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Synthetic lethality

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https://www.readbyqxmd.com/read/28430577/synthetic-lethal-interaction-between-the-tumour-suppressor-stag2-and-its-paralog-stag1
#1
Lorena Benedetti, Matteo Cereda, LeeAnn Monteverde, Nikita Desai, Francesca D Ciccarelli
Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430101/synthetic-temperature-inducible-lethal-gene-circuits-in-escherichia-coli
#2
Stephanie C Pearce, Ralph L McWhinnie, Francis E Nano
Temperature sensitivity is often used as a way to attenuate micro-organisms to convert them into live vaccines. In this work, we explore the use of temperature-sensitive (TS) genetic circuits that express lethal genes as a widely applicable approach to TS attenuation. We tested different combinations of TS repressors and cognate promoters controlling the expression of genes encoding restriction endonucleases inserted at four different non-essential sites in the Escherichia coli chromosome. We found that the presence of the restriction endonuclease genes did not affect the viability of the host strains at the permissive temperature, but that expression of the genes at elevated temperatures killed the strains to varying extents...
April 22, 2017: Microbiology
https://www.readbyqxmd.com/read/28429680/the-inhibitory-effects-of-hydamtiq-a-novel-parp-inhibitor-on-growth-in-human-tumor-cell-lines-with-defective-dna-damage-response-pathways
#3
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play key roles in the regulation of cellular processes (e.g. DNA damagerepair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells with dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP1 activity.The aim of this study was to evaluate the growth inhibitory effects of a novel PARPI, HYDAMTIQ, on human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
April 20, 2017: Oncology Research
https://www.readbyqxmd.com/read/28428242/mapping-the-synthetic-dosage-lethality-network-of-cdk1-cdc28
#4
Christine Zimmermann, Ignacio Garcia, Manja Omerzu, Pierre Chymkowitch, Beibei Zhang, Jorrit M Enserink
Cdk1 (Cdc28 in yeast) is a cyclin dependent kinase (CDK) essential for cell cycle progression and cell division in normal cells. However, CDK activity also underpins proliferation of tumor cells, making it a relevant study subject. While numerous targets and processes regulated by Cdc28 have been identified, the exact functions of Cdc28 are only partially understood. To further explore the functions of Cdc28 we systematically overexpressed approximately 4800 genes in wild-type cells and in cells with artificially reduced Cdc28 activity...
April 19, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28427225/enhancing-synthetic-lethality-of-parp-inhibitor-and-cisplatin-in-brca-proficient-tumour-cells-with-hyperthermia
#5
Arlene L Oei, Caspar M van Leeuwen, Vidhula R Ahire, Hans M Rodermond, Rosemarie Ten Cate, Anneke M Westermann, Lukas J A Stalpers, Johannes Crezee, H Petra Kok, Przemek M Krawczyk, Roland Kanaar, Nicolaas A P Franken
BACKGROUND: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28426773/correction-cdk1-is-a-synthetic-lethal-target-for-kras-mutant-tumours
#6
Sara Costa-Cabral, Rachel Brough, Asha Konde, Marieke Aarts, James Campbell, Eliana Marinari, Jenna Riffell, Alberto Bardelli, Christopher Torrance, Christopher J Lord, Alan Ashworth
[This corrects the article DOI: 10.1371/journal.pone.0149099.].
2017: PloS One
https://www.readbyqxmd.com/read/28426098/targeting-chromatin-defects-in-selected-solid-tumors-based-on-oncogene-addiction-synthetic-lethality-and-epigenetic-antagonism
#7
D Morel, G Almouzni, J-C Soria, S Postel-Vinay
Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28424408/synthetic-lethality-of-glutaminolysis-inhibition-autophagy-inactivation-and-asparagine-depletion-in-colon-cancer
#8
Jiaqiu Li, Ping Song, Liyuan Zhu, Neelum Aziz, Qiyin Zhou, Yulong Zhang, Wenxia Xu, Lifeng Feng, Dingwei Chen, Xian Wang, Hongchuan Jin
Cancer cells reprogram metabolism to coordinate their rapid growth. They addict on glutamine metabolism for adenosine triphosphate generation and macromolecule biosynthesis. In this study, we report that glutamine deprivation retarded cell growth and induced prosurvival autophagy. Autophagy inhibition by chloroquine significantly enhanced glutamine starvation induced growth inhibition and apoptosis activation. Asparagine deprivation by L-asparaginase exacerbated growth inhibition induced by glutamine starvation and autophagy blockage...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423600/systematic-screening-of-isogenic-cancer-cells-identifies-dusp6-as-context-specific-synthetic-lethal-target-in-melanoma
#9
Stephanie Wittig-Blaich, Rainer Wittig, Steffen Schmidt, Stefan Lyer, Melanie Bewerunge-Hudler, Sabine Gronert-Sum, Olga Strobel-Freidekind, Carolin Müller, Markus List, Aleksandra Jaskot, Helle Christiansen, Mathias Hafner, Dirk Schadendorf, Ines Block, Jan Mollenhauer
Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies.We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419468/activation-of-the-akt-creb-signaling-axis-by-a-proline-rich-heptapeptide-confers-resistance-to-stress-induced-cell-death-and-inflammation
#10
Johannes Herkel, Jörg Schrader, Neta Erez, Ansgar W Lohse, Irun R Cohen
Cell stress of various kinds can lead to the induction of cell death and a damaging inflammatory response. Hence, a goal of therapeutic cell-stress management is to develop agents that might effectively regulate undesirable cell death and inflammation. To that end, we developed a synthetic peptide of 7 amino acids based on structural mimicry to a functional domain of p53, a key factor in the responses of cells to stressful stimuli. This heptapeptide, which we term Stressin-1, was found to inhibit both cell death and the secretion of inflammatory mediators by various cell types in response to different stressful agents in vitro...
April 17, 2017: Immunology
https://www.readbyqxmd.com/read/28417948/erbb-family-signalling-a-paradigm-for-oncogene-addiction-and-personalized-oncology
#11
REVIEW
Nico Jacobi, Rita Seeboeck, Elisabeth Hofmann, Andreas Eger
ErbB family members represent important biomarkers and drug targets for modern precision therapy. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. This review summarizes the current understanding of ErbB proteins in cell signalling and cancer and describes the molecular rationale of prominent cases of ErbB oncoprotein addiction in different cancer types. In addition, we have highlighted experimental technologies for the development of innovative cancer cell models that accurately predicted clinical ErbB drug efficacies...
April 12, 2017: Cancers
https://www.readbyqxmd.com/read/28415695/detection-of-copb2-as-a-kras-synthetic-lethal-partner-through-integration-of-functional-genomics-screens
#12
Eleni G Christodoulou, Hai Yang, Franziska Lademann, Christian Pilarsky, Andreas Beyer, Michael Schroeder
Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA.Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414727/trypanosoma-brucei-tbif1-inhibits-the-essential-f1-atpase-in-the-infectious-form-of-the-parasite
#13
Brian Panicucci, Ondřej Gahura, Alena Zíková
The mitochondrial (mt) FoF1-ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF), but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF), which lacks a canonical respiratory chain. This unconventional dependence on FoF1-ATPase is required to maintain the essential mt membrane potential (Δψm). Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool...
April 17, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28414320/inhibition-of-dna2-nuclease-as-a-therapeutic-strategy-targeting-replication-stress-in-cancer-cells
#14
S Kumar, X Peng, J Daley, L Yang, J Shen, N Nguyen, G Bae, H Niu, Y Peng, H-J Hsieh, L Wang, C Rao, C C Stephan, P Sung, G Ira, G Peng
Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity...
April 17, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28409399/pro-apoptotic-signaling-induced-by-retinoic-acid-and-dsrna-is-under-the-control-of-interferon-regulatory-factor-3-in-breast-cancer-cells
#15
Ana R Bernardo, José M Cosgaya, Ana Aranda, Ana M Jiménez-Lara
Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells...
April 13, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28403011/emerging-roles-of-lipid-metabolism-in-cancer-progression
#16
Cyril Corbet, Olivier Feron
PURPOSE OF REVIEW: Lipid metabolism in cancer cells and tumor-associated stromal cells was recently identified to contribute to disease progression particularly in response to changes in tumor microenvironment such as acidosis and hypoxia. RECENT FINDINGS: New molecular mechanisms driving lipid metabolism in various cancers were elicited through genetic silencing, pharmacological inhibition of key metabolic enzymes, including those involved in fatty acid oxidation and synthesis, and modulation of diet composition...
April 11, 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/28398005/nanotherapy-for-duchenne-muscular-dystrophy
#17
REVIEW
Michael E Nance, Chady H Hakim, N Nora Yang, Dongsheng Duan
Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials...
April 11, 2017: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
https://www.readbyqxmd.com/read/28395540/olaparib-for-the-treatment-of-breast-cancer
#18
Marie Robert, Jean-Sébastien Frenel, Carole Gourmelon, Anne Patsouris, Paule Augereau, Mario Campone
Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors...
April 11, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28394614/a-synthetic-macromolecular-antibiotic-platform-for-inhalable-therapy-against-aerosolized-intracellular-alveolar-infections
#19
Debobrato Das, Jasmin Chen, Selvi Srinivasan, Abby Michelle Kelly, Brian Lee, Hye-Nam Son, Frank Radella, Timothy E West, Daniel M Ratner, Anthony J Convertine, Shawn J Skerrett, Patrick S Stayton
Lung-based intracellular bacterial infections remain one of the most challenging infectious disease settings. For example, the current standard for treating Franciscella tularensis pneumonia (tularemia) relies on prolonged administration of oral and intravenous antibiotics that poorly achieve and sustain pulmonary drug bioavailability. Inhalable antibiotic formulations are approved and in clinical development for upper respiratory infections, but sustained drug dosing from inhaled antibiotics against alveolar intracellular infections remains a current unmet need...
April 10, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28388479/effects-of-bacillus-thuringiensis-strains-virulent-to-varroa-destructor-on-larvae-and-adults-of-apis-mellifera
#20
Eva Vianey Alquisira-Ramírez, Guadalupe Peña-Chora, Víctor Manuel Hernández-Velázquez, Andrés Alvear-García, Iván Arenas-Sosa, Ramón Suarez-Rodríguez
The sublethal effects of two strains of Bacillus thuringiensis, which were virulent in vitro to Varroa destructor, were measured on Apis mellifera. The effects of five concentrations of total protein (1, 5, 25, 50 and 100μg/mL) from the EA3 and EA26.1 strains on larval and adult honey bees were evaluated for two and seven days under laboratory conditions. Based on the concentrations evaluated, total protein from the two strains did not affect the development of larvae, the syrup consumption, locomotor activity or proboscis extension response of adults...
April 4, 2017: Ecotoxicology and Environmental Safety
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