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https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#1
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
July 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28736556/ras-signaling-inhibitors-attenuate-disease-in-adjuvant-induced-arthritis-via-targeting-pathogenic-antigen-specific-th17-type-cells
#2
Morad Zayoud, Victoria Marcu-Malina, Einav Vax, Jasmine Jacob-Hirsch, Galit Elad-Sfadia, Iris Barshack, Yoel Kloog, Itamar Goldstein
The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28734009/kit-mutations-and-cd117-overexpression-are-markers-of-better-progression-free-survival-in-vulvar-melanomas
#3
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/28729121/multiple-myeloma-genomics-a-systematic-review
#4
REVIEW
Casey J Weaver, Joseph D Tariman
OBJECTIVES: This integrative review describes the genomic variants that have been found to be associated with poor prognosis in patients diagnosed with multiple myeloma (MM). Second, it identifies MM genetic and genomic changes using next-generation sequencing, specifically whole-genome sequencing or exome sequencing. DATA SOURCE: A search for peer-reviewed articles through PubMed, EBSCOhost, and DePaul WorldCat Libraries Worldwide yielded 33 articles that were included in the final analysis...
July 18, 2017: Seminars in Oncology Nursing
https://www.readbyqxmd.com/read/28724666/braf-inhibitors-amplify-the-pro-apoptotic-activity-of-mek-inhibitors-by-inducing-er-stress-in-nras-mutant-melanoma
#5
Heike Niessner, Tobias Sinnberg, Corinna Kosnopfel, Keiran S M Smalley, Daniela Beck, Christian Praetorius, Marion Mai, Stefan Beissert, Dagmar Kulms, Martin Schaller, Claus Garbe, Keith T Flaherty, Dana Westphal, Ines Wanke, Friedegund Meier
<p>NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma...
July 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28721890/the-prognostic-value-of-braf-c-kit-and-nras-mutations-in-melanoma-patients-with-brain-metastases
#6
Paul W Sperduto, Wen Jiang, Paul D Brown, Steve Braunstein, Penny Sneed, Daniel A Wattson, Helen A Shih, Ananta Bangdiwala, Ryan Shanley, Natalie A Lockney, Kathryn Beal, Emil Lou, Thomas Amatruda, William A Sperduto, John P Kirkpatrick, Norman Yeh, Laurie E Gaspar, Jason K Molitoris, Laura Masucci, David Roberge, James Yu, Veronica Chiang, Minesh Mehta
PURPOSE: Brain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients. METHODS AND MATERIALS: We created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005)...
August 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28720667/mapk-pathway-and-tert-promoter-gene-mutation-pattern-and-its-prognostic-value-in-melanoma-patients%C3%AF-a-retrospective-study-of-2793-cases
#7
Xue Bai, Yan Kong, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Xuan Wang, Lili Mao, Bixia Tang, Siming Li, Bin Lian, Xieqiao Yan, Li Zhou, Jie Dai, Jun Guo, Lu Si
Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathological characteristics and disease prognosis in Asian population.<br /><br />Experimental Design: 2793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and TERT promoter region by Sanger sequencing. Mutations were correlated to clinicopathological features and overall survival...
July 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28717400/treatment-of-nras-mutated-advanced-or-metastatic-melanoma-rationale-current-trials-and-evidence-to-date
#8
REVIEW
Amélie Boespflug, Julie Caramel, Stephane Dalle, Luc Thomas
The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15-25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment...
July 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28715145/the-autophagy-receptor-adaptor-p62-is-up-regulated-by-uva-radiation-in-melanocytes-and-in-melanoma-cells
#9
Ashley Sample, Baozhong Zhao, Chunli Wu, Steven Qian, Xianglin Shi, Andrew Aplin, Yu-Ying He
UVA (315-400 nm) is the most abundant in sunlight and is used in indoor tanning beds. However, much remains to be understood about the regulation of the UVA damage response in melanocytes and melanoma. Here we show that UVA, but not the shorter waveband UVB (280-315 nm), up-regulates adaptor protein p62 in an Nrf2- and ROS-dependent manner, suggesting a UVA-specific effect on p62 regulation. UVA-induced p62 up-regulation was inhibited by a mitochondria-targeted antioxidant or Nrf2 knockdown. In addition, p62 knockdown inhibited UVA-induced ROS production and Nrf2 up-regulation...
July 17, 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28714107/the-braf-and-nras-mutation-prevalence-in-dermoscopic-subtypes-of-acquired-naevi-reveals-constitutive-mapk-pathway-activation
#10
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
https://www.readbyqxmd.com/read/28710706/synchronous-and-metastatic-papillary-and-follicular-thyroid-carcinomas-with-unique-molecular-signatures
#11
Vincent Cracolici, Ibro Mujacic, Sabah Kadri, Mir Alikhan, Nifang Niu, Jeremy P Segal, Lauren E Rosen, David H Sarne, Adam Morgan, Samy Desouky, Nicole A Cipriani
Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis...
July 14, 2017: Endocrine Pathology
https://www.readbyqxmd.com/read/28700778/frequent-gnaq-gna11-and-eif1ax-mutations-in-iris-melanoma
#12
Simone L Scholz, Inga Möller, Henning Reis, Daniela Süßkind, Johannes A P van de Nes, Sonia Leonardelli, Bastian Schilling, Elisabeth Livingstone, Tobias Schimming, Annette Paschen, Antje Sucker, Rajmohan Murali, Klaus-Peter Steuhl, Dirk Schadendorf, Henrike Westekemper, Klaus G Griewank
Purpose: The most common malignant intraocular tumors with a high mortality in adults are uveal melanomas. Uveal melanomas arise most frequently in the choroid or ciliary body (97%) and rarely in the iris (3%). Whereas conjunctival and posterior uveal (ciliary body and choroidal) melanomas have been studied in more detail genetically, little data exist regarding iris melanomas. Methods: In our study, we genetically analyzed 19 iris melanomas, 8 ciliary body melanomas, 3 ring melanomas, and 4 iris nevi...
July 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28698100/adenosquamous-gallbladder-carcinoma-multigene-hotspot-mutational-profiling-reveals-a-monoclonal-origin-of-the-two-components
#13
Francesca Galuppini, Roberta Salmaso, Elisa Valentini, Cristiano Lanza, Isacco Maretto, Donato Nitti, Massimo Rugge, Matteo Fassan
Adenosquamous carcinoma (ASC) of the gallbladder is a rare malignant tumor that is characterized by a coexisting of glandular and squamous components. In a case of ASC, we performed hotspot multigene mutational profiling of 164 hotspot regions of eleven cancer-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53) in the two microdissected components. Both tumor phenotypes resulted characterized by a p.E542K point mutation in the PIK3CA gene, whereas adenocarcinoma component revealed also a TP53 Q331* homozygous stop mutation...
August 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28694139/systematic-review-and-meta-analysis-of-the-nitrate-reductase-assay-for-drug-susceptibility-testing-of-mycobacterium-tuberculosis-and-the-detection-limits-in-liquid-medium
#14
Miri Kwak, Won-Kyu Lee, Young Ju Lim, Seung Heon Lee, Sungweon Ryoo
Recently, the need for rapid, reliable, and low-cost drug susceptibility testing (DST) methods has increased due to the emergence of multidrug-resistant Mycobacterium tuberculosis. Colorimetric methods of DST provide results more quickly than standard culture methods and are inexpensive than molecular methods. Thus, colorimetric methods, such as the nitrate reductase assay (NRA), are being recommended. We searched Medline PubMed for reports on the NRA for DST of M. tuberculosis written in English and published within the last five years...
July 8, 2017: Journal of Microbiological Methods
https://www.readbyqxmd.com/read/28692456/focal-necrotizing-myopathy-with-dropped-head-syndrome-induced-by-cobimetinib-in-metastatic-melanoma
#15
Marie-Léa Gauci, Pauline Laly, Leonard-Louis Sarah, Anthony Behin, Jérémy Gottlieb, Isabelle Madelaine-Chambrin, Barouyr Baroudjian, Laetitia Da-Meda, Samia Mourah, Maxime Battistella, Nicole Basset Seguin, Martine Bagot, Cécile Pages, Laetitia Vercellino, Thierry Maisonobe, Céleste Lebbé
Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction...
July 7, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28688743/-detection-of-ras-genes-mutation-using-the-cobas-%C3%A2-method-in-a-private-laboratory-of-pathology-medical-and-economical-study-in-comparison-to-a-public-platform-of-molecular-biology-of-cancer
#16
Anne-Flore Albertini, Delphine Raoux, Frédéric Neumann, Stéphane Rossat, Farid Tabet, Florence Pedeutour, Valérie Duranton-Tanneur, Valérie Kubiniek, Olivier Vire, Nicolas Weinbreck
In France, determination of the mutation status of RAS genes for predictive response to anti-EGFR targeted treatments is carried out by public platforms of molecular biology of cancer created by the French National Cancer Institute. This study aims to demonstrate the feasibility of these analyses by a private pathology laboratory (MEDIPATH) as per the requirements of accreditation. We retrospectively studied the mutation status of KRAS and NRAS genes in 163 cases of colorectal metastatic cancer using the Cobas(®) technique...
July 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28685592/investigation-of-correlation-between-mutational-status-in-key-egfr-signaling-genes-and-prognosis-of-stage-ii-colorectal-cancer
#17
Li Li, Bei-Bei Ni, Qing-Hua Zhong, Yan-Hui Liu, Ming-Hui Zhang, Ke-Ping Zhang, Dai-Ci Chen, Lei Wang
AIM: To investigate the relationship between mutations of key genes in the EGFR signaling pathway and the prognosis of stage II colorectal cancer patients without chemotherapy. MATERIALS & METHODS: The incidence of KRAS, NRAS, BRAF, PIK3CA mutations and deficient DNA mismatch repair were assessed in 160 stage II colorectal cancer patients who had been treated by radical operation without adjuvant chemotherapy. RESULTS: Mutations in KRAS, BRAF or PIK3CA were associated with poor prognosis, while the deficient DNA mismatch repair status was not associated with the prognosis...
July 7, 2017: Future Oncology
https://www.readbyqxmd.com/read/28685087/heterogeneity-in-the-colorectal-primary-tumor-and-the-synchronous-resected-liver-metastases-prior-to-and-after-treatment-with-an-anti-egfr-monoclonal-antibody
#18
Daniela Adua, Francesca Di Fabio, Giorgio Ercolani, Michelangelo Fiorentino, Elisa Gruppioni, Annalisa Altimari, Fabiola Lorena Rojas Limpe, Nicola Normanno, Antonio Daniele Pinna, Carmine Pinto
Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody...
July 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28682649/targeting-ras-signaling-in-aml-ralb-is-a-small-gtpase-with-big-potential
#19
Emily J Pomeroy, Craig E Eckfeldt
Acute myeloid leukemia (AML) is a devastating malignancy for which novel treatment approaches are desperately needed. Ras signaling is an attractive therapeutic target for AML because a large proportion of AMLs have mutations in NRAS, KRAS, or genes that activate Ras signaling, and key Ras effectors are activated in virtually all AML patient samples. This has inspired efforts to develop Ras-targeted treatment strategies for AML. Due to the inherent difficulty and disappointing efficacy of targeting Ras proteins directly, many have focused on inhibiting Ras effector pathways...
July 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28681063/circulating-tumour-dna-for-monitoring-treatment-response-to-anti-pd-1-immunotherapy-in-melanoma-patients
#20
Atsuko Ashida, Kaori Sakaizawa, Hisashi Uhara, Ryuhei Okuyama
Anti-programmed cell death-1 (anti-PD-1) antibody shows high therapeutic efficacy in patients with advanced melanoma. However, assessment of its therapeutic activity can be challenging because of tumour enlargement associated with intratumoural inflammation. Because circulating tumour DNA (ctDNA) correlates with tumour burden, we assessed the value of ctDNA levels as an indicator of tumour changes. Quantification of ctDNA (BRAFmutant or NRASmutant) levels by droplet digital PCR in 5 patients with BRAF or NRAS mutant melanoma during the treatment course showed dynamic changes corresponding to radiological and clinical alterations...
July 6, 2017: Acta Dermato-venereologica
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