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https://www.readbyqxmd.com/read/27920137/oncogenic-met-as-an-effective-therapeutic-target-in-non-small-cell-lung-cancer-resistant-to-egfr-inhibitors-the-rise-of-the-phoenix
#1
Livio Trusolino
Anecdotal reports have shown that concomitant inhibition of EGFR and MET can be clinically effective in patients with non-small cell lung cancer carrying EGFR mutations and MET amplification, but large phase III trials in genetically unselected individuals have failed to confirm the benefit of this combination therapy. A new study corroborates the evidence that lung cancer susceptibility to EGFR and MET blockade is sustained by genetically based activation of both targets and identifies a mutation in MET that confers acquired resistance to standard MET inhibitors hitting the active kinase, yet is vulnerable to other MET-directed compounds with a different binding mode...
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27910927/novel-chemoimmunotherapeutic-strategy-for-hepatocellular-carcinoma-based-on-a-genome-wide-association-study
#2
Kaku Goto, Dorcas A Annan, Tomoko Morita, Wenwen Li, Ryosuke Muroyama, Yasuo Matsubara, Sayaka Ito, Ryo Nakagawa, Yasushi Tanoue, Masahisa Jinushi, Naoya Kato
Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#3
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27908660/targeting-of-multiple-senescence-promoting-genes-and-signaling-pathways-by-triptonide-induces-complete-senescence-of-acute-myeloid-leukemia-cells
#4
Yanyan Pan, Mei Meng, Nana Zheng, Zhifei Cao, Ping Yang, Xiaodong Xi, Quansheng Zhou
Leukemia cells aberrantly overexpress senescence-suppression telomerase reverse transcriptase (TERT) and down-regulate key senescence-promoting genes to escape complete senescence, resulting in immortalization and malignant progression. Accordingly, induction of complete senescence is a sensible strategy for anti-leukemia therapy. However, effective senescence-based anti-leukemia drugs with low toxicity are currently lacking. In this study, we found that triptonide (chemical name diterpene triepoxide), a small molecule derived from the herb Tripterygium wilfordii Hook, strongly induced complete senescence in cultured acute myeloid leukemia (AML) cell lines, and potently inhibited growth and colony formation of U937 and HL-60 AML cell line with IC50 values of 7...
November 28, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27885096/promoting-fluoroscopic-personal-radiation-protection-equipment-unfamiliarity-facts-and-fears
#5
Stephen Balter
An incomplete understanding of risk can cause inappropriate fear. Personal protective equipment (PPE) offered for the prevention of brain cancer in interventional fluoroscopists (IR-PPE). Similar items are offered for cell-phone use (RF-PPE). Publications on fluoroscopy staff brain cancer and similar papers on cell-phone induced brain cancer were reviewed. An internet safety product search was performed, which resulted in many tens of thousands of hits. Vendor claims for either ionizing radiation or radio frequency products seldom addressed the magnitude of the risk...
November 24, 2016: Radiation Protection Dosimetry
https://www.readbyqxmd.com/read/27884978/estrogen-receptor-negativity-in-breast-cancer-a-cause-or-consequence
#6
Vijaya Narasihma Reddy Gajulapalli, Vijaya Lakshmi Malisetty, Suresh Kumar Chitta, Bramanandam Manavathi
Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of ERα expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate estrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable, to answer that two important approaches are considered: 1) Understanding the cellular origin of heterogeneity and ER negativity in breast cancers, and 2) characterization of molecular regulators of endocrine resistance...
November 24, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27881238/rational-identification-of-natural-organic-compounds-to-target-the-intermolecular-interaction-between-foxm-and-dna-in-colorectal-cancer
#7
Chunling Dong, Peng Yan, Juxun Wang, Hailian Mu, Shuli Wang, Fangchun Guo
The oncogenic transcription factor forkhead box M (Foxm) is overexpressed in human colorectal cancer (CRC). Targeting the protein interaction with its cognate DNA has been established as an attractive approach to anti-CRC chemotherapy. State-of-the-art molecular dynamics (MD) simulations revealed that the Foxm adopts considerably different conformations to interact with and without its DNA partner; the holo conformation is tightly packed as a typical globulin configuration, whereas the apo form is locally unstructured that exhibits intrinsic disorder in DNA recognition helix, indicating that DNA binding can help the Foxm refolding...
November 9, 2016: Bioorganic Chemistry
https://www.readbyqxmd.com/read/27876705/genome-wide-gain-of-function-screen-for-genes-that-induce-epithelial-to-mesenchymal-transition-in-breast-cancer
#8
Dubravka Škalamera, Mareike Dahmer-Heath, Alexander J Stevenson, Cletus Pinto, Esha T Shah, Sheena M Daignault, Nur Akmarina B M Said, Melissa Davis, Nikolas K Haass, Elizabeth D Williams, Brett G Hollier, Erik W Thompson, Brian Gabrielli, Thomas J Gonda
Epithelial to mesenchymal transition (EMT) is a developmental program that has been implicated in progression, metastasis and therapeutic resistance of some carcinomas. To identify genes whose overexpression drives EMT, we screened a lentiviral expression library of 17000 human open reading frames (ORFs) using high-content imaging to quantitate cytoplasmic vimentin. Hits capable of increasing vimentin in the mammary carcinoma-derived cell line MDA-MB-468 were confirmed in the non-tumorigenic breast-epithelial cell line MCF10A...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27874094/identification-of-polo-like-kinase-1-interaction-inhibitors-using-a-novel-cell-based-assay
#9
Karine Normandin, Jean-François Lavallée, Marie Futter, Alexandre Beautrait, Jean Duchaine, Sébastien Guiral, Anne Marinier, Vincent Archambault
Polo-like kinase 1 (Plk1) plays several roles in cell division and it is a recognized cancer drug target. Plk1 levels are elevated in cancer and several types of cancer cells are hypersensitive to Plk1 inhibition. Small molecule inhibitors of the kinase domain (KD) of Plk1 have been developed. Their selectivity is limited, which likely contributes to their toxicity. Polo-like kinases are characterized by a Polo-Box Domain (PBD), which mediates interactions with phosphorylation substrates or regulators. Inhibition of the PBD could allow better selectivity or result in different effects than inhibition of the KD...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27862655/mourning-dr-alfred-g-knudson-the-two-hit-hypothesis-tumor-suppressor-genes-and-the-tuberous-sclerosis-complex
#10
REVIEW
Okio Hino, Toshiyuki Kobayashi
On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome...
November 11, 2016: Cancer Science
https://www.readbyqxmd.com/read/27860401/probing-an-allosteric-pocket-of-cdk2-with-small-molecules
#11
Michael S Christodoulou, Fabiana Caporuscio, Valentina Restelli, Luca Carlino, Giuseppe Cannazza, Elisa Costanzi, Cinzia Citti, Leonardo Lo Presti, Pasquale Pisani, Roberto Battistutta, Massimo Broggini, Daniele Passarella, Giulio Rastelli
The availability of well characterized allosteric modulators is of crucial importance for investigating allosteric regulation of protein function. In a recently identified inactive conformation of CDK2 an open allosteric pocket has been detected and proposed as a site to accommodate allosteric inhibitors. Previous structure-based approaches allowed the identification of a hit compound expected to bind to this pocket. Here, we report the characterization of this compound by X-ray crystallography, which surprisingly provided a chemical structure different from the one previously reported...
November 18, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27856238/evaluation-of-known-and-novel-inhibitors-of-orai1-mediated-store-operated-ca-2-entry-in-mda-mb-231-breast-cancer-cells-using-a-fluorescence-imaging-plate-reader-assay
#12
Iman Azimi, Jack U Flanagan, Ralph J Stevenson, Marco Inserra, Irina Vetter, Gregory R Monteith, William A Denny
The Orai1 Ca(2+) permeable ion channel is an important component of store operated Ca(2+) entry (SOCE) in cells. It's over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays...
November 7, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27853354/development-of-novel-her2-inhibitors-against-gastric-cancer-derived-from-flavonoid-source-of-syzygium-alternifolium-through-molecular-dynamics-and-pharmacophore-based-screening
#13
Tirumalasetty Muni Chandra Babu, Aluru Rammohan, Vijaya Bhaskar Baki, Savita Devi, Duvvuru Gunasekar, Wudayagiri Rajendra
Continuous usage of synthetic chemotherapeutic drugs causes adverse effects, which prompted for the development of alternative therapeutics for gastric cancer from natural source. This study was carried out with a specific aim to screen gastroprotective compounds from the fruits of Syzygium alternifolium (Myrtaceae). Three flavonoids, namely, 1) 5-hydroxy-7,4'-dimethoxy-6,8-di-C-methylflavone, 2) kaempferol-3-O-β-d-glucopyranoside, and 3) kaempferol-3-O-α-l-rhamnopyranoside were isolated from the above medicinal plant by employing silica gel column chromatography and are characterized by NMR techniques...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27848153/previous-gwas-hits-in-relation-to-young-onset-breast-cancer
#14
Min Shi, Katie M O'Brien, Dale P Sandler, Jack A Taylor, Dmitri V Zaykin, Clarice R Weinberg
PURPOSE: Genome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered. METHODS: Using a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs...
November 15, 2016: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/27836755/discovery-of-the-first-dual-g-triplex-g-quadruplex-stabilizing-compound-a-new-opportunity-in-the-targeting-of-g-rich-dna-structures
#15
Jussara Amato, Alessia Pagano, Sandro Cosconati, Giorgio Amendola, Iolanda Fotticchia, Nunzia Iaccarino, Jessica Marinello, Alessio De Magis, Giovanni Capranico, Ettore Novellino, Bruno Pagano, Antonio Randazzo
BACKGROUND: Guanine-rich DNA motifs can form non-canonical structures known as G-quadruplexes, whose role in tumorigenic processes makes them attractive drug-target candidates for cancer therapy. Recent studies revealed that the folding and unfolding pathways of G-quadruplexes proceed through a quite stable intermediate named G-triplex. METHODS: Virtual screening was employed to identify a small set of putative G-triplex ligands. The G-triplex stabilizing properties of these compounds were analyzed by CD melting assay...
November 9, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27830373/precision-of-mri-ultrasound-fusion-biopsy-in-prostate-cancer-diagnosis-an-ex-vivo-comparison-of-alternative-biopsy-techniques-on-prostate-phantoms
#16
N Westhoff, F P Siegel, D Hausmann, M Polednik, J von Hardenberg, M S Michel, M Ritter
PURPOSE: Comparing the accuracy of MRI/ultrasound-guided target-biopsy by transrectal biopsy (TRB) with elastic versus rigid image fusion versus transperineal biopsy (TPB) with rigid image fusion in a standardized setting. METHODS: Target-biopsy of six differently sized and located lesions was performed on customized CIRS 070L prostate phantoms. Lesions were only MRI-visible. After prior MRI for lesion location, one targeted biopsy per lesion was obtained by TRB with elastic image fusion with Artemis™ (Eigen, USA), TRB with rigid image fusion with real-time virtual sonography (Hitachi, Japan) and TPB with rigid image fusion with a brachytherapy approach (Elekta, Sweden), each on a phantom of 50, 100 and 150 ml prostate volume...
November 9, 2016: World Journal of Urology
https://www.readbyqxmd.com/read/27825120/trans-ethnic-follow-up-of-breast-cancer-gwas-hits-using-the-preferential-linkage-disequilibrium-approach
#17
Qianqian Zhu, Lori Shepherd, Kathryn L Lunetta, Song Yao, Qian Liu, Qiang Hu, Stephen A Haddad, Lara Sucheston-Campbell, Jeannette T Bensen, Elisa V Bandera, Lynn Rosenberg, Song Liu, Christopher A Haiman, Andrew F Olshan, Julie R Palmer, Christine B Ambrosone
Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA)...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27822214/spongionella-secondary-metabolites-promising-modulators-of-immune-response-through-cd147-receptor-modulation
#18
Jon Andoni Sánchez, Amparo Alfonso, Ines Rodriguez, Eva Alonso, José Manuel Cifuentes, Roberto Bermudez, Mostafa E Rateb, Marcel Jaspars, Wael E Houssen, Rainer Ebel, Jioji Tabudravu, Luís M Botana
The modulation of the immune system can have multiple applications such as cancer treatment, and a wide type of processes involving inflammation where the potent chemotactic agent cyclophilin A (Cyp A) is implicated. The Porifera phylum, in which Spongionella is encompassed, is the main producer of marine bioactive compounds. Four secondary metabolites obtained from Spongionella (Gracilin H, A, L, and Tetrahydroaplysulphurin-1) were described to hit Cyp A and to block the release of inflammation mediators. Based on these results, some role of Spongionella compounds on other steps of the signaling pathway mediated by this chemotactic agent can be hypothesized...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27821623/optimization-of-a-luminescence-based-high-throughput-screening-assay-for-detecting-apyrase-activity
#19
John R Veloria, Ashwini K Devkota, Eun Jeong Cho, Kevin N Dalby
Apyrase is a calcium-activated enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), adenosine monophosphate (AMP), and Pi It is currently used in studies involving cancer and platelet aggregation in humans, as well as herbicide resistance in plants. Inhibitors of apyrase are being investigated for their use to suppress tumors and combat herbicide resistance. Only a few inhibitors of apyrase have been reported, many of which were identified through automated screening using a 96-well plate format and colorimetric phosphate detection...
November 7, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27818922/a-high-throughput-screening-assay-for-eukaryotic-elongation-factor-2-kinase-inhibitors
#20
Ting Xiao, Rui Liu, Christopher G Proud, Ming-Wei Wang
Eukaryotic elongation factor 2 kinase (eEF2K) inhibitors may aid in the development of new therapeutic agents to combat cancer. Purified human eEF2K was obtained from an Escherichia coli expression system and a luminescence-based high-throughput screening (HTS) assay was developed using MH-1 peptide as the substrate. The luminescent readouts correlated with the amount of adenosine triphosphate remaining in the kinase reaction. This method was applied to a large-scale screening campaign against a diverse compound library and subsequent confirmation studies...
November 2016: Acta Pharmaceutica Sinica. B
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