keyword
MENU ▼
Read by QxMD icon Read
search

Synthetic lethality

keyword
https://www.readbyqxmd.com/read/28735000/application-of-pharmacometrics-and-quantitative-systems-pharmacology-to-cancer-therapy-the-example-of-luminal-a-breast-cancer
#1
REVIEW
Brett Fleisher, Kayla Andrews, Ashley A Brown, Sihem Ait-Oudhia
Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC...
July 19, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28730479/analysis-of-drug-resistance-using-kinome-wide-functional-screens
#2
Katherine R Singleton, Keith T Earley, Lynn E Heasley
The clinical success of tyrosine kinase inhibitors specific for BCR-ABL-, EGFR-, ALK-, and ROS1-driven cancers continues to spur the quest to match specific oncogene-defined tumor types with an appropriate molecularly targeted therapy. Unfortunately, responses to these agents are not durable with intrinsic or acquired resistance limiting benefit. Additionally, efforts to identify the appropriate targets of new drugs have focused on nonfunctional assays such as large-scale sequencing for somatic mutations or analysis of gene copy number...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28723932/the-nucleoid-occlusion-factor-noc-controls-dna-replication-initiation-in-staphylococcus-aureus
#3
Ting Pang, Xindan Wang, Hoong Chuin Lim, Thomas G Bernhardt, David Z Rudner
Successive division events in the spherically shaped bacterium Staphylococcus aureus are oriented in three alternating perpendicular planes. The mechanisms that underlie this relatively unique pattern of division and coordinate it with chromosome segregation remain largely unknown. Thus far, the only known spatial regulator of division in this organism is the nucleoid occlusion protein Noc that inhibits assembly of the cytokinetic ring over the chromosome. However, Noc is not essential in S. aureus, indicating that additional regulators are likely to exist...
July 19, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28723660/poly-adp-ribose-polymerase-inhibitors-as-radiosensitizers-a-systematic-review-of-pre-clinical-and-clinical-human-studies
#4
REVIEW
Paul Lesueur, François Chevalier, Jean-Baptiste Austry, Waisse Waissi, Hélène Burckel, Georges Noël, Jean-Louis Habrand, Yannick Saintigny, Florence Joly
BACKGROUND: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28718810/dna2-an-important-player-in-dna-damage-response-or-just-another-dna-maintenance-protein
#5
REVIEW
Elzbieta Pawłowska, Joanna Szczepanska, Janusz Blasiak
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM)...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28713291/an-expanding-world-of-novel-psychoactive-substances-opioids
#6
REVIEW
Jolanta B Zawilska
The abuse of novel psychoactive substances (NPS) has been increasing dramatically worldwide since late 2000s. By the end of 2015, more than 560 NPS had been reported to the European Monitoring Centre for Drugs and Drug Addiction. Although the most popular compounds are synthetic cannabinoids and psychostimulatory derivatives of cathinone (so-called β-keto-amphetamines), novel synthetic opioids have recently emerged on the recreational drug market. They include fentanyl (a potent narcotic analgesic) and its analogs (e...
2017: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/28710008/identifying-synthetic-lethal-targets-using-crispr-cas9-system
#7
Jaspreet Kaur Dhanjal, Navaneethan Radhakrishnan, Durai Sundar
Synthetic lethality occurs when co-occurrence of two genetic events is unfavorable for the survival of the cell or organism. The conventional approach of high throughput screening of synthetic lethal targets using chemical compounds has been replaced by RNAi technology. CRISPR/Cas9, an RNA guided endonuclease system is the most recent technology for this work. Here, we have discussed the major considerations involved in designing a CRISPR/Cas9 based screening experiment for identification of synthetic lethal targets...
July 11, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28707218/the-dna-damage-response-pathway-in-normal-hematopoiesis-and-malignancies
#8
REVIEW
Domenico Delia, Shuki Mizutani
In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations...
July 13, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28701475/hif-activation-causes-synthetic-lethality-between-the-vhl-tumor-suppressor-and-the-ezh1-histone-methyltransferase
#9
Abhishek A Chakraborty, Eijiro Nakamura, Jun Qi, Amanda Creech, Jacob D Jaffe, Joshiawa Paulk, Jesse S Novak, Kshithija Nagulapalli, Samuel K McBrayer, Glenn S Cowley, Javier Pineda, Jiaxi Song, Yaoyu E Wang, Steven A Carr, David E Root, Sabina Signoretti, James E Bradner, William G Kaelin
Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity...
July 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28701309/arhgap18-protects-against-thoracic-aortic-aneurysm-formation-by-mitigating-the-synthetic-and-pro-inflammatory-smooth-muscle-cell-phenotype
#10
Renjing Liu, Lisa Lo, Angelina J Lay, Yang Zhao, Ka Ka Ting, Elizabeth N Robertson, Andrew G Sherrah, Sorour R Jarrah, Haibo Li, Zhaoxiong Zhou, Brett D Hambly, David R Richmond, Richmond W Jeremy, Paul G Bannon, Matthew A Vadas, Jennifer Gamble
Rationale: Thoracic aortic aneurysm (TAA) is a potentially lethal condition which can affect individuals of all ages. TAA may be complicated by the sudden onset of life threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the non-syndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and/or reverse the disease phenotype. Objective: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMC), in the pathogenesis of TAA...
July 12, 2017: Circulation Research
https://www.readbyqxmd.com/read/28699540/dna-base-excision-repair-the-achilles-heel-of-tumour-cells-and-their-microenvironment
#11
M Poletto, A J Legrand, G L Dianov
Our current understanding of cancer suggests that every tumour has individual features. Approaches to cancer treatment require thorough comprehension of the mechanisms triggering genomic instability and protecting cancer cells from therapeutic treatments. Base excision repair (BER) is a frontline DNA repair system that is responsible for maintaining genome integrity. The BER pathway prevents the occurrence of disease, including cancer, by constantly repairing DNA base lesions and DNA single strand breaks caused by endogenous and exogenous mutagens...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28699516/induction-of-synthetic-lethality-by-natural-compounds-targeting-cancer-signaling
#12
Lee Farrand, Sanguine Byun
Despite the breakthroughs that have been achieved, significant unmet needs relating to the inadequate efficacy and toxicity of currently-available cancer therapies remain. Kinase inhibitors are a class of agents that target signaling factors responsible for the survival of malignant cells, and may address at least some of these issues. The concept of synthetic lethality provides a potential solution to counteract pathway redundancies, and refers to situations in which a mutation in one of two particular genes alone permits cell survival, while simultaneous mutation in both results in cell death...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28693887/novel-1-2-4-triazole-derivatives-as-antitumor-agents-against-hepatocellular-carcinoma
#13
Rasha R Radwan, Nashwa H Zaher, Marwa G El-Gazzar
Fifteen novel 1,2,3-triazole derivatives were prepared in series of synthetic steps starting from 4-amino-5-hydrazino-4H-1,2,4-triazole-3-thiol 1. The structures of the obtained compounds were verified through micoanalytical and spectral data. All the compounds were screened for their anticancer activity against liver human cancer cell lines (HEPG2) using Doxorubicin as standard. The most promising triazolothiadiazine derivative 12 was further tested for its degree of toxicity by estimating the median lethal dose (LD 50) and its antitumor activity through inhibiting the angiogenesis and progression of tumor against diethylnitrosamine (DENA)/CCl4 induced hepatocellular carcinoma (HCC) in rats...
July 8, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28691904/synthetic-lethality-between-the-cohesin-subunits-stag1-and-stag2-in-diverse-cancer-contexts
#14
Petra van der Lelij, Simone Lieb, Julian Jude, Gordana Wutz, Catarina P Santos, Katrina Falkenberg, Andreas Schlattl, Jozef Ban, Raphaela Schwentner, Thomas Hoffmann, Heinrich Kovar, Francisco X Real, Todd Waldman, Mark A Pearson, Norbert Kraut, Jan-Michael Peters, Johannes Zuber, Mark Petronczki
Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines...
July 10, 2017: ELife
https://www.readbyqxmd.com/read/28689308/triheptanoin-a-rescue-therapy-for-cardiogenic-shock-in-carnitine-acylcarnitine-translocase-deficiency
#15
Sidharth Mahapatra, Amitha Ananth, Nancy Baugh, Mihaela Damian, Gregory M Enns
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare long-chain fatty acid oxidation disorder (LC-FAOD) with high mortality due to cardiomyopathy or lethal arrhythmia. Triheptanoin (UX007), an investigational drug composed of synthetic medium odd-chain triglycerides, is a novel therapy in development for LC-FAOD patients. However, cases of its safe and efficacious use to reverse severe heart failure in CACT deficiency are limited. Here, we present a detailed report of an infant with CACT deficiency admitted in metabolic crisis that progressed into severe cardiogenic shock who was successfully treated by triheptanoin...
July 9, 2017: JIMD Reports
https://www.readbyqxmd.com/read/28678836/epistasis-in-genomic-and-survival-data-of-cancer-patients
#16
Dariusz Matlak, Ewa Szczurek
Cancer aggressiveness and its effect on patient survival depends on mutations in the tumor genome. Epistatic interactions between the mutated genes may guide the choice of anticancer therapy and set predictive factors of its success. Inhibitors targeting synthetic lethal partners of genes mutated in tumors are already utilized for efficient and specific treatment in the clinic. The space of possible epistatic interactions, however, is overwhelming, and computational methods are needed to limit the experimental effort of validating the interactions for therapy and characterizing their biomarkers...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28676354/cry46ab-from-bacillus-thuringiensis-tk-e6-is-a-new-mosquitocidal-toxin-with-aerolysin-type-architecture
#17
Tohru Hayakawa, Akira Sakakibara, Sho Ueda, Yoshinao Azuma, Toru Ide, So Takebe
Cry46Ab is a Cry toxin derived from Bacillus thuringiensis TK-E6. Cry46Ab is not significantly homologous to other mosquitocidal Cry or Cyt toxins and is classified as an aerolysin-type pore-forming toxin based on structural similarity. In this study, the potency of Cry46Ab was assessed for its potential application to mosquito control. A synthetic Cry46Ab gene, cry46Ab-S1, was designed to produce recombinant Cry46Ab as a glutathione-S-transferase fusion in Escherichia coli. Recombinant Cry46Ab showed apparent toxicity to Culex pipiens larvae, with a 50% lethal dose of 1...
July 1, 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28675450/synthetic-essentiality-targeting-tumor-suppressor-deficiencies-in-cancer
#18
REVIEW
Di Zhao, Ronald A DePinho
In this review, we summarize recent work exploring a novel conceptual approach termed "synthetic essentiality" as a means for targeting specific tumor suppressor gene deficiencies in cancer. With the aid of extensive publically available cancer genome and clinical databases, "synthetic essentiality" could be utilized to identify synthetic essential genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency. Synthetic essentiality expands the existing concepts for therapeutic strategies, including oncogene addiction, tumor maintenance, synthetic, and collateral lethality, to provide a framework for the discovery of cancer-specific vulnerabilities...
July 4, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28673972/fancm-brca1-and-blm-cooperatively-resolve-the-replication-stress-at-the-alt-telomeres
#19
Xiaolei Pan, William C Drosopoulos, Louisa Sethi, Advaitha Madireddy, Carl L Schildkraut, Dong Zhang
In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28673584/parp-inhibitors-in-acute-myeloid-leukaemia-therapy-how-a-synthetic-lethality-approach-can-be-a-valid-therapeutic-alternative
#20
Grigore Aristide Gafencu, Ciprian Ionuț Tomuleasa, Gabriel Ghiaur
Acute myeloid leukaemia (AML) is a malignancy in need of new therapeutic options. The current standard of care chemotherapy, leads to complete remission (CR) in the vast majority of adult patients under the age of 60. In contrast, CR rates in patients over the age of 60 reaches only 40-60%. While achievement of a CR is an important stepping stone in the treatment of AML, the majority of these patients experience relapse and die of their disease without adequate consolidation chemotherapy. Blood and marrow transplantation (BMT) can improve outcome in a select patient with AML but unfortunately, it is not a valid treatment option for the majority of older patients...
July 2017: Medical Hypotheses
keyword
keyword
16878
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"