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.

Chinese Medicine Plaster as A New Treatment for Surgical Site Infection in Patients with Cesarean Delivery: A Randomized, Double-Blind, Controlled Trial.

OBJECTIVE: To evaluate the efficacy of Chinese plaster containing rhubarb and mirabilite on surgical site infection (SSI) in patients with cesarean delivery (CD) by performing a randomized controlled trial. METHODS: This randomized controlled trial included 560 patients with CD due to fetal head descent enrolled at a tertiary teaching center between December 31, 2018 and October 31, 2021. Eligible patients were randomly assigned to a Chinese medicine (CM) group (280 cases) or a placebo group (280 cases) by a random number table, and were treated with CM plaster (made by rhubarb and mirabilite) or a placebo plaster, respectively. Both courses of treatment lasted from the day 1 of CD, followed day 2 until discharge. The primary outcome was the total number of patients with superficial, deep and organ/space SSI. The secondary outcome was duration of postoperative hospital stay, antibiotic intake, and unplanned readmission or reoperation due to SSI. All reported efficacy and safety outcomes were confirmed by a central adjudication committee that was unaware of the study-group assignments. RESULTS: During the recovery process after CD, the rates of localized swelling, redness and heat were significantly lower in the CM group than in the placebo group [7.55% (20/265) vs. 17.21% (47/274), P<0.01]. The durution of postoperative antibiotic intake was shorter in the CM group than in the placebo group (P<0.01). The duration of postoperative hospital stay was significantly shorter in the CM group than in the placebo group (5.49 ± 2.68 days vs. 8.96 ± 2.35 days, P<0.01). The rate of postoperative C-reactive protein elevation (≽100 mg/L) was lower in the CM group than in the placebo group [27.6% (73/265) vs. 43.8% (120/274), P<0.01]. However, there was no difference in purulent drainage rate from incision and superficial opening of incision between the two groups. No intestinal reactions and skin allergies were found in the CM group. CONCLUSIONS: CM plaster containing rhubarb and mirabilite had an effect on SSI. It is safe for mothers and imposes lower economic and mental burdens on patients undergoing CD. (Registration No. ChiCTR2100054626).

Subwavelength dichroic demultiplexer based on double Fabry-Perot cavities.

Plasmonic demultiplexers hold promise for the realization of the subwavelength and high-splitting ratio dichroic splitter and have a wide range of applications from optical communication, and manipulation to ultrafast data treatment. However, this vision has not been realized for a long time due to lacking the suitable splitting structure design, which limits its further development of integrated photonic circuits. Here, we demonstrate a plasmonic demultiplexer with subwavelength feature size (0.54 µm) and broadband spectral (620-870 nm) range, and high-splitting ratio (17 dB in experiments and 20 dB in calculations). It consists of two adjacent Fabry-Perot cavities (covered by PMMA polymer) and coupling gratings, which are integrated with the Au waveguide. The relatively simple double cavities design of our device has a simple theoretical analysis and fabrication process. Our work has relevance for various optical applications, such as multiple wavelength photodetectors and optical multichannel interconnects.

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.

[Characteristics and Influencing Factors of Stable Hydrogen and Oxygen Isotopes in Groundwater in the Permafrost Region of the Source Region of the Yangtze River].

We use 84 rainfall samples collected during June to September 2017 from the Dongkemadi basin, source region of the Yangtze River, China, to analyze the characteristics and influencing factors of stable isotopes in groundwater, and further discuss the groundwater recharge sources. The results showed that the range of groundwater δ18 O values in this permafrost region varied from -15.3‰ to -12.5‰ (mean -14.0‰). The range of δD values in groundwater varied from -108.9‰ to -91.7‰ (mean -100.2‰). Compared with local atmospheric precipitation, groundwater isotopes were relatively enriched. The slope and intercept of the groundwater line (GL) in the study area were both lower than of those of the global and local meteoric water lines (GMWL and LMWL), thus indicating that groundwater in the study area was subjected to evaporation during rainfall recharge of groundwater. The d-excess values of groundwater varied from 4.9‰ to 25.0‰ (mean 11.6‰), which was close to the average d-excess value determined for global average rainfall (10‰), but lower than that of rainfall in the study area (15.1‰). The influencing factors on the composition and variation of groundwater isotopes were different in different periods. The permafrost active layer was relatively thin during periods of increasing air temperature, and groundwater isotopes were significantly affected by air temperature. A temperature decrease during the latter part of the sampling period, when the thickness of the permafrost active layer was still increasing, further increased the retention time of infiltrating rainfall in the soil, thereby eventually leading to evaporation that strengthened the enrichment of heavy isotopes in the groundwater. According to the topographic characteristics of the Dongkemadi basin, the isotopic characteristics of the groundwater, and the factors influencing the isotopic composition, we conclude that rainfall was the main source of groundwater recharge. The results of this study provide a scientific basis for studying water cycle processes in the permafrost regions of the source region of the Yangtze River.

[Characteristics of Stable Isotopes in Precipitation and Moisture Sources in the Headwaters of the Yangtze River].

Based on the stable isotopes of 73 precipitation samples continuously collected from May to October 2014 and related meteorological statistics in the Dongkemaldi Basin, the characteristics of δD, δ18O, and d-excess of precipitation, as well as the correlations between δ18O and the rainfall amount and air temperature were analyzed. The moisture sources were tracked by the HYSPLIT model to further estimate the contribution of different water vapor sources to the rainfall amount. The results showed that the range of δ18O and δD values varied from -26.5‰ to 1.9‰ and -195.2‰ to 34.0‰, respectively; meanwhile, the δ18O and δD values in precipitation fluctuated greatly with time in response to water vapor transport from different moisture sources of the Qinghai-Tibet Plateau. The slope and intercept of the Local Meteoric Water Line (LMWL) were both higher than those of the Global Meteoric Water Line (GMWL) and close to the LMWL in the northern area of the Qinghai-Tibet Plateau. The relationship between δ18O and δD in different precipitation types showed significant differences, which were mainly related to the source of water vapor and meteorological conditions during the process of precipitation formation. Because of the influence of local evaporation and the transport process of water vapor, the d-excess values of atmospheric precipitation were relatively large; the δ18O in precipitation had a significant amount effect, but had no temperature effect, thus indicating that the rainfall amount was more effective in controlling the stable isotope content of atmospheric precipitation than temperature. The modeled trajectory of vapor sources showed that water vapor of precipitation was mainly derived from the marine vapor carried by the southwest monsoon, local moisture, and the westerly water vapor, and their contributions to the rainfall amount were 43%, 36%, and 21%, respectively. The results of this study can contribute to further understanding of the atmospheric circulation characteristics and water cycle process of the Dongkemadi basin in the headwaters of the Yangtze River.

[Chemical Characteristics and Ionic Sources of Precipitation in the Source Region of the Yangtze River].

Using 64 precipitation samples collected from June to September 2013 in the Dongkemadi Basin in the source region of the Yangtze River, the pH, conductivity, and main ionic concentration characteristics of precipitation were analyzed. The main ionic sources of precipitation and their relationships with atmospheric circulation were examined using factor analysis, correlation analysis, enrichment factor analysis, and backward trajectory analysis. The results showed that the range of precipitation pH values varied from 5.26 to 9.25 with a weighted average of 6.70, and conductivity ranged from 0.23 to 28.70 µS·cm-1 with a weighted average of 3.45 µS·cm-1. The conductivity of precipitation was lower than for the Mt. Waliguan basin (China Global Atmosphere Watch baseline observatory). The total ionic concentrations in the precipitation ranged from 7.0 to 376.9 µeq·L-1 with a weighted average of 40.8 µeq·L-1. The ranked order of ionic concentrations was HCO3- > NH4+ > Ca2+ > NO3- > SO42- > Na+ > Cl- > K+ > Mg2+. HCO3-, NH4+,Ca2+, and NO3- were the dominant ions, which accounted for 74.75% of the total ionic concentration. Fractional acidity (FA) analysis showed that 97.8% of the precipitation acidity was neutralized by alkaline constituents. Neutral factor (NF) analysis indicated that NH4+ and Ca2+ were the dominant neutralization constituents in the precipitation. The precipitation ions in this study area were mainly derived from terrestrial material, while input from marine sources was relatively low. Backward trajectory analysis revealed that the total ionic concentrations varied significantly between the different sources, which followed the order of local sources>westerly sources>monsoon sources. This indicates that different atmospheric circulation conditions and air mass sources have a significant influence on the chemical composition of precipitation in this area. To some extent, the chemical characteristics of precipitation could reflect the air quality and background values for remote areas due to the limited effect of human activities. The results of this study provide a scientific basis for the protection of water quality and the assessment of the impact of human activities on the atmospheric environment in the source region of the Yangtze River.

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.

Possible involvement of the oxLDL/LOX-1 system in the pathogenesis and progression of human intervertebral disc degeneration or herniation.

Epidemiological studies have concluded that hyperlipidemia and atherosclerosis were related to intervertebral disc degeneration (IVDD). The presence of oxidized low density lipoprotein (ox-LDL) and the expression of lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) have not been explored in this tissue. In this study, we investigated the presence of ox-LDL and the expression of its receptor LOX-1 in non-degenerated, degenerated or herniated human intervertebral discs (IVDs). The expression of LOX-1 and matrix metalloproteinase 3 (MMP3) were studied after incubating nucleus pulposus cells (NPCs) with ox-LDL. The presence of ox-LDL and LOX-1 was positively related with the extent of IVDD in nucleus pulposus (NP), end-plate cartilage and outer annulus fibrous, but not with the extent of degeneration of inter annulus fibrous. Ox-LDL significantly reduced the viability of human NPCs in a dose and time-dependent manner, and increased the expression of MMP3 induced by LOX-1. Pretreatment with anti-human LOX-1 monoclonal antibody reversed these effects. Ox-LDL, principally mediated by LOX-1, enhanced MMP3 production in NPCs through the NF-κB signaling pathway. In conclusion, increased accumulation of ox-LDL and LOX-1 in IVDs indicates a specific role of the receptor-ligand interaction in degeneration or herniation of IVDs.

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.

Hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced severe acute pancreatitis by inhibiting ROS and NF-κB pathway.

Hydrogen (H2), a new antioxidant, was reported to reduce (•)OH and ONOO(-) selectively and inhibit certain proinflammatory mediators to product, without disturbing metabolic redox reactions or ROS involved in cell signaling. We herein aim to explore its protective effects on acute renal injury in sodium taurocholate-induced acute pancreatitis and its possible mechanisms. Rats were injected with hydrogen-rich saline (HRS group) or normal saline (SO and SAP group) through tail intravenously (6 mL/kg) and compensated subcutaneously (20 mL/kg) after successful modeling. Results showed that hydrogen-rich saline attenuated the following: (1) serum Cr and BUN, (2) pancreatic and renal pathological injuries, (3) renal MDA, (4) renal MPO, (5) serum IL-1ß, IL-6, and renal TNF-α, HMGB1, and (6) tyrosine nitration, IκB degradation, and NF-κB activation in renal tissues. In addition, it increased the level of IL-10 and SOD activity in renal tissues. These results proved that hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced acute pancreatitis, presumably because of its detoxification activity against excessive ROS, and inhibits the activation of NF-κB by affecting IκB nitration and degradation. Our findings highlight the potential value of hydrogen-rich saline as a new therapeutic method on acute renal injury in severe acute pancreatitis clinically.

[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.

Salidroside stimulates osteoblast differentiation through BMP signaling pathway.

Salidroside (SAL) is one of main active components of Rhodiola rosea L. and possesses diverse pharmacological effects. However, the direct role of SAL in bone metabolism remains elusive. In this study, effects of SAL on osteoblast differentiation of murine pluripotent mesenchymal cell line C3H10T1/2 and osteoblastic cell line MC3T3-E1 were examined. We first identified SAL as a potential BMP2 activator in a cell-based screening assay. SAL (0.5-10 µM) could slightly promote the proliferation and greatly increase the alkaline phosphatase (ALP) activity in both cells. Furthermore, SAL increased the mRNA expressions of osteoblast marker genes in either C3H10T1/2 or MC3T3-E1 cells after treatment for different time. Moreover, the mineralization of C3H10T1/2 cells assayed by Alizarin red S staining was dose-dependently increased by SAL. Mechanistically, SAL increased the mRNA level of genes involved in the regulation of BMP signaling pathway, including BMP2, BMP6 and BMP7 and enhanced the phosphorylation of Smad1/5/8 and ERK1/2. The osteogenic effect of SAL was abolished by BMP antagonist noggin or by BMP receptor kinase inhibitor dorsomorphin. Further in vivo study demonstrated that SAL reversed bone loss in ovariectomized rats. Collectively, our findings indicate that SAL regulates bone metabolism through BMP signaling pathway.

[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.

Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized rats.

In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro. Compound 8a was found to significantly affect the bone formation rate of tested SAMP6 mice. Compound 1 showed an improved bone quality in SAMP6 mice and also showed activity in OVX rats. We have demonstrated that substituted benzothiophene and benzofuran derivatives, especially compounds 1 and 8a, enhance BMP-2 expression in vitro and in vivo and stimulate bone formation and trabecular connectivity restoration in vivo. The compounds represent potential leads in the development of a new class of anabolic agents.

Synthesis and evaluation of 1-(benzo[b]thiophen-2-yl)ethanone analogues as novel anti-osteoporosis agents acting on BMP-2 promotor.

A novel series of 1-(benzo[b]thiophen-2-yl)ethanone analogues were prepared and evaluated for enhancing BMP-2 expression. Compounds 1-5, 7, 8, 12, 13 and 16, with upregulation rate values of 35.6%, 27.9%, 39.8%, 32.0%, 37.1%, 30.2%, 28.0%, 33.5%, 22.8% and 27.3% in vitro, respectively, at a concentration of 4muM, exhibited potent effect for enhancing BMP-2 expression. We also found that compounds 1 and 12 produced a dose-dependent increase on bone histology and histomorphometry, and effectively reduced bone defects induced by ovariectomy in an ovariectomized rat model (OVX).