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https://www.readbyqxmd.com/read/29351497/screen-targeting-lung-and-prostate-cancer-oncogene-identifies-novel-inhibitors-of-rgs17-and-problematic-chemical-substructures
#1
Christopher R Bodle, Josephine H Schamp, Joseph B O'Brien, Michael P Hayes, Meng Wu, Jonathan A Doorn, David L Roman
Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein-coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers...
January 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29351057/global-gene-expression-response-in-mouse-models-of-dna-repair-deficiency-after-gamma-irradiation
#2
Nils Rudqvist, Evagelia C Laiakis, Shanaz A Ghandhi, Suresh Kumar, Jeffrey D Knotts, Mashkura Chowdhury, Albert J Fornace, Sally A Amundson
In the event of an improvised nuclear device or "dirty bomb" in a highly populated area, potentially hundreds of thousands of people will require screening to ensure that exposed individuals receive appropriate treatment. For this reason, there is a need to develop tools for high-throughput radiation biodosimetry. Gene expression represents an emerging approach to biodosimetry and could potentially provide an estimate of both absorbed dose and individual radiation-induced injury. Since approximately 2-4% of humans are thought to be radiosensitive, and would suffer greater radiological injury at a given dose than members of the general population, it is of interest to explore the potential impact of such sensitivity on the biodosimetric gene expression signatures being developed...
January 19, 2018: Radiation Research
https://www.readbyqxmd.com/read/29350269/exome-analysis-in-34-sudden-unexplained-death-sud-victims-mainly-identified-variants-in-channelopathy-associated-genes
#3
Jacqueline Neubauer, Maria Rita Lecca, Giancarlo Russo, Christine Bartsch, Argelia Medeiros-Domingo, Wolfgang Berger, Cordula Haas
Sudden cardiac death (SCD) is one of the major causes of mortality worldwide, mostly involving coronary artery disease in the elderly. In contrary, sudden death events in young victims often represent the first manifestation of undetected genetic cardiac diseases, which remained without any symptoms during lifetime. Approximately 30% of these sudden death cases have no definite cardiac etiology after a comprehensive medicolegal investigation and are therefore termed as sudden unexplained death (SUD) cases. Advances in high-throughput sequencing approaches have provided an efficient diagnostic tool to identify likely pathogenic variants in cardiovascular disease-associated genes in otherwise autopsy-negative SUD cases...
January 19, 2018: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/29350181/a-single-continuous-metric-to-define-tiered-serum-neutralization-potency-against-hiv
#4
Peter Hraber, Bette Korber, Kshitij Wagh, David Montefiori, Mario Roederer
HIV-1 Envelope (Env) variants are grouped into tiers by their neutralization-sensitivity phenotype. This helped to recognize that tier-1 neutralization responses can be elicited readily, but do not protect against new infections. Tier-3 viruses are the least sensitive to neutralization. Because most circulating viruses are tier 2, vaccines that elicit neutralization responses against them are needed. While tier classification is widely used for viruses, a way to rate serum or antibody neutralization responses in comparable terms is needed...
January 19, 2018: ELife
https://www.readbyqxmd.com/read/29350071/disclosing-respiratory-coinfections-a-broad-range-panel-assay-for-avian-respiratory-pathogens-on-a-nanofluidic-pcr-platform
#5
Guillaume Croville, Charlotte Foret, Pauline Heuillard, Alexis Senet, Mattias Delpont, Mohammed Mouahid, Mariette F Ducatez, Faouzi Kichou, Jean-Luc Guerin
Respiratory syndromes (RS) are among the most significant pathological conditions in food animals and are caused by complex coactions of pathogens and environmental factors. In poultry, low pathogenic avian Influenza A viruses, metapneumoviruses, infectious bronchitis virus, infectious laryngotracheitis virus, Mycoplasma spp. Escherichia coli and/or Ornithobacterium rhinotracheale (ORT) in turkeys, are considered as key co-infectious agents of respiratory syndromes. Aspergillus sp., Pasteurella multocida, Avibacterium paragallinarum or Chlamydia psittaci may also be involved in respiratory outbreaks...
January 19, 2018: Avian Pathology: Journal of the W.V.P.A
https://www.readbyqxmd.com/read/29348850/novel-indazole-based-small-compounds-enhance-trail-induced-apoptosis-by-inhibiting-the-mkk7-tiprl-interaction-in-hepatocellular-carcinoma
#6
Ji-Yong Yoon, Jeong-Ju Lee, Sujin Gu, Myoung Eun Jung, Hyun-Soo Cho, Jung Hwa Lim, Soo Young Jun, Jun-Ho Ahn, Ju-Sik Min, Min-Hyuk Choi, Su-Jin Jeon, Yong-Jae Lee, Areum Go, Yun-Jeong Heo, Cho-Rok Jung, Gildon Choi, Kwangho Lee, Moon-Kook Jeon, Nam-Soon Kim
Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348827/molecular-genetic-profiling-and-high-throughput-in-vitro-drug-screening-in-nut-midline-carcinoma-an-aggressive-and-fatal-disease
#7
Anja Stirnweiss, Joyce Oommen, Rishi S Kotecha, Ursula R Kees, Alex H Beesley
NUT midline carcinoma (NMC) is a rare and aggressive cancer, with survival typically less than seven months, that can arise in people of any age. Genetically, NMC is defined by the chromosomal fusion of NUTM1 with a chromatin-binding partner, typically the bromodomain-containing protein BRD4. However, little is known about other genetic aberrations in this disease. In this study, we used a unique panel of cell lines to describe the molecular-genetic features of NMC. Next-generation sequencing identified a recurring high-impact mutation in the DNA-helicase gene RECQL5 in 75% of lines studied, and biological signals from mutation-signature and network analyses consistent with a general failure in DNA-repair...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348631/dynamic-all-optical-drug-screening-on-cardiac-voltage-gated-ion-channels
#8
Jonas Streit, Sonja Kleinlogel
Voltage-gated ion channels (VGCs) are prime targets for the pharmaceutical industry, but drug profiling on VGCs is challenging, since drug interactions are confined to specific conformational channel states mediated by changes in transmembrane potential. Here we combined various optogenetic tools to develop dynamic, high-throughput drug profiling assays with defined light-step protocols to interrogate VGC states on a millisecond timescale. We show that such light-induced electrophysiology (LiEp) yields high-quality pharmacological data with exceptional screening windows for drugs acting on the major cardiac VGCs, including hNav1...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348557/sensitizing-tumor-cells-to-conventional-drugs-hsp70-chaperone-inhibitors-their-selection-and-application-in-cancer-models
#9
Vladimir F Lazarev, Dmitry V Sverchinsky, Elena R Mikhaylova, Pavel I Semenyuk, Elena Y Komarova, Sergey A Niskanen, Alina D Nikotina, Anton V Burakov, Viktor G Kartsev, Irina V Guzhova, Boris A Margulis
Hsp70 chaperone controls proteostasis and anti-stress responses in rapidly renewing cancer cells, making it an important target for therapeutic compounds. To date several Hsp70 inhibitors are presented with remarkable anticancer activity, however their clinical application is limited by the high toxicity towards normal cells. This study aimed to develop assays to search for the substances that reduce the chaperone activity of Hsp70 and diminish its protective function in cancer cells. On our mind the resulting compounds alone should be safe and function in combination with drugs widely employed in oncology...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348210/toward-dynamic-structural-biology-two-decades-of-single-molecule-f%C3%A3-rster-resonance-energy-transfer
#10
REVIEW
Eitan Lerner, Thorben Cordes, Antonino Ingargiola, Yazan Alhadid, SangYoon Chung, Xavier Michalet, Shimon Weiss
Classical structural biology can only provide static snapshots of biomacromolecules. Single-molecule Förster resonance energy transfer (smFRET) paved the way for studying dynamics in macromolecular structures under biologically relevant conditions. Since its first implementation in 1996, smFRET experiments have confirmed previously hypothesized mechanisms and provided new insights into many fundamental biological processes, such as DNA maintenance and repair, transcription, translation, and membrane transport...
January 19, 2018: Science
https://www.readbyqxmd.com/read/29347843/combinatorial-design-and-virtual-screening-of-potent-anti-tubercular-fluoroquinolone-and-isothiazoloquinolone-compounds-utilizing-qsar-and-pharmacophore-modelling
#11
S Nandi, S Ahmed, A K Saxena
The virulence of tuberculosis infections resistant to conventional combination drug regimens cries for the design of potent fluoroquinolone compounds to be used as second line antimycobacterial chemotherapeutics. One of the most effective in silico methods is combinatorial design and high throughput screening by a ligand-based pharmacophore prior to experiment. The combinatorial design of a series of 3850 fluoroquinolone and isothiazoloquinolone compounds was then screened virtually by applying a topological descriptor based quantitative structure activity relationship (QSAR) for predicting highly active congeneric quinolone leads against Mycobacterium fortuitum and Mycobacterium smegmatis...
February 2018: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29346010/identification-and-correction-of-additive-and-multiplicative-spatial-biases-in-experimental-high-throughput-screening
#12
Bogdan Mazoure, Iurie Caraus, Robert Nadon, Vladimir Makarenkov
Data generated by high-throughput screening (HTS) technologies are prone to spatial bias. Traditionally, bias correction methods used in HTS assume either a simple additive or, more recently, a simple multiplicative spatial bias model. These models do not, however, always provide an accurate correction of measurements in wells located at the intersection of rows and columns affected by spatial bias. The measurements in these wells depend on the nature of interaction between the involved biases. Here, we propose two novel additive and two novel multiplicative spatial bias models accounting for different types of bias interactions...
January 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29344898/methods-for-high-throughput-drug-combination-screening-and-synergy-scoring
#13
Liye He, Evgeny Kulesskiy, Jani Saarela, Laura Turunen, Krister Wennerberg, Tero Aittokallio, Jing Tang
Gene products or pathways that are aberrantly activated in cancer but not in normal tissue hold great promises for being effective and safe anticancer therapeutic targets. Many targeted drugs have entered clinical trials but so far showed limited efficacy mostly due to variability in treatment responses and often rapidly emerging resistance. Toward more effective treatment options, we will need multi-targeted drugs or drug combinations, which selectively inhibit the viability and growth of cancer cells and block distinct escape mechanisms for the cells to become resistant...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29343688/wee1-inhibitor-mk1775-sensitizes-kras-mutated-nsclc-cells-to-sorafenib
#14
Elisa Caiola, Roberta Frapolli, Michele Tomanelli, Rossana Valerio, Alice Iezzi, Marina C Garassino, Massimo Broggini, Mirko Marabese
Non-Small-Cell Lung Cancer (NSCLC) is a poorly chemosensitive tumor and targeted therapies are only used for about 15% of patients where a specific driving and druggable lesion is observed (EGFR, ALK, ROS). KRAS is one of the most frequently mutated genes in NSCLC and patients harboring these mutations do not benefit from specific treatments. Sorafenib, a multi-target tyrosine kinase inhibitor, was proposed as a potentially active drug in KRAS-mutated NSCLC patients, but clinical trials results were not conclusive...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343120/an-update-on-the-advancing-high-throughput-screening-techniques-for-patch-clamp-based-ion-channel-screens-implications-for-drug-discovery
#15
Alison Obergrussberger, Tom A Goetze, Nina Brinkwirth, Nadine Becker, Søren Friis, Markus Rapedius, Claudia Haarmann, Ilka Rinke-Weiß, Sonja Stölzle-Feix, Andrea Brüggemann, Michael George, Niels Fertig
Automated patch clamp (APC) devices have become commonplace in many industrial and academic labs. Their ease-of-use and flexibility have ensured that users can perform routine screening experiments and complex kinetic experiments on the same device without the need for months of training and experience. APC devices are being developed to increase throughput and flexibility. Areas covered: Experimental options such as temperature control, internal solution exchange and current clamp have been available on some APC devices for some time, and are being introduced on other devices...
January 17, 2018: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29342416/identification-of-novel-quinazolinedione-derivatives-as-ror%C3%AE-t-inverse-agonist
#16
Yoshiyuki Fukase, Ayumu Sato, Yoshihide Tomata, Atsuko Ochida, Mitsunori Kono, Kazuko Yonemori, Keiko Koga, Toshitake Okui, Masashi Yamasaki, Yasushi Fujitani, Hideyuki Nakagawa, Ryoukichi Koyama, Masaharu Nakayama, Robert Skene, Bi-Ching Sang, Isaac Hoffman, Junya Shirai, Satoshi Yamamoto
Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity...
December 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29341586/development-of-a-novel-cytopathic-effect-based-phenotypic-screening-assay-against-cryptosporidium
#17
Alexander T Chao, Boon Heng Lee, Kah Fei Wan, Jeremy Selva, Bin Zou, Peter Gedeck, David Beer, Thierry T Diagana, Ghislain Bonamy, Ujjini H Manjunatha
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis is nitazoxanide, which shows limited efficacy in immunocompromised children, the most vulnerable patient population. Thus, new therapeutics and in vitro infection models are urgently needed to address the current unmet medical need. Toward this aim, we have developed novel cytopathic effect (CPE)-based Cp and Ch assays in human colonic tumor (HCT-8) cells and compared them to traditional imaging formats...
January 17, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29341164/patient-derived-organoid-models-help-define-personalized-management-of-gastrointestinal-cancer
#18
REVIEW
M R Aberle, R A Burkhart, H Tiriac, S W M Olde Damink, C H C Dejong, D A Tuveson, R M van Dam
BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models...
January 2018: British Journal of Surgery
https://www.readbyqxmd.com/read/29340841/an-efficient-gene-disruption-method-using-a-positive-negative-split-selection-marker-and-agrobacterium-tumefaciens-mediated-transformation-for-nomuraea-rileyi
#19
Yu Su, Zhongkang Wang, Changwen Shao, Yuanli Luo, Li Wang, Youping Yin
Targeted gene disruption via Agrobacterium tumefaciens-mediated transformation (ATMT) and homologous recombination is the most common method used to identify and investigate the functions of genes in fungi. However, the gene disruption efficiency of this method is low due to ectopic integration. In this study, a high-efficiency gene disruption strategy based on ATMT and the split-marker method was developed for use in Nomuraea rileyi. The β-glucuronidase (gus) gene was used as a negative selection marker to facilitate the screening of putative transformants...
January 16, 2018: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/29338757/a-rapid-high-resolution-method-for-resolving-dna-topoisomers
#20
Lesley A Mitchenall, Rachel E Hipkin, Michael M Piperakis, Nicolas P Burton, Anthony Maxwell
OBJECTIVE: Agarose gel electrophoresis has been the mainstay technique for the analysis of DNA samples of moderate size. In addition to separating linear DNA molecules, it can also resolve different topological forms of plasmid DNAs, an application useful for the analysis of the reactions of DNA topoisomerases. However, gel electrophoresis is an intrinsically low-throughput technique and suffers from other potential disadvantages. We describe the application of the QIAxcel Advanced System, a high-throughput capillary electrophoresis system, to separate DNA topoisomers, and compare this technique with gel electrophoresis...
January 16, 2018: BMC Research Notes
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