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chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone.resistance to chemotherapy is a major obstacle to the effective treatment of many tumor types. although many anticancer therapies can alter tumor growth, in most cases the effect is not long lasting. consequently, there is a significant need for new agents with low susceptibility to common drug resistance mechanisms in order to improve response rates and potentially extend survival. approximately 30% of the women diagnosed with early-stage disease in turn progress to metastatic breast cancer, fo ...201021050423
prediction and analysis of the modular structure of cytochrome p450 monooxygenases.cytochrome p450 monooxygenases (cyps) form a vast and diverse family of highly variable sequences. they catalyze a wide variety of oxidative reactions and are therefore of great relevance in drug development and biotechnological applications. despite their differences in sequence and substrate specificity, the structures of cyps are highly similar. although being in research focus for years, factors mediating selectivity and activity remain vague.201020950472
conformational plasticity and structure/function relationships in cytochromes p450.the cytochrome p450s are a superfamily of enzymes that are found in all kingdoms of living organisms, and typically catalyze the oxidative addition of atomic oxygen to an unactivated c-c or c-h bond. over 8000 nonredundant sequences of putative and confirmed p450 enzymes have been identified, but three-dimensional structures have been determined for only a small fraction of these. while all p450 enzymes for which structures have been determined share a common global fold, the flexibility and mod ...201020446763
endometrial carcinoma: a review of chemotherapy, drug resistance, and the search for new agents.adenocarcinoma of the endometrium represents the most common gynecologic malignancy in developed countries. although early-stage cancers are effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent endometrial cancer. taxane-based therapy consistently demonstrates the highest response rates in the firs ...201020930101
microtubule-binding agents: a dynamic field of cancer therapeutics.microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to dna as a therapeutic target in cancer. the screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. in ...201020885410
optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer.the epothilone b analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. ixabepilone is approved by the fda for treatment of patients with metastatic breast cancer (mbc) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. ixabepilone is generally well tole ...201020886213
detecting and understanding the roles of nitric oxide in biology.we are pursuing a dual strategy for investigating the chemistry of nitric oxide as a biological signaling agent. in one approach, metal-based fluorescent sensors for the detection of no in living cells are evaluated, and a sensor based on a copper fluorescein complex has proved to be a valuable lead compound. sensors of this class permit identification of no from both inducible and constitutive forms of nitric oxide synthase and facilitate investigation of different no functions in response to e ...201020666391
read length and repeat resolution: exploring prokaryote genomes using next-generation sequencing technologies.there are a growing number of next-generation sequencing technologies. at present, the most cost-effective options also produce the shortest reads. however, even for prokaryotes, there is uncertainty concerning the utility of these technologies for the de novo assembly of complete genomes. this reflects an expectation that short reads will be unable to resolve small, but presumably abundant, repeats.201020634954
identification of the viridicatumtoxin and griseofulvin gene clusters from penicillium aethiopicum.penicillium aethiopicum produces two structurally interesting and biologically active polyketides: the tetracycline-like viridicatumtoxin 1 and the classic antifungal agent griseofulvin 2. here, we report the concurrent discovery of the two corresponding biosynthetic gene clusters (vrt and gsf) by 454 shotgun sequencing. gene deletions confirmed that two nonreducing pkss (nrpkss), vrta and gsfa, are required for the biosynthesis of 1 and 2, respectively. both pkss share similar domain architectu ...201020534346
ixabepilone as monotherapy or in combination for the treatment of advanced breast cancer.advanced breast cancer represents a therapeutic challenge for oncologists. chemotherapy with anthracyclines and taxanes has improved survival in this setting, but resistant and refractory disease is common. ixabepilone, an epothilone, is a recently approved chemotherapeutic agent, both as a single agent and in combination with capecitabine, with efficacy in patients with resistant advanced disease. in this review, the distinctive properties of this drug are discussed, as well as the clinical evi ...201024367163
the mixed lineage nature of nitrogen transport and assimilation in marine eukaryotic phytoplankton: a case study of micromonas.the prasinophyte order mamiellales contains several widespread marine picophytoplankton (≤ 2 μm diameter) taxa, including micromonas and ostreococcus. complete genome sequences are available for two micromonas isolates, ccmp1545 and rcc299. we performed in silico analyses of nitrogen transporters and related assimilation genes in ccmp1545 and rcc299 and compared these with other green lineage organisms as well as chromalveolata, fungi, bacteria, and archaea. phylogenetic reconstructions of ammon ...201020457585
a phase i/ii trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas.ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. a phase i/ii and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. a modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m(2), in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (eiaed). in the phase i study, the ...201020449631
recognition of (2s)-aminomalonyl-acyl carrier protein (acp) and (2r)-hydroxymalonyl-acp by acyltransferases in zwittermicin a biosynthesis.polyketide synthases elongate a polyketide backbone by condensing carboxylic acid precursors that are thioesterified to either coenzyme a or an acyl carrier protein (acp). two of the three known acp-linked extender units, (2s)-aminomalonyl-acp and (2r)-hydroxymalonyl-acp, are found in the biosynthesis of the agriculturally important antibiotic zwittermicin a. we previously reconstituted the formation of (2s)-aminomalonyl-acp and (2r)-hydroxymalonyl-acp from the primary metabolites l-serine and 1 ...201020353188
phase i trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary.ixabepilone is a semisynthetic epothilone b analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. we carried out a phase i trial of ixabepilone plus pegylated liposomal doxorubicin (pld) in patients with advanced taxane-pretreated ovarian and breast cancer.201020357034
mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole c1.disorazoles are polyene macrodiolides isolated from a myxobacterium fermentation broth. disorazole c1 was newly synthesized and found to depolymerize microtubules and cause mitotic arrest. here we examined the cellular responses to disorazole c1 in both non-cancer and cancer cells and compared our results to vinblastine and taxol.201020181182
a phase ii trial of the epothilone b analog ixabepilone (bms-247550) in patients with metastatic melanoma.ixabepilone (bms-247550), an epothilone b analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. in an open label, one-arm, multi-center phase ii trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naïve (previously untreated) and previously treated patients with metastatic melanoma.201020098694
total synthesis and evaluation of c26-hydroxyepothilone d derivatives for photoaffinity labeling of beta-tubulin.three photoaffinity labeled derivatives of epothilone d were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. the key step for the asymmetric synthesis of (s,e)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (r)-me-cbs-oxazaborolidine. for the synthesis of (5s)-5,7-di[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric noyor ...201019954175
nuclear export of proteins and drug resistance in cancer.the intracellular location of a protein is crucial to its normal functioning in a cell. cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. crm1-mediated export is increased in various cancers. proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, apc, p53, brac1, foxo proteins, ini1/hsnf5, galectin-3, bok, nucleophosmin, rassf2, merlin, p21 ...201122209898
nuclear export of proteins and drug resistance in cancer.the intracellular location of a protein is crucial to its normal functioning in a cell. cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. crm1-mediated export is increased in various cancers. proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, apc, p53, brac1, foxo proteins, ini1/hsnf5, galectin-3, bok, nucleophosmin, rassf2, merlin, p21 ...201122209898
beyond taxanes: the next generation of microtubule-targeting agents.taxanes are a standard first-line option for metastatic breast cancer (mbc), but their utility may be limited by primary or acquired resistance. new microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. this article reviews these alternative microtubule-targeting agents and their potential clinical benefits for mbc patients. relevant clinical data were compiled through searches within pubmed and congress abst ...201122113255
beyond taxanes: the next generation of microtubule-targeting agents.taxanes are a standard first-line option for metastatic breast cancer (mbc), but their utility may be limited by primary or acquired resistance. new microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. this article reviews these alternative microtubule-targeting agents and their potential clinical benefits for mbc patients. relevant clinical data were compiled through searches within pubmed and congress abst ...201122113255
phase i clinical, pharmacokinetic, and pharmacodynamic study of kos-862 (epothilone d) in patients with advanced solid tumors and lymphoma.to determine the maximum tolerated dose and safety of the epothilone, kos-862, in patients with advanced solid tumors or lymphoma.201122072399
phase i clinical, pharmacokinetic, and pharmacodynamic study of kos-862 (epothilone d) in patients with advanced solid tumors and lymphoma.to determine the maximum tolerated dose and safety of the epothilone, kos-862, in patients with advanced solid tumors or lymphoma.201122072399
enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis. 201122017381
enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis. 201122017381
natural products for cancer chemotherapy.for over 40 years, natural products have served us well in combating cancer. the main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. the microbes serve as a major source of natural products with anti-tumour activity. a number of these products were first discovered as antibiotics. another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. a vast array of biological metabolites can be obtained from the marine w ...201121375717
solving the problem: genome annotation standards before the data deluge.the promise of genome sequencing was that the vast undiscovered country would be mapped out by comparison of the multitude of sequences available and would aid researchers in deciphering the role of each gene in every organism. researchers recognize that there is a need for high quality data. however, different annotation procedures, numerous databases, and a diminishing percentage of experimentally determined gene functions have resulted in a spectrum of annotation quality. ncbi in collaboratio ...201122180819
joint scaling laws in functional and evolutionary categories in prokaryotic genomes.we propose and study a class-expansion/innovation/loss model of genome evolution taking into account biological roles of genes and their constituent domains. in our model, numbers of genes in different functional categories are coupled to each other. for example, an increase in the number of metabolic enzymes in a genome is usually accompanied by addition of new transcription factors regulating these enzymes. such coupling can be thought of as a proportional 'recipe' for genome composition of th ...201121937509
joint scaling laws in functional and evolutionary categories in prokaryotic genomes.we propose and study a class-expansion/innovation/loss model of genome evolution taking into account biological roles of genes and their constituent domains. in our model, numbers of genes in different functional categories are coupled to each other. for example, an increase in the number of metabolic enzymes in a genome is usually accompanied by addition of new transcription factors regulating these enzymes. such coupling can be thought of as a proportional 'recipe' for genome composition of th ...201121937509
formal synthesis of (+)-sorangicin a.the formal synthesis of (+)-sorangicin a was completed by two independent routes. both approaches feature a cross metathesis reaction to form the c29-c30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. formation of the c15-c16 olefin to unite the dihydropyran fragment with the rest of the molecule was achieved by either a cross metathesis reaction or a julia-kocienski olefination.201121834570
prombase: a web resource for various genomic features and predicted promoters in prokaryotic genomes.as more and more genomes are being sequenced, an overview of their genomic features and annotation of their functional elements, which control the expression of each gene or transcription unit of the genome, is a fundamental challenge in genomics and bioinformatics.201121781326
expansion of type ii caax proteases reveals evolutionary origin of γ-secretase subunit aph-1.intramembrane proteases are responsible for a number of regulated proteolysis events occurring within or near the plasma and intracellular membranes. members of one large and diverse family of putative intramembrane metalloproteases are widely distributed in all domains of life, including the type ii caax prenyl proteases and their prokaryotic homologs with putative bacteriocin-related functions. we used sensitive sequence similarity searches to expand this large cpbp (caax proteases and bacteri ...201121570408
engineering microbial factories for synthesis of value-added products.microorganisms have become an increasingly important platform for the production of drugs, chemicals, and biofuels from renewable resources. advances in protein engineering, metabolic engineering, and synthetic biology enable redesigning microbial cellular networks and fine-tuning physiological capabilities, thus generating industrially viable strains for the production of natural and unnatural value-added compounds. in this review, we describe the recent progress on engineering microbial factor ...201121526386
discovering the unknown: improving detection of novel species and genera from short reads.high-throughput sequencing technologies enable metagenome profiling, simultaneous sequencing of multiple microbial species present within an environmental sample. since metagenomic data includes sequence fragments ("reads") from organisms that are absent from any database, new algorithms must be developed for the identification and annotation of novel sequence fragments. homology-based techniques have been modified to detect novel species and genera, but, composition-based methods, have not been ...201121541181
drugs that target dynamic microtubules: a new molecular perspective.microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. as such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), ...201121381049
recent advances in bacterial heme protein biochemistry.recent progress in genetics, fed by the burst in genome sequence data, has led to the identification of a host of novel bacterial heme proteins that are now being characterized in structural and mechanistic terms. the following short review highlights very recent work with bacterial heme proteins involved in the uptake, biosynthesis, degradation, and use of heme in respiration and sensing.201121339081
soraphen a, an inhibitor of acetyl coa carboxylase activity, interferes with fatty acid elongation.acetyl coa carboxylase (acc1 and acc2) generates malonyl coa, a substrate for de novo lipogenesis (dnl) and an inhibitor of mitochondrial fatty acid β-oxidation (fao). malonyl coa is also a substrate for microsomal fatty acid elongation, an important pathway for saturated (sfa), mono- (mufa) and polyunsaturated fatty acid (pufa) synthesis. despite the interest in acc as a target for obesity and cancer therapy, little attention has been given to the role acc plays in long chain fatty acid synthes ...201121184748
soraphen a, an inhibitor of acetyl coa carboxylase activity, interferes with fatty acid elongation.acetyl coa carboxylase (acc1 and acc2) generates malonyl coa, a substrate for de novo lipogenesis (dnl) and an inhibitor of mitochondrial fatty acid β-oxidation (fao). malonyl coa is also a substrate for microsomal fatty acid elongation, an important pathway for saturated (sfa), mono- (mufa) and polyunsaturated fatty acid (pufa) synthesis. despite the interest in acc as a target for obesity and cancer therapy, little attention has been given to the role acc plays in long chain fatty acid synthes ...201121184748
two enzymes of a complete degradation pathway for linear alkylbenzenesulfonate (las) surfactants: 4-sulfoacetophenone baeyer-villiger monooxygenase and 4-sulfophenylacetate esterase in comamonas testosteroni kf-1.complete biodegradation of the surfactant linear alkylbenzenesulfonate (las) is accomplished by complex bacterial communities in two steps. first, all las congeners are degraded into about 50 sulfophenylcarboxylates (spc), one of which is 3-(4-sulfophenyl)butyrate (3-c(4)-spc). second, these spcs are mineralized. 3-c(4)-spc is mineralized by comamonas testosteroni kf-1 in a process involving 4-sulfoacetophenone (sap) as a metabolite and an unknown inducible baeyer-villiger monooxygenase (bvmo) t ...201223001656
heterologous production of 4-o-demethylbarbamide, a marine cyanobacterial natural product.heterologous expression of the barbamide biosynthetic gene cluster, obtained from the marine cyanobacterium moorea producens, in the terrestrial actinobacterium streptomyces venezuelae, resulted in the production of a new barbamide congener 4-o-demethylbarbamide, demonstrating the potential of this approach for investigating the assembly and tailoring of complex marine natural products.201223148802
molecular characterization of a cold-active recombinant xylanase from flavobacterium johnsoniae and its applicability in xylan hydrolysis.a novel xylanase gene, xyn10a, was cloned from flavobacterium johsoniae, overexpressed in a flavobacterial expression system, the recombinant enzyme purified by ni-affinity chromatography, and enzyme structure and activity analyzed. xyn10a was found to be a modular xylanase with an fn3 accessory domain on its n-terminal and a catalytic region on the c-terminal. the optimum ph and temperature for xyn10a was 8.0 and 30 °c, but xyn10a retained 50% activity at 4 °c, indicating that xyn10a is a cold- ...201223196234
molecular characterization of a cold-active recombinant xylanase from flavobacterium johnsoniae and its applicability in xylan hydrolysis.a novel xylanase gene, xyn10a, was cloned from flavobacterium johsoniae, overexpressed in a flavobacterial expression system, the recombinant enzyme purified by ni-affinity chromatography, and enzyme structure and activity analyzed. xyn10a was found to be a modular xylanase with an fn3 accessory domain on its n-terminal and a catalytic region on the c-terminal. the optimum ph and temperature for xyn10a was 8.0 and 30 °c, but xyn10a retained 50% activity at 4 °c, indicating that xyn10a is a cold- ...201223196234
whole genome analysis of leptospira licerasiae provides insight into leptospiral evolution and pathogenicity.the whole genome analysis of two strains of the first intermediately pathogenic leptospiral species to be sequenced (leptospira licerasiae strains var010 and mmd0835) provides insight into their pathogenic potential and deepens our understanding of leptospiral evolution. comparative analysis of eight leptospiral genomes shows the existence of a core leptospiral genome comprising 1547 genes and 452 conserved genes restricted to infectious species (including l. licerasiae) that are likely to be pa ...201223145189
doric 5.0: an updated database of oric regions in both bacterial and archaeal genomes.replication of chromosomes is one of the central events in the cell cycle. chromosome replication begins at specific sites, called origins of replication (orics), for all three domains of life. however, the origins of replication still remain unknown in a considerably large number of bacterial and archaeal genomes completely sequenced so far. the availability of increasing complete bacterial and archaeal genomes has created challenges and opportunities for identification of their orics in silico ...201223093601
doric 5.0: an updated database of oric regions in both bacterial and archaeal genomes.replication of chromosomes is one of the central events in the cell cycle. chromosome replication begins at specific sites, called origins of replication (orics), for all three domains of life. however, the origins of replication still remain unknown in a considerably large number of bacterial and archaeal genomes completely sequenced so far. the availability of increasing complete bacterial and archaeal genomes has created challenges and opportunities for identification of their orics in silico ...201223093601
effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils.several low-molecular-weight phenolic acids are present in the blood of septic patients at high levels. the microbial origin of the most of phenolic acids in the human body was shown previously, but pathophysiological role of the phenolic acids is not clear. sepsis is associated with the excessive production of reactive oxygen species (ros) in both the circulation and the affected organs. in this work the influence of phenolic acids on ros production in mitochondria and neutrophils was investiga ...201223061754
comparative proteome analysis of milnesium tardigradum in early embryonic state versus adults in active and anhydrobiotic state.tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. however, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. high-throughpu ...201223029181
bacterial biosynthetic gene clusters encoding the anti-cancer haterumalide class of molecules: biogenesis of the broad spectrum antifungal and anti-oomycete compound, oocydin a.haterumalides are halogenated macrolides with strong antitumor properties, making them attractive targets for chemical synthesis. unfortunately, current synthetic routes to these molecules are inefficient. the potent haterumalide, oocydin a, was previously identified from two plant-associated bacteria through its high bioactivity against plant pathogenic fungi and oomycetes. in this study, we describe oocydin a (ooc) biosynthetic gene clusters identified by genome sequencing, comparative genomic ...201223012376
kinetics of co recombination to the heme in geobacillus stearothermophilus nitric oxide synthase.we report the kinetics of co rebinding to the heme in his134ser, ile223val and his134ser/ile223ser mutants of geobacillus stearothermophilus nitric oxide synthase (gsnos). the amplitudes of the two observed kinetics phases, which are insensitive to co concentration, depend on enzyme concentration. we suggest that two forms of gsnos are in equilibrium under the conditions employed (6.1-27 µm gsnos with 20 or 100% co atmosphere). the kinetics of co rebinding to the heme do not depend on the identi ...201223976816
kinetics of co recombination to the heme in geobacillus stearothermophilus nitric oxide synthase.we report the kinetics of co rebinding to the heme in his134ser, ile223val and his134ser/ile223ser mutants of geobacillus stearothermophilus nitric oxide synthase (gsnos). the amplitudes of the two observed kinetics phases, which are insensitive to co concentration, depend on enzyme concentration. we suggest that two forms of gsnos are in equilibrium under the conditions employed (6.1-27 µm gsnos with 20 or 100% co atmosphere). the kinetics of co rebinding to the heme do not depend on the identi ...201223976816
a dictionary based informational genome analysis.in the post-genomic era several methods of computational genomics are emerging to understand how the whole information is structured within genomes. literature of last five years accounts for several alignment-free methods, arisen as alternative metrics for dissimilarity of biological sequences. among the others, recent approaches are based on empirical frequencies of dna k-mers in whole genomes.201222985068
statistical approaches to use a model organism for regulatory sequences annotation of newly sequenced species.a major goal of bioinformatics is the characterization of transcription factors and the transcriptional programs they regulate. given the speed of genome sequencing, we would like to quickly annotate regulatory sequences in newly-sequenced genomes. in such cases, it would be helpful to predict sequence motifs by using experimental data from closely related model organism. here we present a general algorithm that allow to identify transcription factor binding sites in one newly sequenced species ...201222984403
natural products as a rich source of tau-targeting drugs for alzheimer's disease.alzheimer's disease (ad) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the usa. although the cause of ad is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. drug discovery for ad based on the cholinergic and amyloid theories have not been effective. in this article we summarize tau-based natural products as ad therapeutics from a variety of biological sources, including the ...201222924511
diversity of p450 enzymes in the biosynthesis of natural products.diverse oxygenation patterns of natural products generated by secondary metabolic pathways in microorganisms and plants are largely achieved through the tailoring reactions catalysed by cytochrome p450 enzymes (p450s). p450s are a large family of oxidative hemoproteins found in all life forms from prokaryotes to humans. understanding the reactivity and selectivity of these fascinating c-h bond-activating catalysts will advance their use in generating valuable pharmaceuticals and products for med ...201222820933
differentiating between models of epothilone binding to microtubules using tubulin mutagenesis, cytotoxicity, and molecular modeling.microtubule stabilizers are powerful antimitotic compounds and represent a proven cancer treatment strategy. several classes of compounds in clinical use or trials, such as the taxanes and epothilones, bind to the same region of β-tubulin. determining how these molecules interact with tubulin and stabilize microtubules is important both for understanding the mechanism of action and enhancing chemotherapeutic potential, for example, minimizing side effects, increasing solubility, and overcoming r ...201222807375
drug discovery prospect from untapped species: indications from approved natural product drugs.due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. we analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. case histories of recently approved drugs reveal useful ...201222808057
prioritization of a plant polysaccharide over a mucus carbohydrate is enforced by a bacteroides hybrid two-component system.bacteroides is a dominant genus within the intestinal microbiota of healthy humans. key adaptations of the bacteroides to the dynamic intestinal ecosystem include a diverse repertoire of genes involved in sensing and processing numerous diet- and host-derived polysaccharides. one such adaptation is the carbohydrate-sensing hybrid two-component system (htcs) family of signalling sensors, which has been widely expanded within the bacteroides. using bacteroides thetaiotaomicron as a model, we have ...201222686399
influence of a mannan binding family 32 carbohydrate binding module on the activity of the appended mannanase.in general, cellulases and hemicellulases are modular enzymes in which the catalytic domain is appended to one or more noncatalytic carbohydrate binding modules (cbms). cbms, by concentrating the parental enzyme at their target polysaccharide, increase the capacity of the catalytic module to bind the substrate, leading to a potentiation in catalysis. clostridium thermocellum hypothetical protein cthe_0821, defined here as c. thermocellum man5a, is a modular protein comprising an n-terminal signa ...201222562994
constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance.the advent of organic synthesis and the understanding of the molecule as they occurred in the nineteenth century and were refined in the twentieth century constitute two of the most profound scientific developments of all time. these discoveries set in motion a revolution that shaped the landscape of the molecular sciences and changed the world. organic synthesis played a major role in this revolution through its ability to construct the molecules of the living world and others like them whose p ...201222743704
delineation of structural domains and identification of functionally important residues in dna repair enzyme exonuclease vii.exonuclease vii (exovii) is a bacterial nuclease involved in dna repair and recombination that hydrolyses single-stranded dna. exovii is composed of two subunits: large xsea and small xseb. thus far, little was known about the molecular structure of exovii, the interactions between xsea and xseb, the architecture of the nuclease active site or its mechanism of action. we used bioinformatics methods to predict the structure of xsea, which revealed four domains: an n-terminal ob-fold domain, a mid ...201222718974
(z)-1-aryl-3-arylamino-2-propen-1-ones, highly active stimulators of tubulin polymerization: synthesis, structure-activity relationship (sar), tubulin polymerization, and cell growth inhibition studies.tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. a series of (z)-1-aryl-3-arylamino-2-propen-1-one (10) were synthesized and evaluated for antiproliferative activity in cell-based assay. the most active compound (z)-1-(2-bromo-3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenylamino)prop-2-en-1-one (10ae) was tested in 20 tumor cell lines including multidrug resistant phenotype and was found to induce apoptosis in all these cell line ...201222587519
genome sizes and the benford distribution.data on the number of open reading frames (orfs) coded by genomes from the 3 domains of life show the presence of some notable general features. these include essential differences between the prokaryotes and eukaryotes, with the number of orfs growing linearly with total genome size for the former, but only logarithmically for the latter.201222629319
rapid identification of high-confidence taxonomic assignments for metagenomic data.determining the taxonomic lineage of dna sequences is an important step in metagenomic analysis. short dna fragments from next-generation sequencing projects and microbes that lack close relatives in reference sequenced genome databases pose significant problems to taxonomic attribution methods. our new classification algorithm, rita (rapid identification of taxonomic assignments), uses the agreement between composition and homology to accurately classify sequences as short as 50 nt in length by ...201222532608
advances in the management of metastatic breast cancer: options beyond first-line chemotherapy.this article provides an overview of recent advances in chemotherapy that may be used for the treatment of patients with locally advanced or metastatic breast cancer (mbc). key phase ii and iii trial data for eribulin mesylate, ixabepilone, and nab-paclitaxel, published since 2006, are discussed on the basis of recency, depth, and quality.eribulin mesylate is the first monotherapy to significantly increase overall survival in patients with pretreated mbc, but nab-paclitaxel offers a novel and sa ...201222514495
polyketide proofreading by an acyltransferase-like enzyme.trans-acyltransferase polyketide synthases (trans-at pkss) are an important group of bacterial enzymes producing bioactive polyketides. one difference from textbook pkss is the presence of one or more free-standing at-like enzymes. while one homolog loads the pks with malonyl units, the function of the second copy (at2) was unknown. we studied the two ats pedc and pedd involved in pederin biosynthesis in an uncultivated symbiont. pedd displayed malonyl- but not acetyltransferase activity toward ...201222444588
alternative sigma factor σh activates competence gene expression in lactobacillus sakei.alternative sigma factors trigger various adaptive responses. lactobacillus sakei, a non-sporulating meat-borne bacterium, carries an alternative sigma factor seemingly orthologous to σ(h) of bacillus subtilis, best known for its contribution to the initiation of a large starvation response ultimately leading to sporulation. as the role of σ(h)-like factors has been little studied in non-sporulating bacteria, we investigated the function of σ(h) in l. sakei.201222409597
eukaryote to gut bacteria transfer of a glycoside hydrolase gene essential for starch breakdown in plants.lateral gene transfer (lgt) between bacteria constitutes a strong force in prokaryote evolution, transforming the hierarchical tree of life into a network of relationships between species. in contrast, only a few cases of lgt from eukaryotes to prokaryotes have been reported so far. the distal animal intestine is predominantly a bacterial ecosystem, supplying the host with energy from dietary polysaccharides through carbohydrate-active enzymes absent from its genome. it has been suggested that l ...201222934241
characterization of species-specific repeats in 613 prokaryotic species.prokaryotes are in general believed to possess small, compactly organized genomes, with repetitive sequences forming only a small part of them. nonetheless, many prokaryotic genomes in fact contain species-specific repeats (>85 bp long genomic sequences with less than 60% identity to other species) as we have previously demonstrated. however, it is not known at present how frequent such species-specific repeats are and what their functional roles in bacterial genomes may be. therefore, we have c ...201222368180
an evolutionary network of genes present in the eukaryote common ancestor polls genomes on eukaryotic and mitochondrial origin.to test the predictions of competing and mutually exclusive hypotheses for the origin of eukaryotes, we identified from a sample of 27 sequenced eukaryotic and 994 sequenced prokaryotic genomes 571 genes that were present in the eukaryote common ancestor and that have homologues among eubacterial and archaebacterial genomes. maximum-likelihood trees identified the prokaryotic genomes that most frequently contained genes branching as the sister to the eukaryotic nuclear homologues. among the arch ...201222355196
tracing lifestyle adaptation in prokaryotic genomes.lifestyle adaptation of microbes due to changes in their ecological niches or acquisition of new environments is a major driving force for genetic changes in their respective genomes. moving into more specialized niches often results in the acquisition of new gene sets via horizontal gene transfer to utilize previously unavailable metabolites, while genetic ballast is shed by gene loss and/or gene inactivation. in some cases, larger genome rearrangements can be observed, such as the incorporatio ...201222363326
bacterial degradation of benzoate: cross-regulation between aerobic and anaerobic pathways.we have studied for the first time the transcriptional regulatory circuit that controls the expression of the box genes encoding the aerobic hybrid pathway used to assimilate benzoate via coenzyme a (coa) derivatives in bacteria. the promoters responsible for the expression of the box cluster in the β-proteobacterium azoarcus sp., their cognate transcriptional repressor, the boxr protein, and the inducer molecule (benzoyl-coa) have been characterized. the boxr protein shows a significant sequenc ...201222303008
synthesis of isotopically labeled epothilones.the epothilones, including epothilones b and d, are macrocyclic lactones, which have potent cytotoxicities and promote the polymerization of tubulin to mictotubules by binding to and stabilizing the tubulin polymer. they have a very similar mechanism of action to paclitaxel (taxol®). the determination of the microtubule-binding conformation of the epothilones is an important piece of information in designing improved analogs for possible clinical use, and internuclear distance information that w ...201324307484
synthesis of isotopically labeled epothilones.the epothilones, including epothilones b and d, are macrocyclic lactones, which have potent cytotoxicities and promote the polymerization of tubulin to mictotubules by binding to and stabilizing the tubulin polymer. they have a very similar mechanism of action to paclitaxel (taxol®). the determination of the microtubule-binding conformation of the epothilones is an important piece of information in designing improved analogs for possible clinical use, and internuclear distance information that w ...201324307484
computational identification and analysis of orphan assembly-line polyketide synthases.the increasing availability of dna sequence data offers an opportunity for identifying new assembly-line polyketide synthases (pkss) that produce biologically active natural products. we developed an automated method to extract and consolidate all multimodular pks sequences (including hybrid pks/non-ribosomal peptide synthetases) in the national center for biotechnology information (ncbi) database, generating a non-redundant catalog of 885 distinct assembly-line pkss, the majority of which were ...201324301183
computational identification and analysis of orphan assembly-line polyketide synthases.the increasing availability of dna sequence data offers an opportunity for identifying new assembly-line polyketide synthases (pkss) that produce biologically active natural products. we developed an automated method to extract and consolidate all multimodular pks sequences (including hybrid pks/non-ribosomal peptide synthetases) in the national center for biotechnology information (ncbi) database, generating a non-redundant catalog of 885 distinct assembly-line pkss, the majority of which were ...201324301183
characteristics of polygalacturonate lyase c from bacillus subtilis 7-3-3 and its synergistic action with pela in enzymatic degumming.an alkaline polygalacturonate lyase (pgl) from bacillus subtilis 7-3-3, pelc, with diverse depolymerization abilities for different pectin substrates was found. the pgl activity of pelc decreased with increasing degree of methyl esterification of the substrate. pela and pelc displayed notable synergistic effects in the enzymatic degumming of ramie fibers. gum loss rates increased by 62% when pelc was used to replace up to three-eighths of the pela dose (pelc, 60 u g(-1) ramie fibers). to the bes ...201324236123
rhizosphere microbiome assemblage is affected by plant development.there is a concerted understanding of the ability of root exudates to influence the structure of rhizosphere microbial communities. however, our knowledge of the connection between plant development, root exudation and microbiome assemblage is limited. here, we analyzed the structure of the rhizospheric bacterial community associated with arabidopsis at four time points corresponding to distinct stages of plant development: seedling, vegetative, bolting and flowering. overall, there were no sign ...201324196324
rhizosphere microbiome assemblage is affected by plant development.there is a concerted understanding of the ability of root exudates to influence the structure of rhizosphere microbial communities. however, our knowledge of the connection between plant development, root exudation and microbiome assemblage is limited. here, we analyzed the structure of the rhizospheric bacterial community associated with arabidopsis at four time points corresponding to distinct stages of plant development: seedling, vegetative, bolting and flowering. overall, there were no sign ...201324196324
synthesis of c11-desmethoxy soraphen a1α: a natural product analog that inhibits acetyl-coa carboxylase.a synthesis of c11-desmethoxy soraphen a1α is described that proceeds in just 14 steps from readily available starting materials. this natural product analog was identified as a target of interest in a program aimed at identifying novel natural product-inspired inhibitors of acetyl-coa carboxylase (acc) as potential anticancer therapeutics. while describing the most efficient synthesis of a soraphen a1α analog (total syntheses of the natural product have been reported that proceed in 25 to ≥40 l ...201324639892
a potential source for cellulolytic enzyme discovery and environmental aspects revealed through metagenomics of brazilian mangroves.the mangroves are among the most productive and biologically important environments. the possible presence of cellulolytic enzymes and microorganisms useful for biomass degradation as well as taxonomic and functional aspects of two brazilian mangroves were evaluated using cultivation and metagenomic approaches. from a total of 296 microorganisms with visual differences in colony morphology and growth (including bacteria, yeast and filamentous fungus), 179 (60.5%) and 117 (39.5%) were isolated fr ...201324160319
dna assembly techniques for next-generation combinatorial biosynthesis of natural products.natural product scaffolds remain important leads for pharmaceutical development. however, transforming a natural product into a drug entity often requires derivatization to enhance the compound's therapeutic properties. a powerful method by which to perform this derivatization is combinatorial biosynthesis, the manipulation of the genes in the corresponding pathway to divert synthesis towards novel derivatives. while these manipulations have traditionally been carried out via restriction digesti ...201324127070
dna assembly techniques for next-generation combinatorial biosynthesis of natural products.natural product scaffolds remain important leads for pharmaceutical development. however, transforming a natural product into a drug entity often requires derivatization to enhance the compound's therapeutic properties. a powerful method by which to perform this derivatization is combinatorial biosynthesis, the manipulation of the genes in the corresponding pathway to divert synthesis towards novel derivatives. while these manipulations have traditionally been carried out via restriction digesti ...201324127070
high-level expression of a novel thermostable and mannose-tolerant β-mannosidase from thermotoga thermarum dsm 5069 in escherichia coli.mannan is one of the primary polysaccharides in hemicellulose and is widely distributed in plants. β-mannosidase is an important constituent of the mannan-degrading enzyme system and it plays an important role in many industrial applications, such as food, feed and pulp/paper industries as well as the production of second generation bio-fuel. therefore, the mannose-tolerant β-mannosidase with high catalytic efficiency for bioconversion of mannan has a great potential in the fields as above.201324099409
a markovian analysis of bacterial genome sequence constraints.the arrangement of nucleotides within a bacterial chromosome is influenced by numerous factors. the degeneracy of the third codon within each reading frame allows some flexibility of nucleotide selection; however, the third nucleotide in the triplet of each codon is at least partly determined by the preceding two. this is most evident in organisms with a strong g + c bias, as the degenerate codon must contribute disproportionately to maintaining that bias. therefore, a correlation exists between ...201324010012
interactions in the microbiome: communities of organisms and communities of genes.a central challenge in microbial community ecology is the delineation of appropriate units of biodiversity, which can be taxonomic, phylogenetic, or functional in nature. the term 'community' is applied ambiguously; in some cases, the term refers simply to a set of observed entities, while in other cases, it requires that these entities interact with one another. microorganisms can rapidly gain and lose genes, potentially decoupling community roles from taxonomic and phylogenetic groupings. trai ...201323909933
interactions in the microbiome: communities of organisms and communities of genes.a central challenge in microbial community ecology is the delineation of appropriate units of biodiversity, which can be taxonomic, phylogenetic, or functional in nature. the term 'community' is applied ambiguously; in some cases, the term refers simply to a set of observed entities, while in other cases, it requires that these entities interact with one another. microorganisms can rapidly gain and lose genes, potentially decoupling community roles from taxonomic and phylogenetic groupings. trai ...201323909933
a reductive coupling strategy towards ripostatin a.synthetic studies on the antibiotic natural product ripostatin a have been carried out with the aim to construct the c9-c10 bond by a nickel(0)-catalyzed coupling reaction of an enyne and an epoxide, followed by rearrangement of the resulting dienylcyclopropane intermediate to afford the skipped 1,4,7-triene. a cyclopropyl enyne fragment corresponding to c1-c9 has been synthesized in high yield and demonstrated to be a competent substrate for the nickel(0)-catalyzed coupling with a model epoxide ...201323946853
class iii β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel.critics have suggested that neoadjuvant chemotherapy (nact) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. β-tubulins are chemotherapeutic targets of taxanes and epothilones. class iii β-tubulin overexpression has been linked to chemoresistance and hypoxia. herein, we describe changes in class iii β-tubulin in patients with advanced ovarian carcinoma in response to nact, in relationship to clinical outcome, and between ...201324005572
class iii β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel.critics have suggested that neoadjuvant chemotherapy (nact) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. β-tubulins are chemotherapeutic targets of taxanes and epothilones. class iii β-tubulin overexpression has been linked to chemoresistance and hypoxia. herein, we describe changes in class iii β-tubulin in patients with advanced ovarian carcinoma in response to nact, in relationship to clinical outcome, and between ...201324005572
scalable metagenomic taxonomy classification using a reference genome database.deep metagenomic sequencing of biological samples has the potential to recover otherwise difficult-to-detect microorganisms and accurately characterize biological samples with limited prior knowledge of sample contents. existing metagenomic taxonomic classification algorithms, however, do not scale well to analyze large metagenomic datasets, and balancing classification accuracy with computational efficiency presents a fundamental challenge.201323828782
structure diversity of nitric oxide synthases (nos): the emergence of new forms in photosynthetic organisms. 201323847637
treatment of neuroblastoma and rhabdomyosarcoma using rgd-modified liposomal formulations of patupilone (epo906).patupilone (epo906) is a microtubule stabilizer with a potent antitumor effect. integrin αvβ3-binding (rgd) liposomes were loaded with epo906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma.201323818777
anthracimycin, a potent anthrax antibiotic from a marine-derived actinomycete.licensed to kill: a new antibiotic, anthracimycin (see scheme), produced by a marine-derived actinomycete in saline culture, shows significant activity toward bacillus anthracis, the bacterial pathogen responsible for anthrax infections. chlorination of anthracimycin gives a dichloro derivative that retains activity against gram-positive bacteria, such as anthrax, but also shows activity against selected gram-negative bacteria.201323776159
tubulin-β-iii overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones.uterine serous carcinoma (usc) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. overexpression of tubulin-β-iii and p-glycoprotein has been linked to paclitaxel resistance in many cancers but has been undercharacterized among uscs. epothilones have demonstrated activity in certain paclitaxel-resistant malignancies. in this study, relationships are clarified, in uscs relative to ovarian serous carcinomas (oscs), between tubulin-β-iii and p-glycoprotein expressi ...201323585021
molecular cloning, expression of mind gene from lactobacillus acidophilus vtcc-b-871 and analyses to identify lactobacillus rhamnosus pn04 from vietnam hottuynia cordata thunb.the mind gene encoding an inhibitor cell division mind homolog from lactobacillus acidophilus vtcc-b-871 was cloned. we showed that there were 97 % homology between mind genes of l. acidophilus vtcc-b-871 and lactobacillus rhamnosus gg and lactobacillus rhamnosus lc705. based on the analysis of the dna sequence data from the l. rhamnosus genome project and sequenced mind gene of l. acidophilus vtcc-b-871, a pair of primers was designed to identified the different mind genes from l. acidophilus a ...201324426140
the structure of a streptomyces avermitilis α-l-rhamnosidase reveals a novel carbohydrate-binding module cbm67 within the six-domain arrangement.α-l-rhamnosidases hydrolyze α-linked l-rhamnosides from oligosaccharides or polysaccharides. we determined the crystal structure of the glycoside hydrolase family 78 streptomyces avermitilis α-l-rhamnosidase (sarha78a) in its free and l-rhamnose complexed forms, which revealed the presence of six domains n, d, e, f, a, and c. in the ligand complex, l-rhamnose was bound in the proposed active site of the catalytic module, revealing the likely catalytic mechanism of sarha78a. glu(636) is predicted ...201323486481
chemotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer: an overview.anthracyclines and taxanes are cytotoxic agents that are commonly used for the treatment of breast cancer, including in the adjuvant, neoadjuvant, and metastatic setting. each drug class of is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). this may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. ...201323440080
new-old hemoglobin-like proteins of symbiotic dinoflagellates.symbiotic dinoflagellates are unicellular photosynthetic algae that live in mutualistic symbioses with many marine organisms. within the transcriptome of coral endosymbionts symbiodinium sp. (type c3), we discovered the sequences of two novel and highly polymorphic hemoglobin-like genes and proposed their 3d protein structures. at the protein level, four isoforms shared between 87 and 97% sequence identity for hb-1 and 78-99% for hb-2, whereas between hb-1 and hb-2 proteins, only 15-21% sequence ...201323610627
a general framework of persistence strategies for biological systems helps explain domains of life.the nature and cause of the division of organisms in superkingdoms is not fully understood. assuming that environment shapes physiology, here we construct a novel theoretical framework that helps identify general patterns of organism persistence. this framework is based on jacob von uexküll's organism-centric view of the environment and james g. miller's view of organisms as matter-energy-information processing molecular machines. three concepts describe an organism's environmental niche: scope, ...201323443991
locoregional interaction of ixabepilone (ixempra) after breast cancer radiation.radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. we observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (ixempra; bristol-myers squibb, princeton, nj) after radiation. we therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy.201323404814
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