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Vascular tumors mutations

Robert Roskoski
Because mutations, overexpression, and dysregulation of protein kinases play essential roles in the pathogenesis of many illnesses, this enzyme family has become one of the most important drug targets in the past 20 years. The US FDA has approved 48 small molecule protein kinase inhibitors, nearly all of which are orally effective with the exceptions of netarsudil (which is given as an eye drop) and temsirolimus (which is given intravenously). Of the 48 approved drugs, the majority (25) target receptor protein-tyrosine kinases, ten target non-receptor protein-tyrosine kinases, and 13 target protein-serine/threonine protein kinases...
March 12, 2019: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Bita Geramizadeh, Zahra Maleki
BACKGROUND: The nomenclature "Non-invasive Follicular Neoplasm with Papillary-like Nuclear Features (NIFTP)" was introduced in 2016. While NIFTP differs from classic papillary thyroid carcinoma (PTC) in imaging, cytomorphology, histology, molecular profile, treatment, follow up, outcome, and behavior, it largely overlaps with follicular variant of PTC at imaging and cytomorphology. Herein, we review the literature for better understanding NIFTP, and its impact on patient care...
March 13, 2019: Endocrine
Riikka Siitonen, Emilia Peuhu, Anu K Autio, Heidi Liljenbäck, Elina Mattila, Olli Metsälä, Meeri Käkelä, Tiina Saanijoki, Ingrid Dijkgraaf, Sirpa Jalkanen, Johanna Ivaska, Anne Roivainen
Shank-associated RH domain-interacting protein (SHARPIN, alias SIPL1) is a cytosolic protein that plays a key role in activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates positron emission tomography (PET) imaging of integrin upregulation during tumor angiogenesis...
March 8, 2019: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Satoshi Yamasaki, Takayuki Amemiya, Yukimitsu Yabuki, Katsuhisa Horimoto, Kazuhiko Fukui
Recent progress in molecular biology has revealed that many non-coding RNAs regulate gene expression or catalyze biochemical reactions in tumors, viruses and several other diseases. The tertiary structure of RNA molecules and RNA-RNA/protein interaction sites are of increasing importance as potential targets for new medicines that treat a broad array of human diseases. Current RNA drugs are split into two groups: antisense RNA molecules and aptamers. In this report, we present a novel workflow to predict RNA tertiary structures and RNA-RNA/protein interactions using the KNIME environment, which enabled us to assemble a combination of RNA-related analytical tools and databases...
March 6, 2019: Journal of Computer-aided Molecular Design
Nazanin K Majd, Nicolas R Metrus, Fernando Santos-Pinheiro, Christopher R Trevino, Gregory N Fuller, Jason T Huse, Caroline Chung, Leena Ketonen, Mark D Anderson, Marta Penas-Prado
Astroblastoma is a rare glial neoplasm composed of cells that have broad processes oriented perpendicular to central vessels and often demonstrate vascular sclerosis. The WHO 2016 classification does not specify a grading system for astroblastoma, and categorizes them as well-differentiated or malignant. These broad classification rubrics, however, do not accurately predict clinical outcome. Genetic profiling of astroblastoma has therefore been of particular interest in the recent years. These efforts, although in small number, have revealed heterogeneous molecular findings that may explain astroblastoma's unpredictable clinical outcome...
February 2019: Cancer Genetics
Nobuhiko Seki, Maika Natsume, Ryosuke Ochiai, Terunobu Haruyama, Masashi Ishihara, Yoko Fukasawa, Takahiko Sakamoto, Shigeru Tanzawa, Ryo Usui, Takeshi Honda, Shuji Ota, Yasuko Ichikawa, Kiyotaka Watanabe
In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising...
January 2019: Case Reports in Oncology
Maiya J Mao, Donna E Leonardi
Isocitrate dehydrogenases (IDHs) are enzymes involved in the production of α-ketoglutarate (αkg) in normal cellular metabolism. Cells with IDH mutations reduce αkg to 2-hydroxyglutarate (2HG), an oncometabolite, and 2HG directly transforms normal cells to malignant cells through histone demethylation and epigenetic dysregulation. However, whether IDH mutations affect cancer stromal cells is elusive, and little is known whether 2HG may impact the tumor microenvironment. We hypothesized that the IDH mutant cancer secretome and metabolites would stimulate primitive vascular-endothelial genesis...
2019: American Journal of Cancer Research
Song Wu, Tong Ou, Nianzeng Xing, Jiang Lu, Shengqing Wan, Changxi Wang, Xi Zhang, Feiya Yang, Yi Huang, Zhiming Cai
Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conduct whole-genome and targeted sequencing in urothelial bladder carcinomas (UBCs, the most common type of bladder cancer). Recurrent mutations in noncoding regions affecting gene regulatory elements and structural variations (SVs) leading to gene disruptions are prevalent. Notably, we find recurrent ADGRG6 enhancer mutations and FRS2 duplications which are associated with higher protein expression in the tumor and poor prognosis...
February 12, 2019: Nature Communications
Farres Obeidin, Lawrence J Jennings, Borislav A Alexiev
Sinonasal glomangiopericytoma (SNGP) is a neoplasm arising in the nasal cavity and paranasal sinuses that shows perivascular myoid differentiation. The diagnosis of SNGP may be diagnostically challenging due to a large number of potential mimics. In the present study, we sought to characterize the histological and molecular features of six cases of SNGP found in prior surgical pathology records over a 15-year period. The average age at diagnosis was 48.5 years (range: 31-78 years), and the male-to-female ratio was 1:1...
February 3, 2019: Pathology, Research and Practice
Hans Kristian Bø, Ole Solheim, Kjell-Arne Kvistad, Erik Magnus Berntsen, Sverre Helge Torp, Anne Jarstein Skjulsvik, Ingerid Reinertsen, Daniel Høyer Iversen, Geirmund Unsgård, Asgeir Store Jakola
OBJECTIVEExtent of resection (EOR) and residual tumor volume are linked to prognosis in low-grade glioma (LGG) and there are various methods for facilitating safe maximal resection in such patients. In this prospective study the authors assess radiological and clinical results in consecutive patients with LGG treated with 3D ultrasound (US)-guided resection under general anesthesia.METHODSConsecutive LGGs undergoing primary surgery guided with 3D US between 2008 and 2015 were included. All LGGs were classified according to the WHO 2016 classification system...
February 1, 2019: Journal of Neurosurgery
Anna Latysheva, Kyrre Eeg Emblem, Petter Brandal, Einar Osland Vik-Mo, Jens Pahnke, Kjetil Røysland, John K Hald, Andrés Server
PURPOSE: According to the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) of 2016, oligodendrogliomas are now defined primarily by a specific molecular signature (presence of IDH mutation and 1p19q codeletion). The purpose of our study was to assess the value of dynamic susceptibility contrast MR imaging (DSC-MRI) and diffusion-weighted imaging (DWI) to characterize oligodendrogliomas and to distinguish them from astrocytomas. METHODS: Seventy-one adult patients with untreated WHO grade II and grade III diffuse infiltrating gliomas and known 1p/19q codeletion status were retrospectively identified and analyzed using relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps based on whole-tumor volume histograms...
February 2, 2019: Neuroradiology
Mauro Cives, Eleonora Pelle', Davide Quaresmini, Francesca Maria Rizzo, Marco Tucci, Franco Silvestris
<br>Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross-talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including VEGF, PDGF, FGF, semaphorins and angiopoietins, that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher then epithelial tumors...
January 30, 2019: Neuroendocrinology
Philip M Boone, Rachel M Scott, Stefan J Marciniak, Elizabeth P Henske, Benjamin A Raby
A genetic influence on spontaneous pneumothoraces - those occurring without a traumatic or iatrogenic cause - is supported by several lines of evidence: 1) Pneumothorax can cluster in families (i.e. familial spontaneous pneumothorax); 2) Mutations in the FLCN gene have been found in both familial and sporadic cases; and 3) Pneumothorax is a known complication of several genetic syndromes. Herein we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1-antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis (LAM), Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others...
January 25, 2019: American Journal of Respiratory and Critical Care Medicine
Tao Sun, Rameshwar Patil, Anna Galstyan, Dmytro Klymyshyn, Hui Ding, Alexandra Chesnokova, Webster K Cavenee, Frank B Furnari, Vladimir A Ljubimov, Ekaterina S Shatalova, Shawn Wagner, Debiao Li, Adam N Mamelak, Serguei I Bannykh, Chirag G Patil, Jeremy D Rudnick, Jethro Hu, Zachary B Grodzinski, Arthur Rekechenetskiy, Vida Falahatian, Alexander V Lyubimov, Yongmei L Chen, Lai Sum Leoh, Tracy R Daniels-Wells, Manuel L Penichet, Eggehard Holler, Alexander V Ljubimov, Keith L Black, Julia Y Ljubimova
There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix (ECM), including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients...
January 18, 2019: Cancer Research
Olga Nigro, Tiziana Tartaro, Alessandro Tuzi, Alice Giaquinto, Matteo B Suter, Graziella Pinotti
Neurofibromatosis type 2 (NF-2) is an autosomal dominant inherited disease caused by heterozygous mutations in the NF-2 tumor suppressor gene. It is characterized by the development of multiple benign tumors in the central nervous system. A majority of these tumors can be treated with surgery or radiotherapy in the case of the symptomatic disease. Cytotoxic chemotherapy has no established role in the treatment of NF-2. Vascular endothelial growth factor (VEGF) is a critical mediator of tumor angiogenesis and vessel permeability...
January 11, 2019: Anti-cancer Drugs
Dawn H Siegel
Infantile hemangiomas (IH) are the most common vascular tumor of infancy with an estimated 80,000 annual diagnoses in the United States. The genetic mechanisms underlying IH and the related multi-organ birth defect syndromes, PHACE (an acronym for Posterior fossa brain malformations, segmental facial Hemangiomas, Arterial anomalies, Cardiac defects, Eye anomalies, and sternal clefting or supraumbilical raphe) and LUMBAR (an acronym for Lower body hemangiomas, Urogenital anomalies, Myelopathy, Bone deformities, Anorectal malformations/Arterial anomalies, Renal anomalies) remain unsolved...
December 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
J H Francis, T Milman, H Grossniklaus, D M Albert, R Folberg, G M Levitin, S E Coupland, F Catalanotti, D Rabady, C Kandoth, K J Busam, D H Abramson
PURPOSE: GNAQ mutations have been identified in port wine stains (both syndromic and non-syndromic) and melanocytic ocular neoplasms. This study investigates the presence of GNAQ mutations in diffuse- (those associated with Sturge-Weber syndrome (SWS)) and solitary choroidal hemangiomas. PARTICIPANTS: Tissue from 11 patients with the following diagnoses: port wine stain (n = 3), diffuse choroidal hemangioma (n = 1), solitary choroidal hemangioma (n = 6), choroidal nevus (n =1) METHODS: Ten specimens were interrogated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 468 key cancer genes in formalin-fixed, paraffin-embedded tumors...
December 8, 2018: Ophthalmology
Beth A Hellerstedt, Nicholas J Vogelzang, Harriet M Kluger, Christopher A Yasenchak, Dana T Aftab, David A Ramies, Michael S Gordon, Primo Lara
INTRODUCTION: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non-small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. PATIENTS AND METHODS: Patients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1...
October 24, 2018: Clinical Lung Cancer
Tatsuya Nagano, Motoko Tachihara, Yoshihiro Nishimura
Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes...
December 9, 2018: Current Cancer Drug Targets
Abdulaziz Oqalaa Almubarak, Anwar Ul Haq, Ibrahim Alzahrani, Essam Al Shail
Lhermitte-Duclos disease is a rare condition with less than 250 cases reported in the literature. It was considered a neoplastic or hamartomatous growth in the cerebellum. It commonly presents with symptoms of high intracranial pressure or obstructive hydrocephalus. Surgical resection is often curative. The lesion is associated with PTEN gene mutation, and it is considered to be one of the diagnostic criteria of Cowden's syndrome. Vascular tumors are reported in this syndrome, including glioblastomas and meningiomas...
December 5, 2018: Journal of Neurological Surgery. Part A, Central European Neurosurgery
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