15A overexpression activated, while RPS15A knockdown inhibited the Akt/IKK-ß signalling axis in GC cells. And both Akt inhibitor LY294002 and IKK inhibitor Bay117082 neutralized the p65 and p-p65 nuclear translocation induced by RPS15A overexpression. Collectively, our findings suggest that RPS15A activates the NF-κB pathway through Akt/IKK-ß signalling axis, and consequently promotes EMT and GC metastasis. This newly identified RPS15A/Akt/IKK-ß/NF-κB signalling pathway may be a potential therapeutic target to prevent GC progression.

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients.

We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

Study protocol of a randomized phase III trial of comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma: PREACT.

BACKGROUND: The prognosis of patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma is still dismal. There are no standard treatment strategies for these patients. Multidisciplinary team (MDT) approach is a good choice for making a high-quality decision. Generally, MDT will recommend these patients to receive preoperative chemotherapy or preoperative chemoradiation based on all kinds of treatment guidelines. However, the preferred preoperative treatment is still not established. In order to solve this problem, we carry out this randomized phase III trial of comparing preoperative chemoradiation with preoperative chemotherapy in patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma. METHODS: Eligible patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma are randomized to receive preoperative chemoradiation or preoperative chemotherapy, followed by surgery and postoperative chemotherapy. In the preoperative chemoradiation arm (Pre-CRT), patients receive two cycles of S-1 and oxaliplatin (SOX), chemoradiation, then followed by surgery and three more cycles of SOX chemotherapy. In the preoperative chemotherapy arm (Pre-CT), patients receive three cycles of SOX, following surgery three more cycles of SOX are given. The primary endpoint of this trial is to verify that preoperative chemoradiation could significantly improve the 3-year disease free survival (DFS) of patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma compared to preoperative chemotherapy. DISCUSSION: The results from this trial will provide important information about whether preoperative chemoradiation could improve survival compared to preoperative chemotherapy among patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03013010. First posted January 6, 2017.

Prognostic Value of Inflammatory Biomarkers in Gastric Cancer Patients and the Construction of a Predictive Model.

BACKGROUND: It is known that inflammation promotes cancer development. However, a few studies have evaluated the prognostic significance of inflammatory biomarkers in gastric cancer (GC). METHODS: In this study, 2,334 patients who underwent gastrectomy for GC at Fudan University Shanghai Cancer Center between 2003 and 2007 were retrospectively analyzed, and 1,227 patients were found to be eligible. The preoperative serum neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) levels were analyzed. A nomogram was constructed with the Cox proportional hazards regression model in the training set (n = 818) to predict the probability of overall survival (OS) and disease-free survival (DFS). The predictive accuracy and discriminative ability were determined using the concordance index (C-index) and calibration curve. RESULTS: We found that lower AGR and LMR values were correlated with decreased OS, lower LMR values, and higher NLR values with a decreased DFS. Other significant factors were included to construct the nomogram. The discriminative ability of the nomogram was higher than that of the eighth American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system (0.746 for TNM v.s. 0.654 for the nomogram, p < 0.001). CONCLUSIONS: The nomogram yielded a more accurate prognostic prediction in GC patients after gastrectomy, suggesting great clinical value.

Effect of perioperative blood transfusion on prognosis of patients with gastric cancer: a retrospective analysis of a single center database.

BACKGROUND: The association between perioperative blood transfusion and the prognosis of patients with gastric cancer is still unclear. METHODS: A total of 1581 patients with gastric cancer who underwent curative gastrectomy from 2000 to 2008 were evaluated. Perioperative blood transfusion was defined as the transfusion of packed red blood cells within seven days before surgery, during surgery, or within the postoperative hospitalization period. The association between perioperative blood transfusion and prognosis was evaluated using univariate and multivariate Cox regression analyses. RESULTS: Of 1581 patients, 298 patients (19%) received perioperative blood transfusion. Perioperative blood transfusion correlated with older age (P < 0.001); larger tumor size (P < 0.001); and more advanced stage (P < 0.001). Five-year survival rate was 40% in patients who had perioperative blood transfusion and 55% patients who did not have perioperative blood transfusion, and the difference was statistically significant (P < 0.001). Multivariate analysis showed that perioperative blood transfusion was defined as independent prognostic factor. Perioperative blood transfusion was associated with worse outcomes in patients with stage III (P < 0.001). CONCLUSIONS: Perioperative blood transfusion independently correlated with poorer prognosis in patients with gastric cancer.

microRNAs expression profile related with response to preoperative radiochemotherapy in patients with locally advanced gastric cancer.

BACKGROUND: It is urgent to find some biochemical markers for predicting the radiochemotherapy sensitivity. microRNAs have a huge potential as a predictive biomarker in gastric cancer. The current study aims to identify the microRNAs related to the radiochemotherapy sensitivity in gastric cancer. METHODS: From April 2012 to August 2014, 40 patients with locally advanced gastric cancer were included into the clinical trial in the Fudan University Shanghai Cancer Center. The lesion specimens of 15 patients were obtained by gastroendoscopy before treatment, and the RNA was extracted. microRNAs array was used to identify the microRNAs with different expression level between sensitive group and non-sensitive group. The microRNAs identified in the array were further confirmed by TaqMan Real-time PCR. RESULTS: 2006 microRNAs were identified by microRNA array, including 302 highly expressed microRNAs and 1704 lowly expressed microRNAs between non-sensitive group and sensitive group. According to the statistical significance (p < 0.05) and expression level (more than twofold or less than 0.5 times), 9 microRNAs were identified. Finally, we chose 6 microRNAs like miR-16-2-3p, miR-340-5p, miR-338-3p, miR-142-3p, miR-142-5p and miR-582-5p to determine the sensitive group and non-sensitive group. TaqMan Real-time PCR confirmed the results of microRNA array. CONCLUSIONS: microRNA array can be used to select the microRNAs associated with radiochemotherapy sensitivity in gastric cancer. miR-338-3p and miR-142-3p may be promising predictive biomarkers for such patients. TRIAL REGISTRATION: Trial Registration number: NCT03013010 . Name of registry: Phase II Study of Neoadjuvant Chemotherapy Wtih S1 + Oxaliplatin (SOX) Regimen Followed by Chemoradiation Concurrent With S-1 in Patients With Potentially Resectable Gastric Carcinoma. Date registered: December 31, 2013. The trial was prospectively registered.

Phase II trial of preoperative chemoradiation plus perioperative SOX chemotherapy in patients with locally advanced gastric cancer.

BACKGROUND AND PURPOSE: The ideal treatment strategy of patients with locally advanced gastric adenocarcinoma is unclear. The aim of this study is to evaluate the efficacy and feasibility of preoperative chemoradiation in these patients. PATIENTS AND METHODS: All patients underwent laparoscopic exploration or exploratory laparotomy before chemoradiation. Patients received one cycle of S-1 and oxalipatin followed by concurrent radiation and chemotherapy, then underwent another cycle of S-1 and oxalipatin. Surgery was performed 6-8 weeks after completing radiochemotherapy. The rate of curative gastrectomy and survival were investigated. This trial was registered with ClinicalTrial.gov, number NCT02024217. RESULTS: From April 2012 to August 2014, 40 patients were enrolled in the trial, and 36 patients were assessable. The most common hematologic toxic effects were leukopenia (80.6%), neutropenia (69.4%), and thrombocytopenia (50%); the most common nonhematologic toxic effects were anorexia (50%), nausea (22.3%), and vomiting (13.9%). There were no treatment related deaths. A total of 33 patients underwent second exploratory laparotomy after preoperative chemoradiation, and 24 (67%) patients received curative gastrectomy. The rates of pathological complete response (pCR) were 13.9%. The medial survival time (MST) was 30.3 months. CONCLUSION: Preoperative chemoradiation may be an effective treatment strategy among patients with locally advanced gastric adenocarcinoma.

Pd-Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten-Membered Heterocycles.

We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten-membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd-SIPHOX catalyst, a wide range of benzofuran- as well as indole-fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten-membered heterocycles was also discovered.

Palladium-Titanium Relay Catalysis Enables Switch from Alkoxide-π-Allyl to Dienolate Reactivity for Spiro-Heterocycle Synthesis.

Reported herein is the divergent syntheses of [5,5] and [6,5] spiro-heterocycles under Lewis-acid-assisted palladium catalysis. In particular, an unprecedented switch from alkoxide-π-allyl to dienolate reactivity was achieved by the use of palladium-titanium relay catalysis, and represents umpolung reactivity of vinylethylene carbonates. This method uses a simple procedure and commercially available catalysts, and delivers both classes of spiro-heterocycles, bearing three contiguous stereocenters, in high yield and uniformly excellent diastereoselectivity.

Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation.

The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.

Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression.

DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR) = 0.82, 95% confidence interval (CI) = 0.69-0.98; P = 0.03], whereas two XRCC4 SNPs were associated with a worse survival (HR = 1.26, 95% CI = 1.03-1.54 for the rs10040363G allele, P = 0.02; and HR = 1.30, 95% CI = 1.06-1.59 for the rs2075685T allele, P = 0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P < 0.05 for all) but not for patients without chemotherapy (P > 0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (Ptrend = 0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data (ERCC1: HR = 1.31 [1.08-1.58]; P = 0.006). These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors.

Circular RNAs play an important role in late-stage gastric cancer: Circular RNA expression profiles and bioinformatics analyses.

Gastric cancer is one of the most common tumors of the digestive system. Here, analysis of the expression profiles of circular RNAs in advanced gastric adenocarcinoma and adjacent normal mucosa tissues revealed differential expression of 306 circular RNAs, among which 273 were predicted to exert regulatory effects on target microRNAs. The downstream pathway networks of circular RNA-microRNA were mapped and the node genes were identified. In particular, we found that the expression of hsa_circ_0058246 was elevated in tumor specimens of patients with poor clinical outcomes. Our collective findings indicate that circular RNAs play a critical role in gastric cancer tumorigenesis. Data from this study provide a new perspective on the molecular pathways underlying metastasis and recurrence of gastric cancer and highlight potential therapeutic targets that may contribute to more effective diagnosis and treatment of the disease.