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951.
RP Wurz L Liu K Yang N Nishimura Y Bo LH Pettus S Caenepeel DJ Freeman JD McCarter EL Mullady TS Miguel L Wang N Zhang KL Andrews DA Whittington J Jiang R Subramanian PE Hughes MH Norman 《Bioorganic & medicinal chemistry letters》2012,22(17):5714-5720
Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193nM (91ng/mL). 相似文献
952.
Pho MT Swaminathan S Kumarasamy N Losina E Ponnuraja C Uhler LM Scott CA Mayer KH Freedberg KA Walensky RP 《PloS one》2012,7(4):e36001
Background
Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India.Methods
We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm3, and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH).Results
Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence.Conclusions
Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care. 相似文献953.
954.
Background
Multilevel analyses are ideally suited to assess the effects of ecological (higher level) and individual (lower level) exposure variables simultaneously. In applying such analyses to measures of ecologies in epidemiological studies, individual variables are usually aggregated into the higher level unit. Typically, the aggregated measure includes responses of every individual belonging to that group (i.e. it constitutes a self-included measure). More recently, researchers have developed an aggregate measure which excludes the response of the individual to whom the aggregate measure is linked (i.e. a self-excluded measure). In this study, we clarify the substantive and technical properties of these two measures when they are used as exposures in multilevel models.Methods
Although the differences between the two aggregated measures are mathematically subtle, distinguishing between them is important in terms of the specific scientific questions to be addressed. We then show how these measures can be used in two distinct types of multilevel models—self-included model and self-excluded model—and interpret the parameters in each model by imposing hypothetical interventions. The concept is tested on empirical data of workplace social capital and employees'' systolic blood pressure.Results
Researchers assume group-level interventions when using a self-included model, and individual-level interventions when using a self-excluded model. Analytical re-parameterizations of these two models highlight their differences in parameter interpretation. Cluster-mean centered self-included models enable researchers to decompose the collective effect into its within- and between-group components. The benefit of cluster-mean centering procedure is further discussed in terms of hypothetical interventions.Conclusions
When investigating the potential roles of aggregated variables, researchers should carefully explore which type of model—self-included or self-excluded—is suitable for a given situation, particularly when group sizes are relatively small. 相似文献955.
Soumya Swaminathan Pradeep Aravindan Menon Narendran Gopalan Venkatesan Perumal Ramesh Kumar Santhanakrishnan Ranjani Ramachandran Ponnuraja Chinnaiyan Sheik Iliayas Padmapriyadarsini Chandrasekaran Pooranaganga Devi Navaneethapandian Thiruvalluvan Elangovan Mai Tuyet Pho Fraser Wares Narayanan Paranji RamaIyengar 《PloS one》2012,7(12)
Background
The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown.Methods
An open-label randomized clinical trial was performed and analyzed for equivalence. Seven hundred and twelve HIV-infected, ART-naïve patients without active TB were randomized to receive either ethambutol 800 mg and isoniazid 300 mg daily for six-months (6EH) or isoniazid 300 mg daily for 36-months (36H). Drugs were dispensed fortnightly and adherence checked by home visits. Patients had chest radiograph, sputum smear and culture performed every six months, in addition to investigations if they developed symptoms. The primary endpoint was incident TB while secondary endpoints were all-cause mortality and adverse events. Survival analysis was performed on the modified intent to treat population (m-ITT) and rates compared.Findings
Tuberculosis developed in 22 (6.4%) of 344 subjects in the 6EH arm and 13 (3.8%) of 339 subjects in the 36H arm with incidence rates of 2.4/100py (95%CI- 1.4–3.5) and 1.6/100py (95% CI-0.8–3.0) with an adjusted rate ratio (aIRR) of 1.6 (0.8–3.2). Among TST-positive subjects, the aIRR of 6EH was 1.7 (0.6–4.3) compared to 36H, p = 0.8. All-cause mortality and toxicity were similar in the two arms. Among 15 patients with confirmed TB, 4 isolates were resistant to isoniazid and 2 were multidrug-resistant.Interpretation
Both regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients.The trial is registered at ClinicalTrials.gov, . NCT00351702相似文献956.
In an endeavor to screen bioactive compounds present in vegetables with effective mechanism using in silico method lead us to develop a vegetable phytochemicals and their target database (VPTD). The VPTD is a unique bioinformatics resource that compiles information about phytochemicals from vegetables and their mechanism. VPTD contains 2496 phytochemicals from 27 vegetables, their 3D images and their 1337 possible biological mechanism. Each phytochemical contain records of seven data fields providing detailed information on name, source, amount present, structure and mechanistic information. This information has been manually extracted and manually verified from numerous sources, including other electronic databases, textbooks and scientific journals. VPTD is fully searchable and supports extensive text search. The main focus of the VPTD is on providing possible mechanism of phytochemicals, which will help in discovery of potential drugs from one of the common bioresource-vegetable. VPTD is freely available. AVAILABILITY: The database is available for free at http://www/vptd.in. 相似文献
957.
Sivaramakrishnan V Thiyagarajan C Kalaivanan S Selvakumar R Anusuyadevi M Jayachandran KS 《Bioinformation》2012,8(10):466-473
In spite of availability of moderately protective vaccine and antibiotics, new antibacterial agents are urgently needed to decrease the global incidence of Klebsiella pneumonia infections. MurF ligase, a key enzyme, which participates in the bacterial cell wall assembly, is indispensable to existence of K. pneumonia. MurF ligase lack mammalian vis-à-vis and have high specificity, uniqueness, and occurrence only in eubacteria, epitomizing them as promising therapeutic targets for intervention. In this study, we present a unified approach involving homology modeling and molecular docking studies on MurF ligase enzyme. As part of this study, a homology model of K. pneumonia (MurF ligase) enzyme was predicted for the first time in order to carry out structurebased drug design. The accuracy of the model was further validated using different computational approaches. The comparative molecular docking study on this enzyme was undertaken using different phyto-ligands from Desmodium sp. and a known antibiotic Ciprofloxacin. The docking analysis indicated the importance of hotspots (HIS 281 and ASN 282) within the MurF binding pocket. The Lipinski's rule of five was analyzed for all ligands considered for this study by calculating the ADME/Tox, drug likeliness using Qikprop simulation. Only ten ligands were found to comply with the Lipinski rule of five. Based on the molecular docking results and Lipinki values 6-Methyltetrapterol A was confirmed as a promising lead compound. The present study should therefore play a guiding role in the experimental design and development of 6-Methyltetrapterol A as a bactericidal agent. 相似文献
958.
959.
Current liver transplantation strategies face severe shortcomings owing to scarcity of donors, immunogenicity, prohibitive costs and poor survival rates. Due to the lengthy list of patients requiring transplant, high mortality rates are observed during the endless waiting period. Tissue engineering could be an alternative strategy to regenerate the damaged liver and improve the survival and quality of life of the patient. The development of an ideal scaffold for liver tissue engineering depends on the nature of the scaffold, its architecture and the presence of growth factors and recognition motifs. Biomimetic scaffolds can simulate the native extracellular matrix for the culture of hepatocytes to enable them to exhibit their functionality both in vitro and in vivo. This review highlights the physiology and pathophysiology of liver, the current treatment strategies, use of various scaffolds, incorporation of adhesion motifs, growth factors and stem cells that can stabilize and maintain hepatocyte cultures for a long period. 相似文献
960.
Huang R Vivekanandan S Brender JR Abe Y Naito A Ramamoorthy A 《Journal of molecular biology》2012,416(1):108-120
Calcitonin is a 32-residue peptide hormone known for its hypocalcemic effect and its inhibition of bone resorption. While calcitonin has been used in therapy for osteoporosis and Paget's disease for decades, human calcitonin (hCT) forms fibrils in aqueous solution that limit its therapeutic application. The molecular mechanism of fiber formation by calcitonin is not well understood. Here, high-resolution structures of hCT at concentrations of 0.3 mM and 1 mM have been investigated using NMR spectroscopy. Comparing the structures of hCT at different concentrations, we discovered that the peptide undergoes a conformational transition from an extended to a β-hairpin structure in the process of molecular association. This conformational transition locates the aromatic side chains of Tyr12 and Phe16 in a favorable way for intermolecular π-π stacking, which is proposed to be a crucial interaction for peptide association and fibrillation. One-dimensional (1)H NMR experiments confirm that oligomerization of hCT accompanies the conformational transition at 1 mM concentration. The effect of the polyphenol epigallocatechin 3-gallate (EGCG) on hCT fibrillation was also investigated by NMR and electron microscopy, which show that EGCG efficiently inhibits fibril formation of hCT by preventing the initial association of hCT before fiber formation. The NMR experiments also indicate that the interaction between aromatic rings of EGCG and the aromatic side chains of the peptide may play an important role in inhibiting fibril formation of hCT. 相似文献