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Background: Steroid-induced osteonecrosis of the femoral head (ONFH) is aseptic necrosis of the femoral head caused by glucocorticoid use. Once necrotic femoral head necrosis occurs, it irreversibly affects the quality of life seriously. Studies have shown that the susceptibility to steroid-induced ONFH is likely to be related to the variation of miRNA-coding genes. Therefore, this study aimed was to investigate the effect of MIR3142HG on steroid-induced ONFH. Methods: Agena MassARRAY was used to genotype MIR3142HG gene rs1582417, rs2431689, rs7727155, and rs17057846 in 199 patients and 725 healthy people. A genetic model and haplotype analysis were used to evaluate the relationship between the MIR3142HG polymorphism and the risk of steroid-induced ONFH. The odds ratio and 95% confidence intervals were obtained through logistic regression to assess the influence of gene polymorphisms on the occurrence of steroid-induced ONFH. Results: The consequences show that rs7727115 is a protective factor, it could reduce the risk of steroid-induced ONFH, and rs1582417 could increase the risk of steroid-induced ONFH. In the genetic model, rs1582417 was associated with increased risk of alcohol-induced ONFH in dominant model and log-additive model. rs7727115 showed a decreased risk in codominant model, dominant model, and log-additive model. In addition, rs2431689 is related to HDL-C (p = 0.012) and ApoA1 (p = 0.010) levels, and rs17057846 (p = 0.024) is related to ApoB levels. Thelinkage analysis indicated 3 single-nucleotide polymorphisms (rs2431689, rs7727115, and rs17057846) in MIR3142HG with significant chain imbalance. In addition, haplotype “GGG” of MIR3142HG was found out and is harmful for steroid-induced ONFH. Conclusion: Our results first confirm that the genetic polymorphism of MIR3142HG is associated with steroid-induced ONFH susceptibility in Chinese Han population.

Background The proto-oncogene c-MET (mesenchymal-epithelial transition factor gene) plays a critical role in cellular proliferation, survival, migration, and invasion in cancers. The aim of this study is to explore the relationship between c-MET expression and the clinicopathological characteristics of colorectal cancer (CRC) patients. Methods A total of 337 enrolled patients were collected in present study. Here, the c-MET and EGFR expression were detected by immunohistochemistry (IHC). The mutational statuses of KRAS in exons 2, 3, and 4, NRAS in exons 2, 3, and 4, and BRAF in exon 15 from formalin-fixed sections were detected by direct DNA sequencing. Results Our results showed that high c-MET expression was significantly associated with tumor perineural invasion (P=0.007) and gender (P=0.016). High level c-MET expression (c-MET-high) in the primary tumors was observed in 68.2% of patients. In the 337 enrolled patients, 43.2% of patients had KRAS mutations, 3.3% of patients had NRAS mutations, and 4.7% of patients had BRAF mutations. However, KRAS, NRAS, and BRAF gene mutations had no association with c-MET protein levels in primary tumors. Additionally, c-MET protein expression had a strong correlation with EGFR expression (P=0.002). The survival time was not significantly longer for patients with c-MET-high primary tumors than for those with c-MET-low primary tumors. Conclusions c-MET immunohistochemistry was significantly higher in primary tumors with perineural invasion, female gender, and EGFR high expression. However, c-MET-high in the primary tumors was not significantly associated with longer survival compared with c-MET-low tumors. Further studies are required to investigate c-MET as potential molecular marker of progression and to test the possibility of its incorporation as a new therapeutic target.

Introduction Steroid-induced osteonecrosis of the femoral head (ONFH) is a disease of the bone. Metabolism and genetic factors are generally considered to play an important role. The purpose of this study was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in MIR17HG and MIR155HG and the risk of steroid-induced ONFH in the population of northern China. Methods A total of 199 steroid-induced ONFH patients and 506 healthy controls were recruited for the study. Four SNPs of MIR17HG and seven SNPs of MIR155HG were genotyped by Sequenom MassARRAY. ORs and 95% CIs were used to evaluate the relationship between these SNPs and steroid-induced ONFH. Results In the codominant model, patients with the MIR17HG SNPs (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.79, p = 0.039); in the recessive model, patients with the MIR17HG SNP (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.78, p = 0.032). Stratified analysis showed that a MIR17HG SNP (rs7318578) and the MIR155HG SNPs (rs77218221, rs11911469, rs34904192 and rs4143370) were closely related to different unornamented phenotypes of steroid-induced ONFH. Analysis of the clinical indicators revealed significant differences in high-density lipoprotein (HDL-C) levels between the ONFH group and the control group (p = 0.005). In the MIR17HG SNP (rs75267932), patients with different genotypes had different levels of triglyceride (TG). The MIR155HG SNPs (rs77699734, rs1893650, and rs34904192) showed differences in triglyceride (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels in patients with different genotypes. Conclusion Our results confirm that MIR17HG and MIR155HG gene mutations are associated with steroid-induced ONFH susceptibility in the population of northern China, providing new evidence for the early detection and prevention of ONFH.

Background: Steroid-induced osteonecrosis of the femoral head (ONFH) is aseptic necrosis of the femoral head caused by glucocorticoid use. Once necrotic femoral head necrosis occurs, it irreversibly affects the quality of life seriously. Studies have shown that the susceptibility to steroid-induced ONFH is likely to be related to the variation of miRNA coding genes. Therefore, this study aimed was to investigate the effect of MIR3142HG on steroid-induced ONFH.Methods: Agena MassARRAY was used to genotype MIR3142HG gene rs1582417, rs2431689, rs7727155 and rs17057846 in 199 patients and 506 healthy people. A genetic model and haplotype analysis were used to evaluate the relationship between the MIR3142HG polymorphism and the risk of steroid-induced ONFH. The odds ratio (OR) and 95% confidence intervals (CIs) were obtained through logistic regression to assess the influence of gene polymorphisms on the occurrence of steroid-induced ONFH.Results: The consequences show that rs7727115(OR=0.76,p=0.036) is a protective factor, it could reduce the risk of steroid-induced ONFH, rs1582417(OR=1.28, p=0.041) could increase the risk of steroid-induced ONFH. Stratified analysis , according to each clinical index shows that MIR3142HG TC-CC genotype facilitated the risk of steroid-induced ONFH in male ( pp=0.012) and ApoA1 (p=0.010) levels, and rs17057846 (p=0.024) is related to ApoB levels.The linkage analysis indicated that three SNPs (rs2431689, rs7727115 and rs17057846) in MIR3142HG with significant chain imbalance. In addition, haplotype “GGG” of MIR3142HG was found out is harmful for steroid-induced ONFH.Conclusion: Our results firstly confirm that the genetic polymorphism of MIR3142HG is associated with steroid-induced ONFH susceptibility in Chinese Han population.

Matrine (Mat) is an alkaloid of tetracycline quinazine, and previous studies have demonstrated its specific effect on relieving rheumatoid arthritis (RA). However, the effect of Mat on joint synovial angiogenesis in the pathogenesis of RA has not been elucidated. In this study, body weight, joint swelling, arthritis index (AI) score, histopathological changes, immunohistochemical, and western blot- were used in collagen-induced arthritis (CIA) rats to detect pro-inflammatory factors and, - expression levels of key cytokines and proteins along the hypoxia-inducible factor (HIF)-endothelial growth factor (VEGF)-angiopoietin (Ang) axis and VEGF-phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) pathway. In vitro experiments were conducted to observe the effect of Mat on the proliferation, migration and lumen formation of RA-fibroblast-like synovial cells (FLS) and human umbilical vein endothelial cells (HUVECs). Results showed that Mat reduced the degree of paw swelling and AI score in CIA rats, joint synovial tissue proliferation, inflammatory cell infiltration, and neovascularization; moreover, it down-regulated the expression levels of inflammatory factors interleukin-1β, interferon-γ, and pro-angiogenic factors VEGF, placental growth factor, HIF-α, Ang-1, Ang-2, Tie-2, and phosphorylation-Akt in the ankle joint of CIA rats. In addition, the in vitro experiments showed that Mat inhibited the proliferation and migration of RA-FLS and inhibited the proliferation and lumen formation of HUVECs. Therefore, Mat exerts an anti-angiogenesis effect by regulating the HIF-VEGF-Ang axis and inhibiting the PI3K/Akt signaling pathway. This inhibits the pathogenesis and improve the symptoms of RA, and may be offered as a candidate drug for the treatment of RA.

To investigate the efficacy of Zhonglun'a-decoction-containing serum (ZHONGL-CS) on the in vitro apoptosis of fibroblast-like synoviocytes (FLS) from rats with collagen-induced arthritis (CIA) by investigating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway.A CIA rat model was established using bovine type Ⅱ collagen. FLS were isolated, cultured and identified. A cell counting kit-8 was used to detect cell activity. The half maximal inhibitory concentration (IC50) was calculated. Experimental subjects were divided into control, CIA, ZHONGL-CS, JAK2 inhibitor AG490, and ZHONGLCS with AG490 groups. The in vitro cell cycle and apoptosis rate were detected in FLS by flow cytometry. Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, cyclin D1, phosphorylated JAK2, STAT1, and STAT3 protein expressions in FLS were examined by Western blotting. JAK2, STAT1 and STAT3 mRNA levels were examined by quantitative real-time polymerase chain reaction.Compared with the CIA group, FLS proliferation was inhibited, the FLS G0/G1 cell cycle was arrested, and the rate of FLS apoptosis was increased in the ZHONGL-CS group. In the ZHONGLCS group, the protein levels of Bcl-2 and cyclin D1 were reduced compared with the CIA group and the levels of Bax and caspase-3 in FLS were increased. In the ZHONGL-CS group, the expressions of JAK2, STAT1, and STAT3 mRNA and the levels of phosphorylated JAK2, STAT1, and STAT3 proteins were reduced.ZHONGL-CS may induce FLS apoptosis in CIA rats. Activation of the JAK/STAT signaling pathway was inhibited in FLS in vitro.

To investigate the efficacy and mechanisms of matrine, a component derived from Sophora flavescens in treatment of rheumatoid arthritis (RA), a rat model of RA was established. Compared to control rats, matrine significantly mitigated inflammation and severity of RA (paw volume and articular index (AI) score). Using either mice splenic T cells stimulated with PMA/ionomycin or rat splenic T cells, the levels of Th1 and Th2 responses were determined by flow cytometry, quantitative RT-PCR, and ELISA. Furthermore, the levels of NF-κBp65 (RelA), IκBα, and phosphor-IκBα in T cells were determined by Western blot. Our study found that matrine modulated the imbalance of Th1 and Th2 cytokine responses in rats with RA by reducing the levels of Th1 cytokines (IFN-γ, TNF-α, IL-1β), but increasing Th2 cytokine (IL-4 and IL-10) through attenuating the NF-κB signaling in T cells, suggesting matrine as a promising drug for intervention of RA.

// Xin Li 1 , Shijiang Xing 1 and Qiumei Dong 2 1 Department of Medical Oncology, Xiaolan People's Hospital Affiliated to Southern Medical University, Zhongshan, China 2 Department of Medical Oncology, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Correspondence to: Qiumei Dong, email: hrbsh@163.com Keywords: Down syndrome, non-small-cell lung cancer, EGFR mutation, trisomy 21, EGFR-TKIs resistance Received: February 07, 2017 Accepted: April 03, 2017 Published: April 25, 2017 ABSTRACT Background : Solid tumors have a markedly decreased incidence in individuals with Down syndrome (DS), including lung cancers. Methods: The clinical presentation of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) in DS was reported and literature on the subject reviewed. Results: In individuals with DS, the risk of lung cancer appears markedly lower. EGFR mutation and EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance also exist in DS with lung cancer. Conclusions: Clinicians should consider EGFR mutation and EGFR-TKIs resistance in lung cancer patients with DS.

To investigate the efficacy and mechanisms of matrine, a component derived from Sophora flavescens in treatment of rheumatoid arthritis (RA), a rat model of RA was established. Compared to control rats, matrine significantly mitigated inflammation and severity of RA (paw volume and articular index (AI) score). Using either mice splenic T cells stimulated with PMA/ionomycin or rat splenic T cells, the levels of Th1 and Th2 responses were determined by flow cytometry, quantitative RT-PCR, and ELISA. Furthermore, the levels of NF-κBp65 (RelA), IκBα, and phosphor-IκBα in T cells were determined by Western blot. Our study found that matrine modulated the imbalance of Th1 and Th2 cytokine responses in rats with RA by reducing the levels of Th1 cytokines (IFN-γ, TNF-α, IL-1β), but increasing Th2 cytokine (IL-4 and IL-10) through attenuating the NF-κB signaling in T cells, suggesting matrine as a promising drug for intervention of RA.

The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast‑like characteristics. After treatment of FLS with varying conc-entrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apoptosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.

To investigate the expression of orotate phosphoribosyltransferase (OPRT) in colorectal carcinoma and analyze its correlations with the toxicities of chemotherapy.The expression of OPRT mRNA was detected using RT-PCR in colorectal carcinoma tissues and paired adjacent normal tissues from 58 patients receiving FOLFOX6 regimen chemotherapy. The toxicities of the chemotherapy were recorded, and the correlations between OPRT mRNA expression and the toxicities were analyzed.OPRT mRNA expression was significantly higher in the tumor tissues than in the corresponding normal tissues (P=0.001), but OPRT expression in the tumor tissues was not correlated with the toxicities of the chemotherapy (P0.05). OPRT level in the normal tissues showed a significant positive correlation with the occurrence of diarrhea in these cases (P=0.013).OPRT expression in colorectal carcinoma tissues is not correlated with the toxicities of 5-FU-based regimen, but OPRT expression in the normal tissues can help predict the toxicities associated with 5-FU.