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Synthetic lethality

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https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#1
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27921290/-bath-salts-the-new-york-city-medical-examiner-experience-a-3-year-retrospective-review
#2
Stephen J deRoux, William A Dunn
"Bath salts" are synthetic derivatives of cathinones, compounds found in the leaves of Catha edulis, which possesses amphetamine-like properties. At the New York City Office of Chief Medical Examiner, we conducted a 3-year retrospective analysis of deaths in which cathinones were detected. Two categories emerged; those in which cathinones were a contributory cause of death (15 cases) and those in which they were an incidental finding (15 cases). Of the former group, 13 were associated with additional intoxicants; two deaths were attributed solely to cathinone intoxication, both survived 10 h: a man whose postmortem blood methylone concentration was 0...
December 6, 2016: Journal of Forensic Sciences
https://www.readbyqxmd.com/read/27915244/antifungal-activity-in-vitro-and-in-vivo-of-a-salmon-protamine-peptide-and-its-derived-cyclic-peptide-against-candida-albicans
#3
Jun-Ichi Nagao, Tamaki Cho, Makoto Mitarai, Keishi Iohara, Kazumi Hayama, Shigeru Abe, Yoshihiko Tanaka
Protamine peptides (PP) derived from salmon are 14-mer consisting of 10 arginine residues. We investigated the in vitro and in vivo antifungal activity of PP against Candida albicans PP showed the concentration-dependent dual mode of action; fungicidal activity and inhibitory activity of hyphal development in vitro. At lethal concentration of PP, intracellular accumulation of PP was energy-dependent but independent of endocytosis that resulted in ATP efflux and the generation of reactive oxygen species in the cells...
December 2, 2016: FEMS Yeast Research
https://www.readbyqxmd.com/read/27903826/synthetic-biology-approaches-to-biological-containment-pre-emptively-tackling-potential-risks
#4
REVIEW
Leticia Torres, Antje Krüger, Eszter Csibra, Edoardo Gianni, Vitor B Pinheiro
Biocontainment comprises any strategy applied to ensure that harmful organisms are confined to controlled laboratory conditions and not allowed to escape into the environment. Genetically engineered microorganisms (GEMs), regardless of the nature of the modification and how it was established, have potential human or ecological impact if accidentally leaked or voluntarily released into a natural setting. Although all evidence to date is that GEMs are unable to compete in the environment, the power of synthetic biology to rewrite life requires a pre-emptive strategy to tackle possible unknown risks...
November 30, 2016: Essays in Biochemistry
https://www.readbyqxmd.com/read/27902462/the-synthetic-lethal-killing-of-rad54b-deficient-colorectal-cancer-cells-by-parp1-inhibition-is-enhanced-with-sod1-inhibition
#5
Erin N McAndrew, Chloe C Lepage, Kirk J McManus
Colorectal cancer (CRC) is a leading cause of cancer-related death throughout the world. Despite improved screening efforts, most CRCs are diagnosed at late stages when surgery alone is not curative. Moreover, the low 5-year survival rate (~8-13%) for those living with stage IV CRC highlights the need for better treatment options. Many current chemotherapeutic approaches are non-specific and associated with side effects due to their tendency to target both normal and cancer cells. To address this issue, synthetic lethal (SL) approaches are now being explored in cancer and are defined as the lethal combination of two independently viable mutations/deletions...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27898521/pathogenesis-and-heterogeneity-of-ovarian-cancer
#6
Paul T Kroeger, Ronny Drapkin
PURPOSE OF REVIEW: The most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), was originally thought to develop from the ovarian surface epithelium. However, recent data suggest that the cells that undergo neoplastic transformation and give rise to the majority of HGSOC are from the fallopian tube. This development has impacted both translational research and clinical practice, revealing new opportunities for early detection, prevention, and treatment of ovarian cancer...
November 26, 2016: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/27894958/poly-adp-ribose-polymerase-inhibitors-selectively-induce-cytotoxicity-in-tcf3-hlf-positive-leukemic-cells
#7
Jinhua Piao, Shiori Takai, Takahiro Kamiya, Takeshi Inukai, Kanji Sugita, Kazuma Ohyashiki, Domenico Delia, Mitsuko Masutani, Shuki Mizutani, Masatoshi Takagi
Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors...
November 25, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27880943/tp53-mutations-expression-and-interaction-networks-in-human-cancers
#8
Xiaosheng Wang, Qingrong Sun
Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation...
November 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27879333/the-genome-wide-interaction-network-of-nutrient-stress-genes-in-escherichia-coli
#9
Jean-Philippe Côté, Shawn French, Sebastian S Gehrke, Craig R MacNair, Chand S Mangat, Amrita Bharat, Eric D Brown
: Conventional efforts to describe essential genes in bacteria have typically emphasized nutrient-rich growth conditions. Of note, however, are the set of genes that become essential when bacteria are grown under nutrient stress. For example, more than 100 genes become indispensable when the model bacterium Escherichia coli is grown on nutrient-limited media, and many of these nutrient stress genes have also been shown to be important for the growth of various bacterial pathogens in vivo To better understand the genetic network that underpins nutrient stress in E...
November 22, 2016: MBio
https://www.readbyqxmd.com/read/27872183/roles-of-the-essential-protein-ftsa-in-cell-growth-and-division-in-streptococcus-pneumoniae
#10
Andrea Mura, Daniela Fadda, Amilcar J Perez, Madeline L Danforth, Daniela Musu, Ana Isabel Rico, Marcin Krupka, Dalia Denapaite, Ho-Ching T Tsui, Malcolm E Winkler, Pavel Branny, Miguel Vicente, William Margolin, Orietta Massidda
: Streptococcus pneumoniae is an ovoid-shaped Gram-positive bacterium that grows by carrying out peripheral and septal peptidoglycan (PG) synthesis, analogous to model bacilli such as Escherichia coli and Bacillus subtilis In the model bacilli, FtsZ and FtsA proteins assemble into a ring at midcell and are dedicated to septal PG synthesis, but not peripheral PG synthesis; hence inactivation of FtsZ or FtsA results in long filamentous cells unable to divide. Here we demonstrate that FtsA and FtsZ colocalize at midcell in S...
November 21, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27869444/-brca1-and-brca2-pathologists-starting-kit
#11
Petr Škapa
Dysfunction of tumor suppressor genes BRCA1 and BRCA2 is involved in the pathogenesis of malignant tumors, especially breast and ovarian carcinoma. BRCA1/2 genes may be inactivated by germinal and somatic mutations or epigenetic changes. Germinal mutations are responsible for the hereditary breast and ovarian carcinoma syndrome. Defects of BRCA1/2 genes lead to the failure of homologous recombination, the basic mechanism for DNA double strand break repair. The resultant genomic instability is associated with a high risk of malignant transformation of the cell, but it also results in a higher sensitivity of tumors to platinum-based chemotherapeutic compounds which damage DNA structure directly...
2016: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/27866836/physiological-suppression-of-lipotoxic-liver-damage%C3%A2-by-complementary-actions-of-hdac3-and%C3%A2-scap-srebp
#12
Romeo Papazyan, Zheng Sun, Yong Hoon Kim, Paul M Titchenell, David A Hill, Wenyun Lu, Manashree Damle, Min Wan, Yuxiang Zhang, Erika R Briggs, Joshua D Rabinowitz, Mitchell A Lazar
Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective...
November 10, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27863247/a-dietary-fiber-deprived-gut-microbiota-degrades-the-colonic-mucus-barrier-and-enhances-pathogen-susceptibility
#13
Mahesh S Desai, Anna M Seekatz, Nicole M Koropatkin, Nobuhiko Kamada, Christina A Hickey, Mathis Wolter, Nicholas A Pudlo, Sho Kitamoto, Nicolas Terrapon, Arnaud Muller, Vincent B Young, Bernard Henrissat, Paul Wilmes, Thaddeus S Stappenbeck, Gabriel Núñez, Eric C Martens
Despite the accepted health benefits of consuming dietary fiber, little is known about the mechanisms by which fiber deprivation impacts the gut microbiota and alters disease risk. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria, we elucidated the functional interactions between dietary fiber, the gut microbiota, and the colonic mucus barrier, which serves as a primary defense against enteric pathogens. We show that during chronic or intermittent dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier...
November 17, 2016: Cell
https://www.readbyqxmd.com/read/27856791/synthetic-lethality-and-beyond
#14
Himisha Beltran
No abstract text is available yet for this article.
November 16, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27843638/kras-driven-lung-adenocarcinoma-combined-ddr1-notch-inhibition-as-an-effective-therapy
#15
REVIEW
Chiara Ambrogio, Ernest Nadal, Alberto Villanueva, Gonzalo Gómez-López, Timothy P Cash, Mariano Barbacid, David Santamaría
Understanding the early evolution of cancer heterogeneity during the initial steps of tumorigenesis can uncover vulnerabilities of cancer cells that may be masked at later stages. We describe a comprehensive approach employing gene expression analysis in early lesions to identify novel therapeutic targets and the use of mouse models to test synthetic lethal drug combinations to treat human Kirsten rat sarcoma viral oncogene homologue (KRAS)-driven lung adenocarcinoma.
2016: ESMO Open
https://www.readbyqxmd.com/read/27831832/silencing-of-cdk2-but-not-cdk1-separates-mitogenic-from-anti-apoptotic-signaling-sensitizing-p53-defective-cells-for-synthetic-lethality
#16
Tatyana S Nekova, Susanne Kneitz, Hermann Einsele, Ralf Bargou, Gernot Stuhler
Small molecule inhibitors targeting CDK1/CDK2 have been clinically proven effective against a variety of tumors, albeit at the cost of profound off target toxicities. To separate potential therapeutic from toxic effects, we selectively knocked down CDK1 or CDK2 in p53 mutated HACAT cells by siRNA silencing. Using dynamic, cell cycle wide proteome arrays, we observed minor changes in overall abundance of proteins critically involved in cell cycle transition despite profound G2/M or G1/S arrest, respectively...
November 10, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27830682/-identification-of-new-genes-that-affect-psi-prion-toxicity-in-saccharomyces-cerevisiae-yeast
#17
A G Matveenko, M V Belousov, S A Bondarev, S E Moskalenko, G A Zhouravleva
Translation termination is an important step in gene expression. Its correct processing is governed by eRF1 (Sup45) and eRF3 (Sup35) proteins. In Saccharomyces cerevisiae, mutations in the corresponding genes, as well as Sup35 aggregation in [PSI^(+)] cells that propagate the prion form of Sup35 lead to inaccurate stop codon recognition and, consequently, nonsense suppression. The presence of stronger prion variants results in the more efficient suppression of nonsense mutations. Previously, we proposed a synthetic lethality test that enables the identification of genes that may influence either translation termination factors or [PSI^(+)] manifestation...
September 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27829138/targeting-stromal-glutamine-synthetase-in-tumors-disrupts-tumor-microenvironment-regulated-cancer-cell-growth
#18
Lifeng Yang, Abhinav Achreja, Tsz-Lun Yeung, Lingegowda S Mangala, Dahai Jiang, Cecil Han, Joelle Baddour, Juan C Marini, Joseph Ni, Ryuichi Nakahara, Stephen Wahlig, Lisa Chiba, Sun Hye Kim, Joshua Morse, Sunila Pradeep, Archana Sidalaghatta Nagaraja, Monika Haemmerle, Noh Kyunghee, Mathew Derichsweiler, Thomas Plackemeier, Imelda Mercado-Uribe, Gabriel Lopez-Berestein, Tyler Moss, Prahlad T Ram, Jinsong Liu, Xiongbin Lu, Samuel C Mok, Anil K Sood, Deepak Nagrath
Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway...
November 8, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27826804/fitness-evaluation-of-ruditapes-philippinarum-exposed-to-ni
#19
F Savorelli, L Manfra, M Croppo, A Tornambè, D Palazzi, S Canepa, P L Trentini, A M Cicero, C Faggio
In this study, long-term effects of Ni, a widespread heavy metal in the aquatic ecosystems, have been determined on growth and lethality of the clam Ruditapes philippinarum, a known bioindicator of the marine environment. Three/four-month-old bivalves have been exposed to different concentrations of Ni dissolved in synthetic seawater. Growth and lethality as endpoints after 28 days of treatment have been observed. Obtained results are the following: EC25 = 3.97 ± 0.94 and 9.45 ± 1.59 mg/L and NOEC = 1...
November 8, 2016: Biological Trace Element Research
https://www.readbyqxmd.com/read/27820830/budding-yeast-rif1-controls-genome-integrity-by-inhibiting-rdna-replication
#20
Maksym Shyian, Stefano Mattarocci, Benjamin Albert, Lukas Hafner, Aleksandra Lezaja, Michael Costanzo, Charlie Boone, David Shore
The Rif1 protein is a negative regulator of DNA replication initiation in eukaryotes. Here we show that budding yeast Rif1 inhibits DNA replication initiation at the rDNA locus. Absence of Rif1, or disruption of its interaction with PP1/Glc7 phosphatase, leads to more intensive rDNA replication. The effect of Rif1-Glc7 on rDNA replication is similar to that of the Sir2 deacetylase, and the two would appear to act in the same pathway, since the rif1Δ sir2Δ double mutant shows no further increase in rDNA replication...
November 2016: PLoS Genetics
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