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https://www.readbyqxmd.com/read/28528303/discovery-of-a-potent-dual-alk-and-egfr-t790m-inhibitor
#1
Jaebong Jang, Jung Beom Son, Ciric To, Magda Bahcall, So Young Kim, Seock Yong Kang, Mierzhati Mushajiang, Younho Lee, Pasi A Jänne, Hwan Geun Choi, Nathanael S Gray
The mutational activations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are validated oncogenic events and the targets of approved drugs to treat non-small cell lung cancer (NSCLC). Here we report highly potent dual small molecule inhibitors of both ALK and EGFR, particularly the T790M mutant which confers resistance to first generation EGFR inhibitors. Dual ALK/EGFR inhibitors may provide an efficient approach to prevent resistance that arises as a consequence of clinically reported reciprocal activation mechanisms...
May 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28528220/properties-of-the-tapasin-homologue-tapbpr
#2
REVIEW
Andreas Neerincx, Louise H Boyle
The presentation of antigenic peptides by MHC class I molecules plays a vital role in generating T cell responses against infection and cancer. Over the last two decades the central role of tapasin as a peptide editor that influences the loading and optimisation of peptides onto MHC class I molecules has been extensively characterised. Recently, it has become evident that the tapasin-related protein, TAPBPR, functions as a second peptide editor which influences the peptides displayed by MHC class I molecules...
May 18, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28527393/a-combination-of-platelet-features-allows-detection-of-early-stage-cancer
#3
Siamack Sabrkhany, Marijke J E Kuijpers, Sander M J van Kuijk, Linda Sanders, Sharo Pineda, Steven W M Olde Damink, Anne-Marie C Dingemans, Arjan W Griffioen, Mirjam G A Oude Egbrink
BACKGROUND: Detection of early-stage cancer significantly improves patient survival. As platelets play an important role in cancer progression, we aimed to investigate whether platelets can be used for the discovery of early-stage cancer. METHODS: Patients with lung (n = 86) or head of pancreas (n = 42) cancer were included, as were healthy sex- and age-matched controls (n = 92). Blood was collected before initiation of treatment. Platelet count, volume and activation status were quantified in whole blood...
May 17, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28527373/-i-don-t-believe-it-acceptance-and-skepticism-of-genetic-health-information-among-african-american-and-white-smokers
#4
Erika A Waters, Linda Ball, Sarah Gehlert
RATIONALE: Effective translation of genomics research into practice depends on public acceptance of genomics-related health information. OBJECTIVE: To explore how smokers come to accept or reject information about the relationship between genetics and nicotine addiction. METHODS: Thirteen focus groups (N = 84) were stratified by education (seven < Bachelor's degree, six ≥ Bachelor's degree) and race (eight black, five white). Participants viewed a 1-min video describing the discovery of a genetic variant associated with increased risk of nicotine addiction and lung cancer...
May 3, 2017: Social Science & Medicine
https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#5
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#6
Carl U Bialucha, Scott D Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno LaFont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P Wagner, GiNell Elliott, Artur Veloso, Jessica C Piel, Meghan M Flaherty, Keith G Mansfield, Emily K Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J Meyer, Jason E Faris, Mary J Janatpour, Vivien W Chan, Nicholas C Yoder, Kalli C Catcott, Molly A McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A Engelman, Seth A Ettenberg, William R Sellers, Emma Lees
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development...
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526414/a-novel-sirt1-inhibitor-4bb-induces-apoptosis-in-hct116-human-colon-carcinoma-cells-partially-by-activating-p53
#7
Ananga Ghosh, Amrita Sengupta, Guru Pavan Kumar Seerapu, Ali Nakhi, E V Venkat Shivaji Ramarao, Navneet Bung, Gopalakrishnan Bulusu, Manojit Pal, Devyani Haldar
The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28525844/the-discovery-of-novel-potent-err-alpha-inverse-agonists-for-the-treatment-of-triple-negative-breast-cancer
#8
Yongli Du, Lianhua Song, Liudi Zhang, Hao Ling, Yanhui Zhang, Haifei Chen, Huijie Qi, Xiaojin Shi, Qunyi Li
The estrogen-related receptor α (ERRα) is an orphan receptor and a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor micro environments. Here we describe the discovery of novel potent inverse agonists of ERRα. In vitro, compound 11 potently inhibits ERRα's transcriptional activity by preventing endogenous PGC-1α and ERRα binding and suppresses the proliferation of different human cancer cell lines and the migration of breast cancer cells (MDA-MB-231)...
April 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28524181/common-pitfalls-in-preclinical-cancer-target-validation
#9
REVIEW
William G Kaelin
An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness...
May 19, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28524002/mirna-expression-in-bladder-cancer-and-their-potential-role-in-clinical-practice
#10
Ana Blanca, Liang Cheng, Rodolfo Montironi, Holger Moch, Francesco Massari, Michelangelo Fiorentino, Maria Rosaria Raspollini, Marina Scarpelli, Antonio Lopez-Beltran
To date more than 3000 miRNA sequences have been described in humans and reg¬istered at miRBase since their discovery. However, the functions of only a few of these miRNAs have been experimentally determined using deep sequencing technology. Aberrant miRNA expression has been associated with differentiation, invasion and metastasis in several cancers. In this context, recent reports have suggested that miRNAs play important roles in the regulation of target genes by binding to complementary regions of messenger transcripts to repress their translation or regulate degradation...
May 18, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28522905/strategies-used-by-helicobacter-pylori-to-establish-persistent-infection
#11
REVIEW
Amin Talebi Bezmin Abadi
Helicobacter pylori (H. pylori) is a Gram-negative and motile bacterium that colonizes the hostile microniche of the human stomach, then persists for the host's entire life, if not effectively treated. Clinically, H. pylori plays a causative role in the development of a wide spectrum of diseases including chronic active gastritis, peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Due to the global distribution of H. pylori, it is no exaggeration to conclude that smart strategies are contributing to adaptation of the bacterium to its permanent host...
April 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28521821/intratumoral-and-peritumoral-radiomics-for-the-pretreatment-prediction-of-pathological-complete-response-to-neoadjuvant-chemotherapy-based-on-breast-dce-mri
#12
Nathaniel M Braman, Maryam Etesami, Prateek Prasanna, Christina Dubchuk, Hannah Gilmore, Pallavi Tiwari, Donna Pletcha, Anant Madabhushi
BACKGROUND: In this study, we evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on pretreatment breast cancer dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). METHODS: A total of 117 patients who had received NAC were retrospectively analyzed. Within the intratumoral and peritumoral regions of T1-weighted contrast-enhanced MRI scans, a total of 99 radiomic textural features were computed at multiple phases...
May 18, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28521657/several-inhibitors-of-the-plk1-polo-box-domain-turn-out-to-be-non-specific-protein-alkylators
#13
Vincent Archambault, Karine Normandin
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD)...
May 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#14
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
May 18, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28521438/identification-of-differentially-expressed-genes-between-early-stage-adenocarcinoma-and-squamous-cell-carcinoma-lung-cancer-using-meta-analysis-methods
#15
Tianjiao Wang, Lei Zhang, Pu Tian, Suyan Tian
Lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC) are two major subtypes of non-small cell lung cancer (NSCLC). Previous studies have demonstrated that fundamental differences exist in the underlying mechanisms of tumor development, growth and invasion between these subtypes. The investigation of differentially-expressed genes (DEGs) between these two NSCLC subtypes is useful for determining and understanding such differences. The present study aimed to identify those DEGs using meta-analysis and the data from four microarray experiments, consisting of 164 AC and 161 SCC samples...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28521404/silencing-tak1-alters-gene-expression-signatures-in-bladder-cancer-cells
#16
Jimin Chen, Nan Zhang, Jiaming Wen, Zhewei Zhang
The aim of the present study was to identify the differentially expressed genes (DEGs) that are induced by the silencing of transforming growth factor-β-activated kinase 1 (TAK1) in bladder cancer cells and to analyze the potential biological effects. Dataset GSE52452 from mutant fibroblast growth factor receptor 3 (FGFR3) bladder cancer cells transfected with control siRNA or TAK1-specific siRNA was downloaded from Gene Expression Omnibus. The DEGs between the two groups were identified using Limma package following data pre-processing by Affy in Bioconductor...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28521364/chemotherapy-and-post-traumatic-stress-in-the-causation-of-cognitive-dysfunction-in-breast-cancer-patients
#17
Kerstin Hermelink, Markus Bühner, Philipp Sckopke, Franziska Neufeld, Judith Kaste, Varinka Voigt, Karin Münzel, Rachel Wuerstlein, Nina Ditsch, Karin Hellerhoff, Dorothea Rjosk-Dendorfer, Michael Braun, Franz Edler von Koch, Kristin Härtl, Stephan Hasmüller, Ingo Bauerfeind, Gerlinde Debus, Peter Herschbach, Sven Mahner, Nadia Harbeck
Background: Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress. Methods: Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function...
October 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28521327/epigenomics-pharmacoepigenomics-and-personalized-medicine-in-cervical-cancer
#18
Shama Prasada Kabekkodu, Sanjiban Chakrabarty, Supriti Ghosh, Angela Brand, Kapaettu Satyamoorthy
Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events...
May 19, 2017: Public Health Genomics
https://www.readbyqxmd.com/read/28521156/2-oxo-3-4-dihydropyrimido-4-5-d-pyrimidinyl-derivatives-as-new-irreversible-pan-fibroblast-growth-factor-receptor-fgfr-inhibitors
#19
Xueqiang Li, Christopher P Guise, Rana Taghipouran, Yuliana Yosaatmadja, Amir Ashoorzadeh, Woo-Kyong Paik, Christopher J Squire, Shuang Jiang, Jinfeng Luo, Yong Xu, Zheng-Chao Tu, Xiaoyun Lu, Xiaomei Ren, Adam V Patterson, Jeff B Smaill, Ke Ding
A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC50 values...
April 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28520425/furan-and-lactam-jadomycin-biosynthetic-congeners-isolated-from-streptomyces-venezuelae-isp5230-cultured-with-n%C3%AE%C2%B5-trifluoroacetyl-l-lysine
#20
Stephanie M Forget, Andrew W Robertson, David P Overy, Russell G Kerr, David L Jakeman
Angucycline antibiotics are composed of a classical four-ring angularly linked polyaromatic backbone. Differential cyclization chemistry of the A- and B-rings in jadomycin biosynthesis led to the discovery of two new furan analogues, while oxidation led to a ring-opened form of the jadomycin Nε-trifluoroacetyl-l-lysine (TFAL) congener. The compounds were isolated from Streptomyces venezuelae ISP5230 cultures grown with TFAL. Biosynthetic incorporation using d-[1-(13)C]-glucose in cultures enabled the unambiguous assignment of the aldehyde, alcohol, and amide functionalities present in these new congeners through NMR spectroscopy...
May 18, 2017: Journal of Natural Products
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