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https://www.readbyqxmd.com/read/28721067/phase-i-dose-escalation-study-of-long-acting-pasireotide-in-patients-with-neuroendocrine-tumors
#1
James C Yao, Jennifer A Chan, Alain C Mita, Madan G Kundu, Karina Hermosillo Reséndiz, Ke Hu, Shoba Ravichandran, Jonathan R Strosberg, Edward M Wolin
This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28719729/synthesis-of-c-glucosylated-octaketide-anthraquinones-in-n-benthamiana-using-a-multispecies-based-biosynthetic-pathway
#2
Johan Andersen-Ranberg, Kenneth Thermann Kongstad, Majse Nafisi, Dan Staerk, Finn Okkels, Uffe Hasbro Mortensen, Birger Lindberg Møller, Rasmus John Normand Frandsen, Rubini Kannangara
Carminic acid is a C-glucosylated octaketide anthraquinone and the main constituent of the natural dye carmine (E120) possessing unique coloring, stability and solubility properties. Despite being used since ancient times, longstanding efforts to elucidate its route of biosynthesis have been unsuccessful. Herein is reported a novel combination of enzymes derived from a plant (Aloe arborescens, Aa), a bacterium (Streptomyces sp R1128, St), and an insect (Dactylopius coccus, Dc) that allows for the biosynthesis of the C-glucosylated anthraquinone, dcII, a precursor for carminic acid...
July 18, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28701150/physiological-roles-of-sigma-factor-sigd-in-corynebacterium-glutamicum
#3
Hironori Taniguchi, Tobias Busche, Thomas Patschkowski, Karsten Niehaus, Miroslav Pátek, Jörn Kalinowski, Volker F Wendisch
BACKGROUND: Sigma factors are one of the components of RNA polymerase holoenzymes, and an essential factor of transcription initiation in bacteria. Corynebacterium glutamicum possesses seven genes coding for sigma factors, most of which have been studied to some detail; however, the role of SigD in transcriptional regulation in C. glutamicum has been mostly unknown. RESULTS: In this work, pleiotropic effects of sigD overexpression at the level of phenotype, transcripts, proteins and metabolites were investigated...
July 12, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/28695854/the-putative-polyketide-cyclase-msmeg_0129-from-mycobacterium-smegmatis-purification-crystallization-and-x-ray-crystallographic-analysis
#4
Shuping Zheng, Ying Zhou, Joy Fleming, Yafeng Zhou, Wei Liu, Lijun Bi
Mycobacterium tuberculosis Rv0164 has previously been identified as a human T-cell antigen that induces significant production of IFN-γ in human peripheral blood mononuclear cells. M. smegmatis MSMEG_0129 shares 59% sequence identity with Rv0164. Based on sequence alignment, both proteins are predicted to be members of the cyclase/dehydrase family, which is part of a large group of enzymes referred to as type II polyketide synthases (PKSs). In biosynthetic pathways mediated by type II PKSs, cyclases catalyze the conversion of linear poly-β-ketones to cyclized intermediates...
July 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28694866/strategies-in-megasynthase-engineering-fatty-acid-synthases-fas-as-model-proteins
#5
REVIEW
Manuel Fischer, Martin Grininger
Megasynthases are large multienzyme proteins that produce a plethora of important natural compounds by catalyzing the successive condensation and modification of precursor units. Within the class of megasynthases, polyketide synthases (PKS) are responsible for the production of a large spectrum of bioactive polyketides (PK), which have frequently found their way into therapeutic applications. Rational engineering approaches have been performed during the last 25 years that seek to employ the "assembly-line synthetic concept" of megasynthases in order to deliver new bioactive compounds...
2017: Beilstein Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28694801/the-gata-type-transcription-factor-csm1-regulates-conidiation-and-secondary-metabolism-in-fusarium-fujikuroi
#6
Eva-Maria Niehaus, Julia Schumacher, Immo Burkhardt, Patrick Rabe, Eduard Spitzer, Martin Münsterkötter, Ulrich Güldener, Christian M K Sieber, Jeroen S Dickschat, Bettina Tudzynski
GATA-type transcription factors (TFs) such as the nitrogen regulators AreA and AreB, or the light-responsive TFs WC-1 and WC-2, play global roles in fungal growth and development. The conserved GATA TF NsdD is known as an activator of sexual development and key repressor of conidiation in Aspergillus nidulans, and as light-regulated repressor of macroconidia formation in Botrytis cinerea. In the present study, we functionally characterized the NsdD ortholog in Fusarium fujikuroi, named Csm1. Deletion of this gene resulted in elevated microconidia formation in the wild-type (WT) and restoration of conidiation in the non-sporulating velvet mutant Δvel1 demonstrating that Csm1 also plays a role as repressor of conidiation in F...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28690095/evolution-of-polyketide-synthesis-in-a-dothideomycete-forest-pathogen
#7
I Kutay Ozturk, Pranav Chettri, Pierre-Yves Dupont, Irene Barnes, Rebecca L McDougal, Geromy G Moore, Andre Sim, Rosie E Bradshaw
Fungal secondary metabolites have many important biological roles and some, like the toxic polyketide aflatoxin, have been intensively studied at the genetic level. Complete sets of polyketide synthase (PKS) genes can now be identified in fungal pathogens by whole genome sequencing and studied in order to predict the biosynthetic potential of those fungi. The pine needle pathogen Dothistroma septosporum is predicted to have only three functional PKS genes, a small number for a hemibiotrophic fungus. One of these genes is required for production of dothistromin, a polyketide virulence factor related to aflatoxin, whose biosynthetic genes are dispersed across one chromosome rather than being clustered...
July 6, 2017: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/28685195/characterization-of-three-pathway-specific-regulators-for-high-production-of-monensin-in-streptomyces-cinnamonensis
#8
Zheng-Kun Tang, Xiao-Mei Li, Ai-Ping Pang, Chun-Yan Lin, Yue Zhang, Jie Zhang, Jianjun Qiao, Guang-Rong Zhao
Monensin, a polyether ionophore antibiotic, is produced by Streptomyces cinnamonensis and worldwide used as a coccidiostat and growth-promoting agent in the field of animal feeding. The monensin biosynthetic gene cluster (mon) has been reported. In this study, the potential functions of three putatively pathway-specific regulators (MonH, MonRI, and MonRII) were clarified. The results from gene inactivation, complementation, and overexpression showed that MonH, MonRI, and MonRII positively regulate monensin production...
July 7, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28682630/elucidation-of-the-cryptic-methyl-group-epimerase-activity-of-dehydratase-domains-from-modular-polyketide-synthases-using-a-tandem-modules-epimerase-assay
#9
Xinqiang Xie, Ashish Garg, Chaitan Khosla, David E Cane
Dehydratase (DH) domains of cryptic function are often found in polyketide synthase (PKS) modules that produce epimerized (2S)-2-methyl-3-ketoacyl-ACP (acyl carrier protein) intermediates. A combination of tandem equilibrium isotope exchange (EIX) and a newly developed Tandem Modules Epimerase assay revealed the intrinsic epimerase activity of NanDH1 and NanDH5, from modules 1 and 5, respectively, of the nanchangmycin (1) PKS as well of NigDH1, from module 1 of the nigericin (3) PKS. Unexpectedly, all three epimerase-active DH domains were also found to possess intrinsic dehydratase activity, whereas the conventional DH domains, EryDH4, from module 4 of the erythromycin synthase, and NanDH2 from module 2 of the nanchangmycin synthase, were shown to have cryptic epimerase activity...
July 7, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28665343/tricholides-a-and-b-and-unnarmicin-d-new-hybrid-pks-nrps-macrocycles-isolated-from-an-environmental-collection-of-trichodesmium-thiebautii
#10
Matthew J Bertin, Alexandre F Roduit, Jiadong Sun, Gabriella E Alves, Christopher W Via, Miguel A Gonzalez, Paul V Zimba, Peter D R Moeller
Bioassay-guided isolation of the lipophilic extract of Trichodesmium thiebautii bloom material led to the purification and structure characterization of two new hybrid polyketide-non-ribosomal peptide (PKS-NRPS) macrocyclic compounds, tricholides A and B (1 and 2). A third macrocyclic compound, unnarmicin D (3), was identified as a new depsipeptide in the unnarmicin family, given its structural similarity to the existing compounds in this group. The planar structures of 1-3 were determined using 1D and 2D NMR spectra and complementary spectroscopic and spectrometric procedures...
June 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28661575/next-generation-phenotyping-in-emanuel-and-pallister-killian-syndrome-using-computer-aided-facial-dysmorphology-analysis-of-2d-photos
#11
Thomas Liehr, Nic Acquarola, Kate Pyle, Stephanie St-Pierre, Murney Rinholm, Omri Bar, Kathleen Wilhelm, Isolde Schreyer
High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of Next Generation Phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely considering of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the Facial Dysmorphology Novel Analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pallister-Killian Syndrome (PKS) from 2D facial photos...
June 29, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28639229/pharmacokinetics-of-mhaa4549a-an-anti-influenza-a-monoclonal-antibody-in-healthy-subjects-challenged-with-influenza%C3%A2-a-virus-in-a-phase-iia-randomized-trial
#12
Rong Deng, Ai Ping Lee, Mauricio Maia, Jeremy J Lim, Tracy Burgess, Priscilla Horn, Michael A Derby, Elizabeth Newton, Jorge A Tavel, William D Hanley
BACKGROUND AND OBJECTIVES: MHAA4549A, a human anti-influenza immunoglobulin (Ig) G1 monoclonal antibody, is being developed to treat patients hospitalized for influenza A infection. This study examined the pharmacokinetics (PKs) of MHAA4549A in a phase IIa, randomized, double-blind, dose-ranging trial in healthy volunteers challenged with influenza A virus. METHODS: Serum PK data were collected from 60 subjects in three single-dose groups (400, 1200, or 3600 mg) who received MHAA4549A intravenously 24-36 h after inoculation with the influenza A virus...
June 21, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28633821/enhanced-production-of-hypocrellin-a-by-ultrasound-stimulation-in-submerged-cultures-of-shiraia-bambusicola
#13
Chun Xiao Sun, Yan Jun Ma, Jian Wen Wang
Hypocrellin A (HA), a naturally occurring fungal perylenequinone, is widely used in clinic to treat skin diseases and developed as a photodynamic therapy (PDT) agent against cancers. In this study, a low intensity ultrasound (US, 0.28W/cm(2) at 40kHz) was conducted thrice of repeated US exposure (5-min) with an interval of 12h to stimulate HA production of Shiraia bambusicola after 72h of the initial submerged cultures. US not only increased the content of HA by 177.2% in mycelia, but stimulated the release of HA into the medium with the highest total production of HA (247...
September 2017: Ultrasonics Sonochemistry
https://www.readbyqxmd.com/read/28632895/genome-mining-reveals-high-incidence-of-putative-lipopeptide-biosynthesis-nrps-pks-clusters-containing-fatty-acyl-amp-ligase-genes-in-biofilm-forming-cyanobacteria
#14
Tomáš Galica, Pavel Hrouzek, Jan Mareš
Cyanobacterial lipopeptides exhibit antimicrobial and antifungal bioactivities with potential for use in pharmaceutical research. However, due to their haemolytic activity and cytotoxic effects against human cells, they may pose a health issue if produced in substantial amounts in the environment. In bacteria, lipopeptides can be synthesized via several well-evidenced mechanisms. In one of them, fatty acyl-AMP ligase (FAAL) initiates the biosynthesis by activation of a fatty acyl residue. We have performed a bioinformatic survey of the cyanobacterial genomic information available in the public databases for the presence of FAAL-containing non-ribosomal peptide synthetase/polyketide synthetase (NRPS/PKS) biosynthetic clusters, as a genetic basis for lipopeptide biosynthesis...
June 20, 2017: Journal of Phycology
https://www.readbyqxmd.com/read/28631514/pharmacokinetics-and-dosing-requirements-of-digoxin-in-pregnant-women-treated-for-fetal-supraventricular-tachycardia
#15
Ana Martin-Suarez, J German Sanchez-Hernandez, Fabiola Medina-Barajas, J Samuel Pérez-Blanco, Jose M Lanao, Luisa Garcia-Cuenllas Alvarez, M Victoria Calvo
BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded...
July 6, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28625782/complex-sexual-deception-in-an-orchid-is-achieved-by-co-opting-two-independent-biosynthetic-pathways-for-pollinator-attraction
#16
Haiyang Xu, Björn Bohman, Darren C J Wong, Claudia Rodriguez-Delgado, Adrian Scaffidi, Gavin R Flematti, Ryan D Phillips, Eran Pichersky, Rod Peakall
Sexually deceptive orchids lure their specific male pollinators using volatile semiochemicals that mimic female sex pheromones. To date, the semiochemicals known to be involved consist of blends of chemically and biosynthetically related compounds. In contrast, we report that (S)-β-citronellol and 2-hydroxy-6-methylacetophenone, two biosynthetically distinct compounds, are the active semiochemicals in Caladenia plicata, which is pollinated by male Zeleboria sp. thynnine wasps. They are also sex pheromone components of the female Zeleboria...
July 10, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28623508/clinical-pharmacokinetic-characteristics-of-cebranopadol-a-novel-first-in-class-analgesic
#17
Elke Kleideiter, Chiara Piana, Shaonan Wang, Robert Nemeth, Michael Gautrois
BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients...
June 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28620891/population-pharmacokinetic-modeling-of-olaratumab-an-anti-pdgfr%C3%AE-human-monoclonal-antibody-in-patients-with-advanced-and-or-metastatic-cancer
#18
Gary Mo, John R Baldwin, Debra Luffer-Atlas, Robert L Ilaria, Ilaria Conti, Michael Heathman, Damien M Cronier
BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population...
June 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28620184/transcriptomic-analysis-of-the-regulation-of-lipid-fraction-migration-and-fatty-acid-biosynthesis-in-schizochytrium-sp
#19
Lujing Ren, Xuechao Hu, Xiaoyan Zhao, Shenglan Chen, Yi Wu, Dan Li, Yadong Yu, Lingjun Geng, Xiaojun Ji, He Huang
Schizochytrium sp. is the main source of docosahexaenoic acid-rich oil, which is widely used in food additive and pharmaceutical industry. In this study, using RNA-seq, comparative transcriptomic analyses were performed at four stages of DHA fermentation by Schizochytrium sp to get potential genes related to cell transition from cell growth to lipid accumulation and then to lipid turnover. 1406, 385, 1384 differently expressed genes were identified by comparisons in pairs of S2 vs S1, S3 vs S2 and S4 vs S3...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28618182/mechanism-and-regulation-of-sorbicillin-biosynthesis-by-penicillium-chrysogenum
#20
Fernando Guzmán-Chávez, Oleksandr Salo, Yvonne Nygård, Peter P Lankhorst, Roel A L Bovenberg, Arnold J M Driessen
Penicillium chrysogenum is a filamentous fungus that is used to produce β-lactams at an industrial scale. At an early stage of classical strain improvement, the ability to produce the yellow-coloured sorbicillinoids was lost through mutation. Sorbicillinoids are highly bioactive of great pharmaceutical interest. By repair of a critical mutation in one of the two polyketide synthases in an industrial P. chrysogenum strain, sorbicillinoid production was restored at high levels. Using this strain, the sorbicillin biosynthesis pathway was elucidated through gene deletion, overexpression and metabolite profiling...
July 2017: Microbial Biotechnology
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