解析COMT基因Met多态与子宫内膜异位症的关系

目的探讨COMT基因Met多态与子宫内膜异位症的相关性。方法该研究选择的观察组对象60例,均为该院收治的子宫内膜异位症者,与40例对照组非内异症及腺肌病的女性采用PCR-RFLP法进行COMT基因分型,回顾相关资料。结果观察组野生纯和型(G/G)基因型、突变杂合型(G/A)基因型、突变纯合型基因型频率与对照组比较差异无统计学意义(P>0.05)。两组G等位基因频率(观察组72.9%,对照组27.1%)与A等位基因频率(观察组70%,对照组30%)比较差异无统计学意义(P>0.05)。COMTC/G(OR=1)、G/A(OR=0.516,95%CI为0.186-1.442)、A/A(OR=0.451,95%CI=0.166-1.234),3种基因型相对危度分析差异无统计学意义(P>0.05)。提示子宫内膜异位症的发生与COMT基因多态无明显相关性。结论子宫内膜异位症的发生与COMT基因Met多态无相关性,在临床治疗中可作为参考依据。     

内镜下记忆合金支架植入治疗晚期食管癌性狭窄临床研究

目的探讨内镜直视下置入记忆合金支架治疗晚期食管癌所致管道狭窄的临床疗效和安全性。方法回顾性分析2009～2011年收治、失去手术治疗机会并接受内镜直视下带膜镍钛记忆合金网格支架植入术的晚期食管癌患者,根据临床和预后综合评价其疗效和安全性。结果所有患者均一次性成功放置内支架,支架置入后吞咽功能明显改善且无严重并发症。结论内镜下置入带膜记忆合金支架治疗晚期食管癌操作简单、疗效可靠、安全性高,是适用于临床推广的姑息性非手术治疗方法。     

The Impact of Employment Counseling on Substance User Treatment Participation and Outcomes

The nationally representative Alcohol and Drug Services Study (ADSS, 1996–1999) is used to examine employment counseling's impact on treatment participation and on postdischarge abstinence and employment. Employment counseling (EC) is among the more frequently received ancillary services in substance user treatment. The ADSS study sample showed it was received by 13% of all (N = 988) nonmethadone outpatient clients, and 42% of the 297 clients with a need for it. Clients who received needed EC (met need) are compared to clients who did not receive needed EC (unmet need). Met-need clients had significantly longer treatment duration and greater likelihood of employment postdischarge than unmet-need clients. Both groups were as likely to complete treatment and be abstinent at follow-up. Implications are discussed. Future needed research and unresolved critical issues are also noted.     

Saracatinib impairs the peritoneal dissemination of diffuse‐type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors

Diffuse‐type gastric carcinomas (DGC) exhibit more aggressive progression and poorer prognosis than intestinal‐type and other gastric carcinomas. To identify potential therapeutic targets, we examined protein tyrosine phosphorylation in a panel of DGC and other gastric cancer cell lines. Protein tyrosine phosphorylation was significantly enhanced or altered in DGC cell lines compared with that in other gastric cancer cell lines. Affinity purification and mass spectrometry analysis of tyrosine‐phosphorylated proteins identified Met as a protein that is preferentially expressed and phosphorylated in DGC cell lines. Unexpectedly, Met inhibitors blocked cell growth, Met downstream signaling and peritoneal dissemination in vivo in only a subset of cell lines that exhibited remarkable overexpression of Met. Likewise, only cell lines with overexpression of fibroblast growth factor receptor 2 (FGFR2) or phosphorylation of FRS2 were sensitive to an FGFR2 inhibitor. A Src inhibitor saracatinib impaired growth in cell lines that are insensitive to both Met and FGFR2 inhibitors. Saracatinib also effectively impaired peritoneal dissemination of Met‐independent and FGFR2‐independent SGC cells. Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors. These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.     

Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway‐induced resistance to vascular endothelial growth factor receptor inhibitor

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF‐induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.     

Immunohistochemical analysis of hepatocyte growth factor and c-Met in plasma cell disease

Wader K F, Fagerli U‐M, Børset M, Lydersen S, Hov H, Sundan A, Bofin A & Waage A
(2012) Histopathology 60 ,443–451
Immunohistochemical analysis of hepatocyte growth factor and c‐Met in plasma cell disease Aims: Interaction with the bone marrow microenvironment is important for homing and survival of myeloma cells. One cytokine involved in this process is hepatocyte growth factor (HGF). HGF, by binding to the receptor tyrosine kinase c‐Met, mediates a broad range of tumour progression activities. Our aims were to investigate whether HGF and c‐Met are present in bone marrow and extramedullary tumours from patients with monoclonal plasma cell disease, and whether c‐Met is activated. Methods and results: Expression of HGF, c‐Met and phospho‐c‐Met was studied by immunohistochemistry in biopsies from 80 patients with monoclonal plasma cell disease. Cytoplasmic staining for HGF in plasma cells was demonstrated in 58 of 68 biopsies from multiple myeloma patients (85%), but also in biopsies from nine of 10 healthy individuals. Membranous staining for c‐Met was found in 25 of 63 multiple myeloma patients (40%) and in none of 10 healthy individuals. Membranous staining for phospho‐c‐Met was found in biopsies from 15 of 21 c‐Met‐positive myeloma patients (71%). Conclusions: Our data point to c‐Met expression as one of the factors that distinguishes normal from malignant plasma cells, and indicate that the HGF/c‐Met system is activated in multiple myeloma patients.     

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

Hepatocyte growth factor/scatter factor—Met signaling in tumorigenicity and invasion/metastasis

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector of cells expressing the Met tyrosine kinase receptor. While HGF/SF-Met signaling clearly plays a role in a variety of normal cellular processes, this signaling pathway has also been implicated in the generation and metastatic spread of tumors. This review discusses in detail several model systems that have been developed to investigate the role of HGF/SF-Met signaling in malignancy and describes additional data regarding the expression of these molecules in human tumors. Collectively the findings support a role for this receptor-ligand pair in human malignancy.Abbreviations ECM/BM Extracellular matrix/basement membrane - HGF/SF Hepatocyte growth factor/scatter factor - uPA Urokinase-type plasminogen activator - uPAR Urokinase-type plasminogen activator receptor