Experimental investigation of seismic response of precast concrete panels with castellated keys support pillar connections under in-plane cyclic loading.

The reliable joint connection between precast members is vital to resisting earthquake loads in precast concrete structures. To further improve the convenience of precast construction, this paper presents a new horizontal joint of precast concrete panels with castellated keys supports pillar connections based on the stable mechanical properties of the wet concrete joint. To examine the seismic response of this connection type, a series of in-plane cyclic loading tests were carried out using six full-size precast specimens and one cast-in-place specimen for comparison. The influences of axial compression ratio, joint width, and joint concrete strength on the seismic indicators of the precast concrete panel were considered in the design of specimens. The test results showed all specimens had the same damage process, and the ultimate failure modes combined compression and bending. The precast specimens exhibited similar seismic performance to the cast-in-place specimen, especially whose joint concrete strength is higher than the precast concrete panel. Based on the load-displacement test curve, a hysteretic curve model that included both the envelope curve and the stiffness degradation law was proposed. The predictions from the model showed good compatibility with the experimental results, and the model can be used as a reference for analyzing the elastic-plastic response of the precast concrete panels with castellated keys supporting pillar connections.

GLP-1 alleviates NLRP3 inflammasome-dependent inflammation in perivascular adipose tissue by inhibiting the NF-κB signalling pathway.

OBJECTIVES: To study the effect of glucagon-like peptide 1 (GLP-1) on NLR family pyrin domain containing 3 (NLRP3) inflammasome-induced inflammation in perivascular adipose tissue (PVAT) of Zucker diabetic fatty (ZDF) rats and the underlying role of nuclear factor (NF)-κB signalling. METHODS: Thirty ZDF rats were randomly divided into three study groups: DM (0.9% saline, subcutaneously); DM+GLP-1 (liraglutide, s.c.); and NF-κB+GLP-1 (betulinic acid then liraglutide, s.c.). Ten Zucker lean rats were examined as normal controls. PVAT from ZDF (DM) rats was examined for inflammasome mRNA. Protein levels of NLRP3, cleaved caspase-1, caspase-1, gasdermin D (GSDMD), interleukin (IL)-1ß and IL-18 in PVAT were compared between control, DM and DM+GLP-1 groups. Protein levels of NLRP3, IL-1ß, IL-18 and NF-κB in PVAT were compared between control, DM, DM+GLP-1 and NF-κB+GLP-1 groups. RESULTS: The inflammasome most abundantly expressed in ZDF rat PVAT was NLRP3. NLRP3, cleaved caspase-1, IL-1ß, IL-18, and GSDMD were markedly upregulated in DM versus control tissue, and GLP-1 reversed this effect. Inhibition of NLRP3 inflammasome-associated inflammation by GLP-1 was lost by activation of NF-κB with betulinic acid. CONCLUSION: GLP-1 may alleviate NLRP3 inflammasome-dependent inflammation in PVAT by inhibiting NF-κB signalling.

Long noncoding AFAP1-antisense RNA 1 is upregulated and promotes tumorigenesis in gastric cancer.

Long noncoding RNA serves important roles in gastric cancer (GC). However, the prognostic significance and tumorigenesis effect of AFAP1-antisense RNA 1 (AS1) in GC remain to be clarified. The present study was conducted in order to determine the expression level of AFAP1-AS1 by reverse transcription-quantitative polymerase chain reaction. It was demonstrated that AFAP1-AS1 expression level was higher in GC tissues in comparison with adjacent tissues. By analyzing 66 GC tissue specimens, AFAP1-AS1 expression level was found to be markedly associated with tumor size, clinical stage and differentiation. By performing multivariate Cox regression test, AFAP1-AS1 expression level was confirmed to be an independent factor for poor prognosis in patients with GC. Furthermore, SGC-7901 and BGC-823 cells were used for further investigation following transfection of an AFAP1-AS1 short hairpin RNA lentiviral vector. Knockdown of AFAP1-AS1 significantly inhibited GC cell proliferation, migration and invasion abilities in vitro. Finally, nude mice experiments confirmed that downregulation of AFAP1-AS1 in GC cells suppressed tumor growth in vivo. In conclusion, the results of the present study suggested that AFAP1-AS1 may serve as a valuable prognostic indicator and therapeutic target for GC.

Synergistic antitumor effects of cMet inhibitor in combination with anti-VEGF in colorectal cancer patient-derived xenograft models.

cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo. Our results showed that combination treatment significantly inhibited tumor growth in two PDX models. While volitinib treatment alone induced moderate improvement in tumor growth inhibition, combination treatment synergistically reduced microvessel density, suppressed proliferation, and increased apoptosis in PDX models. Further analysis showed synergistic inhibition of MAPK and PI3K/Akt pathways by volitinib and apatinib. Taken together, our data provide a rationale to targeting both cMet and VEGF in the treatment of cMet overexpressing CRC in clinical trials.

Individualized drug screening based on next generation sequencing and patient derived xenograft model for pancreatic cancer with bone metastasis.

The efficacy of traditional chemoradiotherapies for pancreatic cancer remains limited, and no effective targeted therapies or screening tests are currently available. Therefore more individualized drug screening is warranted for the clinical treatment of pancreatic cancer. A patient­derived xenograft (PDX) model of pancreatic cancer bone metastasis was established, and next­generation sequencing (NGS) was used to investigate the molecular characteristics of the cancer and screen for potential drugs. Immunohistochemical analysis was performed to validate that the PDX retained the molecular characteristics from the patient. Using NGS technology, 13 pancreatic­cancer­associated polymorphisms/mutations were identified out of 416 genes sequenced. Based on the sequencing results and associated literatures, AZD6244, a highly selective inhibitor against mitogen­activated protein kinase kinase 1 (MEK1), was chosen as a potential therapy. AZD6244, a highly selective MEK1 inhibitor, was evaluated as effective for the pancreatic cancer PDX model, and thus may provide potential efficacy in the clinical treatment of the patient with pancreatic cancer investigated in the present study. The feasibility of the novel NGS­PDX based drug­screening pattern was demonstrated, and has a potential to improve individua-lized treatment for cancer.

TGFß1-Induced LncRNA UCA1 Upregulation Promotes Gastric Cancer Invasion and Migration.

According to recent studies, long noncoding RNA urothelial carcinoma associated 1 (UCA1) is involved in the development and progression of many malignant tumors, including gastric cancer (GC). We validated the detailed role of UCA1 in human GC cell lines and GC tissues so as to determine its exact function and the underlying mechanism of GC invasion and migration. In our research, lncRNA-UCA1 was specifically upregulated in GC tissues and cell lines, and augmented GC cell proliferation, and invasive and migratory capabilities. High UCA1 expression in GC was related with poorer prognosis (poorer invasion depth, lymph node metastasis, advanced TNM [T is for the original (primary) tumor, N for nearby (regional) lymph nodes that are involved, and M for distant metastasis] stage, and shorter overall survival). Epithelial mesenchymal transition (EMT), associated with malignancy of cancers, was reported to be responsible for invasion and migration of cancer cells. Transforming growth factor ß1 (TGFß1)-induced EMT was well evaluated. UCA1 silence reduced the protein levels of EMT-related factors, vimentin and snail, while promoted E-cadherin and zonula occludens-1 protein levels in GC cells; the effect of UCA1 could be partly restored by TGFß1 treatment. Taken together, UCA1 might regulate the tumor proliferation, invasion, and metastasis under TGFß1 induction. Taken together, UCA1 might present a potential oncogenic factor by promoting GC cell proliferation, invasion, and migration. UCA1 could serve as a novel biomarker for prognosis and a novel therapeutic target of GC treatment.

Poorer prognosis and higher prevalence of BRAF (V600E) mutation in synchronous bilateral papillary thyroid carcinoma.

BACKGROUND: The clinical significance of synchronous bilateral papillary thyroid carcinoma (SBiPTC) has not been fully defined, and the prevalence of BRAF (V600E) mutation in SBiPTC remains unknown. The purpose of this study is to compare the clinical outcomes and BRAF (V600E) mutation incidence of SBiPTC patients with those of unilateral papillary thyroid carcinoma (UiPTC) patients. METHODS: From 1997 to 2008, a total of 903 patients with papillary thyroid cancer were treated at a single institution. Of 891 studied patients, 177 (19.9%) had SBiPTC and 714 had UiPTC. SBiPTC was defined as cancer diagnosed in both thyroid lobes at the same time or within a period of 3 months. The mean follow-up time was 6 years, ranging from 2.5 to 13.5 years. Rates of disease-free survival (DFS) and overall survival (OS) were calculated and compared. BRAF (V600E) mutation was determined by polymerase chain reaction (PCR) amplification and DNA sequencing. RESULTS: Compared with UiPTC patients, patients with SBiPTC were more likely to have larger tumor size, extrathyroidal invasion, lymph node metastasis, and more advanced stage. The 5-year DFS rate was 86.0% for SBiPTC patients and 94.0% for UiPTC patients (p = 0.013). The prevalence of BRAF (V600E) mutation in the SBiPTC group was significantly higher than that in the UiPTC group (65.7% vs. 50.4%; p = 0.038). CONCLUSIONS: Patients with SBiPTC present with more advanced tumor stage and have shorter disease-free survival than UiPTC patients. Poorer outcomes of these patients may be at least partially explained by the high incidence of BRAF (V600E) mutation.