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https://www.readbyqxmd.com/read/28087712/pdx1-dynamically-regulates-pancreatic-ductal-adenocarcinoma-initiation-and-maintenance
#1
Nilotpal Roy, Kenneth K Takeuchi, Jeanine M Ruggeri, Peter Bailey, David Chang, Joey Li, Laura Leonhardt, Sapna Puri, Megan T Hoffman, Shan Gao, Christopher J Halbrook, Yan Song, Mats Ljungman, Shivani Malik, Christopher V E Wright, David W Dawson, Andrew V Biankin, Matthias Hebrok, Howard C Crawford
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087534/mechanisms-of-horizontal-cell-to-cell-transfer-of-wolbachia-spp-in-drosophila-melanogaster
#2
Pamela M White, Jose E Pietri, Alain Debec, Shelbi Russell, Bhavin Patel, William Sullivan
: Wolbachia is an intracellular endosymbiont present in most arthropod and filarial nematode species. Transmission between hosts is primarily vertical, taking place exclusively through the female germline, though horizontal transmission has also been documented. Several studies indicate that Wolbachia is capable of transfer between somatic and germline cells during nematode development and in adult flies. However, the mechanisms underlying horizontal cell-to-cell transfer remain largely unexplored...
January 13, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28067626/broad-aox-expression-in-a-genetically-tractable-mouse-model-does-not-disturb-normal-physiology
#3
Marten Szibor, Praveen K Dhandapani, Eric Dufour, Kira M Holmström, Yuan Zhuang, Isabelle Salwig, Ilka Wittig, Juliana Heidler, Zemfira Gizatullina, Timur Gainutdinov, German Mouse Clinic Consortium, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Jatin Nandania, Vidya Velagapudi, Astrid Wietelmann, Pierre Rustin, Frank N Gellerich, Howard T Jacobs, Thomas Braun
Plants and many lower organisms, but not mammals, express alternative oxidases (AOX) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell-lines, Drosophila disease models and, most recently, in the mouse, where multiple, lentivector-AOX transgenes conferred substantial expression in specific tissues...
December 14, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28053109/matrix-metalloproteinase-activity-in-infections-by-an-encephalitic-virus-mouse-adenovirus-type-1
#4
Shanna L Ashley, Carla D Pretto, Matthew T Stier, Padma Kadiyala, Luiza Castro-Jorge, Tien-Huei Hsu, Robert Doherty, Kelly E Carnahan, Maria G Castro, Pedro R Lowenstein, Katherine R Spindler
: Mouse adenovirus type 1 (MAV-1) infection causes encephalitis in susceptible strains of mice and alters the permeability of infected brains to small molecules, which indicates disruption of the blood-brain barrier (BBB). In pathologic conditions, matrix metalloproteinases (MMPs) can disrupt the BBB through their proteolytic activity on basement membrane and tight junction proteins. We examined whether MAV-1 infection alters MMP activity in vivo and in vitro. Infected MAV-1-susceptible SJL mice had higher MMP2 and MMP9 activity in brains, measured by gelatin zymography, than mock infected mice...
January 4, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28053067/drug-discovery-in-fish-flies-and-worms
#5
Kevin Strange
Nonmammalian model organisms such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. An interdisciplinary approach that strategically combines the study of nonmammalian and mammalian animal models with diverse experimental tools has and will continue to provide deep molecular and genetic understanding of human disease and will significantly enhance the discovery and application of new therapies to treat those diseases...
December 2016: ILAR Journal
https://www.readbyqxmd.com/read/28046451/th-cd-209-04-fuzzy-robust-optimization-in-intensity-modulated-proton-therapy-planning-to-account-for-range-and-patient-setup-uncertainties
#6
Y An, M Bues, S Schild, W Liu
PURPOSE: We propose to apply a robust optimization model based on fuzzy-logic constraints in the intensity-modulated proton therapy (IMPT) planning subject to range and patient setup uncertainties. The purpose is to ensure the plan robustness under uncertainty and obtain the best trade-off between tumor dose coverage and organ-at-risk(OAR) sparing. METHODS: Two IMPT plans were generated for 3 head-and-neck cancer patients: one used the planning target volume(PTV) method; the other used the fuzzy robust optimization method...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28044325/robust-treatment-planning-with-conditional-value-at-risk-chance-constraints-in-intensity-modulated-proton-therapy
#7
Yu An, Steven E Schild, Martin Bues, Wei Liu, Jianming Liang
BACKGROUND AND PURPOSE: Intensity-modulated proton therapy (IMPT) is highly sensitive to range uncertainties and uncertainties caused by setup variation. The conventional inverse treatment planning of IMPT based on the planning target volume (PTV) is not often sufficient to ensure robustness of treatment plans. We applied a probabilistic framework (chance-constrained optimization) in IMPT planning to hedge against the influence of uncertainties. MATERIAL AND METHODS: We retrospectively selected one patient with lung cancer, one patient with head and neck (H&N) cancer, and one with prostate cancer for this analysis...
November 19, 2016: Medical Physics
https://www.readbyqxmd.com/read/28031481/xenopus-piwi-proteins-interact-with-a-broad-proportion-of-the-oocyte-transcriptome
#8
James A Toombs, Yuliya A Sytnikova, Gung-Wei Chirn, Ignatius Ang, Nelson C Lau, Michael D Blower
Piwi proteins utilize small RNAs (piRNAs) to recognize and repress target transcripts such as transposable elements (TE). However, the extensive diversity in piRNA sequences also suggests that Piwi/piRNA complexes interact with many transcripts beyond TEs. To examine the extent of Piwi interaction with target RNAs, we used Ribonucleoprotein-Immunoprecipitation (RIP) and Cross-linking and Immunoprecipitation (CLIP) to identify thousands of transcripts that associate with the Piwi proteins XIWI and XILI (Piwi-protein-Associated Transcripts, PATs) from early stage oocytes of X...
December 28, 2016: RNA
https://www.readbyqxmd.com/read/27986751/a-case-matched-gender-comparison-transcriptomic-screen-identifies-eif4e-and-eif5-as-potential-prognostic-and-tractable-biomarkers-in-male-breast-cancer
#9
Matthew P Humphries, Sree Sundara Rajan, Alastair Droop, Charlotte Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gábor Cserni, Jo Dent, Laura Fulford, Lee B Jordan, J Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Maria Mottolese, Elena Provenzano, Sami Shousha, Mark Stephens, Rosemary A Walker, Janina Kulka, Ian O Ellis, Margaret Jeffery, Helene H Thygesen, Vera Cappelletti, Maria G Daidone, Ingrid A Hedenfalk, Marie-Louise Fjällskog, Davide Melisi, Lucy Stead, Abeer Shaaban, Valerie Speirs
PURPOSE: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. EXPERIMENTAL DESIGN: A transcriptomic investigation of male and female BC was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n=477, training; n=220, validation set) and quantified in pre- and post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27975234/pharmacokinetics-and-derivation-of-an-anticancer-dosing-regimen-for-the-novel-anti-cancer-agent-isobutyl-deoxynyboquinone-ib-dnq-a-nqo1-bioactivatable-molecule-in-the-domestic-felid-species
#10
Alycen P Lundberg, Joshua M Francis, Malgorzata Pajak, Elizabeth I Parkinson, Kathryn L Wycislo, Thomas J Rosol, Megan E Brown, Cheryl A London, Levent Dirikolu, Paul J Hergenrother, Timothy M Fan
Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent...
December 14, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27965032/molecular-insights-into-allosteric-modulation-of-class-c-g-protein-coupled-receptors
#11
REVIEW
Katie Leach, Karen J Gregory
Class C G protein-coupled receptors (GPCRs) recognise diverse extracellular stimuli and are highly tractable drug targets for a host of different psychiatric, neurological and metabolic disorders. Discovery efforts focussed on allosteric modulators for Class C GPCRs have been highly fruitful, with diverse chemotypes identified for multiple Class C members. Indeed, a positive allosteric modulator of the calcium-sensing receptor, cinacalcet, was one of the first GPCR allosteric ligands to enter the clinic. Despite this success, allosteric modulator discovery and development remains challenging...
December 11, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27964882/identification-and-validation-of-small-molecule-modulators-of-the-nusb-nuse-interaction
#12
Peter J Cossar, Cong Ma, Christopher P Gordon, Joseph I Ambrus, Peter J Lewis, Adam McCluskey
Formation of highly possessive antitermination complexes is crucial for the efficient transcription of stable RNA in all bacteria. A key step in the formation of these complexes is the protein-protein interaction (PPI) between N-utilisation substances (Nus) B and E and thus this PPI offers a novel target for a new antibiotic class. A pharmacophore developed via a secondary structure epitope approach was utilised to perform an in silico screen of the mini-Maybridge library (56,000 compounds) which identified 25 hits of which five compounds were synthetically tractable leads...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27942524/ck1%C3%AE-a-pharmacologically-tractable-achilles-heel-of-wnt-driven-cancers
#13
COMMENT
Jit Kong Cheong, David M Virshup
Aberrant Wnt signaling has been widely accepted to be a key driver of a subset of human cancers and a heavily scrutinized molecular pathway for the development of personalized medicine. In a recently published issue of Science Translational Medicine, Rosenberg and coworkers reported that the delta isoform of the CK1 family of serine/threonine kinases (CK1δ), an important mediator of intracellular Wnt signaling, is amplified and overexpressed in human breast tumors. They further demonstrated that pharmacological inhibition of CK1δ is efficacious for these cancers and implicate β-catenin signaling as a key target of CK1δ...
November 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/27941820/isolated-pores-dissected-from-human-two-pore-channel-2-are-functional
#14
Christopher J Penny, Taufiq Rahman, Altin Sula, Andrew J Miles, B A Wallace, Sandip Patel
Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27918908/likelihood-ratio-sequential-sampling-models-of-recognition-memory
#15
Adam F Osth, Simon Dennis, Andrew Heathcote
The mirror effect - a phenomenon whereby a manipulation produces opposite effects on hit and false alarm rates - is benchmark regularity of recognition memory. A likelihood ratio decision process, basing recognition on the relative likelihood that a stimulus is a target or a lure, naturally predicts the mirror effect, and so has been widely adopted in quantitative models of recognition memory. Glanzer, Hilford, and Maloney (2009) demonstrated that likelihood ratio models, assuming Gaussian memory strength, are also capable of explaining regularities observed in receiver-operating characteristics (ROCs), such as greater target than lure variance...
February 2017: Cognitive Psychology
https://www.readbyqxmd.com/read/27916527/dynamic-mrna-transport-and-local-translation-in-radial-glial-progenitors-of-the-developing-brain
#16
Louis-Jan Pilaz, Ashley L Lennox, Jeremy P Rouanet, Debra L Silver
In the developing brain, neurons are produced from neural stem cells termed radial glia [1, 2]. Radial glial progenitors span the neuroepithelium, extending long basal processes to form endfeet hundreds of micrometers away from the soma. Basal structures influence neuronal migration, tissue integrity, and proliferation [3-7]. Yet, despite the significance of these distal structures, their cell biology remains poorly characterized, impeding our understanding of how basal processes and endfeet influence neurogenesis...
December 19, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27902356/luciferase-tagged-wild-type-and-tropism-deficient-mouse-cytomegaloviruses-reveal-early-dynamics-of-host-colonization-following-peripheral-challenge
#17
Helen Farrell, Martha Oliveira, Kate Macdonald, Joseph Yunis, Michael Mach, Kimberley Bruce, Philip Stevenson, Rhonda Cardin, Nicholas Davis-Poynter
Cytomegaloviruses (CMVs) establish persistent, systemic infections and cause disease by maternal-foetal transfer, suggesting that their dissemination is a key target for antiviral intervention. Late clinical presentation has meant that human CMV (HCMV) dissemination is not well understood. Murine CMV (MCMV) provides a tractable model. Whole mouse imaging of virus-expressed luciferase has proved a useful way to track systemic infections. MCMV, in which the abundant lytic gene M78 was luciferase-tagged via a self-cleaving peptide (M78-LUC), allowed serial, unbiased imaging of systemic and peripheral infection without significant virus attenuation...
December 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27885283/induced-protein-degradation-an-emerging-drug-discovery-paradigm
#18
Ashton C Lai, Craig M Crews
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination...
November 25, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27881166/using-the-social-amoeba-dictyostelium-to-study-the-functions-of-proteins-linked-to-neuronal-ceroid-lipofuscinosis
#19
REVIEW
Robert J Huber
Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a debilitating neurological disorder that affects both children and adults. Thirteen genetically distinct genes have been identified that when mutated, result in abnormal lysosomal function and an excessive accumulation of ceroid lipofuscin in neurons, as well as other cell types outside of the central nervous system. The NCL family of proteins is comprised of lysosomal enzymes (PPT1/CLN1, TPP1/CLN2, CTSD/CLN10, CTSF/CLN13), proteins that peripherally associate with membranes (DNAJC5/CLN4, KCTD7/CLN14), a soluble lysosomal protein (CLN5), a protein present in the secretory pathway (PGRN/CLN11), and several proteins that display different subcellular localizations (CLN3, CLN6, MFSD8/CLN7, CLN8, ATP13A2/CLN12)...
November 24, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27873256/cell-based-fluorescent-screen-to-identify-inhibitors-of-bacterial-translation-initiation
#20
Federica Briani
A strategy that can be applied to the research of new molecules with antibacterial activity is to look for inhibitors of essential bacterial processes within large collections of chemically heterogeneous compounds. The implementation of this approach requires the development of proper assays aimed at the identification of molecules interfering with specific cell pathways and potentially applicable to the high throughput analysis of large chemical library. Here, I describe a fluorescence-based whole-cell assay in Escherichia coli devised to find inhibitors of the translation initiation pathway...
2017: Methods in Molecular Biology
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