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https://www.readbyqxmd.com/read/29156751/identification-of-potential-tissue-specific-cancer-biomarkers-and-development-of-cancer-versus-normal-genomic-classifiers
#1
Akram Mohammed, Greyson Biegert, Jiri Adamec, Tomáš Helikar
Machine learning techniques for cancer prediction and biomarker discovery can hasten cancer detection and significantly improve prognosis. Recent "OMICS" studies which include a variety of cancer and normal tissue samples along with machine learning approaches have the potential to further accelerate such discovery. To demonstrate this potential, 2,175 gene expression samples from nine tissue types were obtained to identify gene sets whose expression is characteristic of each cancer class. Using random forests classification and ten-fold cross-validation, we developed nine single-tissue classifiers, two multi-tissue cancer-versus-normal classifiers, and one multi-tissue normal classifier...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156643/melanoma-genetic-abnormalities-tumor-progression-clonal-evolution-and-tumor-initiating-cells
#2
REVIEW
Ugo Testa, Germana Castelli, Elvira Pelosi
Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future...
November 20, 2017: Medical Sciences: Open Access Journal
https://www.readbyqxmd.com/read/29156384/targeting-fgfr-pathway-in-breast-cancer
#3
J Perez-Garcia, E Muñoz-Couselo, J Soberino, F Racca, J Cortes
Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes. Although currently there are only a few targeted therapies approved for metastatic breast cancer, the discovery of druggable kinase gene alterations has radically changed cancer treatment by providing novel and successfully actionable drug targets...
November 17, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/29155559/crafting-of-neuroprotective-octapeptide-from-taxol-binding-pocket-of-%C3%AE-tubulin
#4
Prasenjit Mondal, Gaurav Das, Juhee Khan, Krishnangsu Pradhan, Surajit Ghosh
Microtubules play crucial role in maintaining the shape and function of neurons. During progression of Alzheimer's disease (AD), severe destabilization of microtubule occurs, which leads to the permanent disruption of signal transduction process and memory loss. Thus, microtubule stabilization is one of the key requirements for the treatment of AD. Taxol, a microtubule stabilizing anti-cancer drug has been considered as potential anti-AD drug but never tested in AD patients, likely because of its' toxic nature and poor brain exposure...
November 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29154949/a-novel-microscopy-based-assay-identifies-extended-synaptotagmin-1-esyt1-as-a-positive-regulator-of-anoctamin-1-traffic
#5
Joana R Lérias, Madalena C Pinto, Hugo M Botelho, Nikhil T Awatade, Margarida C Quaresma, Iris A L Silva, Podchanart Wanitchakool, Rainer Schreiber, Rainer Pepperkok, Karl Kunzelmann, Margarida D Amaral
An attractive possibility to treat Cystic Fibrosis (CF), a severe condition caused by dysfunctional CFTR, an epithelial anion channel, is through the activation of alternative (non-CFTR) anion channels. Anoctamin 1 (ANO1) was demonstrated to be a Ca(2+)-activated chloride channel (CaCC) and thus of high potential to replace CFTR. Despite that ANO1 is expressed in human lung CF tissue, it is present at the cell surface at very low levels. In addition, little is known about regulation of ANO1 traffic, namely which factors promote its plasma membrane (PM) localization...
November 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29154817/cancer-stem-cell-like-population-is-preferentially-suppressed-by-egfr-tkis-in-egfr-mutated-pc-9-tumor-models
#6
Fan Yang, Yang Li, Bin Liu, Jiacong You, Qinghua Zhou
AIMS: Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal. RESULTS: In this study, we described a potent activation of β-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated β-catenin signaling via phosphorylation of EGFR and AKT in EGFR-mutated PC-9 lung cancer cells...
November 14, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29153893/selective-atp-competitive-leads-of-cdk4-discovery-by-3d-qsar-pharmacophore-mapping-and-molecular-docking-approach
#7
Rohini Rondla, Lavanya Souda PadmaRao, Vishwanath Ramatenki, Aboubakr Haredi-Abdel-Monsef, Sarita Rajender Potlapally, Uma Vuruputuri
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val(96), Arg(101), and Glu(144) residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib...
November 14, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29153852/the-therapeutic-potential-of-pten-modulation-targeting-strategies-from-gene-to-protein
#8
REVIEW
Niall M McLoughlin, Carolin Mueller, Tom N Grossmann
Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic suitability has been called into question due to its "risky" profile as a tumor suppressor. To evaluate PTEN function and its various roles in disease a number of molecules have so far been developed. However, intrinsic problems associated with phosphatase inhibition and PTEN's complex regulation via post-translational modifications hinder straightforward access to selective modulators...
November 13, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29153505/structural-basis-for-the-inhibitory-effects-of-ubistatins-in-the-ubiquitin-proteasome-pathway
#9
Mark A Nakasone, Timothy A Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A Castañeda, Jennifer L Goeckeler-Fried, Frank Parlati, Tsui-Fen Chou, Ortal Hayat, Daoning Zhang, Christina M Camara, Steven M Bonn, Urszula K Nowicka, Susan Krueger, Michael H Glickman, Jeffrey L Brodsky, Raymond J Deshaies, David Fushman
The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it...
November 15, 2017: Structure
https://www.readbyqxmd.com/read/29153034/advances-in-maldi-mass-spectrometry-within-drug-discovery
#10
Dale S Cornett, Michael D Scholle
Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses. Existing and standard quantitation methods of IDO1 substrate and metabolite(s) are based on the total level of Trp and its metabolites determined by liquid chromatography tandem mass spectrometry analysis in human plasma, cerebrospinal fluid, and brain...
December 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29152737/molecular-mechanisms-of-drug-resistance-in-ovarian-cancer
#11
REVIEW
Leyla Norouzi-Barough, Mohammad Reza Sarookhani, Mohammadreza Sharifi, Sahar Moghbelinejad, Saranaz Jangjoo, Rasoul Salehi
Ovarian cancer is the most lethal malignancy among the gynecological cancers, with a 5-year survival rate, mainly due to being diagnosed at advanced stages, recurrence and resistance to the current chemotherapeutic agents. Drug resistance is a complex phenomenon and the number of known involved genes and cross-talks between signaling pathways in this process is growing rapidly. Thus, discovering and understanding the underlying molecular mechanisms involved in chemo-resistance are crucial for management of treatment and identifying novel and effective drug targets as well as drug discovery to improve therapeutic outcomes...
November 19, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29152453/targeting-the-stem-cell-properties-of-adult-breast-cancer-cells-using-combinatorial-strategies-to-overcome-drug-resistance
#12
Naira V Margaryan, Elisabeth A Seftor, Richard E B Seftor, Mary J C Hendrix
Purpose of review: Cancer is a major public health problem worldwide. In aggressive cancers, which are heterogeneous in nature, there exists a paucity of targetable molecules that can be used to predict outcome and response to therapy in patients, especially those in the high risk category with a propensity to relapse following chemotherapy. This review addresses the challenges pertinent to treating aggressive cancer cells with inherent stem cell properties, with a special focus on triple-negative breast cancer (TNBC)...
September 2017: Current Molecular Biology Reports
https://www.readbyqxmd.com/read/29151852/ancient-oncogenesis-infection-and-human-evolution
#13
REVIEW
Riaan F Rifkin, Marnie Potgieter, Jean-Baptiste Ramond, Don A Cowan
The recent discovery that malignant neoplastic lesions date back nearly 2 million years ago not only highlights the antiquity of cancer in the human lineage, but also provides remarkable insight into ancestral hominin disease pathology. Using these Early Pleistocene examples as a point of departure, we emphasize the prominent role of viral and bacterial pathogens in oncogenesis and evaluate the impact of pathogens on human evolutionary processes in Africa. In the Shakespearean vernacular "what's past is prologue," we highlight the significance of novel information derived from ancient pathogenic DNA...
December 2017: Evolutionary Applications
https://www.readbyqxmd.com/read/29151783/gastric-microbiota-tracing-the-culprit
#14
REVIEW
Cristian Vasile Petra, Aronel Rus, Dan Lucian Dumitraşcu
The gastric environment has been long time considered bacteria-free, but the discovery of Helicobacter pylori (H. pylori) in 1982 superseded this conception. Over the last decades new diagnostic methods have been developed, starting with culture-dependent and advancing to culture-independent ones. These modern techniques provide new insight into the composition and influence of this ecosystem on the entire gastrointestinal tract. H. pylori is no longer considered the only microorganism in the stomach, other non-H...
2017: Clujul Medical (1957)
https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#15
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29150396/identification-of-pyruvate-dehydrogenase-kinase-1-inhibitors-with-anti-osteosarcoma-activity
#16
Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang
Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 μM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells...
October 31, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29149401/introduction-how-we-encountered-tctp-and-our-purpose-in-studying-it
#17
Adam Telerman, Robert Amson
In this brief introduction, we describe our encounter with TCTP. Back in 2000, we discovered TCTP in two quite different ways: first, we looked at protein partners of TSAP6 and one of them was TCTP. Then, in collaboration with Sidney Brenner, we performed a high-throughput differential screening comparing the parental cancer cells with revertants. The results indicated that TCTP was of the most differentially expressed genes. These two approaches were carried out only months apart. They guided our research and led to the discoveries of drugs that inhibit the function of TCTP...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#18
Muzammal Hussain, Yang Zhou, Yu Song, H M Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29148252/sex-hormone-binding-globulin-shbg-is-a-potential-early-diagnostic-biomarker-for-gastric-cancer
#19
Chao-Wen Cheng, Che-Chang Chang, Yudha Nur Patria, Ruei-Ting Chang, Yun-Ru Liu, Fu-An Li, Hsiu-Ming Shih, Ching-Yu Lin
The use of blood plasma biomarkers in gastric cancer (GC) management is limited due to a lack of reliable biomarkers. An LC-MS/MS assay and a bioinformatic analysis were performed to identify blood plasma biomarkers in a GC discovery cohort. The data obtained were verified and validated by western blotting and an ELISA in an independent study cohort. A label-free quantification analysis of the MS data using PEAKS7 software found that four plasma proteins of apolipoprotein C-1, gelsolin, sex hormone-binding globulin (SHBG), and complement component C4-A were significantly overexpressed in GC patients...
November 17, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29147605/egfr-mutation-correlates-with-uninflamed-phenotype-and-weak-immunogenicity-causing-impaired-response-to-pd-1-blockade-in-non-small-cell-lung-cancer
#20
Zhong-Yi Dong, Jia-Tao Zhang, Si-Yang Liu, Jian Su, Chao Zhang, Zhi Xie, Qing Zhou, Hai-Yan Tu, Chong-Rui Xu, Li-Xu Yan, Yu-Fa Li, Wen-Zhao Zhong, Yi-Long Wu
Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy...
2017: Oncoimmunology
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