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https://www.readbyqxmd.com/read/29156805/circulating-tumor-dna-shows-variable-clonal-response-of-breast-cancer-during-neoadjuvant-chemotherapy
#1
Ji-Yeon Kim, Donghyun Park, Dae-Soon Son, Seok Jin Nam, Seok Won Kim, Hae Hyun Jung, Yeon Jeong Kim, Gahee Park, Woong-Yang Park, Jeong Eon Lee, Yeon Hee Park
Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer (BC). In this study, we aimed to identify genetic alterations during the process of tumor clonal evolution and examine if ctDNA level well indicated clinical response to neoadjuvant chemotherapy (NAC) and BC recurrence. We performed targeted ultra-deep sequencing of plasma DNAs, matched germline DNAs and tumor DNAs from locally advanced BC patients. Serial plasma DNAs were collected at diagnosis, after the 1(st) cycle of NAC and after curative surgery...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156785/in-silico-and-in-vitro-identification-of-inhibitory-activities-of-sorafenib-on-histone-deacetylases-in-hepatocellular-carcinoma-cells
#2
Tsang-Pai Liu, Yi-Han Hong, Pei-Ming Yang
Although sorafenib has been approved for treating hepatocellular carcinoma (HCC), clinical results are not satisfactory. Polypharmacology (one drug with multiple molecular targets) is viewed as an attractive strategy for identifying novel mechanisms of a drug and then rationally designing more-effective next-generation therapeutic agents. In this study, a polypharmacological study of sorafenib was performed by mining the next-generation Connectivity Map (CMap) database, CLUE (https://clue.io/). We found that sorafenib may act as a histone deacetylase (HDAC) inhibitor based on similar gene expression profiles...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156777/patients-with-nsclc-may-display-a-low-ratio-of-p-t790m-vs-activating-egfr-mutations-in-plasma-at-disease-progression-implications-for-personalised-treatment
#3
Marzia Del Re, Paola Bordi, Iacopo Petrini, Eleonora Rofi, Francesca Mazzoni, Lorenzo Belluomini, Enrico Vasile, Giuliana Restante, Francesco Di Costanzo, Alfredo Falcone, Antonio Frassoldati, Ron H N van Schaik, Christi M J Steendam, Antonio Chella, Marcello Tiseo, Riccardo Morganti, Romano Danesi
Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156772/stat3-and-stat5a-are-potential-therapeutic-targets-in-castration-resistant-prostate-cancer
#4
Sambit K Mohanty, Kader Yagiz, Dinesh Pradhan, Daniel J Luthringer, Mahul B Amin, Serhan Alkan, Bekir Cinar
Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH)...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156708/a-preclinical-evaluation-of-the-mek-inhibitor-refametinib-in-her2-positive-breast-cancer-cell-lines-including-those-with-acquired-resistance-to-trastuzumab-or-lapatinib
#5
John O'Shea, Mattia Cremona, Clare Morgan, Malgorzata Milewska, Frankie Holmes, Virginia Espina, Lance Liotta, Joyce O'Shaughnessy, Sinead Toomey, Stephen F Madden, Aoife Carr, Naomi Elster, Bryan T Hennessy, Alex J Eustace
Purpose: The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib. Methods: A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156680/vemurafenib-resistance-via-de-novo-rbm-genes-mutations-and-chromosome-5-aberrations-is-overcome-by-combined-therapy-with-palbociclib-in-thyroid-carcinoma-with-braf-v600e
#6
Zeus A Antonello, Nancy Hsu, Manoj Bhasin, Giovanni Roti, Mukta Joshi, Paul Van Hummelen, Emily Ye, Agnes S Lo, S Ananth Karumanchi, Christine R Bryke, Carmelo Nucera
Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAF(V600E) represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAF(WT/V600E)-positive PTC patient-derived cells with P16(-/-) (CDKN2A(-/-))...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156677/overcoming-resistance-to-single-agent-therapy-for-oncogenic-braf-gene-fusions-via-combinatorial-targeting-of-mapk-and-pi3k-mtor-signaling-pathways
#7
Payal Jain, Amanda Silva, Harry J Han, Shih-Shan Lang, Yuankun Zhu, Katie Boucher, Tiffany E Smith, Aesha Vakil, Patrick Diviney, Namrata Choudhari, Pichai Raman, Christine M Busch, Tim Delaney, Xiaodong Yang, Aleksandra K Olow, Sabine Mueller, Daphne Haas-Kogan, Elizabeth Fox, Phillip B Storm, Adam C Resnick, Angela J Waanders
Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156535/hdacis-class-i-cancer-stem-cell-and-phytochemicals-cancer-therapy-and-prevention-implications
#8
REVIEW
Sahar Bayat, Mahmoud Shekari Khaniani, Jalal Choupani, Mohammad Reza Alivand, Sima Mansoori Derakhshan
Epigenetics is independent of the sequence events that physically affect the condensing of chromatin and genes expression. The unique epigenetic memories of various cells trigger exclusive gene expression profiling. According to different studies, the aberrant epigenetic signatures and impaired gene expression profiles are master occurrences in cancer cells in which oncogene and tumor suppressor genes are affected. Owing to the facts that epigenetic modifications are performed earlier than expression and are reversible, the epigenetic reprogramming of cancer cells could be applied potentially for their prevention, control, and therapy...
November 16, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29156516/synergistic-anticancer-activity-of-20-s-ginsenoside-rg3-and-sorafenib-in-hepatocellular-carcinoma-by-modulating-pten-akt-signaling-pathway
#9
Mingxia Lu, Zhenghua Fei, Ganlu Zhang
Sorafenib, a multikinase inhibitor for hepatocellular carcinoma treatment, inhibits the Raf/MAPK/ERK signaling pathway. However, PI3K/Akt signaling pathway is activated by Sorafenib and cross-talks with the Raf/MAPK/ERK signaling pathway, leading to drug resistance. 20(S)-Ginsenoside Rg3 has been reported with significant anticancer effect to numerous carcinomas by inhibition of PI3K-Akt signaling pathway. Hence, we aim to examine the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib via modulation of PTEN/Akt signaling pathway...
November 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29156492/bayesian-monotonic-errors-in-variables-models-with-applications-to-pathogen-susceptibility-testing
#10
Glen DePalma, Bruce A Craig
Drug dilution (MIC) and disk diffusion (DIA) are the 2 most common antimicrobial susceptibility assays used by hospitals and clinics to determine an unknown pathogen's susceptibility to various antibiotics. Since only one assay is commonly used, it is important that the 2 assays give similar results. Calibration of the DIA assay to the MIC assay is typically done using the error-rate bounded method, which selects DIA breakpoints that minimize the observed discrepancies between the 2 assays. In 2000, Craig proposed a model-based approach that specifically models the measurement error and rounding processes of each assay, the underlying pathogen distribution, and the true monotonic relationship between the 2 assays...
November 20, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/29156457/discovery-of-novel-thiazol-2-amines-and-their-analogues-as-bioactive-molecules-design-synthesis-docking-and-biological-evaluation
#11
Anil Kumar Verma, Abha Bishnoi, Shaheen Fatma, Huda Parveen, Vineeta Singh
A simple and highly efficient procedure for the synthesis of novel thiazol-2-amines, via Mannich reaction with secondary amines, is described. The newly synthesized derivatives 8(a-e) and 9(a-e) were characterized by (1)H NMR, (13)C NMR, IR, Mass spectroscopy and elemental analysis. All the derivatives were evaluated for their in-vitro anti-microbial activity against a panel of pathogenic strains of bacteria and fungi. The SAR showed that the secondary amines had a significant impact on the in-vitro antimicrobial activity of this class of agents...
November 20, 2017: Drug Research
https://www.readbyqxmd.com/read/29156381/structure-based-methods-to-predict-mutational-resistance-to-diarylpyrimidine-non-nucleoside-reverse-transcriptase-inhibitors
#12
Syeda Maryam Azeem, Alecia N Muwonge, Nehaben Thakkar, Kristina W Lam, Kathleen M Frey
Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is a leading cause of HIV treatment failure. Often included in antiviral therapy, NNRTIs are chemically diverse compounds that bind an allosteric pocket of enzyme target reverse transcriptase (RT). Several new NNRTIs incorporate flexibility in order to compensate for lost interactions with amino acid conferring mutations in RT. Unfortunately, even successful inhibitors such as diarylpyrimidine (DAPY) inhibitor rilpivirine are affected by mutations in RT that confer resistance...
November 9, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29156244/isolation-and-characterization-of-polyvalent-bacteriophages-infecting-multi-drug-resistant-salmonella-serovars-isolated-from-broilers-in-egypt
#13
Mayada Mahmoud, Ahmed Askora, Ahmed Barakat Barakat, Omar El-Farouk Rabie, Sayed Emam Hassan
In this study, we isolated and characterized three phages named as Salmacey1, Salmacey2 and Salmacey3, infecting multi drug resistant Salmonella serovars isolated from broilers in Egypt. The most prevalent Salmonella serovars were S. typhimurium, S. enteritidis, and S. kentucky. All these Salmonella serovars were found to be resistant to more than two of the ten antimicrobial agents tested. Only S. kentucky was found to be resistant to seven antimicrobial agents. Examination of these phage particles by transmission electron microscopy (TEM), demonstrated that two phages (Salmacey1, Salmacey2) were found to belong to family Siphoviridae, and Salmacey3 was assigned to the family Myoviridae...
November 14, 2017: International Journal of Food Microbiology
https://www.readbyqxmd.com/read/29156151/limited-evidence-of-fungicide-driven-triazole-resistant-i-aspergillus-fumigatus-i-in-hamilton-canada
#14
Eta Ashu, Ga Young Kim, Patrick Roy-Gayos, Kelly Dong, Adrian Forsythe, Victoria Giglio, Gregory Korfanty, Deborah Yamamura, Jianping Xu
Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause aspergillosis in humans. Over the last decade there have been increasing global reports of treatment failure due to triazole resistance. An emerging hypothesis states that agricultural triazole fungicide use causes clinical triazole-resistance. Here we test this hypothesis in Hamilton, Ontario, Canada by examining a total of 195 agricultural, urban and clinical isolates using 9 highly polymorphic microsatellite markers. For each isolate, the in vitro susceptibilities to itraconazole and voriconazole, two triazole drugs commonly used in the management of patients, were also determined...
November 20, 2017: Canadian Journal of Microbiology
https://www.readbyqxmd.com/read/29156005/abiofilm-a-resource-of-anti-biofilm-agents-and-their-potential-implications-in-targeting-antibiotic-drug-resistance
#15
Akanksha Rajput, Anamika Thakur, Shivangi Sharma, Manoj Kumar
Biofilms play an important role in the antibiotic drug resistance, which is threatening public health globally. Almost, all microbes mimic multicellular lifestyle to form biofilm by undergoing phenotypic changes to adapt adverse environmental conditions. Many anti-biofilm agents have been experimentally validated to disrupt the biofilms during last three decades. To organize this data, we developed the 'aBiofilm' resource (http://bioinfo.imtech.res.in/manojk/abiofilm/) that harbors a database, a predictor, and the data visualization modules...
November 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29155886/insights-into-the-mechanism-of-isoenzyme-specific-signal-peptide-peptidase-mediated-translocation-of-heme-oxygenase
#16
Bianca Schaefer, Kohji Moriishi, Soenke Behrends
It has recently been shown that signal peptide peptidase (SPP) can catalyze the intramembrane cleavage of heme oxygenase-1 (HO-1) that leads to translocation of HO-1 into the cytosol and nucleus. While there is consensus that translocated HO-1 promotes tumor progression and drug resistance, the physiological signals leading to SPP-mediated intramembrane cleavage of HO-1 and the specificity of the process remain unclear. In this study, we used co-immunoprecipitation and confocal laser scanning microscopy to investigate the translocation mechanism of HO-1 and its regulation by SPP...
2017: PloS One
https://www.readbyqxmd.com/read/29155836/genetic-variation-in-dip5-an-amino-acid-permease-and-pdr5-a-multiple-drug-transporter-regulates-glyphosate-resistance-in-s-cerevisiae
#17
Xiaoqing Rong-Mullins, Apoorva Ravishankar, Kirsten A McNeal, Zachery R Lonergan, Audrey C Biega, J Philip Creamer, Jennifer E G Gallagher
S. cerevisiae from different environments are subject to a wide range of selective pressures, whether intentional or by happenstance. Chemicals classified by their application, such as herbicides, fungicides and antibiotics, can affect non-target organisms. First marketed as RoundUp™, glyphosate is the most widely used herbicide. In plants, glyphosate inhibits EPSPS, of the shikimate pathway, which is present in many organisms but lacking in mammals. The shikimate pathway produces chorismate which is the precursor to all the aromatic amino acids, para-aminobenzoic acid, and Coenzyme Q10...
2017: PloS One
https://www.readbyqxmd.com/read/29155815/allopurinol-attenuates-acute-kidney-injury-following-bothrops-jararaca-envenomation
#18
Pedro Henrique França Gois, Monique Silva Martines, Daniela Ferreira, Rildo Volpini, Daniele Canale, Ceila Malaque, Renato Crajoinas, Adriana Castello Costa Girardi, Maria Heloisa Massola Shimizu, Antonio Carlos Seguro
Snakebites have been recognized as a neglected public health problem in several tropical and subtropical countries. Bothrops snakebites frequently complicate with acute kidney injury (AKI) with relevant morbidity and mortality. To date, the only treatment available for Bothrops envenomation is the intravenous administration of antivenom despite its several limitations. Therefore, the study of novel therapies in Bothrops envenomation is compelling. The aim of this study was to evaluate the protective effect of Allopurinol (Allo) in an experimental model of Bothrops jararaca venom (BJ)-associated AKI...
November 20, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29155673/strengthening-global-surveillance-for-antimicrobial-drug-resistant-neisseria-gonorrhoeae-through-the-enhanced-gonococcal-antimicrobial-surveillance-program
#19
Emily J Weston, Teodora Wi, John Papp
Monitoring trends in antimicrobial drug-resistant Neisseria gonorrhoeae is a critical public health and global health security activity because the number of antimicrobial drugs available to treat gonorrhea effectively is rapidly diminishing. Current global surveillance methods for antimicrobial drug-resistant N. gonorrhoeae have many limitations, especially in countries with the greatest burden of disease. The Enhanced Gonococcal Antimicrobial Surveillance Program is a collaboration between the World Health Organization and the Centers for Disease Control and Prevention...
October 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/29155671/capacity-development-through-the-us-president-s-malaria-initiative-supported-antimalarial-resistance-monitoring-in-africa-network
#20
Eric S Halsey, Meera Venkatesan, Mateusz M Plucinski, Eldin Talundzic, Naomi W Lucchi, Zhiyong Zhou, Celine I Mandara, Hawela Moonga, Busiku Hamainza, Abdoul Habib Beavogui, Simon Kariuki, Aaron M Samuels, Laura C Steinhardt, Don P Mathanga, Julie Gutman, Yves Eric Denon, Aline Uwimana, Ashenafi Assefa, Jimee Hwang, Ya Ping Shi, Pedro Rafael Dimbu, Ousmane Koita, Deus S Ishengoma, Daouda Ndiaye, Venkatachalam Udhayakumar
Antimalarial drug resistance is an evolving global health security threat to malaria control. Early detection of Plasmodium falciparum resistance through therapeutic efficacy studies and associated genetic analyses may facilitate timely implementation of intervention strategies. The US President's Malaria Initiative-supported Antimalarial Resistance Monitoring in Africa Network has assisted numerous laboratories in partner countries in acquiring the knowledge and capability to independently monitor for molecular markers of antimalarial drug resistance...
December 2017: Emerging Infectious Diseases
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