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https://www.readbyqxmd.com/read/28223427/calcium-dependent-enhancement-by-extracellular-acidity-of-the-cytotoxicity-of-mitochondrial-inhibitors-against-melanoma
#1
Fumihito Noguchi, Shigeki Inui, Clare Fedele, Mark Shackleton, Satoshi Itami
Extracellular acidity is a hallmark of cancers and is independent of hypoxia. Since acidity potentiates malignant phenotypes, therapeutic strategies that enhance the targeting of oncogenic mechanisms in an acidic microenvironment should be effective. We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH and in vivo systemic alkalinization with NaHCO3 enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223310/overexpression-of-vitamin-d-receptor-mrna-correlates-with-poor-prognosis-in-ptc
#2
June Young Choi, Jin Wook Yi, Joon-Hyop Lee, Ra-Yeong Song, Hyeong Won Yu, Hyungju Kwon, Young Jun Chai, Su-Jin Kim, Kyu Eun Lee
The purpose of this study was to assess the relationship between vitamin D receptor (VDR) mRNA expression and prognosis in papillary thyroid cancer. RNA sequencing and somatic mutation data from TCGA (the Cancer Genome Atlas) were analyzed. VDR mRNA expression was compared to clinicopathologic variables by linear regression. Tree-based classification was applied to find VDR cutoff and patients were split into low and high VDR group. Logistic regression, Kaplan-Meier analysis, differentially expressed gene (DEG) test, and pathway analysis were performed to assess differences between groups...
February 21, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/28222655/a-cytologic-diagnosis-of-braf-v600e-erdheim-chester-disease-on-pericardial-fluid
#3
P Chasseur, M Kyriakopoulou, B Vokaer, I Beukinga, R Casado Arroyo, E Cogan, B Couturier
We report the case of a 74-year-old woman admitted to the emergency unit for resting dyspnea. Clinical presentation, cardiac MRI and echocardiography were consistent with cardiac tamponade requiring emergency pericardiocentesis. Cytologic examination of the pericardial fluid revealed the presence of CD68(pos) CD1a(neg) S100(neg) foamy histiocytes (Fig. 1). Additional investigations complied with the diagnosis of Erdheim-Chester histiocytosis. Treatment with αIFN was initiated but the patient developed severe neutropenia that contraindicated further administration...
February 22, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28220299/molecular-analysis-of-braf-v600e-mutation-in-multiple-nodules-of-pulmonary-langerhans-cell-histiocytosis
#4
Arno Dimmler, Helene Geddert, Martin Werner, Gerhard Faller
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking-related histiocytic disorder with variable clinical symptoms. Like in other non-pulmonary Langerhans cell proliferations, PLCH has recently been shown to harbour BRAF V600E mutations in a significant subset of cases, thus challenging the concept of PLCH being a reactive disorder. Here, we analysed 38 formalin-fixed and paraffin-embedded PLCH nodules of nine patients for BRAF mutation using two different molecular methods. Using pyrosequencing and allele-specific quantitative PCR (AS-PCR), BRAF V600E mutations were found in 16/38 (42%) and 31/37 (84%) nodules, respectively...
February 20, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28219109/the-use-of-braf-v600e-mutation-specific-immunohistochemistry-in-pediatric-langerhans-cell-histiocytosis
#5
Leomar Y Ballester, Miguel D Cantu, Karen P H Lim, Stephen F Sarabia, Lizmery Suarez Ferguson, C Renee Webb, Carl E Allen, Kenneth L McClain, Carrie A Mohila, Jyotinder N Punia, Angshumoy Roy, Dolores H López-Terrada, M John Hicks, Kevin E Fisher
BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation-specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation-specific BRAF V600E monoclonal antibody (clone VE1) in formalin-fixed, paraffin-embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo-17 y) using allele-specific real-time polymerase chain reaction (PCR) with a limit of detection of 0...
February 20, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28219002/molecular-testing-for-gastrointestinal-cancer
#6
Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho
With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wild-type RAS (KRAS and NRAS exon 2-4). A BRAF mutation is required for predicting poor prognosis...
February 19, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28217853/use-of-cytological-samples-of-metastatic-melanoma-for-ancillary-studies
#7
H M Ko, M A Saieg, G da Cunha Santos, S Kamel-Reid, S L Boerner, W R Geddie
OBJECTIVE: Fine needle aspiration (FNA) is widely used in the diagnosis of metastatic melanoma, both at initial presentation and in the setting of recurrent disease. The purpose of this study was to evaluate the performance of confirmatory immunohistochemistry (IHC) and molecular analysis of the BRAF mutation in cytological preparations of metastatic melanoma. METHODS: A 2-year retrospective review of pathology reports was performed on cytological samples of metastatic melanoma at the University Health Network (Toronto, Canada) and the Santa Casa Medical School (Sao Paulo, Brazil)...
February 20, 2017: Cytopathology: Official Journal of the British Society for Clinical Cytology
https://www.readbyqxmd.com/read/28209747/pediatric-adolescent-and-young-adult-thyroid-carcinoma-harbors-frequent-and-diverse-targetable-genomic-alterations-including-kinase-fusions
#8
Pierre Vanden Borre, Alexa B Schrock, Peter M Anderson, John C Morris, Andreas M Heilmann, Oliver Holmes, Kai Wang, Adrienne Johnson, Steven G Waguespack, Sai-Hong Ignatius Ou, Saad Khan, Kar-Ming Fung, Philip J Stephens, Rachel L Erlich, Vincent A Miller, Jeffrey S Ross, Siraj M Ali
BACKGROUND: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. METHODS: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements...
February 16, 2017: Oncologist
https://www.readbyqxmd.com/read/28197745/crosstalk-signaling-in-targeted-melanoma-therapy
#9
Svenja Meierjohann
Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAF(V600E/K) mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche...
February 14, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#10
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28188776/aurora-a-overexpression-aurka-is-driven-by-foxm1-and-mapk-erk-activation-in-melanoma-cells-harbouring-braf-or-nras-mutations-impact-on-melanoma-prognosis-and-therapy
#11
Joan Anton Puig-Butille, Antònia Vinyals, Josep R Ferreres, Paula Aguilera, Eduard Cabré, Gemma Tell-Martí, Joaquim Marcoval, Francesca Mateo, Luís Palomero, Celia Badenas, Josep M Piulats, Josep Malvehy, Miquel A Pujana, Susana Puig, Àngels Fabra
The cell cycle-related genes AURORA A and Forkhead box M1 (FOXM1) are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF(V600E) mutation. AURKA overexpression may also be driven to increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK-ERK signalling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF(V600E) and ERK inhibition results in reduced AURKA transcription and expression...
February 7, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28188228/time-resolved-phosphoproteome-analysis-of-paradoxical-raf-activation-reveals-novel-targets-of-erk
#12
Peter Kubiniok, Hugo Lavoie, Marc Therrien, Pierre Thibault
Small molecules targeting aberrant RAF activity, like Vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation, and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS-mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream paradoxical ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to Vemurafenib...
February 10, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28185325/a-case-of-high-grade-astrocytoma-with-braf-and-atrx-mutations-following-a-long-standing-course-over-two-decades
#13
Satoshi Nakata 中田 聡, Keishi Horiguchi, Shogo Ishiuchi, Yuhei Yoshimoto, Seiji Yamada, Sumihito Nobusawa, Hayato Ikota, Junko Hirato, Hideaki Yokoo
Pediatric high-grade gliomas are rare and occasionally hard to classify. These tumors often feature a well-demarcated histology and are expected to have a better outcome than ordinary diffuse high-grade gliomas in adults. We herein report a case of circumscribed high-grade glioma that showed a distinct molecular profile and followed an excellent course for 26 years. The patient, a 3-year-old boy at onset, presented with a contrast-enhancing mass in the right temporal lobe and underwent resection. Histologically, the tumor mainly consisted of compact bundles of GFAP-positive spindle cells...
February 9, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28181325/recurrent-copy-number-alterations-in-low-grade-and-anaplastic-pleomorphic-xanthoastrocytoma-with-and-without-braf-v600e-mutation
#14
Rachael A Vaubel, Alissa A Caron, Seiji Yamada, Paul A Decker, Jeanette E Eckel Passow, Fausto J Rodriguez, Amulya A Nageswara Rao, Daniel Lachance, Ian Parney, Robert Jenkins, Caterina Giannini
Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50-60%) (37)...
February 9, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28176151/frequent-braf-v600e-and-absence-of-tert-promoter-mutations-characterize-sporadic-pediatric-papillary-thyroid-carcinomas-in-japan
#15
Naoki Oishi, Tetsuo Kondo, Tadao Nakazawa, Kunio Mochizuki, Tomohiro Inoue, Kazunari Kasai, Ippei Tahara, Tomonori Yabuta, Mitsuyoshi Hirokawa, Akira Miyauchi, Ryohei Katoh
Pediatric papillary thyroid carcinoma (PTC) has unique features but requires further genetic investigation. Moreover, there has been increasing concern about the risk for pediatric PTC in Japan after the Fukushima accident. This study aims to evaluate the frequencies of BRAF and TERT promoter mutations and to examine their significance in non-radiation-associated pediatric PTCs in Japan. We enrolled 81 pediatric PTC patients aged ≤20 years. The control group included 91 adult PTCs from patients >20 years old...
February 7, 2017: Endocrine Pathology
https://www.readbyqxmd.com/read/28173755/melanoma-genome-evolution-across-species
#16
Emily R Kansler, Akanksha Verma, Erin M Langdon, Theresa Simon-Vermot, Alexandra Yin, William Lee, Marc Attiyeh, Olivier Elemento, Richard M White
BACKGROUND: Cancer genomes evolve in both space and time, which contributes to the genetic heterogeneity that underlies tumor progression and drug resistance. In human melanoma, identifying mechanistically important events in tumor evolution is hampered due to the high background mutation rate from ultraviolet (UV) light. Cross-species oncogenomics is a powerful tool for identifying these core events, in which transgenically well-defined animal models of cancer are compared to human cancers to identify key conserved alterations...
February 7, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28159677/clinicopathological-and-molecular-features-of-a-large-cohort-of-gastrointestinal-stromal-tumors-gists-and-review-of-the-literature-braf-mutations-in-kit-pdgfra-wildtype-gists-are-rare-events
#17
Sebastian Huss, Hlen Pasternack, Michaela Angelika Ihle, Sabine Merkelbach-Bruse, Birthe Heitkötter, Wolfgang Hartmann, Marcel Trautmann, Heidrun Gevensleben, Reinhard Büttner, Hans-Ulrich Schildhaus, Eva Wardelmann
In KIT/PDGFRA wild-type gastrointestinal stromal tumors (wt-GISTs), BRAF mutations are regarded as alternative pathogenic event driving tumorigenesis. In our study, we aimed at analyzing a large cohort (n=444) of GISTs for BRAF mutations using molecular and immunohistochemical methods. More than 3000 GIST samples from caucasian patients were available in our GIST and Sarcoma Registry NRW. Of these, we selected 172 wt-GISTs to evaluate the frequency of BRAF mutations. Furthermore, 272 GISTs with a representative KIT and PDGFRA mutational status were selected...
January 31, 2017: Human Pathology
https://www.readbyqxmd.com/read/28157711/the-repurposed-anthelmintic-mebendazole-in-combination-with-trametinib-suppresses-refractory-nrasq61k-melanoma
#18
Cynthia M Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F Petricoin, Michael B Atkins, Stephen W Byers, Dean S Rosenthal
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28150740/tert-promoter-mutations-and-ki-67-labeling-index-as-a-prognostic-marker-of-papillary-thyroid-carcinomas-combination-of-two-independent-factors
#19
Michiko Matsuse, Tomonori Yabuta, Vladimir Saenko, Mitsuyoshi Hirokawa, Eijun Nishihara, Keiji Suzuki, Shunichi Yamashita, Akira Miyauchi, Norisato Mitsutake
Although most papillary thyroid carcinomas (PTCs) have a good prognosis, a small but certain fraction shows aggressive behavior. Therefore, a novel and well-performing molecular marker is needed. In the present study, we assessed the impact of the combination of the TERT promoter/BRAF mutations and Ki-67 labeling index (LI) as a prognostic marker in PTC patients. Of 400 PTC samples, 354 were successfully genotyped for both TERT promoter/BRAF and analyzed for Ki-67 LI. Based on the combination of the mutational status and Ki-67 LI, the cases were categorized into three groups: high-, middle-, and low-risk...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28146266/how-i-manage-patients-with-hairy-cell-leukaemia
#20
REVIEW
Philip A Thompson, Farhad Ravandi
Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition...
February 1, 2017: British Journal of Haematology
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