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https://www.readbyqxmd.com/read/29778085/braf-and-mek-inhibitor-therapy-eliminates-nestin-expressing-melanoma-cells-in-human-tumors
#1
Deon B Doxie, Allison R Greenplate, Jocelyn S Gandelman, Kirsten E Diggins, Caroline E Roe, Kimberly B Dahlman, Jeffrey A Sosman, Mark C Kelley, Jonathan M Irish
Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAFV 600mut melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM...
May 19, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29777202/aberrant-modulation-of-ribosomal-protein-s6-phosphorylation-confers-acquired-resistance-to-mapk-pathway-inhibitors-in-braf-mutant-melanoma
#2
Ming-Zhao Gao, Hong-Bin Wang, Xiang-Ling Chen, Wen-Ting Cao, Li Fu, Yun Li, Hai-Tian Quan, Cheng-Ying Xie, Li-Guang Lou
BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29776633/molecular-diagnostics-in-colorectal-carcinoma-advances-and-applications-for-2018
#3
REVIEW
Amarpreet Bhalla, Muhammad Zulfiqar, Martin H Bluth
The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis...
June 2018: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/29775633/braf-v600e-mutations-in-nevi-and-melanocytic-tumors-of-uncertain-malignant-potential-meltumps
#4
Ruth Seitz-Alghrouz, Jose Villacorta Hidalgo, Claudia Kayser, Clemens Kreutz, Kristin Technau-Hafsi, Carlos Diaz, Andreas von Deimling, Jens Timmer, Martin Werner, Miroslav Malkovsky, Paul Fisch
No abstract text is available yet for this article.
May 15, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#5
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29774876/-clinicopathological-features-for-epithelioid-glioblastoma-a-newly-defined-tumor-by-the-2016-world-health-organization-classification-of-tumors-of-the-central-nervous-system
#6
Juan Li, Xuebing Ling, Mingyao Lai, Qingjun Hu, Changguo Shan, Linbo Cai
To retrospectively summarize the clinicopathological features of epithelioid glioblastoma (Ep-GBM) and to explore new treatment for Ep-GBM.
 Methods: The clinical data of 13 patients with Ep-GBM, who were treated in our department from March 2016 to July 2017, were retrospectively analyzed. The clinicopathological features were summarized and the efficacy was evaluated.
 Results: The positive rate of BRAFV600E mutant and INI-1 was 76.9% (10/13) and 80% (8/10), respectively, while the median Ki-67 index was 30%...
April 28, 2018: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/29774135/vemurafenib-in-langerhans-cell-histiocytosis-report-of-a-pediatric-patient-and-review-of-the-literature
#7
Anne Heisig, Jan Sörensen, Stefanie-Yvonne Zimmermann, Stefan Schöning, Dirk Schwabe, Hans-Michael Kvasnicka, Raphaela Schwentner, Caroline Hutter, Thomas Lehrnbecher
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29774112/rare-genetic-heterogeneity-within-single-tumor-discovered-for-the-first-time-in-colorectal-liver-metastases-after-liver-resection
#8
Mylène Sebagh, Nelly Bosselut, Alexandre Dos Santos, Marc-Antoine Allard, Aldrick Ruiz, Raphaël Saffroy, Daniel Cherqui, Eric Vibert, Denis Castaing, René Adam, Antonio Sa Cunha, Antoinette Lemoine
Effective individualized treatment of patients with colorectal liver metastases (CLM) requires tumor genotyping, usually based on the analysis of one single sample per patient. Therapy failure may partially be explained by sampling errors and/or intratumoral genetic heterogeneity. We aimed to demonstrate intratumoral genetic heterogeneity in CLM and enable pathologists to select tumor tissue for genotyping. All the tumors of 86 patients who underwent liver resection for a single CLM were reviewed. Of the 86 patients, 66 patients received chemotherapy and 20 patients did not receive chemotherapy before liver resection...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29772692/insurance-coverage-policies-for-pharmacogenomic-and-multi-gene-testing-for-cancer
#9
Christine Y Lu, Stephanie Loomer, Rachel Ceccarelli, Kathleen M Mazor, James Sabin, Ellen Wright Clayton, Geoffrey S Ginsburg, Ann Chen Wu
Insurance coverage policies are a major determinant of patient access to genomic tests. The objective of this study was to examine differences in coverage policies for guideline-recommended pharmacogenomic tests that inform cancer treatment. We analyzed coverage policies from eight Medicare contractors and 10 private payers for 23 biomarkers (e.g., HER2 and EGFR ) and multi-gene tests. We extracted policy coverage and criteria, prior authorization requirements, and an evidence basis for coverage. We reviewed professional society guidelines and their recommendations for use of pharmacogenomic tests...
May 16, 2018: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29772524/high-incidence-of-braf-v600-mutation-in-indian-patients-with-head-and-neck-cancer
#10
Ashna Gauthaman, Anbalagan Moorthy
In cancer cells,  BRAF  is frequently mutated at codon 600 (V600 ) leading to the replacement of valine amino acid with other amino acids. The current study was performed to assess the prevalence of  BRAF V600  mutation in Indian patients with head and neck squamous cell carcinoma (HNSCC). Among the patients, 27% were homozygous, and 71% were heterozygous for the mutation and only 2% showed a wild genotype. Since identification of  BRAF V600  mutation in cancer patients is used for selection of the therapeutic agents, this study shows that all Indian patients with HNSCCmust be screened for this mutation...
June 1, 2018: Frontiers in Bioscience (Elite Edition)
https://www.readbyqxmd.com/read/29771690/heavily-pigmented-epithelioid-melanoma-with-loss-of-protein-kinase-a-regulatory-subunit-%C3%AE-expression
#11
Jarish N Cohen, Jessica A Spies, Fawn Ross, Angela Bohlke, Timothy H McCalmont
Heavily pigmented melanocytic neoplasms are genotypically and phenotypically diverse. Recently, a subset of this histopathologic spectrum was shown to harbor recurrent genetic alterations in the gene-encoding protein kinase A regulatory subunit-α (PRKAR1A). To date, no histopathologic descriptions of melanomas arising from this pathway have been described. We present a case of a darkly pigmented papule arising on the posterior neck of a 28-year-old man. Microscopically, the heavily pigmented compound melanocytic proliferation was centered in the dermis with permeation into the superficial subcutis...
May 16, 2018: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/29771009/primary-tumor-sidedness-is-an-independent-prognostic-marker-for-survival-in-metastatic-colorectal-cancer-results-from-a-large-retrospective-cohort-with-mutational-analysis
#12
Sophia C Kamran, Jeffrey W Clark, Hui Zheng, Darrell R Borger, Lawrence S Blaszkowsky, Jill N Allen, Eunice L Kwak, Jennifer Y Wo, Aparna R Parikh, Ryan D Nipp, Janet E Murphy, Lipika Goyal, Andrew X Zhu, A John Iafrate, Ryan B Corcoran, David P Ryan, Theodore S Hong
Recent reports demonstrate inferior outcomes associated with primary right-sided vs left-sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow-up 30...
May 17, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29770477/braf-v-600e-mutations-and-immunohistochemical-expression-of-ve1-protein-in-low-grade-serous-neoplasms-of-the-ovary
#13
Gulisa Turashvili, Rachel N Grisham, Sarah Chiang, Deborah F Delair, Kay J Park, Robert A Soslow, Rajmohan Murali
AIMS: The most common BRAF mutation in ovarian low-grade serous neoplasms (LGSNs) involves substitution of valine by glutamic acid at position 600 (V600E). Small studies have demonstrated high specificity of immunohistochemistry with mutation-specific monoclonal antibody VE1. We sought to investigate expression of VE1 protein in LGSNs and its correlation with BRAF mutation-associated histological features and BRAF mutation status. METHODS AND RESULTS: We reviewed pathology reports and available slides from ovarian serous borderline tumours (SBTs) and low-grade serous carcinomas (LGSCs) diagnosed between 2000-2012...
May 16, 2018: Histopathology
https://www.readbyqxmd.com/read/29769567/genomic-alterations-of-ground-glass-nodular-lung-adenocarcinoma
#14
Hyun Lee, Je-Gun Joung, Hyun-Tae Shin, Duk-Hwan Kim, Yujin Kim, Hojoong Kim, O Jung Kwon, Young Mog Shim, Ho Yun Lee, Kyung Soo Lee, Yoon-La Choi, Woong-Yang Park, D Neil Hayes, Sang-Won Um
In-depth molecular pathogenesis of ground-glass nodular lung adenocarcinoma has not been well understood. The objectives of this study were to identify genomic alterations in ground-glass nodular lung adenocarcinomas and to investigate whether viral transcripts were detected in these tumors. Nine patients with pure (n = 4) and part-solid (n = 5) ground-glass nodular adenocarcinomas were included. Six were females with a median age of 58 years. We performed targeted exon sequencing and RNA sequencing...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29768711/clinical-resistance-associated-with-a-novel-map2k1-mutation-in-a-patient-with-langerhans-cell-histiocytosis
#15
David O Azorsa, David W Lee, Daniel H Wai, Ranjan Bista, Apurvi R Patel, Eiman Aleem, Michael M Henry, Robert J Arceci
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p...
May 16, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29768357/dysembryoplastic-neuroepithelial-tumor-like-pilocytic-astrocytoma-a-case-report
#16
Jia-Ming Liao, Wei Wang, Jing Xie, Hai-Bo Wu
RATIONALE: Pilocytic astrocytoma (PA) typically shows biphasic pattern with a mixture of loose microcystic and compact regions, in which it is not uncommon to see heterogeneous morphology. However, there has not been reported in the literatures of the PA type that shows similarity to dysembryoplastic neuroepithelial tumor (DNT) in both histological morphology and immunophenotype. PATIENT CONCERNS: The present study described a case of PA affecting the right temporal-occipital lobe in a 22-year-old male patient...
May 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29768105/identification-of-a-recurrent-lmo7-braf-fusion-in-papillary-thyroid-carcinoma
#17
Huiling He, Wei Li, Pearlly Yan, Ralf Bundschuh, Jackson A Killian, Jadwiga Labanowska, Pamela Brock, Rulong Shen, Nyla A Heerema, Albert de la Chapelle
BACKGROUND: The BRAFV600E mutation is the most common driver in papillary thyroid carcinoma (PTC) tumors. In recent years, gene fusions have also been recognized as important drivers of cancer in PTC. Previous studies have suggested that thyroid tumors with fusion genes frequently display an aggressive course. These observations prompted further exploration of gene fusions in PTC tumors. The aim was to search for previously unrecognized gene fusions using thyroid tissue samples from PTC patients...
May 16, 2018: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29767751/clinicopathological-and-molecular-differences-between-right-sided-and-left-sided-colorectal-cancer-in-japanese-patients
#18
Soichiro Natsume, Tatsuro Yamaguchi, Misato Takao, Takeru Iijima, Rika Wakaume, Keiichi Takahashi, Hiroshi Matsumoto, Daisuke Nakano, Shin-Ichiro Horiguchi, Koichi Koizumi, Michiko Miyaki
Background: The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). Methods: We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum...
May 15, 2018: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29767243/inhibitory-roles-of-mir%C3%A2-9-on-papillary-thyroid-cancer-through-targeting-braf
#19
Yi Gu, Nan Yang, Leping Yin, Chao Feng, Tong Liu
MicroRNA‑9 (miR‑9) is reported to be underexpressed in papillary thyroid carcinoma (PTC) tissues; however, the molecular mechanisms underlying the implication of miR‑9 in PTC have yet to be elucidated. The present study aimed to explore the potential roles of miR‑9 in PTC. PTC tissue samples and paired non‑cancerous adjacent tissues were collected from 60 patients with PTC. The human TPC‑1 thyroid gland papillary carcinoma cell line was used to investigate the molecular mechanisms underlying the roles of miR‑9 in PTC...
May 11, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29766713/probing-dna-hybridization-equilibrium-by-cationic-conjugated-polymer-for-highly-selective-detection-and-imaging-of-single-nucleotide-mutation
#20
Zehao Li, Xu Zhou, Lidan Li, Shue Liu, Congshan Wang, Lina Li, Changyuan Yu, Xin Su
Hybridization-based probes emerge as a promising tool for nucleic acid target detection and imaging. However, the single-nucleotide selectivity is still challenging because the specificity of hybridization reaction is typically low at room temperature. We disclose an effective and simple method for highly selective detection and in situ imaging of single-nucleotide mutation (SNM) by taking the advantages of the specific hybridization of short duplex and the signal amplifying effect of cationic conjugated polymer (CCP)...
May 16, 2018: Analytical Chemistry
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