Dengue virus (DENV) causes disease globally, with an estimated 25 to 100 million new infections per year. At present, no effective vaccine is available, and treatment is supportive. In this study, we identified BP2109, a potent and selective small-molecule inhibitor of the DENV NS2B/NS3 protease, by a high-throughput screening assay using a recombinant protease complex consisting of the central hydrophilic portion of NS2B and the N terminus of the protease domain. BP2109 inhibited DENV (serotypes 1 to 4), but not Japanese encephalitis virus (JEV), replication and viral RNA synthesis without detectable cytotoxicity. The compound inhibited recombinant DENV-2 NS2B/NS3 protease with a 50% inhibitory concentration (IC 50 ) of 15.43 ؎ 2.12 M and reduced the reporter expression of the DENV-2 replicon with a 50% effective concentration (EC 50 ) of 0.17 ؎ 0.01 M. Sequencing analyses of several individual clones derived from BP2109-resistant DENV-2 RNAs revealed that two amino acid substitutions (R55K and E80K) are found in the region of NS2B, a cofactor of the NS2B/NS3 protease complex. The introduction of R55K and E80K double mutations into the dengue virus NS2B/NS3 protease and a dengue virus replicon construct conferred 10.3-and 73.8-fold resistance to BP2109, respectively. The E80K mutation was further determined to be the key mutation conferring dengue virus replicon resistance (61.3-fold) to BP2109, whereas the R55K mutation alone did not affect resistance to BP2109. Both the R55K and E80K mutations are located in the central hydrophilic portion of the NS2B cofactor, where extensive interactions with the NS3pro domain exist. Thus, our data provide evidence that BP2109 likely inhibits DENV by a novel mechanism.Dengue virus serotypes 1 to 4 (DENV-1 to -4) belongs to the family Flaviviridae, a group of enveloped RNA viruses that includes the genera Hepacivirus, Flavivirus, and Pestivirus. The genus Flavivirus consists of arthropod-borne disease agents, such as the yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and DENV (14). Many members of the genus Flavivirus are important human pathogens and cause significant morbidity and mortality. DENV alone poses a public health threat to an estimated 2.5 billion people living in areas where dengue is epidemic and leads to 50 to 100 million human infections each year (17,18,38). DENV infection often leads to dengue fever, life-threatening dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS) (15,19,37). Approximately 500,000 cases of DHF and DSS have been reported in over 100 countries and have caused approximately 25,000 deaths per year (16). Despite the tremendous efforts invested in anti-DENV research, no clinically approved vaccine or antiviral therapy for humans is available for DENV (25,32,36). Considering the spread of this epidemic and the severity of DENV, the discovery of an effective anti-DENV drug is now an urgent need.DENV is an enveloped RNA virus that consists of a 10.7-kb single-stranded, positive-polarity genomic RN...

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The incidence of second primary lung cancer was significantly higher in the RT group than in the non-RT group for individuals with previous BC. Patients with BC treated by RT should be extensively surveyed to assess the incidence of subsequent lung cancer.

BackgroundOsteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone.MethodsIn total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up.ResultsAt the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601–0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without.ConclusionsPatients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.