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Modelling somatic growth

James J Hsieh, David Chen, Patricia I Wang, Mahtab Marker, Almedina Redzematovic, Ying-Bei Chen, S Duygu Selcuklu, Nils Weinhold, Nancy Bouvier, Kety H Huberman, Umesh Bhanot, Michael S Chevinsky, Parul Patel, Patrizia Pinciroli, Helen H Won, Daoqi You, Agnes Viale, William Lee, A Ari Hakimi, Michael F Berger, Nicholas D Socci, Emily H Cheng, Jennifer Knox, Martin H Voss, Maurizio Voi, Robert J Motzer
BACKGROUND: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients...
October 14, 2016: European Urology
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
Do Yeon Kim, Jong Hoon Park
Autosomal dominant polycystic kidney disease is caused by mutation of PKD1 (polycystic kidney disease-1) or PKD2 (polycystic kidney disease-2). PKD1 and PKD2 encode PC1 (polycystin-1) and PC2 (polycystin-2), respectively. In addition, the mutation of cilia-associated proteins is also a recognized major factor of pathogenesis, since PC1 and PC2 are located in primary cilium. Abnormalities of PC1 or PC2 lead to aberrant signaling through downstream pathways, such as the negative growth regulation, G protein activation, and canonical and non-canonical Wnt pathways...
2016: Advances in Experimental Medicine and Biology
J Matthew Watson, Alexander Platzer, Anita Kazda, Svetlana Akimcheva, Sona Valuchova, Viktoria Nizhynska, Magnus Nordborg, Karel Riha
In plants, gametogenesis occurs late in development, and somatic mutations can therefore be transmitted to the next generation. Longer periods of growth are believed to result in an increase in the number of cell divisions before gametogenesis, with a concomitant increase in mutations arising due to replication errors. However, there is little experimental evidence addressing how many cell divisions occur before gametogenesis. Here, we measured loss of telomeric DNA and accumulation of replication errors in Arabidopsis with short and long life spans to determine the number of replications in lineages leading to gametes...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Rituparna Das, Till Strowig, Rakesh Verma, Srinivas Koduru, Anja Hafemann, Stephanie Hopf, Mehmet H Kocoglu, Chiara Borsotti, Lin Zhang, Andrew Branagan, Elizabeth Eynon, Markus G Manz, Richard A Flavell, Madhav V Dhodapkar
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes...
October 10, 2016: Nature Medicine
Gianfranco Matrone, John J Mullins, Carl S Tucker, Martin A Denvir
CDK9 is a known regulator of cellular transcription, growth and proliferation. Small molecule inhibitors are currently being developed and assessed in clinical trials as anti-cancer drugs. The zebrafish embryo provides an ideal model to explore the effects of CDK9 inhibition in-vivo. This has not been adequately explored previously at the level of a whole organism. We have compared and contrasted the effects of pharmacological and molecular inhibition of CDK9 on somatic growth, apoptosis and cellular proliferation in zebrafish larvae between 0 to 120 hours post fertilisation (hpf) using flavopiridol, a selective CDK9 antagonist, and CDK9-targeting morpholino...
October 7, 2016: Cell Cycle
David G McFadden, Katerina Politi, Arjun Bhutkar, Frances K Chen, Xiaoling Song, Mono Pirun, Philip M Santiago, Caroline Kim-Kiselak, James T Platt, Emily Lee, Emily Hodges, Adam P Rosebrock, Roderick T Bronson, Nicholas D Socci, Gregory J Hannon, Tyler Jacks, Harold Varmus
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
El-Mokadem Ismail, Kidd Thomas, Pratt Norman, Fleming Stewart, Nabi Ghulam
BACKGROUND: Genetic alterations on chromosome 9p, including inactivation of the tumour suppressor gene, CDKN2A, result in cellular proliferation and growth of tumours. Our aim was to use microsatellite analysis and fluorescence in situ hybridization (FISH) to characterise the architecture of this region. RESULTS: Seventy-five out of 77 clear cell renal cell cancers (tumour/normal pairs) were interpretable for LOH analysis on chromosome 9p (two tumours were excluded, as all five primers were uninformative)...
September 22, 2016: Oncotarget
Obi L Griffith, Szeman Ruby Chan, Malachi Griffith, Kilannin Krysiak, Zachary L Skidmore, Jasreet Hundal, Julie A Allen, Cora D Arthur, Daniele Runci, Mattia Bugatti, Alexander P Miceli, Heather Schmidt, Lee Trani, Krishna-Latha Kanchi, Christopher A Miller, David E Larson, Robert S Fulton, William Vermi, Richard K Wilson, Robert D Schreiber, Elaine R Mardis
Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples...
September 27, 2016: Cell Reports
M K Devlin-Durante, M W Miller, W F Precht, I B Baums
Foundation species such as redwoods, seagrasses and corals are often long-lived and clonal. Genets may consist of hundreds of members (ramets) and originated hundreds to thousands of years ago. As climate change and other stressors exert selection pressure on species, the demography of populations change. Yet, because size does not indicate age in clonal organisms, demographic models are missing data necessary to predict the resilience of many foundation species. Here, we correlate somatic mutations with genet age of corals and provide the first, preliminary estimates of genet age in a colonial animal...
September 27, 2016: Molecular Ecology
Ruxue Wei, Xueming Zhao, Haisheng Hao, Weihua Du, Huabin Zhu
The rabbit is considered an important model animal from which to obtain embryonic stem cells because of the utility of this animal in physiology and reproductive research. Here, we derived rabbit ES-like (rES-like) cells from blastocysts of superovulated Japanese white rabbits using culture medium containing 10(-7)  M melatonin, 10 ng/mL basic fibroblast growth factor, and 1,000 IU/mL human leukemia inhibitory factor. This concentration of melatonin had the most significant positive effects on the proliferation inner cell mass-derived cells (improving rates from 19...
September 20, 2016: Molecular Reproduction and Development
Ying Liang, Kunlong Qiu, Bo Liao, Wen Zhu, Xuanlin Huang, Lin Li, Xiangtao Chen, Keqin Li
MOTIVATION: Many forms of variations exist in the human genome including single nucleotide polymorphism, small insert/deletion (DEL) (indel) and structural variation (SV). Somatically acquired SV may regulate the expression of tumor-related genes and result in cell proliferation and uncontrolled growth, eventually inducing tumor formation. Virus integration with host genome sequence is a type of SV that causes the related gene instability and normal cells to transform into tumor cells...
September 14, 2016: Bioinformatics
Anne-Lise Lecoq, Philippe Zizzari, Mirella Hage, Lyvianne Decourtye, Clovis Adam, Say Viengchareun, Johannes D Veldhuis, Valérie Geoffroy, Marc Lombès, Virginie Tolle, Anne Guillou, Auli Karhu, Laurent Kappeler, Philippe Chanson, Peter Kamenický
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip(+/-)) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip(+/-) mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age...
October 2016: Journal of Endocrinology
Britta Klein, Thomas Haggeney, Daniela Fietz, Sivanjah Indumathy, Kate L Loveland, Mark Hedger, Sabine Kliesch, Wolfgang Weidner, Martin Bergmann, Hans-Christian Schuppe
STUDY QUESTION: Which immune cells and cytokine profiles are characteristic for testicular germ cell neoplasia and what consequences does this have for the understanding of the related testicular immunopathology? SUMMARY ANSWER: The unique immune environment of testicular germ cell neoplasia comprises B cells and dendritic cells as well as high transcript levels of IL-6 and other B cell supporting or T helper cell type 1 (Th1)-driven cytokines and thus differs profoundly from normal testis or inflammatory lesions associated with hypospermatogenesis...
October 2016: Human Reproduction
Marion Krämer, Roland Kupka, S V Subramanian, Sebastian Vollmer
BACKGROUND: Although a strong biological basis exists for a role of iodine in somatic growth failure in childhood, this relation has not been previously studied on a large scale to our knowledge. OBJECTIVE: We investigated if a general association exists between the household unavailability of iodized salt and child growth across countries. DESIGN: We used 89 nationally representative, repeated, cross-sectional and mutually comparable demographic and health surveys that were conducted between 1994 and 2012 across 46 low- and middle-income countries...
October 2016: American Journal of Clinical Nutrition
Karen M Mann, Haoqiang Ying, Joseph Juan, Nancy A Jenkins, Neal G Copeland
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, including cellular proliferation, migration, cellular metabolism and autophagy. 90% of pancreatic cancer patients harbor somatic oncogenic point mutations in KRAS, which lead to constitutive activation of the molecule...
September 3, 2016: Pharmacology & Therapeutics
Nan Wu, Marianne Doorenbos, Dong Feng Chen
Human induced pluripotent stem cells (iPSCs) are a type of stem cells that can be derived from human somatic cells by introducing certain transcription factors. Induced pluripotent stem cells can divide indefinitely and are able to differentiate into every cell type, which make them viable for transplantation and individual disease modeling. Recently, various ocular cells, including corneal epithelial-like cells, retinal pigment epithelium (RPE) cells displaying functions similar to native RPE, photoreceptors, and retinal ganglion cells, have all been successfully derived from iPSCs...
2016: Stem Cells International
Kelly G Sullivan, Maya Emmons-Bell, Michael Levin
A key problem in evolutionary developmental biology is identifying the sources of instructive information that determine species-specific anatomical pattern. Understanding the inputs to large-scale morphology is also crucial for efforts to manipulate pattern formation in regenerative medicine and synthetic bioengineering. Recent studies have revealed a physiological system of communication among cells that regulates pattern during embryogenesis and regeneration in vertebrate and invertebrate models. Somatic tissues form networks using the same ion channels, electrical synapses, and neurotransmitter mechanisms exploited by the brain for information-processing...
July 2016: Communicative & Integrative Biology
Ke Pan, Wen-Xiong Wang
This study investigated the effects of different environmental factors on (137)Cs uptake in three subtropical estuarine fish, and the trophic transfer of (137)Cs in the fish from different preys. Our data showed that salinity, potassium, and temperature had appreciable effects on the dissolved uptake of (137)Cs in the fish, but no conclusive relationship was found between the effects of salinity and potassium concentration on the uptake. The dietary assimilation of (137)Cs was 51-55% in the omnivorous fish Siganus fuscescens when fed with macroalgae or bivalve tissues, and was much lower than those in carnivorous fish Sebastiscus marmoratus and Jarbua terapon (70-79%)...
November 2016: Chemosphere
Balázs Széky, Pálma Silló, Melinda Fábián, Balázs Mayer, Sarolta Kárpáti, Krisztián Németh
Over the past decade a rare cell population called cancer stem cells has been identified in both solid tumors and hematologic cancers. These cells are reminiscent of somatic and embryonic stem cells and play a critical role in the initiation and progression of malignancies. As all stem cells, they are able to undergo asymmetric cell division and hence renew themselves and create various other progenies with heterogenous phenotypes. A growing body of literature suggested that stem cell subpopulations contribute significantly to the growth and metastatic properties of melanoma...
August 2016: Orvosi Hetilap
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