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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
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
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
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
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
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
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
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
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
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
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
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
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
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
Idil Orhon, Nicolas Dupont, Patrice Codogno
The maintenance of cellular homeostasis in response to extracellular stresses by autophagy is vital for the health of various tissues. Extracellular stimuli may include nutrient starvation, endoplasmic reticulum stress, hypoxia, cytotoxic agents, or mechanical stress. The primary cilium (PC) is a microtubule-based sensory organelle that regulates the integration of various extracellular stimuli. The interconnection between macroautophagy/autophagy and the PC is beginning to be illuminated. In this punctum, we discuss our recent study of PC-dependent autophagy in response to fluid flow in kidney epithelial cells...
August 2, 2016: Autophagy
Andreas H Scheel, Sascha Ansén, Anne M Schultheis, Matthias Scheffler, Rieke N Fischer, Sebastian Michels, Martin Hellmich, Julie George, Thomas Zander, Michael Brockmann, Erich Stoelben, Harry Groen, Wim Timens, Sven Perner, Michael von Bergwelt-Baildon, Reinhard Büttner, Jürgen Wolf
Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and association with genetically defined subtypes have not been addressed systematically. Here, we analyzed PD-L1 expression in 436 genetically annotated NSCLC specimens enriched for early stages using PD-L1 antibody 5H1. Expression of PD-L1 was detected in the tumor cells (TC) (34% of cases) and in associated immune cells (IC) (49%) across all stages of NSCLC, either alone or in combination...
May 2016: Oncoimmunology
Bixia Zheng, Chunli Wang, Zhanjun Jia, Zhifeng Liu, Mei Li, Yu Jin, Jian Pan
AIM: Peutz-Jeghers syndrome (PJS) is caused by the germline mutations in serine/threonine kinase 11 (STK11) gene. This study was to investigate the spectrum ofSTK11 gene mutations using multiplex ligation-dependent probe amplification (MLPA) assay in combination of direct sequencing in Chinese children with PJS. METHODS: Nine children who met the clinical criteria for PJS and two presumed PJS patients were enrolled in this study. Patients' clinical information on polyp characteristics, polyp-related complications, family histories, etc were reviewed and analyzed...
June 21, 2016: Journal of Pediatric Gastroenterology and Nutrition
Chang Hun Lee, Hong En Wang, Seung Young Seo, Seong Hun Kim, In Hee Kim, Sang Wook Kim, Soo Teik Lee, Dae Ghon Kim, Myung Kwan Han, Seung Ok Lee
Genome-wide association study in diffusely infiltrating type cholangiocarcinoma (CC) can be limited due to the difficulty of obtaining tumor tissue. We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next-generation sequencing (NGS) of bile and to compare the variations with those of mass-forming type CC. A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography (ERCP) and 17 surgically obtained tumor tissue samples were evaluated. Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis...
August 2016: Experimental and Molecular Pathology
Nayoung Kim, Hwa Young Yim, Ningning He, Cheol-Jung Lee, Ju Hyun Kim, Jin-Sung Choi, Hye Suk Lee, Somin Kim, Euna Jeong, Mee Song, Sang-Min Jeon, Woo-Young Kim, Gordon B Mills, Yong-Yeon Cho, Sukjoon Yoon
Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer effects on STK11 mutant lung cancer cell lines. Restoring STK11 function reduced the efficacy of CGs...
2016: Scientific Reports
Umberto Malapelle, Francesco Morra, Gennaro Ilardi, Roberta Visconti, Francesco Merolla, Aniello Cerrato, Virginia Napolitano, Roberto Monaco, Gianluca Guggino, Guglielmo Monaco, Stefania Staibano, Giancarlo Troncone, Angela Celetti
OBJECTIVES: CCDC6 gene product is a tumor-suppressor pro-apoptotic protein, substrate of ATM, involved in DNA damage response and repair. Altered levels of CCDC6 expression are dependent on post-translational modifications, being the de-ubiquitinating enzyme USP7 responsible of the fine tuning of the CCDC6 stability. Thus, our aim was to investigate CCDC6 and USP7 expression levels in Lung-Neuroendocrine Tumors (L-NETs) to verify if they correlate and may be exploited as novel predictive therapeutic markers...
June 17, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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