Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase

Protein kinases are a large family of cell signaling mediators undergoing intensive research to identify inhibitors or modulators useful for medicine. As one strategy, small-molecule compounds that bind the active site with high affinity can be used to inhibit the enzyme activity. X-ray crystallography is a powerful method to reveal the structures of the kinase active sites, and thus aid in the design of high-affinity, selective inhibitors. However, a limitation still exists in the ability to produce purified kinases in amounts sufficient for crystallography. Furthermore, kinases exist in different conformation states as part of their normal regulation, and the ability to prepare crystals of kinases in these various states also remains a limitation. In this study, the c-Abl, c-Src, and c-Met kinases are produced in high yields in Escherichia coli by using a bicistronic vector encoding the PTP1B tyrosine phosphatase. A 100-fold lower dose of the inhibitor, Imatinib, was observed to inhibit the unphosphorylated form of c-Abl kinase prepared by using this vector, compared to the phosphorylated form produced without PTP1B, consistent with the known selectivity of this inhibitor for the unactivated conformation of the enzyme. Unphosphorylated c-Met kinase produced with this vector was used to obtain the crystal structure, at 2.15-A resolution, of the autoinhibited form of the kinase domain, revealing an intricate network of interactions involving c-Met residues documented previously to cause dysregulation when mutated in several cancers.     

Laparoscopic stapled left lateral segment liver resection—Technique and results

Because of the favorable anatomy of the left lateral segment of the liver, a totally laparoscopic approach to resection is feasible. Herein we describe a technique for laparoscopic stapled resection of the left lateral segment of the liver, including the necessary anatomic criteria for a safe operation and data on clinical outcome. Five patients at our center underwent laparoscopic exploration, ultrasound examination, and resection of segments II and III. After complete mobilization of the left lateral segment and minimal portal dissection, the totally laparoscopic resections were performed with two endoscopic staple loads (4.5 mm Χ 60 mm) applied sequentially across the portal pedicle and the left hepatic vein. The mean operative time was 182 minutes (range 130 to 240 minutes), blood loss was 41 ml (range 25 to 50 ml), and length of hospital stay was 2.2 days (range 1 to 3 days). All three patients with malignancy had negative surgical margins. All five patients returned to normal activity or work by 1 week postoperatively. There were no complications. Patients with isolated malignant and benign diseases of the left lateral segment of the liver are candidates for totally laparoscopic resection, if evaluation demonstrates a normal liver character and hepatic parenchymal thickness less than 3 cm overlying the ligamentum venosum groove. Such patients benefit from the minimally invasive approach, with no compromise in the surgical result as compared to the open approach. Presented at the Fourth Biennial Americas Hepato-Pancreato-Biliary Congress, Miami Beach, Florida, February 28, 2003. Supported in part by a Minnesota Medical Foundation Laparoscopy Training Grant (T.D.S.) and the Richard Lewis Varco Surgical Research Award (B.C.L.).     

ABO Blood Groups and Its Association with Oral Cancer,Oral Potentially Malignant Disorders and Oral Submucous Fibrosis– A Systematic Review and Meta-Analysis

Objective:The study aimed to evaluate the association between ABO blood groups and oral cancer, other potentially malignant disorders (OPMD), and oral submucous fibrosis (OSMF). Materials and methods:A search was conducted in Medline, Cochrane databases, Google Scholar, Scopus, Web of Science and Directory of Open Access Journals (DOAJ) for studies evaluating ABO blood groups as risk factors for oral cancer and OPMD among cases and controls. The PRISMA guidelines were followed for the meta-analysis. Participants included patients with oral cancer, and OPMD diagnosed using histopathologic investigations. Sub-group analysis was conducted to evaluate the association between blood groups and OSMF. Quality was evaluated using the Risk of Bias Assessment tool. Fixed effects model was used to assess the odds ratio for the association. Results:There were 1,352, 414, and 299 cases of oral cancer, OPMD, and OSMF and 11,699, 7,382 and 7,307 controls for analysis respectively. Blood group A was significantly associated with both oral cancer (Odds ratio: 1.27 [95% CI, 1.10, 1.47], P= 0.001) and OPMD (Odds ratio: 1.33 [95% CI, 1.01, 1.47], P= 0.04). No association was noted between blood group B and AB with oral cancer, OPMD, and OSMF. Blood group O was significantly associated with lower chances of oral cancer (Odds ratio: 0.81 [95% CI, 0.71, 0.93], P= 0.002). Conclusion:Meta-analysis suggests blood group A has a greater risk for developing oral cancer and OPMD. Blood group O was associated with lower chances of oral cancer. No association was noted between ABO blood group system with OSMF.Key Words: ABO blood group system, oral cancer, potentially malignant disorders, oral submucous fibrosis