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https://www.readbyqxmd.com/read/28212080/improving-registration-robustness-for-image-guided-liver-surgery-in-a-novel-human-to-phantom-data-framework
#1
Jarrod Collins, Jared Weis, Jon Heiselman, Logan Clements, Amber Simpson, Willam Jarnagin, Michael Miga
In open image-guided liver surgery (IGLS), a sparse representation of the intraoperative organ surface can be acquired to drive image-to-physical registration. We hypothesize that uncharacterized error induced by variation in the collection patterns of organ surface data limits the accuracy and robustness of IGLS registration. Clinical validation of such registration methods is challenged due to the difficulty in obtaining data representative of the true state of organ deformation. We propose a novel human-to-phantom validation framework that transforms surface collection patterns from in vivo IGLS procedures (n=13) onto a well-characterized hepatic deformation phantom for the purpose of validating surface-driven, volumetric nonrigid registration methods...
February 13, 2017: IEEE Transactions on Medical Imaging
https://www.readbyqxmd.com/read/28202661/targeting-pak1
#2
REVIEW
Galina Semenova, Jonathan Chernoff
p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28186211/controlling-the-network-type-in-self-assembled-dipeptide-hydrogels
#3
Catherine Colquhoun, Emily R Draper, Ralf Schweins, Marco Marcello, Devkee Vadukul, Louise C Serpell, Dave J Adams
We show that the same low molecular weight gelator can form gels using three different methods. Gels were formed from a high pH solution either by adding a salt or by adding an acid; gels were also formed by adding water to a solution of the gelator in an organic solvent. The mechanical properties for the gels formed by the different methods are different from one another. We link this to the network type that is formed, as well as the fibrous structures that are formed. The salt-triggered gels show a significant number of fibres that tend to align...
February 10, 2017: Soft Matter
https://www.readbyqxmd.com/read/28163917/mitochondrial-mutations-and-metabolic-adaptation-in-pancreatic-cancer
#4
Rae-Anne Hardie, Ellen van Dam, Mark Cowley, Ting-Li Han, Seher Balaban, Marina Pajic, Mark Pinese, Mary Iconomou, Robert F Shearer, Jessie McKenna, David Miller, Nicola Waddell, John V Pearson, Sean M Grimmond, Leonid Sazanov, Andrew V Biankin, Silas Villas-Boas, Andrew J Hoy, Nigel Turner, Darren N Saunders
BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited...
2017: Cancer & Metabolism
https://www.readbyqxmd.com/read/28135089/the-emergence-of-small-molecule-non-rgd-mimetic-inhibitors-for-rgd-integrins
#5
Lisa M Miller, John M Pritchard, Simon J F Macdonald, Craig Jamieson, Allan J B Watson
The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence (arginine-glycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbβ3 have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin-therapeutics in need of a new strategy...
January 30, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28130450/rab8a-recruited-pi3k%C3%AE-regulates-signaling-and-cytokine-outputs-from-endosomal-toll-like-receptors
#6
Adam A Wall, Lin Luo, Yu Hung, Samuel J Tong, Nicholas D Condon, Antje Blumenthal, Matthew J Sweet, Jennifer L Stow
Lipopolysaccharide (LPS)-mediated activation of Toll-like receptor 4 (TLR4) in macrophages results in the coordinated release of proinflammatory cytokines, followed by regulatory mediators, to ensure that this potentially destructive pathway is tightly regulated. We previously showed that Rab8a recruits PI3Kγ for Akt-dependent signaling during TLR4 activation to limit the production of the pro-inflammatory cytokines IL-6 and IL-12p40, while enhancing the release of the regulatory/anti-inflammatory cytokine IL-10...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28128944/design-and-elaboration-of-a-tractable-tricyclic-scaffold-to-synthesize-drug-like-inhibitors-of-dipeptidyl-peptidase-4-dpp-4-antagonists-of-the-c-c-chemokine-receptor-type-5-ccr5-and-highly-potent-and-selective-phosphoinositol-3-kinase-%C3%AE-pi3k%C3%AE-inhibitors
#7
Carolin Schwehm, Barrie Kellam, Aimie Elizabeth Garces, Prof Stephen J Hill, Nicholas D Kindon, Tracey D Bradshaw, Jin Li, Simon J F Macdonald, James E Rowedder, Leigh A Stoddart, Michael John Stocks
A novel molecular scaffold has been synthesized and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predict-ed physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs...
January 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28107502/rnai-based-functional-genomics-identifies-new-virulence-determinants-in-mucormycosis
#8
Trung Anh Trieu, María Isabel Navarro-Mendoza, Carlos Pérez-Arques, Marta Sanchis, Javier Capilla, Patricia Navarro-Rodriguez, Loida Lopez-Fernandez, Santiago Torres-Martínez, Victoriano Garre, Rosa María Ruiz-Vázquez, Francisco E Nicolás
Mucorales are an emerging group of human pathogens that are responsible for the lethal disease mucormycosis. Unfortunately, functional studies on the genetic factors behind the virulence of these organisms are hampered by their limited genetic tractability, since they are reluctant to classical genetic tools like transposable elements or gene mapping. Here, we describe an RNAi-based functional genomic platform that allows the identification of new virulence factors through a forward genetic approach firstly described in Mucorales...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28106166/rapid-generation-of-hypomorphic-mutations
#9
Laura L Arthur, Joyce J Chung, Preetam Jankirama, Kathryn M Keefer, Igor Kolotilin, Slavica Pavlovic-Djuranovic, Douglas L Chalker, Vojislava Grbic, Rachel Green, Rima Menassa, Heather L True, James B Skeath, Sergej Djuranovic
Hypomorphic mutations are a valuable tool for both genetic analysis of gene function and for synthetic biology applications. However, current methods to generate hypomorphic mutations are limited to a specific organism, change gene expression unpredictably, or depend on changes in spatial-temporal expression of the targeted gene. Here we present a simple and predictable method to generate hypomorphic mutations in model organisms by targeting translation elongation. Adding consecutive adenosine nucleotides, so-called polyA tracks, to the gene coding sequence of interest will decrease translation elongation efficiency, and in all tested cell cultures and model organisms, this decreases mRNA stability and protein expression...
January 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28096221/efficient-crispr-cas9-assisted-gene-targeting-enables-rapid-and-precise-genetic-manipulation-of-mammalian-neural-stem-cells
#10
Raul Bardini Bressan, Pooran Singh Dewari, Maria Kalantzaki, Ester Gangoso, Mantas Matjusaitis, Claudia Garcia-Diaz, Carla Blin, Vivien Grant, Harry Bulstrode, Sabine Gogolok, William C Skarnes, Steven M Pollard
Mammalian neural stem (NS) cell lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NS cells are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting - so critical for functional studies of embryonic stem cells - has not been exploited to date in NS cells...
January 17, 2017: Development
https://www.readbyqxmd.com/read/28087712/pdx1-dynamically-regulates-pancreatic-ductal-adenocarcinoma-initiation-and-maintenance
#11
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
#12
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
#13
Marten Szibor, Praveen K Dhandapani, Eric Dufour, Kira M Holmström, Yuan Zhuang, Isabelle Salwig, Ilka Wittig, Juliana Heidler, Zemfira Gizatullina, Timur Gainutdinov, 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 (AOXs) 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...
February 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28053109/matrix-metalloproteinase-activity-in-infections-by-an-encephalitic-virus-mouse-adenovirus-type-1
#14
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
#15
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
#16
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
#17
Yu An, Jianming Liang, Steven E Schild, Martin Bues, Wei Liu
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...
January 2017: Medical Physics
https://www.readbyqxmd.com/read/28031481/xenopus-piwi-proteins-interact-with-a-broad-proportion-of-the-oocyte-transcriptome
#18
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
#19
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
#20
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
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