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https://www.readbyqxmd.com/read/27896618/loss-of-liver-kinase-b1-causes-planar-polarity-defects-in-cochlear-hair-cells-in-mice
#1
Yuqin Men, Aizhen Zhang, Liwen Zhang, Yecheng Jin, Zhishuo Wang, Jing Zhao, Xiaolin Yu, Jian Zhang, Jiangang Gao
The tumor suppressor gene liver kinase B1 (LKB1), also called STK11, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice (LKB1(Pax2) CKO mice) were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1(Pax2) CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1(Pax2) CKO mice were clustered and misoriented, respectively...
November 28, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27894106/prader-willi-syndrome-due-to-an-unbalanced-de-novo-translocation-t-15-19-q12-p13-3
#2
Vy Dang, Abhilasha Surampalli, Ann M Manzardo, Stephanie Youn, Merlin G Butler, June-Anne Gold, Virginia E Kimonis
Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age...
November 29, 2016: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/27844328/molecular-profiling-of-thymoma-and-thymic-carcinoma-genetic-differences-and-potential-novel-therapeutic-targets
#3
Franz Enkner, Bettina Pichlhöfer, Alexandru Teodor Zaharie, Milica Krunic, Tina Maria Holper, Stefan Janik, Bernhard Moser, Karin Schlangen, Barbara Neudert, Karin Walter, Brigitte Migschitz, Leonhard Müllauer
Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation...
November 14, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/27821076/three-novel-mutations-of-stk11-gene-in-chinese-patients-with-peutz-jeghers-syndrome
#4
Hu Tan, Libin Mei, Yanru Huang, Pu Yang, Haoxian Li, Ying Peng, Chen Chen, Xianda Wei, Qian Pan, Desheng Liang, Lingqian Wu
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. Mutations in the serine-threonine kinase 11 gene (SKT11) are the major cause of PJS. CASE PRESENTATION: Blood samples were collected from six PJS families including eight patients. Mutation screening of STK11 gene was performed in these six families by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay...
November 8, 2016: BMC Medical Genetics
https://www.readbyqxmd.com/read/27812189/mesenchymal-stem-stromal-cells-under-stress-increase-osteosarcoma-migration-and-apoptosis-resistance-via-extracellular-vesicle-mediated-communication
#5
Krishna C Vallabhaneni, Meeves-Yoni Hassler, Anu Abraham, Jason Whitt, Yin-Yuan Mo, Azeddine Atfi, Radhika Pochampally
Studies have shown that mesenchymal stem/stromal cells (MSCs) from bone marrow are involved in the growth and metastasis of solid tumors but the mechanism remains unclear in osteosarcoma (OS). Previous studies have raised the possibility that OS cells may receive support from associated MSCs in the nutrient deprived core of the tumors through the release of supportive macromolecules and growth factors either in vesicular or non-vesicular forms. In the present study, we used stressed mesenchymal stem cells (SD-MSCs), control MSCs and OS cells to examine the hypothesis that tumor-associated MSCs in nutrient deprived core provide pro-proliferative, anti-apoptotic, and metastatic support to nearby tumor cells...
2016: PloS One
https://www.readbyqxmd.com/read/27799657/lkb1-loss-links-serine-metabolism-to-dna-methylation-and-tumorigenesis
#6
Filippos Kottakis, Brandon N Nicolay, Ahlima Roumane, Rahul Karnik, Hongcang Gu, Julia M Nagle, Myriam Boukhali, Michele C Hayward, Yvonne Y Li, Ting Chen, Marc Liesa, Peter S Hammerman, Kwok Kin Wong, D Neil Hayes, Orian S Shirihai, Nicholas J Dyson, Wilhelm Haas, Alexander Meissner, Nabeel Bardeesy
Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation...
October 31, 2016: Nature
https://www.readbyqxmd.com/read/27756406/spatio-temporal-mutation-profiles-of-case-matched-colorectal-carcinomas-and-their-metastases-reveal-unique-de-novo-mutations-in-metachronous-lung-metastases-by-targeted-next-generation-sequencing
#7
Valentina Kovaleva, Anna-Lena Geissler, Lisa Lutz, Ralph Fritsch, Frank Makowiec, Sebastian Wiesemann, Ulrich T Hopt, Bernward Passlick, Martin Werner, Silke Lassmann
BACKGROUND: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. METHODS: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel(TM), MiSeq sequencing and data analyses (Illumina)...
October 18, 2016: Molecular Cancer
https://www.readbyqxmd.com/read/27748796/detection-of-cancer-specific-mutations-in-early-stage-non-small-cell-lung-cancer-using-cell-free-dna-by-targeted-sequencing
#8
Yutong He, Xinyuan Zhang, Liqun Wang, Ziqiang Tian, Qingyi Liu, Jifang Yao, Yueping Liu, Chuanbao Li, Li Min, Baoen Shan
Non-small cell lung cancer (NSCLC) is a major public health problem worldwide and leads to a high mortality. NSCLC is always diagnosed in late stages because of its unapparent symptoms. However, cell-free DNA (cfDNA) may serve as a new potential biomarker to detect early stage of non‑small cell lung cancer. Here we recruited 10 non-small cell lung cancer patients to obtain fresh tumor tissue, peripheral blood lymphocytes (PBLs), and plasma. CfDNAs from 13 elderly people and 7 middle-age smokers were also extracted as controls...
October 12, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27741397/morphological-examination-and-transcriptomic-profiling-to-identify-prednisolone-treatment-in-beef-cattle
#9
Francesca T Cannizzo, Sara Pegolo, Paola Pregel, Elisabetta Manuali, Sonia Salamida, Sara Divari, Frine E Scaglione, Enrico Bollo, Bartolomeo Biolatti, Luca Bargelloni
In livestock production corticosteroids are licensed only for therapy, nevertheless they are often illegally used as growth promoters. The aim of this study was to identify morphological or biomolecular alterations induced by prednisolone (PDN) in experimentally treated beef cattle, since PDN and its metabolites are no longer detectable by LC-MS/MS methods in biological fluids. Moreover, PDN do not induce any histological alterations in thymus, differently from Dexamethasone treatments. Therefore, a marker of illicit treatment for this growth promoter could be useful...
October 14, 2016: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/27734215/time-to-incorporate-germline-multigene-panel-testing-into-breast-and-ovarian-cancer-patient-care
#10
Rossella Graffeo, Luca Livraghi, Olivia Pagani, Aron Goldhirsch, Ann H Partridge, Judy E Garber
PURPOSE: Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer (OC), and of individuals at high risk for these diseases. Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies. Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied, whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes (PTEN, TP53, STK11, CDH1), and particularly those who carry mutations in moderate-penetrance genes (e...
October 12, 2016: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/27731500/new-roles-of-lkb1-in-regulating-adipose-tissue-development-and-thermogenesis
#11
Ziye Xu, Jiaqi Liu, Tizhong Shan
Adipose tissues regulate energy metabolism and reproduction. There are three types of adipocytes (brown, white and beige adipocytes) in mammals. White adipocytes store energy and are closely associated with obesity and other metabolic diseases. The beige and brown adipocytes have numerous mitochondria and high levels of UCP1 that dissipates lipid to generate heat and defend against obesity. The global epidemic of obesity and its associated metabolic diseases urge an imperative need for understating the regulation of adipogenesis...
October 12, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27705915/lkb1-is-a-dna-damage-response-protein-that-regulates-cellular-sensitivity-to-parp-inhibitors
#12
Yi-Shu Wang, Jianfeng Chen, Fengmei Cui, Huibo Wang, Shuai Wang, Wei Hang, Qinghua Zeng, Cheng-Shi Quan, Ying-Xian Zhai, Jian-Wei Wang, Xiang-Feng Shen, Yong-Ping Jian, Rui-Xun Zhao, Kaitlin D Werle, Rutao Cui, Jiyong Liang, Yu-Lin Li, Zhi-Xiang Xu
Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1)...
September 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27699275/synergy-of-radiotherapy-and-pd-1-blockade-in-kras-mutant-lung-cancer
#13
Grit S Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y Li, Kevin A Buczkowski, Aaron K Grant, Soumya Ullas, Kevin Rhee, Jillian D Cavanaugh, Neermala Poudel Neupane, Camilla L Christensen, Jan M Herter, G Mike Makrigiorgos, F Stephen Hodi, Gordon J Freeman, Glenn Dranoff, Peter S Hammerman, Alec C Kimmelman, Kwok-Kin Wong
Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional Kras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1)...
June 16, 2016: JCI Insight
https://www.readbyqxmd.com/read/27687306/whole-exome-sequencing-and-immune-profiling-of-early-stage-lung-adenocarcinoma-with-fully-annotated-clinical-follow-up
#14
H Kadara, M Choi, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, Y Yoo, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Lee, R P Lifton, I I Wistuba, R S Herbst
BACKGROUND: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. METHODS: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n=92)...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27643638/inhibition-of-acetyl-coa-carboxylase-suppresses-fatty-acid-synthesis-and-tumor-growth-of-non-small-cell-lung-cancer-in-preclinical-models
#15
Robert U Svensson, Seth J Parker, Lillian J Eichner, Matthew J Kolar, Martina Wallace, Sonja N Brun, Portia S Lombardo, Jeanine L Van Nostrand, Amanda Hutchins, Lilliana Vera, Laurie Gerken, Jeremy Greenwood, Sathesh Bhat, Geraldine Harriman, William F Westlin, H James Harwood, Alan Saghatelian, Rosana Kapeller, Christian M Metallo, Reuben J Shaw
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo...
October 2016: Nature Medicine
https://www.readbyqxmd.com/read/27615706/widely-metastatic-atypical-pituitary-adenoma-with-mtor-pathway-stk11-f298l-mutation-treated-with-everolimus-therapy
#16
Laura E Donovan, Ashley V Arnal, Shih-Hsiu Wang, Yazmin Odia
Pituitary adenomas are the commonest intracranial tumor, but metastases are rare (0.2% yearly incidence) and portend poor prognosis. CAPecitabine and TEMozolomide improved outcomes for neuroendocrine tumors. However, no chemotherapy is approved for refractory pituitary carcinomas. Next-generation sequencing revealed an actionable mTOR pathway STK11 mutation in a woman with adrenocorticotropic hormone-secreting pituitary carcinoma refractory to six resections, radiation and CAPecitabine and TEMozolomide. Given efficacy in preclinical pancreatic cancer models with STK11 mutations, she received radiation and everolimus leading to clinical improvement and stability on MRI and PET for >6 months...
October 2016: CNS Oncology
https://www.readbyqxmd.com/read/27581326/comprehensive-transcriptome-analysis-identifies-pathways-with-therapeutic-potential-in-locally-advanced-cervical-cancer
#17
Alma Delia Campos-Parra, Alejandra Padua-Bracho, Abraham Pedroza-Torres, Gabriela Figueroa-González, Jorge Fernández-Retana, Oliver Millan-Catalan, Oscar Peralta-Zaragoza, David Cantú de León, Luis A Herrera, Carlos Pérez-Plasencia
OBJECTIVE: The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer (LACC) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC. METHODS: Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, significantly over-expressed genes in LACC were identified; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort, and the protein expression data were obtained from the Human Protein Atlas...
August 28, 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27568332/targeted-molecular-profiling-of-rare-genetic-alterations-in-colorectal-cancer-using-next-generation-sequencing
#18
Mayank Jauhri, Akanksha Bhatnagar, Satish Gupta, Yogender Shokeen, Sachin Minhas, Shyam Aggarwal
Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients...
October 2016: Medical Oncology
https://www.readbyqxmd.com/read/27565922/hot-spot-mutations-in-finnish-non-small-cell-lung-cancers
#19
Satu Mäki-Nevala, Virinder Kaur Sarhadi, Mikko Rönty, Eeva Kettunen, Kirsti Husgafvel-Pursiainen, Henrik Wolff, Aija Knuuttila, Sakari Knuutila
OBJECTIVES: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. MATERIALS AND METHODS: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27550049/a-pyloric-gland-phenotype-ovarian-mucinous-tumor-resembling-lobular-endocervical-glandular-hyperplasia-in-a-patient-with-peutz-jeghers-syndrome
#20
Eun Na Kim, Gu-Hwan Kim, Jiyoon Kim, In Ah Park, Jin Ho Shin, Yun Chai, Kyu-Rae Kim
We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2...
August 22, 2016: Journal of Pathology and Translational Medicine
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