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https://www.readbyqxmd.com/read/28931068/erk1-2-signalling-protects-against-apoptosis-following-endoplasmic-reticulum-stress-but-cannot-provide-long-term-protection-against-bax-bak-independent-cell-death
#1
Nicola J Darling, Kathryn Balmanno, Simon J Cook
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28928884/anti-melanoma-activities-of-haspin-inhibitor-chr-6494-deployed-as-a-single-agent-or-in-a-synergistic-combination-with-mek-inhibitor
#2
Lili Han, Peiling Wang, Yang Sun, Sijing Liu, Jun Dai
Background: Melanoma is a heterogeneous malignancy that presents an immense challenge in therapeutic development. Recent approaches targeting the oncogenic MAP kinase pathways have shown tremendous improvement in the overall survival of patients with advanced melanoma. However, there is still an urgent need for identification of new strategies to overcome drug resistances and to improve therapeutic efficacy. Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) belongs to a selected group of mitotic kinases and is required for normal mitosis progression...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28928360/tumor-associated-b-cells-induce-tumor-heterogeneity-and-therapy-resistance
#3
Rajasekharan Somasundaram, Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A Scolyer, Georgina V Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A Davies, Jennifer Wargo, Brian J Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn, Stephan N Wagner
In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28918496/recurrent-papillary-craniopharyngioma-with-brafv600e-mutation-treated-with-neoadjuvant-targeted-therapy
#4
Elham Rostami, Petra Witt Nyström, Sylwia Libard, Johan Wikström, Olivera Casar-Borota, Olafur Gudjonsson
Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib...
September 16, 2017: Acta Neurochirurgica
https://www.readbyqxmd.com/read/28915798/vemurafenib-plus-cobimetinib-in-unresectable-stage-iiic-or-stage-iv-melanoma-response-monitoring-and-resistance-prediction-with-positron-emission-tomography-and-tumor-characteristics-reposit-study-protocol-of-a-phase-ii-open-label-multicenter-study
#5
Bernies van der Hiel, John B A G Haanen, Marcel P M Stokkel, Daniel S Peeper, Connie R Jimenez, Jos H Beijnen, Bart A van de Wiel, Ronald Boellaard, Alfons J M van den Eertwegh
BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with (18)F-Fluorodeoxyglucose ((18)F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of (18)F-FDG uptake within 2 weeks following treatment...
September 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28910386/dusp5-and-dusp6-two-erk-specific-phosphatases-are-markers-of-a-higher-mapk-signaling-activation-in-braf-mutated-thyroid-cancers
#6
Camille Buffet, Karine Hecale-Perlemoine, Léopoldine Bricaire, Florent Dumont, Camille Baudry, Frédérique Tissier, Jérôme Bertherat, Beatrix Cochand-Priollet, Marie-Laure Raffin-Sanson, Françoise Cormier, Lionel Groussin
BACKGROUND: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. METHODS: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28892804/generation-of-a-potential-prognostic-matrix-for-papillary-thyroid-cancer-that-assesses-age-tumor-size-transforming-growth-factor-%C3%AE-and-brafv600e-mutation
#7
Ping Wang, Yu Lun, Yudong Fu, Fei Wang, Shihua Zhao, Yangyang Wang, Xu Hou
No abstract text is available yet for this article.
September 12, 2017: Oncology Research and Treatment
https://www.readbyqxmd.com/read/28891339/immunotherapy-in-managing-metastatic-melanoma-which-treatment-when
#8
Teresa Amaral, Francisco Meraz-Torres, Claus Garbe
Ten to fifteen percent of melanoma patients develop distant or unresectable metastasis requiring systemic treatment. Around 45% of the patients diagnosed with metastatic cutaneous melanoma harbor a BRAFV600 mutation and derive benefit from combined targeted therapy with MAPK pathway inhibitors. These offer a rapid response that translates into improvement of symptoms and increased quality of life. However, resistance often develops with subsequent progressive disease. Immunotherapy with checkpoint inhibitors may be offered to BRAF-mutated and wild-type patients and is associated with longer and durable responses that can continue over years...
September 9, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28884045/braf-mutation-in-colorectal-carcinomas-with-signet-ring-cell-component
#9
Serap Yalcin, Onder Onguru
OBJECTIVE: : Signet ring cell carcinoma is a rare subtype of colorectal carcinoma (CRC) with an associated BRAFV600E mutation. We investigated frequencies of BRAF mutation in 28 CRCs containing variable signet ring cell component and their relation with clinicopathologic parameters. METHODS: : According to the presence of signet ring cell component, tumors were categorized into groups as follows: 0%-9%, 10%-24%, 25%-49%, and >50%. Genomic DNA was isolated and analyzed for BRAF V600E gene mutation by polymerase chain reaction-restriction fragment length polymorphism...
August 2017: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/28877096/clinical-parameter-for-deciding-the-brafv600e-mutation-test-in-atypia-of-undetermined-significance-follicular-lesion-of-undetermined-significance-thyroid-nodules-us-features-according-to-tirads
#10
Miribi Rho, Eun-Kyung Kim, Hee Jung Moon, Jung Hyun Yoon, Vivian Y Park, Kyunghwa Han, Jin Young Kwak
This study aimed to investigate the usefulness of a thyroid imaging reporting and data system (TIRADS) to select thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology for additional BRAF mutation testing. Three hundred three thyroid nodules were included. Statistical analysis was performed at both patient and nodule levels according to BRAF mutation positivity and clinical factors. Univariate and multivariate logistic regression analyses were performed to assess independent associations between BRAF mutation positivity and clinical factors...
September 4, 2017: Ultrasound Quarterly
https://www.readbyqxmd.com/read/28810314/-clinical-and-pathological-characteristics-of-erdheim-chester-disease-involving-the-lungs
#11
T Lu, S Wang, H Huang, T Wang, M Wang, D R Zhong, R E Feng
Objective: To explore the clinical manifestations, pathological features, differential diagnosis and gene mutation status in patients with pulmonary involvement of Erdheim-Chester disease (ECD). Methods: The clinical data of 4 cases of Erdheim-Chester disease admitted to Peking Union Medical College Hospital from October 2014 to August 2016 were examined for imaging, microscopic and immunohistochemitry findings, and BRAFV600E mutation. The related literatures were reviewed. Results: Among the 4 cases, there were 3 males and 1 female, aging from 7 to 47 years, and the average age was 34...
August 12, 2017: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28806732/loss-of-the-chromatin-modifier-kdm2aa-causes-brafv600e-independent-spontaneous-melanoma-in-zebrafish
#12
Catherine M Scahill, Zsofia Digby, Ian M Sealy, Sonia Wojciechowska, Richard J White, John E Collins, Derek L Stemple, Till Bartke, Marie E Mathers, E Elizabeth Patton, Elisabeth M Busch-Nentwich
KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28805135/intermittent-dosing-of-dabrafenib-and-trametinib-in-metastatic-braf-v600e-mutated-papillary-thyroid-cancer-two-case-reports
#13
Paul S White, Anita Pudusseri, Stephanie L Lee, Omar Eton
BACKGROUND: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective. PATIENTS: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAF(V600E) mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, first in continuous daily dosing, then in a five-week-on and three-week-off schedule...
September 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28802494/toward-a-molecular-genetic-classification-of-spitzoid-neoplasms
#14
REVIEW
Michael T Tetzlaff, Alexandre Reuben, Steven D Billings, Victor G Prieto, Jonathan L Curry
The histopathologic spectrum of Spitzoid neoplasms includes Spitz nevi, atypical Spitz tumors, and Spitzoid melanomas. Advances in molecular genetics have evolved to the point that Spitzoid lesions can now be reasonably classified according to their distinctive molecular-genetic alterations: Spitzoid lesions with (1) 11p amplification and/or HRAS mutations; (2) isolated loss of 6q23 by fluorescence in situ hybridization (FISH); (3) homozygous deletion of 9p21 by FISH; (4) BAP1 loss and BRAFV600 E mutation; (5) translocations involving any of a number of different oncogenic kinase drivers, including ROS1, ALK, NTRK1, NTRK3, MET, BRAF, and RET; and (6) TERT promoter mutations...
September 2017: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/28801450/genomic-analysis-of-hairy-cell-leukemia-identifies-novel-recurrent-genetic-alterations
#15
Benjamin H Durham, Bartlomiej Getta, Sascha Dietrich, Justin Taylor, Helen Won, James M Bogenberger, Sasinya Scott, Eunhee Kim, Young Rock Chung, Stephen S Chung, Jennifer Hüllein, Tatjana Walther, Lu Wang, Sydney X Lu, Christopher C Oakes, Raoul Tibes, Torsten Haferlach, Barry S Taylor, Martin S Tallman, Michael F Berger, Jae H Park, Thorsten Zenz, Omar Abdel-Wahab
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation while ~30% of variant HCL (vHCL) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1- wildtype vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n=53) and vHCL (n=8). The most common genetic alteration in cHCL outside of BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wildtype BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation...
August 11, 2017: Blood
https://www.readbyqxmd.com/read/28791997/-eosinophilic-granuloma-of-the-parietal-bone-of-an-adult-patient-with-braf-mutation
#16
O V Dolzhansky, E M Paltseva, A A Bukaeva, E V Zaklyazminskaya, I A Spivak, D N Fedorov
The paper describes a case of eosinophilic granuloma of the parietal bone in a 32-year-old man. Histological examination revealed a large number of bean-shaped Langerhans cell histiocytes with lobed nuclei and nuclear grooves. The histiocytes alternated with the foci of obvious eosinophilic infiltration and with eosinophilic microabscesses. There were osteoclast-like multinucleated giant cells, bone resorption, and numerous bone rods covered with osteoblast chains. The histiocytes expressed CD1α, langerin, CD68, S100, and p53 (in 90...
2017: Arkhiv Patologii
https://www.readbyqxmd.com/read/28766548/-hairy-cell-leukemia-and-pregnancy
#17
L S Al-Radi, T N Moiseeva, S Yu Smirnova, R G Shmakov
The paper presents experience in following up and treating hairy cell leukemia (HCL) during pregnancy. The combination of HCL and pregnancy was observed in 5 patients. The patients' median age was 35 years (range, 28-42 years). The diagnosis of HCL was based on a conventional examination protocol: clinical blood analysis with the morphological assessment of lymphocytes, a myelogram and trepanobiopsy, immunophenotypic analysis of lymphocytes or bone marrow (in all the patients), cytochemical determination of tartrate-resistant acid phosphatase in 3 patients, and identification of BRAFV600E mutation in 3 patients...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28748614/novel-activating-braf-fusion-identifies-a-recurrent-alternative-mechanism-for-erk-activation-in-pediatric-langerhans-cell-histiocytosis
#18
Sara Zarnegar, Benjamin H Durham, Pallavi Khattar, Neerav N Shukla, Ryma Benayed, Mario E Lacouture, Ehud Lavi, David C Lyden, Eli L Diamond, Ira J Dunkel, Omar Abdel-Wahab
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism...
July 27, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28734009/kit-mutations-and-cd117-overexpression-are-markers-of-better-progression-free-survival-in-vulvar-melanomas
#19
D Dias-Santagata, M A Selim, Y Su, Y Peng, R Vollmer, A Chłopik, G T Marti, K Paral, S Shalin, C R Shea, S Puig, M T Fernandez-Figueras, W Biernat, J Ryś, A Marszalek, M P Hoang
BACKGROUND: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. OBJECTIVES AND METHODS: We evaluated the clinicopathologic features of 95 cases. p53, CD117, Ki-67, neurofibromin, brafv600e, and nrasq61r immunostains; and molecular analyses by either targeted next generation or direct sequencing were performed on available archival materials. RESULTS: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%), and TERT promoter (9%)...
July 22, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/28714107/the-braf-and-nras-mutation-prevalence-in-dermoscopic-subtypes-of-acquired-naevi-reveals-constitutive-mapk-pathway-activation
#20
J M Tan, L N Tom, K Jagirdar, D Lambie, H Schaider, R A Sturm, H P Soyer, M S Stark
BACKGROUND: Acquired naevi can have unique dermoscopic patterns that correspond to distinct microanatomical growth patterns. Previous studies on acquired naevi stratified according to dermoscopic pattern, focused on the frequency of somatic BRAF mutations, whereas NRAS mutations remained to be elucidated. OBJECTIVES: To investigate the BRAF and NRAS mutation prevalence and activation of the MAPK pathway in distinct dermoscopic subtypes of acquired naevi. METHODS: Common mutations present in BRAF and NRAS were assessed in 40 globular, reticular, and peripheral rim of globules (PG) subtypes of acquired naevi from 27 participants (19 male, 8 female; mean age 46...
July 17, 2017: British Journal of Dermatology
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