Guanylate binding protein 5 accelerates gastric cancer progression via the JAK1-STAT1/GBP5/CXCL8 positive feedback loop.

Guanylate binding protein 5 (GBP5) is a member of the interferon (IFN)-inducible large guanosine triphosphate hydrolases (GTPase) family that regulates cell-autonomous immunity and malignant tumor transformation. However, its specific roles and underlying mechanisms GBP5 in gastric cancer (GC) remain unknown. In this study, we aimed to determine the role GBP5 and underlying mechanism of GBP5 in GC cell progression. Potential oncogenic roles of GBP5 in GC as well as its relationship with the tumor immune microenvironment (TIME) were comprehensively evaluated using bioinformatics analysis. Protein expression levels of GBP5 and their correlation with clinicopathological features of patients were assessed using immunohistochemistry. In addition, diverse in vitro functional experiments were performed to identify the functions of GBP5 in GC. Downstream targets of GBP5 were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. GBP5 expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, GBP5 was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, GBP5-induced CXCL8 regulated the JAK1-STAT1 signaling pathway to form a positive feedback loop. Moreover, GBP5 is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new JAK1-STAT1/GBP5/CXCL8 pathway and highlighted the value of GBP5 as a predictive biomarker and novel target for GC intervention.

The Oncolytic Virus in Cancer Diagnosis and Treatment.

Cancer has always been an enormous threat to human health and survival. Surgery, radiotherapy, and chemotherapy could improve the survival of cancer patients, but most patients with advanced cancer usually have a poor survival or could not afford the high cost of chemotherapy. The emergence of oncolytic viruses provided a new strategy for us to alleviate or even cure malignant tumors. An oncolytic virus can be described as a genetically engineered or naturally existing virus that can selectively replicate in cancer cells and then kill them without damaging the healthy cells. There have been many kinds of oncolytic viruses, such as herpes simplex virus, adenovirus, and Coxsackievirus. Moreover, they have different clinical applications in cancer treatment. This review focused on the clinical application of oncolytic virus and predicted the prospect by analyzing the advantages and disadvantages of oncolytic virotherapy.

miR-635 targets KIFC1 to inhibit the progression of gastric cancer.

Accumulating studies have shown that the dysregulation of microRNAs is related to the carcinogenesis and development of gastric cancer (GC), and the role of miR-635 in GC remains largely unknown. miR-635 and Kinesin Family Member C1 (KIFC1) mRNA expression in GC tissues and paracancerous tissues and cells were detected by quantitative real-time PCR. KIFC1 protein expression in GC tissues and paracancerous normal tissues and cells was detected by immunohistochemistry and western blot. Cell proliferation was monitored by Cell Counting Kit-8 assay and 5-bromo-2'-deoxyuridine assay. Transwell assay was employed to detect the migration and invasion of GC cells. The dual-luciferase reporter gene assay was adopted to detect the targeting relationship between miR-635 and KIFC1. Compared with paracancerous tissues, miR-635 expression was remarkably decreased in GC tissues; conversely, KIFC1 expression was significantly increased. Compared with human normal gastric epithelial cell GSE-1, miR-635 expression was markedly decreased in GC cell lines. Meanwhile, KIFC1 expression was significantly increased, and the Kaplan-Meier Plotter database showed that its high expression was remarkably associated with poor prognosis. Additionally, miR-635 can negatively regulate KIFC1. miR-635 can target KIFC1 to inhibit proliferation, migration and invasion of GC cells. Collectively, miR-635 is lowly expressed in GC, and it inhibits proliferation, migration and invasion of GC cells via regulating KIFC1.

Nano-sized titanium alloy particles inhibit the proliferation and promote the apoptosis of bone marrow mesenchymal stem cells in vitro.

Aseptic loosening of artificial joints is the leading cause of failure for patients who receive total joint arthroplasty. Prior reports indicate that bone marrow mesenchymal stem cells (BSMC) are critical in the stabilization of implanted artificial joints, and that deregulated interaction between BMSCs and artificial joint derived particles is a risk factor for aseptic loosening with an unknown mechanism. In the present study, the pathomechanisms whereby titanium and its alloy derived particles facilitate aseptic loosing were investigated in vitro. It was demonstrated that nano­sized titanium alloy particles significantly inhibited the proliferation of BMSCs in a time and concentration dependent manner. Furthermore, it was demonstrated that the particles promoted the apoptosis of BMSCs in the same manner. Bax and Caspase­3 expression of BMSCs were elevated when cultured with the particles. As BMSCs exhibit a critical role in the stabilization of artificial joints, the results of the present study may provide a novel direction for the management of aseptic loosening in clinics.

Chemotherapy Near the End of Life for Chinese Patients with Solid Malignancies.

INTRODUCTION: There are increasing concerns about the negative impacts of chemotherapy near the end of life (EOL). There is discrepancy among different countries about its use, and little is known about the real-world situation in China. PATIENTS AND METHODS: This retrospective study was conducted at six representative hospitals across China. Adult decedents with a record of advanced solid cancer and palliative chemotherapy were consecutively screened from 2010 through 2014. The prevalence of EOL chemotherapy within the last 1 month of life was set as the primary outcome. The correlations among EOL chemotherapy, clinicopathological features, and overall survival (OS) were investigated. RESULTS: A total of 3,350 decedents who had had cancer were consecutively included; 2,098 (62.6%) were male and the median age was 56 years (range, 20-88). There were 177 (5.3%), 387 (11.6%), and 837 (25.0%) patients who received EOL chemotherapy within the last 2 weeks, 1 month, and 2 months of life, respectively. We identified inferior OS (median OS, 7.1 vs. 14.2 months; hazard ratio, 1.37; 95% confidence interval [CI], 1.23-1.53; p < .001), more intensive treatments (e.g., admitted to intensive care unit [ICU] in the last month of life, received cardiopulmonary resuscitation and invasive ventilation support), and hospital death (odds ratio, 1.53; 95% CI, 1.14-2.06; p = .005) among patients who received continued chemotherapy within the last month compared with those who did not. However, subgroup analyses indicated that receiving oral agents correlated with fewer ICU admissions and lower rates of in-hospital death. CONCLUSION: This study showed that EOL chemotherapy is commonly used in China. Intravenous chemotherapy at the EOL significantly correlated with poor outcomes and the role of oral anticancer agents warrants further investigation. The Oncologist 2017;22:53-60Implications for Practice: The role of chemotherapy toward the end of life (EOL) in patients with solid cancers is debatable. This article is believed to be the first to report the current prevalence of EOL chemotherapy in China. This study found that, compared with oral anticancer agents, intravenous chemotherapy at the EOL was significantly associated with poor outcomes. Therefore, the role of oral anticancer agents at the EOL stage deserves further investigation.

Mitogen-Activated Protein Kinases Are Activated in Placental Injury in Rat Model of Acute Pancreatitis in Pregnancy.

OBJECTIVES: To establish a rat model of acute pancreatitis in pregnancy (APIP) and evaluate its general presentations, assess placental injury, and discuss possible mechanisms. METHODS: The APIP rat model was induced by sodium taurocholate in Sprague-Dawley rats of later gestation. Normal and sham-operated (SO) rats in later gestation were set as controls, 3 time points were set in SO and APIP groups to determine optimal modeling time. Histological changes of pancreas and placenta were assessed. Placental injury was determined by immunohistochemistry stain of caspase-3. Serum levels of amylase, lipase, and Ca; proinflammatory cytokines as tumor necrosis factor-α, interleukin-1ß (IL-1ß), IL-6, and anti-inflammatory cytokine IL-10 by enzyme-linked immunosorbent assay; mitogen-activated protein kinases and their phosphorylated forms by Western blotting. RESULTS: Pancreatic necrotizing and placental injury occurred in time-dependent patterns. Serum levels of amylase and lipase significantly increased but Ca decreased; tumor necrosis factor-α, IL-1ß, IL-6, and IL-10 were all increased in the APIP group; c-Jun N-terminal kinase, p38, and ERK1/2 were activated but with different distributing patterns in the placenta. CONCLUSIONS: Placental injury is involved in the rat model of APIP, and a modeling time of 6 hours is optimal and conducive to further studies; c-Jun N-terminal kinase and p38 may play important roles in placental injury during APIP.

[Evaluation of osteogenic effects of BMP2 up-regulator E40071 in vitro].

Bone morphogenetic protein 2(BMP2) plays a key role in bone development and reestablishment. In the study, we screened up-regulators of BMP2 among 20 000 compounds through a cell-based high throughput screening model and a positive compound E40071 [2-(4-(5-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-yl) piperazin-1-yl)ethan-1-ol] was found as the positive hit. The EC(50) value of E40071 was 2.73 µmol·L(-1). In vitro, E40071 upregulated the m RNA levels of BMP2 and the downstream transcription factors, Runx2 and Osx in MC3T3-E1(subclone 14). Protein expression of Runx2 was up-regulated by E40071 through induction of Smad1/5/8 phosphorylation. The alkaline phosphatase(ALP) activity was increased by E40071. Moreover, E40071 promoted the mineralization of MC3T3-E1(subclone 14) by Alizarin red S staining. In addition, E40071 markedly inhibited osteoclast differentiation of mice macrophage Raw264.7 induced by RANKL and reduced the expression of osteoclast differentiation markers, including MMP9 and NFATc1. The results suggest that E40071 is able to promote bone formation activity of osteoblasts and inhibit differentiation of osteoclasts.

[Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors].

This study is to explore new lead compounds by inhibition of Pin1 for anticancer therapy using temperature sensitive mutants. As Pin1 is conserved from yeast to human, we established a high-throughput screening method for Pin1 inhibitors, which employed yeast assay. This method led to the identification of one potent hits, 8-11. In vitro, 8-11 inhibited purified Pin1 enzyme activity with IC50 of (10.40 +/- 1.68) micromol x L(-1), induced G1 phase arrest and apoptosis, showed inhibitory effects on a series of cancer cell proliferation, reduced Cyclin D1 expression, was defined as reciprocally matched for protein-ligand complex in virtual docking analysis and reduced cell migration ability. In vivo, we could observe reduction of tumor volume after treatment with 8-11 in xenograft mice compared with vehicle DMSO treatment. Altogether, these results provide for the first time the involvement of 8-11 in the anticancer activity against Pin1.

[Value of normalization window of tumor vasculature in neoadjuvant chemotherapy for patients with unresectable gastric cancer].

OBJECTIVE: To evaluate the value of normalization window of tumor vasculature (NWTV) in patients with unresectable gastric cancer undergoing neoadjuvant chemotherapy. METHODS: From October 2010 to March 2011, 93 patients with unresectable advanced or locally advanced gastric carcinoma were prospectively collected and randomly divided to Group A(n=30), Group B(n=29), and Group C(n=34). Group A received FOLFOX4 as conventional neoadjuvant chemotherapy. Group B received FOLFOX4 plus bevacizumab. The treatment was adjusted in Group C according to the hypothesis of NWTV with neoadjuvant chemotherapy delivered 5 days after bevacizumab treatment. The efficacy, drug toxicity and clinical outcome were assessed and compared between the three groups. RESULTS: There were no significant differences among the 3 groups in demographics(P>0.05). All the patients completed the neoadjuvant chemotherapy. Efficacy and toxicity between the three groups were comparable(P>0.05). The rates of tumor downstaging in the three groups were 56.7%(17/30), 72.4%(21/29), 85.3%(29/34), respectively, with a significantly lower downstaging rate in Group C as compared to Group A(P<0.05). R0 resection rates were 23.3%(7/30), 27.6%(8/29), 52.9% (18/34), respectively, with significantly higher R0 resection rate in Group C as compared to Group A and Group B(All P<0.05). There was no perioperative death in this cohort. Postoperative complications were comparable among the 3 groups(P>0.05). CONCLUSIONS: Anti-angiogenesis agent can improve the efficacy of neoadjuvant chemotherapy in unresectable gastric cancer. Furthermore, administration according to NWTV may achieve better outcomes.

Mycophenolic acid induces adipocyte-like differentiation and reversal of malignancy of breast cancer cells partly through PPARγ.

Mycophenolic acid (MPA) has been known for decades to be an anticancer and immunosuppressive agent and has significant anticancer properties, but its underlying molecular mechanisms are poorly characterized. Peroxisome proliferator-activated receptor gamma (PPARγ) has a central role in adipocyte differentiation, and MPA has been shown to be a potent PPARγ agonist. Whether PPARγ activation has a putative role in the anticancer efficacy of MPA via induction of adipocyte-like differentiation has not been elucidated. In the present study, MPA was demonstrated to dose-dependently activate PPARγ transcription in the GAL4-hPPARγ (LBD) chimeric receptor assay and PPRE-luc reporter gene assay with an EC(50) of 5.2-9.3 µM. Treatment of the breast cancer cell lines MDA-MB-231 and MCF-7 with MPA resulted in differentiation of adipose tissue that was characterized by accumulation of intracellular lipids, enlargement of cell volume, and permanent withdrawal from the cell cycle at the G1/G0 stage. At a molecular level, the expression of three adipocyte differentiation markers (PPARγ, adipsin D, and aP2) was remarkably induced in differentiated breast cancer cells. However, RNA interference experiments showed that PPARγ-knockdown cannot completely reverse the differentiated state of MDA-MB-231 cells after MPA treatment. These data suggest that the effects of MPA on adipocyte-like terminal differentiation of breast cancer cells are (at least in part) due to PPARγ activation, which is a novel anticancer mechanism of MPA.