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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29332123/braf-nras-and-gnaq-mutations-in-conjunctival-melanocytic-nevi
#2
Jasmine H Francis, Hans E Grossniklaus, Larissa A Habib, Brian Marr, David H Abramson, Klaus J Busam
Purpose: To evaluate BRAF, NRAS, and GNAQ mutations in surgical specimens of common and blue conjunctival melanocytic nevi. Methods: Surgical specimens from 25 conjunctival melanocytic nevi (23 common and 2 blue) of 25 patients were evaluated. All common nevi were analyzed immunohistochemically for the expression of BRAF V600E or NRAS Q61R. One lesion with negative immunoreactivity and for all blue nevi, a hybridization capture-based next-generation sequencing method was employed for mutation analysis...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29332062/cytologic-features-of-malignant-melanoma-with-osteoclast-like-giant-cells
#3
José A Jiménez-Heffernan, Magdalena Adrados, Patricia Muñoz-Hernández, Paloma Fernández-Rico, Ana I Ballesteros-García, Javier Fraga
BACKGROUND: Malignant melanoma showing numerous osteoclast-like giant cells (OGCs) is an uncommon morphologic phenomenon, rarely mentioned in the cytologic literature. The few reported cases seem to have an aggressive clinical behavior. Although most findings support monocyte/macrophage differentiation, the exact nature of OGCs is not clear. CASE: A 57-year-old woman presented with an inguinal lymphadenopathy. Sixteen years before, cutaneous malignant melanoma of the lower limb had been excised...
January 13, 2018: Acta Cytologica
https://www.readbyqxmd.com/read/29331646/progress-in-the-management-of-advanced-thoracic-malignancies-in-2017
#4
REVIEW
Roberto Ferrara, Laura Mezquita, Benjamin Besse
The treatment paradigm of non-small cell lung cancer (NSCLC) underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival (OS) both in unselected pretreated patients and in untreated patients with PD-L1 expression ≥50%. Furthermore, compelling preliminary results were reported for new combinations of anti-PD-1/PD-L1 agents with chemotherapy or anti-CTLA4 inhibitors. The success of the ICIs appeared to extend to patients with small cell lung cancer (SCLC), mesothelioma or thymic tumors...
January 10, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29330617/characterizing-genomic-differences-of-human-cancer-stratified-by-the-tp53-mutation-status
#5
Mengyao Wang, Chao Yang, Xiuqing Zhang, Xiangchun Li
The key roles of the TP53 mutation in cancer have been well established. TP53 is the most frequently mutated gene, and its inactivation is widespread among human cancer types. However, the landscape of genomic alterations in human cancers stratified by the TP53 mutation has not yet been described. We obtained somatic mutation and copy number change data of 6551 regular-mutated samples from the Cancer Genome Atlas (TCGA) and compared significantly mutated genes (SMGs), copy number alterations, mutational signatures and mutational strand asymmetries between cancer samples with and without the TP53 mutation...
January 12, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29329208/advances-in-molecular-profiling-and-categorisation-of-pancreatic-adenocarcinoma-and-the-implications-for-therapy
#6
REVIEW
Rille Pihlak, Jamie M J Weaver, Juan W Valle, Mairéad G McNamara
Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents...
January 12, 2018: Cancers
https://www.readbyqxmd.com/read/29327160/differences-in-histological-features-and-pd-l1-expression-between-sporadic-microsatellite-instability-and-lynch-syndrome-associated-disease-in-japanese-patients-with-colorectal-cancer
#7
Rin Yamada, Tatsuro Yamaguchi, Takeru Iijima, Rika Wakaume, Misato Takao, Koichi Koizumi, Tsunekazu Hishima, Shin-Ichiro Horiguchi
BACKGROUND: The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS: Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis...
January 11, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#8
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29324592/frequent-subclinical-macular-changes-in-combined-braf-mek-inhibition-with-high-dose-hydroxychloroquine-as-treatment-for-advanced-metastatic-braf-mutant-melanoma-preliminary-results-from-a-phase-i-ii-clinical-treatment-trial
#9
Akosua A Nti, Leona W Serrano, Harpal S Sandhu, Katherine E Uyhazi, Ilaina D Edelstein, Elaine J Zhou, Scott Bowman, Delu Song, Tara C Gangadhar, Lynn M Schuchter, Sheryl Mitnick, Alexander Huang, Charles W Nichols, Ravi K Amaravadi, Benjamin J Kim, Tomas S Aleman
PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment...
January 10, 2018: Retina
https://www.readbyqxmd.com/read/29322935/classifying-cancer-genome-aberrations-by-their-mutually-exclusive-effects-on-transcription
#10
Jonathan B Dayton, Stephen R Piccolo
BACKGROUND: Malignant tumors are typically caused by a conglomeration of genomic aberrations-including point mutations, small insertions, small deletions, and large copy-number variations. In some cases, specific chemotherapies and targeted drug treatments are effective against tumors that harbor certain genomic aberrations. However, predictive aberrations (biomarkers) have not been identified for many tumor types and treatments. One way to address this problem is to examine the downstream, transcriptional effects of genomic aberrations and to identify characteristic patterns...
December 21, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/29322354/mutations-of-key-driver-genes-in-colorectal-cancer-progression-and-metastasis
#11
REVIEW
Dongdong Huang, Wenjie Sun, Yuwei Zhou, Peiwei Li, Fang Chen, Hanwen Chen, Dajing Xia, Enping Xu, Maode Lai, Yihua Wu, Honghe Zhang
The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis...
January 10, 2018: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#12
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29320776/v600e-braf-versus-non-v600e-braf-mutated-lung-adenocarcinomas-cytomorphology-histology-coexistence-of-other-driver-mutations-and-patient-characteristics
#13
Kevan J Salimian, Roghayeh Fazeli, Gang Zheng, David Ettinger, Zahra Maleki
OBJECTIVES: We analyzed the morphologic features and clinical characteristics of lung adenocarcinomas (ACAs) harboring mutated BRAF. STUDY DESIGN: A review of the histology/cytology of BRAF-mutated lung ACAs was performed at the Johns Hopkins Hospital from January 1, 2013, to January 1, 2015. Patient demographics, clinical history, and ACA morphology were assessed. RESULTS: Thirty-six cases were identified with a median age of 66 years (range 44-87), 58% (21/36) were female, and 94% (34/36) were current or former smokers...
January 11, 2018: Acta Cytologica
https://www.readbyqxmd.com/read/29320480/pharmacological-activation-of-rev-erbs-is-lethal-in-cancer-and-oncogene-induced-senescence
#14
Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J Kolar, Francesca Puca, Alan Saghatelian, Maksim V Plikus, Inder M Verma, Satchidananda Panda
The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock...
January 10, 2018: Nature
https://www.readbyqxmd.com/read/29317515/intratumoural-heterogeneity-may-hinder-precision-medicine-strategies-in-patients-with-clear-cell-renal-cell-carcinoma
#15
Maria Rosaria Raspollini, Ilaria Montagnani, Rodolfo Montironi, Francesca Castiglione, Guido Martignoni, Liang Cheng, Antonio Lopez-Beltran
Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status...
January 9, 2018: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29316976/clinical-implications-of-the-braf-mutation-in-papillary-thyroid-carcinoma%C3%A2-and-chronic-lymphocytic-thyroiditis
#16
Woon Won Kim, Tae Kwun Ha, Sung Kwon Bae
BACKGROUND: The purpose of this study was to examine the possible prognostics and clinicopathologic characteristics underlying the BRAFV600E mutation and papillary thyroid carcinoma (PTC) coexisting or in absence of chronic lymphocytic thyroiditis (CLT). METHODS: This study was conducted on 172 patients who had undergone total thyroidectomy or unilateral total thyroidectomy for PTC; the patients were then examined for the BRAFV600E mutation using specimens obtained after their surgery from January 2013 to August 2015...
January 9, 2018: Journal of Otolaryngology—Head & Neck Surgery
https://www.readbyqxmd.com/read/29316426/clinical-sequencing-defines-the-genomic-landscape-of-metastatic-colorectal-cancer
#17
Rona Yaeger, Walid K Chatila, Marla D Lipsyc, Jaclyn F Hechtman, Andrea Cercek, Francisco Sanchez-Vega, Gowtham Jayakumaran, Sumit Middha, Ahmet Zehir, Mark T A Donoghue, Daoqi You, Agnes Viale, Nancy Kemeny, Neil H Segal, Zsofia K Stadler, Anna M Varghese, Ritika Kundra, Jianjiong Gao, Aijazuddin Syed, David M Hyman, Efsevia Vakiani, Neal Rosen, Barry S Taylor, Marc Ladanyi, Michael F Berger, David B Solit, Jinru Shia, Leonard Saltz, Nikolaus Schultz
Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29316280/giant-congenital-melanocytic-nevus-with-vascular-malformation-and-epidermal-cysts-associated-with-a-somatic-activating-mutation-in-braf
#18
Heather C Etchevers, Christian Rose, Birgit Kahle, Helmuth Vorbringer, Frédéric Fina, Pauline Heux, Irina Berger, Benjamin Schwarz, Stéphane Zaffran, Nicolas Macagno, Sven Krengel
Giant congenital melanocytic nevi may be symptomatically isolated, or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71-year old patient with a giant congenital melanocytic nevus of the lower back, buttocks and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts then developed within it...
January 5, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29315345/identification-and-functional-analysis-of-sox10-phosphorylation-sites-in-melanoma
#19
Julia C Cronin, Stacie K Loftus, Laura L Baxter, Steve Swatkoski, Marjan Gucek, William J Pavan
The transcription factor SOX10 plays an important role in vertebrate neural crest development, including the establishment and maintenance of the melanocyte lineage. SOX10 is also highly expressed in melanoma tumors, and SOX10 expression increases with tumor progression. The suppression of SOX10 in melanoma cells activates TGF-β signaling and can promote resistance to BRAF and MEK inhibitors. Since resistance to BRAF/MEK inhibitors is seen in the majority of melanoma patients, there is an immediate need to assess the underlying biology that mediates resistance and to identify new targets for combinatorial therapeutic approaches...
2018: PloS One
https://www.readbyqxmd.com/read/29312770/development-of-pulmonary-langerhans-cell-histiocytosis-in-a-patient-with-established-adenocarcinoma-of-the-lung
#20
Or Kalchiem-Dekel, Adina Paulk, Seth J Kligerman, Allen P Burke, Nirav G Shah, Renee K Dixon
Newly-appearing lung nodules on surveillance imaging in patients with pre-existing lung cancer can present a diagnostic dilemma when attempting to differentiate between metastatic disease, infection, and other inflammatory conditions. Here we report a case of an EGFR-/ALK-/BRAF+ metastatic adenocarcinoma patient who underwent lung biopsy for evaluation of upper-lobe predominant lung nodules revealed to represent pulmonary Langerhans cell histiocytosis (PLCH). The patient was a heavy smoker and admitted to increase her smoking habit after initially learning about her diagnosis with lung cancer...
December 2017: Journal of Thoracic Disease
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