Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer

Survival in Nuclear Waste, Extreme Resistance, and Potential Applications Gleaned from the Genome Sequence of Kineococcus radiotolerans SRS30216

Kineococcus radiotolerans SRS30216 was isolated from a high-level radioactive environment at the Savannah River Site (SRS) and exhibits γ-radiation resistance approaching that of Deinococcus radiodurans. The genome was sequenced by the U.S. Department of Energy's Joint Genome Institute which suggested the existence of three replicons, a 4.76 Mb linear chromosome, a 0.18 Mb linear plasmid, and a 12.92 Kb circular plasmid. Southern hybridization confirmed that the chromosome is linear. The K. radiotolerans genome sequence was examined to learn about the physiology of the organism with regard to ionizing radiation resistance, the potential for bioremediation of nuclear waste, and the dimorphic life cycle. K. radiotolerans may have a unique genetic toolbox for radiation protection as it lacks many of the genes known to confer radiation resistance in D. radiodurans. Additionally, genes involved in the detoxification of reactive oxygen species and the excision repair pathway are overrepresented. K. radiotolerans appears to lack degradation pathways for pervasive soil and groundwater pollutants. However, it can respire on two organic acids found in SRS high-level nuclear waste, formate and oxalate, which promote the survival of cells during prolonged periods of starvation. The dimorphic life cycle involves the production of motile zoospores. The flagellar biosynthesis genes are located on a motility island, though its regulation could not be fully discerned. These results highlight the remarkable ability of K radiotolerans to withstand environmental extremes and suggest that in situ bioremediation of organic complexants from high level radioactive waste may be feasible

ПОЛУЧЕНИЕ АКТИВНЫХ КОМПОНЕНТОВ (Tа, Re) БИМЕТАЛЛИЧЕСКИХ КАТАЛИЗАТОРОВ НА МАТРИЦАХ γ-Al2O3 И TiO2

Tantalum methylate of general formula Ta2(OMe)10 was synthesized by electrochemical synthesis as a precursor for obtaining oxomethylate complexes of tantalum and rhenium. The complex is used to prepare catalysts in reactions of cross-condensation and reductive dehydration of alcohols. The catalysts are based on γ-Al2O3 and TiO2. Ultradisperse and nanosized TiO2 is obtained by the supercritical fluid technology. The sample is characterized by different methods (DTA, XRD, DSC). It is shown that annealing at 340°C allows obtaining anatase modification of TiO2 with a specific urface of 27.3 sq.m/g which can serve as a matrix for drawing active components of catalysts. It is shown that the Ta-Re/Al2O3 catalyst allows transforming ethanol and mixtures of ethanol with glycerin into aliphatic hydrocarbons C3-C11. A technological scheme for obtaining active components of the catalysts for cross-condensation and reductive dehydration of alcohols is suggested.Получен оксометилатный комплекс тантала и рения Та4O2(ОСН3)14(RеO4)2 из метилата тантала состава Ta2(OMe)10 и Re2O7, который использован для получения катализаторов в реакциях кросс-конденсации и восстановительной дегидратации спиртов на основе γ-Al2O3 и TiO2, полученного методом сверхкритического флюидного антисольвентного осаждения (SAS). Образцы TiO2 охарактеризованы совокупностью методов (ДТА, ДСК, РФА) и показано, что отжиг при 340°С позволяет получать TiO2 анатазной модификации, который может служить матрицей для нанесения активных компонентов катализаторов. Выявлено различие результатов у неотожженных и отожжённых образцов после проведения ДТА в атмосфере кислорода и ДСК - в атмосфере гелия. Показано, что катализатор Ta-Re/Al2O3 позволяет превращать этанол и смеси этанола с глицерином в алифатические углеводороды С3-С11. Установлено, что оптимальное содержание глицерина составляет 20% об., что обеспечивает снижение выхода тупиковой этан-этиленовой фракции и увеличение выхода целевой фракции углеводородов. Предложена принципиальная технологическая схема получения активных компонентов катализаторов в реакциях кросс-конденсации и восстановительной дегидратации спиртов

Восстановительная дегидратация биоспиртов – перспективный путь получения моторных топлив

The reaction of reduction dehydratation of aliphatic alcohols into the hydrocarbons is the perspective approach for receiving liquid fuel. It opens ways to the industrial method of one-study receiving linear and cyclic alkanes, being high-energy components of aviation fuel, from bioalcohols (ethanol, butanols, pentanols). It has been found that combinated systems based on hydrides of intermetallic compounds are sufficiently effective catalysts and lead to the formation mixture of hydrocarbons with considerable content of isoalkanes. It has been appeared synergetic effect in formation of alkanes in the presence of two-component composition consisting of hydride intermetallic compound and alumoplatinum catalyst.Реакция восстановительной дегидратации алифатических спиртов в углеводороды является перспективным подходом к получению жидкого топлива. Она открывает пути к промышленному методу одностадийного получения линейных и циклических алканов, являющихся высококалорийными компонентами авиационного топлива, из биоспиртов (этанола, бутанолов, пентанолов). Выявлено, что комбинированные системы на основе гидридов интерметаллических соединений являются достаточно эффективными катализаторами и приводят к образованию смеси углеводородов со значительным содержанием изоалканов. Обнаружен синергический эффект в образовании алканов при использовании двухкомпонентной композиции, состоящей из гидрида интерметаллического соединения и алюмоплатинового катализатора

Data Publication with the Structural Biology Data Grid Supports Live Analysis

Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis

New Insights into Fluoroquinolone Resistance in Mycobacterium tuberculosis: Functional Genetic Analysis of gyrA and gyrB Mutations

Fluoroquinolone antibiotics are among the most potent second-line drugs used for treatment of multidrug-resistant tuberculosis (MDR TB), and resistance to this class of antibiotics is one criterion for defining extensively drug resistant tuberculosis (XDR TB). Fluoroquinolone resistance in Mycobacterium tuberculosis has been associated with modification of the quinolone resistance determining region (QRDR) of gyrA. Recent studies suggest that amino acid substitutions in gyrB may also play a crucial role in resistance, but functional genetic studies of these mutations in M. tuberculosis are lacking. In this study, we examined twenty six mutations in gyrase genes gyrA (seven) and gyrB (nineteen) to determine the clinical relevance and role of these mutations in fluoroquinolone resistance. Transductants or clinical isolates harboring T80A, T80A+A90G, A90G, G247S and A384V gyrA mutations were susceptible to all fluoroquinolones tested. The A74S mutation conferred low-level resistance to moxifloxacin but susceptibility to ciprofloxacin, levofloxacin and ofloxacin, and the A74S+D94G double mutation conferred cross resistance to all the fluoroquinolones tested. Functional genetic analysis and structural modeling of gyrB suggest that M330I, V340L, R485C, D500A, D533A, A543T, A543V and T546M mutations are not sufficient to confer resistance as determined by agar proportion. Only three mutations, N538D, E540V and R485C+T539N, conferred resistance to all four fluoroquinolones in at least one genetic background. The D500H and D500N mutations conferred resistance only to levofloxacin and ofloxacin while N538K and E540D consistently conferred resistance to moxifloxacin only. Transductants and clinical isolates harboring T539N, T539P or N538T+T546M mutations exhibited low-level resistance to moxifloxacin only but not consistently. These findings indicate that certain mutations in gyrB confer fluoroquinolone resistance, but the level and pattern of resistance varies among the different mutations. The results from this study provide support for the inclusion of the QRDR of gyrB in molecular assays used to detect fluoroquinolone resistance in M. tuberculosis

Anti–Neutrophil Extracellular Trap Antibodies in Antiphospholipid Antibody–Positive Patients: Results From the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Clinical Database and Repository

OBJECTIVE: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti–neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody–positive patients who did not have lupus. METHODS: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. RESULTS: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)–DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO–DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. CONCLUSION: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens