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Woodridge, IL, United States

Song D.,H. Lee Moffitt Cancer Center and Research Institute | Zhukov T.A.,H. Lee Moffitt Cancer Center and Research Institute | Markov O.,Advanced Life Sciences Inc. | Qian W.,University of Texas at El Paso | Tockman M.S.,H. Lee Moffitt Cancer Center and Research Institute
Analytical and Quantitative Cytology and Histology | Year: 2012

OBJECTIVE: To predict survival of resected stage I non-small cell lung cancer (NSCLC) patients through quantitative analysis and classification of centrosome features. STUDY DESIGN: Disordered centrosome amplification leads to the loss of regulated chromosome segregation, aneuploidy and chromosome instability and may be a biomarker of cancer prognosis. Resected, stage I NSCLC tissues from survivor and fatal cases were immunostained with γ-tubulin and scanned by confocal microscopy. Regions of interest were selected to include 1 cell and at least 1 centrosome. Four hundred forty-six regions were imaged, including 903 centrosomes whose features were extracted and measured. After segmentation, 12 centrosome features were measured. After optimization, 6 nonredundant features were selected for statistical analysis and classification. RESULTS: Two statistical methods showed that for each feature, centrosomes from survivors differed significantly from centrosomes of fatalities. Centrosomes were classified into survival or fatal outcomes by centrosome features using linear discriminant analysis, support vector machines (SVMs) and further optimized using SVMs with bagging. Ten-fold cross-validation was applied. Classification accuracies were 74%, 79% and 85%, respectively. CONCLUSION: Centrosome features can be a prognostic biomarker for resected stage I NSCLC and may indicate patients who would benefit from additional adjuvant therapy. © Science Printers and Publishers, Inc.

Mima T.,Colorado State University | Schweizer H.P.,Colorado State University | Xu Z.-Q.,Advanced Life Sciences Inc.
Journal of Antimicrobial Chemotherapy | Year: 2011

Objectives: Most Burkholderia pseudomallei strains are intrinsically resistant to macrolides, mainly due to AmrAB-OprA- and/or BpeAB-OprB-mediated efflux. We assessed the in vitro anti-B. pseudomallei efficacy of cethromycin, a novel ketolide with broad-spectrum activity against Gram-negative and Gram-positive pathogens. Methods: The 2-fold broth microdilution technique was used to assess the in vitro cethromycin susceptibility of a prototype strain, efflux mutants, and a panel of 60 clinical and environmental strains. Time-kill curves were used to assess the mode of action. Spontaneous resistant mutants were isolated and AmrAB-OprA efflux pump expression assessed by quantitative real-time PCR. Deletion and complementation analyses were performed to demonstrate AmrAB-OprA efflux pump mutant involvement in high-level cethromycin resistance. Results: In contrast to macrolides, cethromycin was a weak substrate of AmrAB-OprA and BpeAB-OprB. Cethromycin was bactericidal at high concentrations and bacteriostatic at MIC levels. The ketolide showed efficacy against clinical and environmental strains of B. pseudomallei, with MIC values ranging from 4 to 64 mg/L. Environmental isolates were consistently more susceptible than clinical isolates. High-level cethromycin resistance (MIC 128 mg/L) was due to constitutive AmrAB-OprA efflux pump overexpression, but other mechanisms also seem to contribute. Conclusions: In contrast to macrolides, which are readily effluxed, cethromycin is weakly extruded in wild-type strains and thus demonstrates significant in vitro anti-B. pseudomallei activity against diverse strains. Acquired high-level cethromycin resistance is caused by constitutive AmrAB-OprA efflux pump overexpression and other, probably non-efflux, mechanisms may also contribute to lower-level acquired resistance. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Rosenzweig J.A.,Texas Southern University | Brackman S.M.,301 University Blvd | Kirtley M.L.,301 University Blvd | Sha J.,301 University Blvd | And 8 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

The Gram-negative plague bacterium, Yersinia pestis, has historically been regarded as one of the deadliest pathogens known to mankind, having caused three major pandemics. After being transmitted by the bite of an infected flea arthropod vector, Y. pestis can cause three forms of human plague: bubonic, septicemic, and pneumonic, with the latter two having very high mortality rates. With increased threats of bioterrorism, it is likely that a multidrug-resistant Y. pestis strain would be employed, and, as such, conventional antibiotics typically used to treat Y. pestis (e.g., streptomycin, tetracycline, and gentamicin) would be ineffective. In this study, cethromycin (a ketolide antibiotic which inhibits bacterial protein synthesis and is currently in clinical trials for respiratory tract infections) was evaluated for antiplague activity in a rat model of pneumonic infection and compared with levofloxacin, which operates via inhibition of bacterial topoisomerase and DNA gyrase. Following a respiratory challenge of 24 to 30 times the 50% lethal dose of the highly virulent Y. pestis CO92 strain, 70 mg of cethromycin per kg of body weight (orally administered twice daily 24 h postinfection for a period of 7 days) provided complete protection to animals against mortality without any toxic effects. Further, no detectable plague bacilli were cultured from infected animals' blood and spleens following cethromycin treatment. The antibiotic was most effective when administered to rats 24 h postinfection, as the animals succumbed to infection if treatment was further delayed. All cethromycin-treated survivors tolerated 2 subsequent exposures to even higher lethal Y. pestis doses without further antibiotic treatment, which was related, in part, to the development of specific antibodies to the capsular and low-calcium-response V antigens of Y. pestis. These data demonstrate that cethromycin is a potent antiplague drug that can be used to treat pneumonic plague. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2003

DESCRIPTION (provided by applicant): The major goal of our proposed project is to advance the development of novel compounds for the treatment of amyloidosis and other protein aggregation diseases. Preliminary work demonstrated that two chalcones inhibited amyloid fibril formation, in vitro, and that further work is warranted. The amyloid diseases that arise from nonimmunoglobulin proteins include adult onset diabetes (type II diabetes), Alzheimer's disease, Down's syndrome, systemic familial amyloidosis, senile amyloid disease and beta 2-microglobulin (dialysis associated) amyloidosis. Effective therapeutic agents that prevent protein aggregation in these diseases have not been developed to date. A commercial market of significant size exists for drugs that treat protein aggregation diseases. It is estimated that 10 million people worldwide suffer from Alzheimer's disease, 6% of the total population have been diagnosed with type II diabetes and that 1/1000 people in developed countries die annually from amyloidosis. In our continuing research efforts to discover small molecules for the treatment of protein disorders caused by protein aggregation, we developed an economical and convenient high-throughput method for screening compounds against fibril formation in microwell plates and identified a number of chalcone molecules as inhibitors of amyloid fibril formation in the in vitro assay. During our Phase I research program, novel chalcones will be designed, based on the molecular modeling analysis, synthesized using a parallel synthesis approach and screened for the inhibitory activity against amyloid fibril formation using LEN VL protein. Furthermore, mutants of the LEN VL protein will be generated for the identification and confirmation of chalcone binding sites, based on molecular modeling analysis. The successful results obtained from this Phase I program will be the foundation of our SBIR Phase II studies. It is anticipated that, at the conclusion of our Phase II program, not only can an ideal candidate be selected for full IND-directed preclincial studies leading to an IND submission and initiation of clinical trials in the SBIR Phase Ill program, but also and, perhaps more importantly, the knowledge gained and technology developed will be applicable and be extended to other protein aggregation diseases.

Advanced Life Sciences Inc. | Date: 2011-10-07

Disclosed are an HCV gene having higher replication efficiency and higher reinfection efficiency than the known HCV gene of genotype 1b, an RNA replicon having this gene, a cell infected with this RNA replicon, which cell allows replication of HCV, and an HCV particle. The hepatitis C virus gene encodes an amino acid sequence wherein the 979th amino acid is threonine; the 1804th amino acid is leucine; and the 1966th amino acid is lysine. An HCV gene which can propagate in vitro and has higher replication efficiency and higher reinfection efficiency than the known HCV gene of genotype 1b was provided.

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