Objective:To investigate the effects of fritinib on angiogenesis, tumor growth and inositol requiring enzyme 1 (IRE1) -apoptosis signal regulating kinase 1 (ASK1) -c-Jun N-terminal kinase (JNK) pathway in triple negative breast cancer.Methods:Triple negative breast cancer cells MDA-MB-231 were taken and divided into normal saline (NS) group, low-dose fritinib (LD) group, medium-dose fritinib (MD) group and high-dose fritinib (HD) group. NS group was added with 100 μmol/L normal saline. LD group, MD group and HD group were added with 25, 50 and 100 μmol/L fritinib, respectively. Cell proliferation was detected by MTT assay, cell apoptosis was detected by flow cytometry, the ability of cells to form mimicry vessels was observed by three-dimensional cell culture, and the related indexes of angiogenesis and IRE1-ASK1-JNK pathway were detected by Western blotting. Twenty triple-negative breast cancer rat models were divided into control group and experimental group by random number table method, with 10 rats in each group. The control group was given normal saline gavage and the experimental group was given 100 μmol/L fritinib gavage. The tumor growth of rats in the two groups was observed and recorded.Results:The 48 h cell proliferation rates of NS group, LD group, MD group and HD group were (85.44±5.58) %, (73.24±4.95) %, (61.53±4.07) % and (50.23±2.97) %, respectively ( F=4.01, P=0.002). Compared with the NS group, the cell proliferation rate in LD, MD and HD groups was significantly decreased in a dose-dependent manner (all P<0.05). The apoptosis rates of NS group, LD group, MD group and HD group were (3.41±0.39) %, (18.75±1.94) %, (24.97±2.58) % and (38.62±3.27) %, respectively ( F=18.99, P<0.001). Compared with the NS group, the apoptosis rate of LD, MD and HD groups was significantly increased in a dose-dependent manner (all P<0.05). The number of mimicry vessels in NS group, LD group, MD group and HD group was 19.58±2.11, 15.67±2.02, 11.57±1.73 and 5.20±1.23, respectively ( F=3.28, P=0.008). Compared with the NS group, the number of mimicry vessels in LD group, MD group and HD group was significantly reduced. The results were dose-dependent (all P<0.05). vascular endothelial growth factor (VEGF) protein expression in NS group, LD group, MD group and HD group was 2.36±0.21, 1.79±0.17, 1.48±0.14 and 0.94±0.10, respectively ( F=5.17, P<0.001). The expression of IRE1 protein was 1.18±0.12, 1.67±0.18, 2.03±0.24 and 2.39±0.28, respectively ( F=5.55, P<0.001). The expression of ASK1 protein was 1.09±0.11, 1.46±0.13, 1.81±0.18, 2.33±0.21 ( F=5.32, P<0.001), respectively. JNK protein expression was 1.01±0.09, 1.48±0.14, 1.86±0.21 and 2.28±0.24, respectively ( F=6.92, P<0.001). Compared with the NS group, VEGF protein expression in LD, MD and HD groups was significantly decreased, and the expressions of IRE1, ASK1 and JNK were significantly increased in a dose-dependent manner (all P<0.05). Compared with the control group, the tumor weight and volume of the experimental group were significantly decreased [ (0.55±0.10) g vs. (1.37±0.15) g, t=14.38, P<0.001; (77.39±3.21) mm 3vs. (118.26±5.34) mm 3, t=20.74, P<0.001], tumor inhibition rate was significantly increased [ (71.23±3.85) % vs. (32.56±3.08) %, t=24.80, P<0.001]. Conclusion:Fritinib has an inhibitory effect on the activity of triple negative breast cancer cells, which can significantly reduce their angiogenesis and inhibit tumor growth. Moreover, it is related to the activation of IRE1-ASK1-JNK pathway.

AIM: To investigate the effect and mechanism of hypoxia inducible factor-1α on intestinal mucosal barrier in sepsis. METHODS: SD rats were randomly divided into 4 groups: sham group, sepsis group, sepsis+HIF-1α stimulant (sepsis+DMOG group), sepsis+HIF-1α inhibitor (sepsis+Bay87-2243 group), 6 rats in each group. Sepsis model was established by cecal ligation and perforation (CLP). The levels of inflammatory markers IL-1β, IL-6, TNF-α, oxidative stress markers MDA and antioxidant factors SOD and CAT were detected by ELISA and the expression of HIF-1α in intestinal mucosa was detected by Western blot. The pathological damage of intestinal mucosa was detected by HE staining. RESULTS: Inflammatory factors, oxidative stress factors and HIF-1α were significantly up-regulated in septic rats (P<0.05). The contents of IL-1β, IL-6, TNF-α and MDA in plasma were significantly decreased by intraperitoneal injection of DMOG (P<0.05); the levels of SOD and CAT in plasma were increased (P<0.05), HIF-1α was up-regulated (P<0.05), and the pathological damage of intestinal mucosa was alleviated, with decreased Chiu's score (P<0.05). Oral administration of Bay87-2243 gave the opposite result. CONCLUSION: HIF-1α has a protective effect on intestinal mucosal injury in sepsis. The mechanism may be related to the alleviation of inflammatory response and inhibition of oxidative stress.

Objective:To systematically review the therapeutic effect of continuous high positive end-expiratory pressure (PEEP) ventilation in patients with non-acute lung injury/acute respiratory distress syndrome (non-ALI/ARDS) under general anesthesia mechanical ventilation in the intensive care unit (ICU).Methods:PubMed, JBI Evidence-based Nursing Center Library, Cochrane Library, Embase, Medline, Wanfang Date, CNKI and VIP Database were searched for randomized controlled trials (RCT) and clinical controlled trials (CCT) using different levels of PEEP for the treatment of patients (uncombined ALI/ARDS) in ICU. The search period was from January 1st, 1990 to November 30th, 2018. Compared with the control group, the experimental group was treated with relatively high levels of PEEP ventilation. Outcome indicators were hospital mortality or 28-day mortality, partial oxygen pressure, and incidence of ARDS, atelectasis, and lung infections, etc. The RevMan 5.3 software was used for Meta-analysis.Results:Twelve articles were included, all of which were RCT studies; with 2 Chinese articles and 10 English articles. Meta-analysis showd that there was no statistically significant difference in the effect of different levels of PEEP on the mortality of patients [hospital mortality: odds ratio ( OR) = 1.06, 95% confidence interval (95% CI) was 0.57 to 1.96, P = 0.85; 28-day mortality: OR = 0.34, 95% CI was 0.09 to 1.32, P = 0.12]. Compared with low PEEP, persistently high PEEP could increase the patient's partial oxygen pressure [weighted mean difference ( WMD) = 48.27, 95% CI was 22.56 to 73.97, P = 0.000 2], prevent the occurrence of ARDS ( OR = 0.32, 95% CI was 0.13 to 0.82, P = 0.02), and decrease the incidence of lung infection ( OR = 0.52, 95% CI was 0.30 to 0.89, P = 0.02), but there was no significant difference in the incidence of atelectasis between the two groups ( OR = 0.69, 95% CI was 0.23 to 2.06, P = 0.51). Conclusion:In the treatment of patients in ICU with non-ALI/ARDS under general anesthesia mechanical ventilation, using relatively high levels of PEEP (10-16 cmH 2O, 1 cmH 2O = 0.098 kPa) instead of low levels of PEEP (≤8 cmH 2O) can significantly increase the partial oxygen pressure and significantly reduce the incidences of ARDS and lung infection.

Objective: To investigate the clinical value of gallbladder-preserving cholelithotomy by natural orifice transumbilical endoscopic surgery on patients with cholecystolithiasis. Methods: A retrospective study was performed on data of 15 patients with cholecystolithiasis, who underwent gallbladder-preserving cholelithotomy by natural orifice transumbilical endoscopic surgery from April 2018 to July 2018. The operative data, including situation of operation, operative time, intraoperative hemorrhage, and postoperative complications were recorded. Results: The procedure was performed successfully in all patients with a mean operative time of 108±12 min (ranged from 92-129 min). The intraoperative hemorrhage was 10-30 mL. Eight patients suffered from slight right upper abdominal pain, and 7 patients felt slight pain in umbilical a week after surgery. No fever, incision infection, umbilical hemia, peritonitis, and ascites were reported. The clear-liquid diet was recommended for one day after operation, and postoperative activity was allowed since the second day after operation. All patients were discharged on the fourth or fifth day, and all recovered to their normal life at one week after discharge. Follow-up showed that the scar was small and hidden in umbilical without visible incision after one month. Ultrasonic examination results showed that gallbladder contractile function worked perfectly in four patients and no gallbladder stone was found after three months. Conclusion Gallbladder-preserving cholelithotomy by natural orifice transumbilical endoscopic surgery is a safe and effective option for patients with cholecystolithiasis, provides excellent cosmetic outcomes, and can be appropriately carried out under the strict control of surgical indications.

Objective To investigate the differences in gene expression profiles of peripheral blood from patients with Keshan disease (KD) and the apoptosis mechanism in KD,to obtain diagnostic markers and establish diagnostic centroids plot for KD.Methods RNA was isolated from ten patients with KD diagnosed according to the clinical criteria for KD in China and ten health controls.The expression profiles were evaluated by Agilent 4 ×44K Whole Human Genome density oligonucleotide microarray analysis.The data were extracted by Agilent Feature Extraction Software t test,Pathway studio analysis and prediction analysis for microarray (PAM) were used to identify differently expressed genes,gene pathways,diagnostic markers and establish diagnostic centroids plot.Results Totally 1 570 up-regulated genes and 1 498 down-regulated genes were identified.Thirty-eight enrichment pathways were also identified,and the highest ranked by Pathway studio analysis was related to apoptosis.Six genes involved in apoptosis pathway were up-regulated in KD included ataxia telangiectasia mutated (ATM),cAMP-dependent protein kinase,protein kinase A (PKA),baculoviral IAP repeat-containing 2 (BIRC2),NLR family,apoptosis inhibitory protein (NAIP),BCL2-1ike 11 (Bim),BCL2-related protein A1 (BCL2A1) and down-regulated were 7 which included caspase 8 (CASP8),BCL2 binding component 3 (BBC3),BCL2--associated athanogene (BAG1),BCL2-associated X protein (BAX),BCL2-1ike 1 (BCL2L1),BCL2-related ovarian killer (BOK),and caspase 6 (CASP6).Forty-two diagnostic markers were obtained through PAM analysis.Conclusions Apoptosis related to genes and pathways might play an important role in the pathogenesis of KD.Forty-two markers could be used as molecular markers for the diagnosis of KD,which is important to the diagnosis of KD.

Objective To evaluate the clinical outcomes of severely resorbed edentulous mandibles with tilted implants and fixed prostheses. Methods Ten patients with severely resorbed edentulous mandibles were en-rolled. Each patient received 4 implants,two posteriors placed tilted implants. Immediate loading of tilted implants were applied in all cases using a fixed provisional prosthesis. All patients were finalized 3-4 months with fixed pros-theses. Results 40/40 implants with initial torque(>35N.cm)were followed 1-1.5 years presenting 100%surviv-al. Conclusion The method of using tilted implants and fixed prostheses in the cases of severely resorbed edentu-lous mandibles can achieve an ideal short-term and medium-term effects.

Objective To explore the enhancement effects and mechanisms of IL-32β on human cervical carcinoma cells C33A to hypoxic/hypoglycemic condition.Methods After cultured in hypoxia/hypoglycemic circumstance and normal circumstance for 20 hours respectively, the mRNA and protein expression of IL-32β in C33A cells were detected by real time-polymerase chain reaction (RT-PCR) and Western blotting respectively.Trypan blue stain was used to detect C33A cells viability in hypoxia/hypoglycemic circumstance and adding 10, 100,500 ng/ml IL-32β circumstance.The xenografted tumor of nude mice was established by intraperitoneal injection, and their volumes were tested for a given time after injecting 0, 1.0 mg/kg IL-32β.siRNA was used to construct IL-32β knockdown cells and detect the expression of VEGF.Results Under the hypoxia/hypoglycemic circumstance, the expressions of IL-32β mRNA were (6.12 ± 0.03) times of the normal circumstance (F =43.16, P ＜ 0.05), the expressions of IL-32β protein were (2.23 ± 0.04) times of the normal circumstance (F =22.32, P ＜ 0.05).The C33A cells viability in hypoxia/hypoglycemic circumstance was (51.92 ± 3.41) ％, whereas, viability in 10 ng/ml IL-32β group was (55.23 ± 3.92) ％ (F =14.25, P ＜ 0.05), viability in 100 ng/ml IL-32β group was (62.52 ± 4.14) ％ (F =35.53, P ＜ 0.01), viability in 500 ng/ml IL-32β group was (69.14 ± 2.45) ％ (F =56.28, P ＜ 0.01).After 28 days, the volume of xenografted tumor of 0 mg/kg IL-32β group was (578 ± 64)mm3, and 1.0 mg/kg IL-32β group up to (1 402 ± 142) mm3 (F =27.84, P ＜ 0.01).In addition, compared with control group, the expression of VEGF in IL-32β knockdown C33A cells was significantly decreased (F =36.85, P ＜ 0.05).Conclusion IL-32β can enhance the resistance to hypoxic/hypoglycemic condition of C33A cells, which is associated with the increase of VEGF.

Objective To analyze the prevalence and economic burden of diabetes in Guandu district of Kunming. Methods We used probability proportional to size (PPS) sampling method to select representative sample of 4595 residents aged 18 or over from this district. Each participant received face to face questionnaire interview and physical examination. We applied different methods to measure the direct,indirect and intangible costs of diabetes. Results In the study population, the overall prevalence of diabetes was 6.2%,and females had higher prevalence of diabetes than males (6.2%vs. 5.6%, <0.05) . The DALY/1000 population of diabetes was 3.52, among which males and females were 5.18 and 6.70, respectively. Mean unit direct costs, indirect costs and intangible costs of diabetes were 3464.49 Yuan,84.48 Yuan and 4 045.97 Yuan,respectively. The total economic burden of diabetes was 401.84 million Yuan. Intangible costs represented the largest component of economic burden of diabetes,followed by direct costs. Conclusion The huge economic burden of diabetes has become the cause for concern in Guandu district. Effective measures are needed to reduce the economic burden of diabetes.

BACKGROUNDKeshan disease (KD) is an endemic cardiomyopathy in China. The etiology of KD is still under debate and there is no effective approach to preventing and curing this disease. Young women of child-bearing age are the most frequent victims in rural areas. The aim of this study was to determine the differences between molecular pathogenic mechanisms in male and female KD sufferers.

METHODSWe extracted RNA from the peripheral blood mononuclear cells of KD patients (12 women and 4 men) and controls (12 women and 4 men). Then the isolated RNA was amplified, labeled and hybridized to Agilent human 4×44k whole genome microarrays. Gene expression was examined using oligonucleotide microarray analysis. A quantitative polymerase chain reaction assay was also performed to validate our microarray results.

RESULTSAmong the genes differentially expressed in female KD patients we identified: HLA-DOA, HLA-DRA, and HLA-DQA1 associated with spontaneous autoimmunity; BMP5 and BMP7, involved in cardiomyocyte differentiation defect; and ADAMTS 8, CCL23, and TNFSF15, implicated in anti-angiogenic activities. These genes are involved in the canonical pathways and networks recognized for the female KD sufferers and might be related to the pathogenic mechanism of KD.

CONCLUSIONOur results might help to explain the higher susceptibility of women to this disease.

ADAM Proteins ; genetics ; ADAMTS Proteins ; Adult ; Autoimmunity ; genetics ; physiology ; Bone Morphogenetic Protein 5 ; genetics ; Bone Morphogenetic Protein 7 ; genetics ; Cardiomyopathies ; genetics ; pathology ; Cell Differentiation ; genetics ; physiology ; Chemokines, CC ; genetics ; Enterovirus Infections ; genetics ; pathology ; Female ; Gene Expression Profiling ; HLA-D Antigens ; genetics ; HLA-DQ alpha-Chains ; genetics ; HLA-DR alpha-Chains ; genetics ; Humans ; Male ; Middle Aged ; Myocytes, Cardiac ; cytology ; metabolism ; Oligonucleotide Array Sequence Analysis ; Sex Factors ; Tumor Necrosis Factor Ligand Superfamily Member 15 ; genetics

OBJECTIVETo observe the effect of nano-Se-chondroitin sulfate on the growth and apoptosis of chondrocytes from patients with Kashin-Beck disease (KBD) exposed to T-2 toxin in vitro.

METHODSSamples of the articular cartilage were obtained from 6 patients with grade II/III KBD diagnosed in line with the National Clinical Diagnostic Criteria of KBD (WS/T 207-2010) for chondrocyte separation and culture in vitro. The separated chondrocytes were treated with synthesized nano-Se-chondroitin sulfate particles and T-2 toxin, alone or in combination, and the cell growth and apoptosis were observed using MTT assay, HE staining and flow cytometry.

RESULTSThe synthesized nano-Se-chondroitin sulfate, with a selenium entrapment ratio of 10.1%, spontaneously formed nanoparticles in distilled water with sizes ranging from 30 to 200 nm. Fourier-transform infrared spectroscopy suggested a possible covalent bond that bound Nano-Se and chondroitin sulfate. Within the concentration range of 50-200 ng/ml, nano-Se-chondroitin sulfate significantly inhibited T-2 toxin-induced apoptosis of the cultured chondrocytes and reduced the early apoptosis rate to (8.64∓1.57)% (P<0.05).

CONCLUSIONNano-Se-chondroitin sulfate can inhibit T-2 toxin-induced apoptosis of cultured chondrocytes from KBD patients in vitro, and serves as a promising candidate therapeutic agent for KBD.

Apoptosis ; drug effects ; Cells, Cultured ; Chondrocytes ; drug effects ; pathology ; Chondroitin Sulfates ; administration & dosage ; pharmacology ; Humans ; Kashin-Beck Disease ; pathology ; Middle Aged ; Nanostructures ; T-2 Toxin ; toxicity