Background Chronic inflammation drives tumor progression by fostering an immunosuppressive tumor microenvironment (TME). Phospholipase A2 (PLA2) contributes to this process through the generation of bioactive lipid mediators. The present study investigated the efficacy and mechanism of magnesium isoglycyrrhizinate (MgIG), a clinical PLA2 inhibitor with anti-tumor potential, in remodeling the inflammatory TME of gastric cancer. Methods Murine gastric cancer (MFC) syngeneic allografts were established in mice to evaluate the anti-tumor effects of MgIG. Cell viability was examined in MFC and human gastric adenocarcinoma (AGS) cell lines. Cytokine and chemokine expression in the tumors was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Key immune cell infiltration within the TME was assessed via immunohistochemistry (IHC). Western blotting was used to investigate the downstream effects of MgIG on signaling pathways. Conditioned medium (CM) from MgIG-treated tumor cells was used to culture murine macrophage (RAW264.7) and human monocytic leukemia (THP-1) cell lines, and polarization markers were analyzed by western blotting, immunofluorescence (IF), and enzyme-linked immunosorbent assay (ELISA). Overexpression of phospholipase A2 group IVA (Pla2g4a in MFC cells and PLA2G4A in AGS cells) was performed to validate the mechanistic pathway. Comparisons were performed using Student's t test or analysis of variance (ANOVA). Survival differences were assessed by the log-rank test. Results MgIG significantly suppressed the growth of MFC gastric cancer allografts, as evidenced by reduced tumor volume and weight (both P < 0.05). Additionally, it prolonged the survival of tumor-bearing mice (P < 0.0001) without inducing hepatotoxicity or gastric tissue damage (ALT, P = 0.7482; AST, P = 0.3293). Mechanistically, MgIG induced treatment-specific regulation of inflammatory mediators within the TME, including reductions in the expression of C-X-C motif chemokine ligand 1 (Cxcl1), interleukin 10 (Il10), Il23a, and key nodes in the toll-like receptor 4 (Tlr4)/TLR6–myeloid differentiation primary response gene 88 (Myd88)–nuclear factor κB (NF-κB) pathway (P < 0.05). Molecular docking suggested a potential interaction between MgIG and PLA2G4A, which was associated with the reduced activation of NF-κB pathway and p65 nuclear translocation (P < 0.05). Furthermore, MgIG reshaped the immune landscape by increasing the infiltration of CD8+ T cells and macrophages while reducing regulatory T cell (Treg) infiltration (P < 0.05). Crucially, CM from MgIG-treated tumor cells polarized tumor-associated macrophages (TAMs) from an M2-like toward an M1-like phenotype, characterized by elevated inducible nitric oxide synthase (iNOS) and IL-12A expression and decreased arginase-1 (Arg-1) and CD206 levels (P < 0.05). This polarization shift was associated with PLA2–NF-κB signaling, as mouse Pla2g4a or human PLA2G4A overexpression reversed the MgIG-induced M1-like polarization (P < 0.05). Conclusions MgIG suppresses gastric cancer progression by remodeling the inflammatory TME, thereby enhancing anti-tumor immunity and inhibiting immune evasion. MgIG enhances cytotoxic T-cell infiltration and, critically, reverses macrophage polarization from an M2-like to an M1-like phenotype, potentially via inhibition of the PLA2–NF-κB signaling axis, with associated suppression of the TLR–MyD88 pathway. These findings suggest that MgIG possesses immunomodulatory functions and indicate its potential as a therapeutic strategy for suppressing inflammation-driven gastric cancer, warranting further clinical investigation.

Abstract Background: To determine the mechanism of magnesium isoglycyrrhizinate in regulating the inflammatory microenvironment to antagonize gastric cancer. Methods: We established MFC xenograft mouse models to investigate the effects of magnesium isoglycyrrhizinate on gastric cancer. A PCR Array chip was deployed to detect the expression level of 96 genes associated with inflammation and immune response. We used immunohistochemistry to stain the key immune cells to observe the density changes in gastric cancer inflammatory microenvironment. The possible mechanism was further investigated in Raw264.7 cells fed with conditioned media from MFC, the expression of M1 and M2 markers were tested by Western blot and ELISA. Results: Magnesium isoglycyrrhizinate reduced the tumor weight, volume and improved survival rate of gastric cancer xenograft mice. From the results of chip screening, changes in inflammation and immune response regulation factors included chemokines and receptors (CXCL1, CXCL2, CXCR1), interleukins and receptors (IL-1β, IL10, IL23A, IL2, IL12, IL1R1), TNF-α and key molecules in NF-κB pathway. Magnesium isoglycyrrhizinate induced the aggregation of CD8 + T cells, reduced Treg infiltration and increased the density of macrophages. M2 macrophage marker Arg1 and cytokines such as IL6, IL10, VEGF-A were down-regulated, on the contrary, the expression of M1 markers iNOS and cytokines IL -12 were up-regulated. Conclusions: Magnesium isoglycyrrhizinate can regulate the inflammatory microenvironment to enhance anti-tumor immunity and suppress immune escape in gastric cancer. Most importantly, it can induce macrophage differentiation into M1 probably through the NF-κB pathway in the cancer inflammatory microenvironment.

Objectives To describe the prevalence of modifiable risk factors for upper digestive tract cancer (UDTC) and its coprevalence, and investigate relevant influencing factors of modifiable UDTC risk factors coprevalence among residents aged 40–69 years in Yangzhong city, China. Design Cross-sectional study. Participants A total of 21 175 participants aged 40–69 years were enrolled in the study. 1962 subjects were excluded due to missing age, marital status or some other selected information. Eventually, 19 213 participants were available for the present analysis. Main outcomes measures Prevalence and coprevalence of eight modifiable UDTC risk factors (overweight or obesity, current smoking, excessive alcohol consumption, insufficient vegetables intake, insufficient fruit intake and the consumption of pickled, fried and hot food) were analysed. Results The prevalence of overweight/obesity, current smoking, excessive alcohol consumption, insufficient vegetables intake, insufficient fruit intake and the consumption of pickled, fried and hot food in this study was 45.3%, 24.1%, 16.2%, 66.1%, 94.5%, 68.1%, 36.0% and 88.4%, respectively. Nearly all (99.9%) participants showed one or more UDTC risk factors, 98.6% of the participants showed at least two risk factors, 92.2% of the participants had at least three risk factors and 69.7% of the participants had four or more risk factors. Multivariate logistic regression analysis revealed that men, younger age, single, higher education, higher annual family income and smaller household size were more likely to present modifiable UDTC risk factors coprevalence. Conclusions The prevalence and coprevalence of modifiable UDTC risk factors are high among participants in Yangzhong city. Extra attention must be paid to these groups who are susceptible to risk factors coprevalence during screening progress. Relative departments also need to make significant public health programmes that aim to decrease modifiable UDTC risk factors coprevalence among residents aged 40–69 years from high-risk areas of UDTC.

Objective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy. Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups. Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group. Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.

e24149 Background: The efficacy and safety of low-dose fentanyl transdermal patch (TDF) in the treatment of opioid-naive patients with moderate-to-severe cancer pain has no tyet been confirmed. There are little international studies, and none in mainland China. The aim of this study was to explore the effect and tolerability of low dose of TDF in opioid-naive patients with Chinese moderate-to-severe cancer pain, and evaluate the influence on quality of life and cognitive function. Methods: A prospective, single-arm, non-randomized, open-label, multicenter trial was conducted with 285 opioid-naivepatients with moderate-to-severe cancer pain in 14 tertiary hospitals in mainland China. The initial analgesic dose of TDF was 12.5 µg/h, pain assessment (pain score, pain relief and pain response rate) was performed every 3 days for a total of 9 cycles.Adverse reactions and events were monitored over 24 days. In the meantime, quality of life and cognitive function of patient were evaluated with EORTC QLQ-C30 and MMSE. Results: 285 patients with 267(92.00%) completed the trial were enrolled. The average age was 60 (range 28-87) and the average effective therapeutic dose was 6.3±6.08mg.The total pain relief rate was 98.12% (mean pain score ±SD, 5.7±0.89 vs 3.9±1.28; P < 0.001). The efficacy of low-dose TDF on pain relief was consistent in groups separated by gender (p < 0.001), age (p < 0.001), types of cancer (p < 0.001), and baseline pain intensity (p < 0.001). There were 79 patients (29.59%) in the low-dose subgroup, and the pain response rate of the low-dose subgroup was better than other dose groups within one week (p = 0.0018).The adverse effects were mild. The most common adverse reactions are constipation 7.87%, followed by nausea 11.24%, vomiting 4.12%, drowsiness 1.87% and urine retention 1.5%.There was no difference in the incidence of adverse reactions between the low-dose subgroup and the other groups (p > 0.05). Meanwhile, TDF improved the quality of life of patients with moderate-to-severe cancer pain (mean± SD: 46.44±16.96 vs. 67.04±18.02;p < 0.05), without impairing cognitive function(mean ±SD, 29.13±1.54 vs. 28.98±1.99; p > 0.05). Conclusions: Low-dose TDF is effective for opioid-naive patients with moderate-to-severe cancer pain. Adverse reactions are mild and the quality of life of patients is improvedwith little losson cognitive function. Further randomized controlled studies are warranted to investigate the value of low-dose TDF in the treatment of opioid intolerant cancer pain. Clinical trial information: ChiCTR-ONC-17014080 .

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 (ClinicalTrials.gov).Lay abstract In this analysis of the FRESCO trial, we evaluated the efficacy and safety of fruquintinib in two different groups of patients (subgroups) with metastatic colorectal cancer - patients who received prior targeted therapy (PTT) and patients who did not (non-PTT). Of the 278 patients treated with fruquintinib, 111 patients received PTT. Patients treated with fruquintinib had longer overall survival and it took longer for their disease to worsen in both PTT and non-PTT subgroups compared with placebo. Patients in both subgroups treated with fruquintinib showed measurable reduction in their tumor size and disease control with similar side effects in patients of both the subgroups. These results suggest that fruquintinib is safe and effective in patients with metastatic colorectal cancer in both subgroups.

[目的]调查中国恶性肿瘤患者的贫血发生率及贫血治疗状况。[方法]对全国97家医院成年恶性肿瘤患者进行开放性、多中心、单次探访、非干预性的横断面调查。通过回顾患者病史,填写贫血调查表格,收集相关数据,如肿瘤类型、疾病分期、肿瘤治疗情况等。根据美国国立癌症研究所（NCI）的贫血分级标准将血红蛋白水平分为5级,以评估贫血的严重程度。[结果]共纳入来自全国97家医院的7324例有效病例,患者平均血红蛋白（Hb）为（114.36±19.60）g/L,贫血发生率为49.24%（3606/7324）,其中1级贫血28.84%,2级贫血15.91%,3级贫血3.66%,4级贫血0.83%。不同肿瘤类型中,泌尿系统肿瘤伴贫血发生率最高（62.89%）,其次是妇科肿瘤（60.32%）和胃肠道肿瘤（51.13%）。在贫血患者中,高达92.84%未给予任何纠正贫血的措施和治疗;接受贫血治疗的患者中,促红细胞生成素（EPO）治疗的比例为44.96%,输血治疗的比例为31.39%,铁剂治疗的比例为6.59%。[结论]目前国内肿瘤相关性贫血发生率较高,但相应的贫血治疗率极低,应加强肿瘤患者的贫血管理。

ETHNOPHARMACOLOGICAL RELEVANCE:Studies have shown that the etiology and pathogenesis of colorectal cancer are closely related to the tumor microenvironment, and the cancer tissue is still in the state of "energy deficit" and has to promote energy generation through high glycolysis. Rhus chinensis Mill is a Chinese herbal medicine used to treat various types of solid tumors in China. Colorectal cancer (CRC) is a heterogeneous disease group caused by abnormal changes in glucose metabolism resulted in lactic acid production, which remodels acidosis.AIM OF THE STUDY:Although previous studies have shown that the active compounds of Rhus chinensis Mill. can inhibit the proliferation of tumor cells, whether its triterpenoids could effectively regulate glycolysis involved in CRC have not been systematically investigated.MATERIALS AND METHODS:In this study, the extraction of triterpenoids extract from Rhus chinensis Mill. was obtained, and cell viability assay, the percentage of apoptosis for CRC cells were counted, and matrigel invasion assay and production of lactic acid and glucose uptake assay was determined. we further examined the expression of the key glycolytic enzymes and acid-sending ion channel (ASIC) family members of SW620 cells, and some key proteins in the glycolytic pathway were further verified.RESULTS:Notably, triterpenoids (TER) of Rhus chinensis Mill. showed effective anti-proliferative activity and significantly altered protein levels associated with CRC cell survival and glycolysis metabolism. TER could down-regulate the expression of ASIC2, in CRC SW620 cell line. Most importantly, the levels of ASIC2 and calcineurin/nuclear factor of activated T cells (NFAT) were also down-regulated by TER. Furthermore, inhibition of activated the ASIC2-mediated calcineurin/NFAT1 pathway and target gene transcript expression of MMP-2 and MMP-9 in parallel to reduce, and resulted in the reduced invasion ability by TER treatment.CONCLUSION:The potential pathways and targets that involved in glycolysis to excert the anti-CRC effects of main compounds in triterpenoids of Rhus chinensis Mill. were predicted by network pharmacology methods. Our findings thus provided rational evidence that inhibition of the ASIC2-induced calcineurin/NFAT pathway by triterpenoids in Rhus chinensis Mill. profoundly suppressed cell growth and invasion in CRC, which target alternative glycolysis in colorectal tumor cells, may be a useful adjuvant therapy in the treatment of colorectal cancer.

目的 探讨胃癌组织中同源盒(HOX) A7和HOXC8蛋白的表达水平及两者与胃癌临床病理特征的关系.方法 收集海军军医大学长征医院2001年1月至2003年5月收治并经病理组织确诊的241例胃腺癌患者的胃癌组织及配对癌旁组织并构建组织芯片,采用免疫组化SP法检测胃癌及对应癌旁组织中HOXA7和HOXC8蛋白的表达情况,分析两蛋白的阳性表达与胃癌临床病理特征(年龄、性别、肿瘤大小、浸润深度、淋巴结转移、分化程度和TNM分期)的关系,根据随访数据分析不同HOXA7和HOXC8表达的预后情况.结果 胃癌中HOXA7和HOXC8阳性染色于肿瘤细胞浆,阳性染色为淡黄、棕黄乃至深褐色,弥漫性分布.胃癌组织中HOXA7和HOXC8的阳性率分别为55.6％(134/241)和60.6％(146/241),均高于癌旁组织的27.8％(67/241)和8.7％(21/241),差异有统计学意义(P＜0.05).HOXA7阳性表达与浸润深度有关(P＜0.05),而与年龄、性别、肿瘤大小、淋巴结转移、分化程度和TNM分期均无关(P＞0.05);HOXC8阳性表达与年龄、肿瘤大小、浸润深度、淋巴结转移和TNM分期有关,而与性别和分化程度无关(P＞0.05).单因素分析显示年龄、浸润深度、淋巴结转移、TNM分期及HOXA7和HOXC8表达均与胃癌患者的预后有关(P＜0.05);HOXA7和HOXC8阳性患者的中位总生存期分别为56.0和24.9个月,均低于阴性患者的75.6和90.0个月,差异有统计学意义(P＜0.05).进一步多因素分析发现HOXC8是胃癌患者不良预后的独立风险因素(RR=0.268,95％CI:0.144～0.498,P＜0.001).结论 HOXA7和HOXC8在胃癌中高表达,且在胃癌的发生发展中起着重要作用,其中HOXC8可作为判断胃癌患者不良预后的重要指标.

Importance Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration ClinicalTrials.gov Identifier: NCT02314819

BACKGROUND:Thirty to 40 % of non-small cell lung cancer (NSCLC) patients developed higher hypertriglyceridemia in the process of treatment with bexarotene. And bioinformatics studies discovered that the expression of slc10a2 was increased in high-grade hypertriglyceridemia patients. So, we will explore the mechanism which may involve in this process.METHODS:We constructed slc10a2 overexpressed A549 cells and H1299 cells as cell models, normal A549 cells and H1299 cells as control. Then we explored the effects of slc10a2 on A549 cells and H1299 cells behaviors, including proliferation, invasion and apoptosis. The expression of apoptotic related genes and anti-cancer genes also been detected.RESULTS:We found that the proliferation and migration were inhibited and the apoptosis of NSCLC cells was accelerated by bexarotene. In addition, overexpressed slc10a2 in NSCLC cells can further suppress the proliferation and migration, and promote apoptosis under the treatment of bexarotene. On the contrary, the opposite results were obtained after slc10a2 gene was silenced in NSCLC cells treated with bexarotene. Moreover, the expression of caspase 3, caspase 7, PTEN, P21, P53, LKB1, TSC2 were increased and the expression of Bcl-2, cyclin D1, c-FLIP were declined in NSCLC cells and slc10a2 overexpressed NSCLC cells with the treatment of bexarotene, and the opposite situations were seen after slc10a2 gene was silenced in NSCLC cells. The further studies revealed the increased expression of slc10a2 activated the expression of peroxisome proliferator-activated receptor γ (PPARγ), then up-regulated PTEN expression and down-regulated mTOR expression.CONCLUSION:These results suggest that bexarotene inhibits the viability of lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

Chemical oxygen demand (COD) is a water quality indicator that is typically measured by lengthy chemical analysis methods in the laboratory, which indicates that obtaining rapid results is difficult.

This study explored potential biomarkers associated with Lauren classification of gastric cancer. We screened microarray datasets on gastric cancer with information of Lauren classification in gene expression omnibus (GEO) database, and compared differentially expressing genes between intestinal-type or diffuse-type gastric cancer. Four sets of microarray data (GSE2669, GSE2680, GDS3438, and GDS4007) were enrolled into analysis. By differential gene analysis, UBE2C, CDH1, CENPF, ERO1L, SCD, SOX9, CKS1B, SPP1, MMP11, and ANLN were identified as the top genes related to intestinal-type gastric cancer, and MGP, FXYD1, FAT4, SIPA1L2, MUC5AC, MMP15, RAB23, FBLN1, ANXA10, and ADH1B were genes related to diffuse-type gastric cancer. We comprehensively validated the biological functions of the intestinal-type gastric cancer related gene UBE2C and evaluated its clinical significance on 1,868 cases of gastric cancer tissues from multiple medical centers of Shanghai, China. The gain of copy number on 20q was found in 4 out of 5 intestinal-type cancer cell lines, and no similar copy number variation (CNV) was found in any diffuse-type cancer cell line. Interfering UBE2C expression inhibited cell proliferation, migration and invasion in vitro, and tumorigenesis in vivo. Knockdown of UBE2C resulted in G2/M blockage in intestinal-type gastric cancer cells. Overexpression of UBE2C activated ERK signal pathway and promoted cancer cell proliferation. U0126, an inhibitor of ERK signaling pathway reversed the oncogenic phenotypes caused by UBE2C. Moreover, overexpression of UBE2C was identified in human intestinal-type gastric cancer. Overexpression of UBE2C protein predicted poor clinical outcome. Taken together, we characterized a group of Lauren classification-associated biomarkers, and clarified biological functions of UBE2C, an intestinal-type gastric cancer associated gene. Overexpression of UBE2C resulted in chromosomal instability that disturbed cell cycle and led to poor prognosis of intestinal-type gastric cancer.

The inorganic pyrophosphatase gene (PPA1) encodes inorganic pyrophosphatase, an enzyme that catalyzes the hydrolysis of inorganic pyrophosphate to orthophosphate, and has been revealed to be dysregulated in several types of human cancer. However, the role of PPA1 in intrahepatic cholangiocarcinoma (ICC) has not yet been determined. The present study detected PPA1 expression and investigated its clinical significance in ICC. Tissue microarray blocks containing 93 ICC specimens were constructed. The protein expression of PPA1 in these specimens was detected by immunohistochemistry. PPA1 was overexpressed in 49.5% of the ICC specimens and was significantly associated with large tumor size, positive margins, T stage, lymph nodal metastases, poorly differentiated tumors and advanced disease stage. Furthermore, PPA1 expression was an indicator of future recurrence and poor survival in patients with ICC. Increased expression of PPA1 is a common event in human ICC and is significantly associated with a poor outcome in patients with ICC, suggesting a potential role for PPA1 in the development and progression of ICC.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

To confirm non‐inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5‐fluorouracil (5‐FU)/cisplatin (FP) as first‐line treatment for advanced gastric cancer (AGC) in Chinese patients.

Background SLC38A1/SNAT1 has been found to play an essential role in human development, but its role in osteosarcoma (OS) has yet to be evaluated. The purpose of this study was to assess the expression of SLC38A1/SNAT1 in patients with OS, and further investigate the mechanisms by which it affects tumor growth and metastasis. Methods Tissue microarray blocks and immunohistochemical studies were carried out to assess the expression of SNAT1 in 165 OS specimens. Its correlation with clinicopathological characteristics was then analyzed. The function of SNAT1 in OS cells was investigated by silencing SNAT1 using SNAT1-shRNA in vitro and in vivo. Results SNAT1 was highly expressed in 85% OS and significantly closely associated with pulmonary metastasis. Patients with high SNAT1 expression survived for shorter periods than those with low SNAT1 expression. Suppression of endogenous SNAT1 led to inhibition of cell proliferation, cell colony formation, and cell migration in vitro, and retarded tumor growth in xenograft models. Silencing SNAT1 reduced expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF. Conclusions Our results indicated that increased expression of SNAT1 is a common event in OS. SNAT1 played an essential role in the development and progression of osteosarcoma, which may serve as a prognostic and therapeutic marker of OS.

目的 探讨乙醛脱氢酶1A1(ALDH1A1)过表达对胃癌细胞增殖、克隆形成和侵袭能力的影响.方法 成功构建过表达ALDH1A1的pEGFP-N1-ALDH1A1真核载体并转染至人胃癌细胞株MKN-28(实验组),同时设空载体组(转染空载体pEGFP-N1的MKN-28细胞)和空白对照组(未行任何干预措施的MKN-28细胞),分别于转染96 h后采用四甲基偶氮唑盐(MTT)法、克隆形成实验及Transwell小室侵袭实验检测ALDH1A1过表达对MKN-28细胞增殖、克隆形成和侵袭能力的影响.结果 实验组转染96 h后的增殖抑制率为(19.26±2.01)％,均低于空载体组和空白对照组,而克隆形成率和穿膜细胞数分别为(25.44±1.74)％和(219.78±12.93)个,均高于空载体组和空白对照组,差异有统计学意义(P＜0.05).空白对照组和空载体组以上指标的差异均无统计学意义(P＞0.05).结论 在MKN-28细胞中过表达ALDH1A1,可增强肿瘤细胞的增殖、克隆形成和侵袭能力,提示ALDH1A1可能参与了胃癌的发生、发展.

Activation of AMP-activated protein kinase (AMPK) suppressed mammalian target of rapamycin (mTOR) pathway, resulting in impaired cancer cell proliferation. Two cohorts (50 and 1072 cases) of patients with resected gastric adenocarcinoma were enrolled in the study. Immunohistochemical staining for p-AMPKa, p-ACC, p-mTOR, p-S6, and p-4EBP1 was performed on the 50-patient cohort. Tissue microarray blocks containing samples from 1072 patients of Chinese ethnicity were used for the immunohistochemical detection of p-AMPKa and p-S6 levels. p-AMPK and p-ACC were frequently inactivated in both cohorts of gastric cancer samples, while p-mTOR, p-S6, and p-4EBP1 were frequently activated in the small cohort of gastric cancer. However, only levels of p-AMPKa and p-S6 were associated with the overall survival of gastric cancer patients. In the larger 1072-patient cohort, downregulation of p-AMPKa and upregulation of p-S6 were associated with tumor progression and were independent predictors of survival after resection of primary gastric cancer. Therefore, reciprocal expression of p-AMPKa and p-S6 may be promising prognostic biomarkers in patients with gastric cancer.