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Genetic Pathways (genetic + pathway)
Selected AbstractsGenetic pathways to glioblastomasNEUROPATHOLOGY, Issue 1 2005Hiroko Ohgaki Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients of different ages and develop through different genetic pathways. Our recent population-based study in the Canton of Zürich, Switzerland, shows that primary glioblastomas develop in older patients (mean age, 62 years) and typically show LOH on chromosome 10q (69%) and other genetic alterations (EGFR amplification, TP53 mutations, p16INK4a deletion, and PTEN mutations) at frequencies of 24,34%. Secondary glioblastomas develop in younger patients (mean, 45 years) and frequently show TP53 mutations (65%) and LOH 10q (63%). Common to both primary and secondary glioblastoma is LOH on 10q, distal to the PTEN locus; a putative suppressor gene at 10q25-qter may be responsible for the glioblastoma phenotype. Of the TP53 point mutations in secondary glioblastomas, 57% were located in hotspot codons 248 and 273, while in primary glioblastomas, mutations were more widely distributed. Furthermore, G:C,A:T mutations at CpG sites were more frequent in secondary than in primary glioblastomas (56% vs 30%). These data suggest that the TP53 mutations in these glioblastoma subtypes arise through different mechanisms. There is evidence that G:C,A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in low-grade astrocytomas with promoter methylation of the O6 -methylguanine-DNA methyltransferase (MGMT) gene than in those without methylation. This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of, G:C,A:T, transitions, at, CpG, sites),, involvement of alkylating agents that produce O6 -methylguanine or related adducts recognized by MGMT cannot be excluded in the pathway leading to secondary glioblastomas. [source] Genetic Analysis of ele Mutants and Comparative Mapping of ele1 Locus in the Control of Organ Internal Asymmetry in Garden PeaJOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 6 2010Xin Li Previous study has shown that during zygomorphic development in garden pea (Pisum sativum L.), the organ internal (IN) asymmetry of lateral and ventral petals was regulated by a genetic locus, SYMMETRIC PETAL 1 (SYP1), while the dorsoventral (DV) asymmetry was determined by two CYC - like TCP genes or the PsCYC genes, KEELED WINGS (K) and LOBED STANDARD 1 (LST1). In this study, two novel loci, ELEPHANT EAR-LIKE LEAF 1 (ELE1) and ELE2 were characterized. These mutants exhibit a similar defect of IN asymmetry as syp1 in lateral and ventral petals, but also display pleiotropic effects of enlarged organ size. Genetic analysis showed that ELE1 and ELE2 were involved in same genetic pathway and the enlarged size of petals but not compound leaves in ele2 was suppressed by introducing k and lst1, indicating that the enlargement of dorsal petal in ele2 requires the activities of K and LST1. An experimental framework of comparative genomic mapping approach was set up to map and clone LjELE1 locus in Lotus japonicus. Cloning the ELE1 gene will shed light on the underlying molecular mechanism during zygomorphic development and further provide the molecular basis for genetic improvement on legume crops. [source] Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entityTHE JOURNAL OF PATHOLOGY, Issue 1 2005Jorge S Reis-Filho Abstract Immunohistochemical analysis of E-cadherin has changed the way lobular neoplasia is perceived. It has helped to classify difficult cases of carcinoma in situ with indeterminate features and led to the identification of new variants of lobular carcinoma. Pleomorphic lobular carcinoma (PLC) and pleomorphic lobular carcinoma in situ (PLCIS), recently described variants of invasive and in situ classic lobular carcinoma, are reported to be associated with more aggressive clinical behaviour. Although PLC/PLCIS show morphological features of classic lobular neoplasia and lack E-cadherin expression, it is still unclear whether these lesions evolve through the same genetic pathway as lobular carcinomas or are high-grade ductal neoplasms that have lost E-cadherin. Here we have analysed a case of extensive PLCIS and invasive PLC associated with areas of E-cadherin-negative carcinoma in situ with indeterminate features, using immunohistochemistry, chromogenic in situ hybridization, high-resolution comparative genomic hybridization (CGH) and array-based CGH. We observed that all lesions lacked E-cadherin and ,-catenin and showed gain of 1q and loss of 16q, features that are typical of lobular carcinomas but are not seen in high-grade ductal lesions. In addition, amplifications of c-myc and HER2 were detected in the pleomorphic components, which may account for the high-grade features in this case and the reported aggressive clinical behaviour of these lesions. Taken together, these data suggest that at least some PLCs may evolve from the same precursor or through the same genetic pathway as classic lobular carcinomas. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Gene activation cascade triggered by a single photoperiodic cycle inducing flowering in Sinapis albaTHE PLANT JOURNAL, Issue 6 2009Maria D'Aloia Summary Molecular genetic analyses in Arabidopsis disclosed a genetic pathway whereby flowering is induced by the photoperiod. This cascade is examined here within the time course of floral transition in the long-day (LD) plant Sinapis alba induced by a single photoperiodic cycle. In addition to previously available sequences, the cloning of CONSTANS (SaCO) and FLOWERING LOCUS T (SaFT) homologues allowed expression analyses to be performed to follow the flowering process step by step. A diurnal rhythm in SaCO expression in the leaves was observed and transcripts of SaFT were detected when light was given in phase with SaCO kinetics only. This occurred when day length was extended or when a short day was shifted towards a ,photophile phase'. The steady-state level of SaFT transcripts in the various physiological situations examined was found to correlate like a rheostat with floral induction strength. Kinetics of SaFT activation were also consistent with previous estimations of translocation of florigen out of leaves, which could actually occur after the inductive cycle. In response to one 22-h LD, initiation of floral meristems by the shoot apical meristem (SAM) started about 2 days after activation of SaFT and was marked by expression of APETALA1 (SaAP1). Meanwhile, LEAFY (SaLFY) was first up-regulated in leaf primordia and in the SAM. FRUITFULL (SaFUL) was later activated in the whole SAM but excluded from floral meristems. These patterns are integrated with previous observations concerning upregulation of SUPPRESSOR OF OVEREXPRESSION OF CO1 (SaSOC1) to provide a temporal and spatial map of floral transition in Sinapis. [source] Congenital Cardiovascular Disease in Turner SyndromeCONGENITAL HEART DISEASE, Issue 1 2008Carolyn A. Bondy MD ABSTRACT Turner syndrome (TS), or monosomy X, occurs in ,1/2000 live born females. Intelligence is normal and short stature is the most obvious and consistent feature of the syndrome. Congenital cardiovascular disease affects ,50% of individuals and is the major cause of premature mortality in adults. Unfortunately, this most important aspect of the syndrome has received little attention outside of pediatric medicine, and adult cardiological follow-up is seriously lacking. This review describes the spectrum of cardiovascular defects with particular attention to identifying risk factors for aortic dissection/rupture. X-chromosome genetic pathways implicated in Turner cardiovascular disease, including premature coronary artery disease, are discussed. Recent guidelines for diagnosis and treatment of girls and women with TS are reviewed. [source] An automated in situ hybridization screen in the medaka to identify unknown neural genesDEVELOPMENTAL DYNAMICS, Issue 3 2005Carole Deyts Abstract Despite the fact that a large body of factors that play important roles in development are known, there are still large gaps in understanding the genetic pathways that govern these processes. To find previously unknown genes that are expressed during embryonic development, we optimized and performed an automated whole-mount in situ hybridization screen on medaka embryos at the end of somitogenesis. Partial cDNA sequences were compared against public databases and identified according to similarities found to other genes and gene products. Among 321 isolated genes showing specific expression in the central nervous system in at least one of five stages of development, 55.14% represented genes whose functions are already documented (in fish or other model organisms). Additionally, 16.51% were identified as conserved unknown genes or genes with unknown function. We provide new data on eight of these genes that presented a restricted expression pattern that allowed for formulating testable hypotheses on their developmental roles, and that were homologous to mammalian molecules of unknown function. Thus, gene expression screening in medaka is an efficient tool for isolating new regulators of embryonic development, and can complement genome-sequencing projects that are producing a high number of genes without ascribed functions. Developmental Dynamics 234:698,708, 2005. © 2005 Wiley-Liss, Inc. [source] From genomes to morphology: a view from amphioxusACTA ZOOLOGICA, Issue 1 2010Peter W. H. Holland Abstract Holland, P.W.H. 2010. From genomes to morphology: a view from amphioxus. ,Acta Zoologica (Stockholm) 91: 81,86 As complete genome sequences are determined from an ever-increasing number of animal species, new opportunities are arising for comparative biology. For zoologists interested in the evolution of shape and form, however, there is a problem. The link between genome sequence and morphology is not direct and is obfuscated by complex and evolving genetic pathways, even when conserved regulatory genes are considered. Nonetheless, a large-scale comparison of genome sequences between extant chordates reveals an intriguing parallel between genotypic and phenotypic evolution. Tunicates have highly altered genomes, with loss of ancestral genes and shuffled genetic arrangements, while vertebrate genomes are also derived through gene loss and genome duplication. The recently sequenced amphioxus genome, in contrast, reveals much greater stasis on the cephalochordate lineage, in parallel to a less derived body plan. The opportunities and challenges for relating genome evolution to morphological evolution are discussed. [source] Genome profiles of familial/bilateral and sporadic testicular germ cell tumorsGENES, CHROMOSOMES AND CANCER, Issue 2 2002Sigrid Marie Kraggerud In order to investigate the genetics of testicular germ cell tumors (TGCTs), we examined 33 TGCTs, including 15 familial/bilateral and 18 sporadic tumors, using comparative genomic hybridization. The frequencies of the histological subtypes were comparable between the two groups. Gains of the whole or parts of chromosome 12 were found in 30 tumors (91%). Furthermore, increased copy number of the whole or parts of chromosomes 7, 8, 17, and X, and decreased copy number of the whole or parts of chromosomes 4, 11, 13, and 18 were observed in ,50% of the tumors. Sixteen smallest regions of overlapping changes were delineated on 12 different chromosomes. The chromosomal copy numbers of familial/bilateral and sporadic TGCTs were comparable, suggesting similar genetic pathways to disease in both groups. However, significant differences were observed between the two main histological subgroups. Gains from 15q and 22q were associated with seminomas (P = 0.005 and P = 0.02, respectively), whereas gain of the proximal 17q (17q11.2,21) and high-level amplification from chromosome arm 12p, and losses from 10q were associated with nonseminomas (P < 0.001, P = 0.04, and P = 0.03, respectively). © 2002 Wiley-Liss, Inc. [source] Cutaneous type adult T-cell leukemia/lymphoma is a characteristic subtype and includes erythema/papule and nodule/tumor subgroupsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2010Tomoko Miyata Abstract We first analyzed the genomic profile of cutaneous type adult T-cell leukemia/lymphoma (ATLL) in an attempt to clarify its clinical and biological characteristics. Genomic gains of 1p, 7q and 18q and loss of 13q were frequently detected. Gain of 1p36.33-32 or loss of 13q33.1-3 indicated poor prognosis. Among cases with generalized lesions, erythema/papule or nodule/tumor cases showed a distinct genomic profile, indicating that these 2 groups were biologically different and developed via different genetic pathways. Furthermore, cases with generalized nodule/tumor lesions tended to progress to aggressive ATLL. [source] A multimodal, multidimensional atlas of the C57BL/6J mouse brainJOURNAL OF ANATOMY, Issue 2 2004Allan MacKenzie-Graham Abstract Strains of mice, through breeding or the disruption of normal genetic pathways, are widely used to model human diseases. Atlases are an invaluable aid in understanding the impact of such manipulations by providing a standard for comparison. We have developed a digital atlas of the adult C57BL/6J mouse brain as a comprehensive framework for storing and accessing the myriad types of information about the mouse brain. Our implementation was constructed using several different imaging techniques: magnetic resonance microscopy, blockface imaging, classical histology and immunohistochemistry. Along with raw and annotated images, it contains database management systems and a set of tools for comparing information from different techniques. The framework allows facile correlation of results from different animals, investigators or laboratories by establishing a canonical representation of the mouse brain and providing the tools for the insertion of independent data into the same space as the atlas. This tool will aid in managing the increasingly complex and voluminous amounts of information about the mammalian brain. It provides a framework that encompasses genetic information in the context of anatomical imaging and holds tremendous promise for producing new insights into the relationship between genotype and phenotype. We describe a suite of tools that enables the independent entry of other types of data, facile retrieval of information and straightforward display of images. Thus, the atlas becomes a framework for managing complex genetic and epigenetic information about the mouse brain. The atlas and associated tools may be accessed at http://www.loni.ucla.edu/MAP. [source] BRAF V599E Mutation is Not Age Dependent: It is Present in Common Melanocytic Nevi in Both Children and AdultsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 1 2005J. Cohen BRAF encodes a serine-threonine kinase, which acts in the RAS/RAF/MAPK pathway transducing regulatory signals from RAS to MEK1/2. Somatic mutations in BRAF have been identified in 53,80% of primary melanomas and 70,90% of common melanocytic nevi. More than 90% of these mutations consist of a valine to glutamate substitution at codon 599 (V599E) of exon 15. While a high prevalence of BRAF mutations in common melanocytic nevi has been reported in adults, nevi in children have not been studied. Of interest, we have previously shown that Spitz nevi in children do not harbor mutations in BRAF. To investigate the association of BRAF mutations with patient age, we studied common melanocytic nevi in children for the V599E activating mutation. Tumor cells were microdissected from 6 common melanocytic nevi in children 10 years of age or younger, and analyzed for the V599E mutation in BRAF by allele-specific PCR and gel electrophoresis. In 6 of 6 (100%) nevi, the V599E mutant allele was observed. Our data suggest that similar genetic pathways are involved in the development of common melanocytic nevi in children and adults. The absence of BRAF mutations in Spitz nevi in children is therefore associated with tumor type, not patient age. [source] Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegansAGING CELL, Issue 2 2009Eric L. Greer Summary Dietary restriction (DR) has the remarkable ability to extend lifespan and healthspan. A variety of DR regimens have been described in species ranging from yeast to mammals. However, whether different DR regimens extend lifespan via universal, distinct, or overlapping pathways is still an open question. Here we examine the genetic pathways that mediate longevity by different DR regimens in Caenorhabditis elegans. We have previously shown that the low-energy sensing AMP-activated protein kinase AMPK/aak-2 and the Forkhead transcription factor FoxO/daf-16 are necessary for longevity induced by a DR regimen that we developed (sDR). Here we find that AMPK and FoxO are necessary for longevity induced by another DR regimen, but are dispensable for the lifespan extension induced by two different DR methods. Intriguingly, AMPK is also necessary for the lifespan extension elicited by resveratrol, a natural polyphenol that mimics some aspects of DR. Conversely, we test if genes previously reported to mediate longevity by a variety of DR methods are necessary for sDR-induced longevity. Although clk-1, a gene involved in ubiquinone biosynthesis, is also required for sDR-induced lifespan extension, we find that four other genes (sir-2.1, FoxA/pha-4, skn-1, and hsf-1) are all dispensable for longevity induced by sDR. Consistent with the observation that different DR methods extend lifespan by mostly independent genetic mechanisms, we find that the effects on lifespan of two different DR regimens are additive. Understanding the genetic network by which different DR regimens extend lifespan has important implications for harnessing the full benefits of DR on lifespan and healthspan. [source] Shuttle craft: a candidate quantitative trait gene for Drosophila lifespanAGING CELL, Issue 5 2004Elena G. Pasyukova Summary Variation in longevity in natural populations is attributable to the segregation of multiple interacting loci, whose effects are sensitive to the environment. Although there has been considerable recent progress towards understanding the environmental factors and genetic pathways that regulate lifespan, little is known about the genes causing naturally occurring variation in longevity. Previously, we used deficiency complementation mapping to map two closely linked quantitative trait loci (QTL) causing female-specific variation in longevity between the Oregon (Ore) and 2b strains of Drosophila melanogaster to 35B9,C3 and 35C3 on the second chromosome. The 35B9,C3 QTL encompasses a 50-kb region including four genes, for one of which, shuttle craft (stc), mutations have been generated. The 35C3 QTL localizes to a 200-kb interval with 15 genes, including three genes for which mutations exist (reduced (rd), guftagu (gft) and ms(2)35Ci). Here, we report quantitative complementation tests to mutations at these four positional candidate genes, and show that ms(2)35Ci and stc are novel candidate quantitative trait genes affecting variation in Drosophila longevity. Complementation tests with stc alleles reveal sex- and allele-specific failure to complement, and complementation effects are dependent on the genetic background, indicating considerable epistasis for lifespan. In addition, a homozygous viable stc allele has a sex-specific effect on lifespan. stc encodes an RNA polymerase II transcription factor, and is an attractive candidate gene for the regulation of longevity and variation in longevity, because it is required for motoneuron development and is expressed throughout development. Quantitative genetic analysis of naturally occurring variants with subtle effects on lifespan can identify novel candidate genes and pathways important in the regulation of longevity. [source] Genetic Control of Acute Ethanol-Induced Behaviors in DrosophilaALCOHOLISM, Issue 8 2000Carol M. Singh Background: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol. Methods: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol-induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure. Results: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol-induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol-induced turning behavior. Conclusions: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently. [source] Genetic pathways to glioblastomasNEUROPATHOLOGY, Issue 1 2005Hiroko Ohgaki Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients of different ages and develop through different genetic pathways. Our recent population-based study in the Canton of Zürich, Switzerland, shows that primary glioblastomas develop in older patients (mean age, 62 years) and typically show LOH on chromosome 10q (69%) and other genetic alterations (EGFR amplification, TP53 mutations, p16INK4a deletion, and PTEN mutations) at frequencies of 24,34%. Secondary glioblastomas develop in younger patients (mean, 45 years) and frequently show TP53 mutations (65%) and LOH 10q (63%). Common to both primary and secondary glioblastoma is LOH on 10q, distal to the PTEN locus; a putative suppressor gene at 10q25-qter may be responsible for the glioblastoma phenotype. Of the TP53 point mutations in secondary glioblastomas, 57% were located in hotspot codons 248 and 273, while in primary glioblastomas, mutations were more widely distributed. Furthermore, G:C,A:T mutations at CpG sites were more frequent in secondary than in primary glioblastomas (56% vs 30%). These data suggest that the TP53 mutations in these glioblastoma subtypes arise through different mechanisms. There is evidence that G:C,A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in low-grade astrocytomas with promoter methylation of the O6 -methylguanine-DNA methyltransferase (MGMT) gene than in those without methylation. This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of, G:C,A:T, transitions, at, CpG, sites),, involvement of alkylating agents that produce O6 -methylguanine or related adducts recognized by MGMT cannot be excluded in the pathway leading to secondary glioblastomas. [source] Genetics of cardiovascular diseases: An overviewNURSING & HEALTH SCIENCES, Issue 2 2005Carmen T Ramirez edd, acnp(c), apn-g(c) Cardiovascular disease is the leading cause of illness and death in the USA, as well as other countries. Advances in genetics have led researchers to identified associations between a number of cardiac syndromes and diagnostic molecular findings. Therefore, a more precise understanding of the molecular pathways involved in cardiovascular diseases is clinically significant. Current literature suggests that while etiologies remain complex, a number of cardiovascular diseases can be linked to specific metabolic inheritable factors. A broad multifactorial model is gradually being replaced with disease specific models where independent genetic and/or teratogenic pathways may lead to a particular outcome. These genetic pathways include chromosome deletions, disruptions (translocations), duplications of particular genetic regions, point mutations involving single genes, or alteration in the ability for a gene to be transcribed into a functional protein. In this review the molecular mechanisms underlying cardiovascular diseases and their clinical manifestations will be explained. [source] A physiological overview of the genetics of flowering time controlPLANT BIOTECHNOLOGY JOURNAL, Issue 1 2005Georges Bernier Summary Physiological studies on flowering time control have shown that plants integrate several environmental signals. Predictable factors, such as day length and vernalization, are regarded as ,primary', but clearly interfere with, or can even be substituted by, less predictable factors. All plant parts participate in the sensing of these interacting factors. In the case of floral induction by photoperiod, long-distance signalling is known to occur between the leaves and the shoot apical meristem (SAM) via the phloem. In the long-day plant, Sinapis alba, this long-distance signalling has also been shown to involve the root system and to include sucrose, nitrate, glutamine and cytokinins, but not gibberellins. In Arabidopsis thaliana, a number of genetic pathways controlling flowering time have been identified. Models now extend beyond ,primary' controlling factors and show an ever-increasing number of cross-talks between pathways triggered or influenced by various environmental factors and hormones (mainly gibberellins). Most of the genes involved are preferentially expressed in meristems (the SAM and the root tip), but, surprisingly, only a few are expressed preferentially or exclusively in leaves. However, long-distance signalling from leaves to SAM has been shown to occur in Arabidopsis during the induction of flowering by long days. In this review, we propose a model integrating physiological data and genes activated by the photoperiodic pathway controlling flowering time in early-flowering accessions of Arabidopsis. This model involves metabolites, hormones and gene products interacting as long- or short-distance signalling molecules. [source] Distribution of corticotropin-releasing hormone in the developing zebrafish brainTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 4 2007Gayathri Chandrasekar Abstract Corticotropin-releasing hormone (CRH) plays a central role in the physiological regulation of the hypothalamus-pituitary-adrenal/interrenal axis mediating endocrine, behavioral, autonomic, and immune responses to stress. Despite the wealth of knowledge about the physiological roles of CRH, the genetic mechanisms by which CRH neurons arise during development are poorly understood. As a first step toward analyzing the molecular and genetic pathways involved in CRH lineage specification, we describe the developmental distribution of CRH neurons in the embryonic zebrafish, a model organism for functional genomics and developmental biology. We searched available zebrafish expressed sequence tag (EST) databases for CRH-like sequences and identified one EST that contained the complete zebrafish CRH open reading frame (ORF). The CRH precursor sequence contained a signal peptide, the CRH peptide, and a cryptic peptide with a conserved sequence motif. RT-PCR analysis showed crh expression in a wide range of adult tissues as well as during embryonic and larval stages. By whole-mount in situ hybridization histochemistry, discrete crh -expressing cell clusters were found in different parts of the embryonic zebrafish brain, including telencephalon, preoptic region, hypothalamus, posterior tuberculum, thalamus, epiphysis, midbrain tegmentum, and rostral hindbrain and in the neural retina. The localization of crh mRNA within the preoptic region is consistent with the central role of CRH in the teleost stress response through activation of the hypothalamic-pituitary-interrenal axis. The widespread distribution of CRH-synthesizing cells outside the preoptic region suggests additional functions of CRH in the embryonic zebrafish brain. J. Comp. Neurol. 505:337,351, 2007. © 2007 Wiley-Liss, Inc. [source] Molecular characterization of the G,-globin-Tag transgenic mouse model of hormone refractory prostate cancer: Comparison to human prostate cancer,THE PROSTATE, Issue 6 2010Alfonso Calvo Abstract BACKGROUND Prostate cancer (PrCa) has a high incidence in Western countries and at present, there is no cure for hormone refractory prostate cancer. Transgenic mouse models have proven useful for understanding mechanisms of prostate carcinogenesis. The characterization of genetically modified mouse PrCa models using high-throughput genomic analyses provides important information to guide appropriate experiment applications for such model. METHODS We have analyzed the transcriptome of the hormone refractory and highly metastatic Fetal Globin-SV40/T-antigen (G,-globin-Tag) transgenic mouse model for PrCa compared to normal mouse prostate tissue. Gene expression patterns found in G,-globin-Tag mouse prostate tumors were compared with publicly available human localized and metastatic prostate tumors (GEO accession # GSE3325) through hierarchical cluster analysis, Pearson's rank correlation coefficient, and Self Organizing Feature Maps (SOM) analyses. RESULTS G,-globin-Tag tumors clustered closely with human metastatic tumors and gene expression patterns had a significant correlation (P,<,0.01), unlike human localized primary tumors (P,>,0.6). Bioinformatic analyses identified deregulated genetic pathways and networks in G,-globin-Tag tumors, which displayed similarities to alterations in human PrCa. Changes in the expression of genes involved in DNA replication and repair (Rb1, p53, Myc, PCNA, DNMT3A) and growth factor signaling pathways (TGF,2, ERK1/2, NRas, and Notch1) are deregulated in the G,-globin-Tag tumors, suggesting their key role in the oncogenic process. Identification of an enrichment of putative binding sites for transcription factors revealed eight transcription factors that may be important in G,-globin-Tag carcinogenesis, including SP1, NF-Y, CREB, Elk1, and E2F. Novel genes related to microtubule regulation were also identified in G,-globin-Tag tumors as potentially important candidate targets for PrCa. Overexpression of stathmin-1, whose expression was increased in human metastatic prostate tumors, was validated in G,-globin-Tag tumors by immunohistochemistry. This protein belongs to the SV40/T-antigen cancer signature identified in previous studies in prostate, breast, and lung cancer mouse models. CONCLUSIONS Our results show that the G,-globin-Tag model for hormone refractory PrCa shares important features with aggressive, metastatic human PrCa. Given the role of stathmin-1 in the destabilization of microtubles and taxane resistance, the G,-globin-Tag model and other SV40/T-antigen driven transgenic models may be useful for testing potential therapies directed at stathmin-1 in human prostate tumors. Prostate 70: 630,645, 2010. Published 2010 Wiley-Liss, Inc. [source] A genome wide association study for QTL affecting direct and maternal effects of stillbirth and dystocia in cattleANIMAL GENETICS, Issue 3 2010H. G. Olsen Summary Dystocia and stillbirth are significant causes of female and neonatal death in many species and there is evidence for a genetic component to both traits. Identifying causal mutations affecting these traits through genome wide association studies could reveal the genetic pathways involved and will be a step towards targeted interventions. Norwegian Red cattle are an ideal model breed for such studies as very large numbers of records are available. We conducted a genome wide association study for direct and maternal effects of dystocia and stillbirth using almost 1 million records of these traits. Genotyping costs were minimized by genotyping the sires of the recorded cows, and using daughter averages as phenotypes. A dense marker map containing 17 343 single nucleotide polymorphisms covering all autosomal chromosomes was utilized. The genotyped sires were assigned to one of two groups in an attempt to ensure independence between the groups. Associations were only considered validated if they occurred in both groups. Strong associations were found and validated on chromosomes 4, 5, 6, 9, 12, 20, 22 and 28. The QTL region on chromosome 6 was refined using LDLA analysis. The results showed that this chromosome most probably contains two QTL for direct effect on dystocia and one for direct effect on stillbirth. Several candidate genes may be identified close to these QTL. Of these, a cluster of genes expected to affect bone and cartilage formation (i.e. SPP1, IBSP and MEPE) are of particular interest and we suggest that these genes are screened in candidate gene studies for dystocia and stillbirth in cattle as well as other species. [source] Baculovirus P35 protein: An overview of its applications across multiple therapeutic and biotechnological arenasBIOTECHNOLOGY PROGRESS, Issue 2 2010Sudhir Sahdev Abstract Baculovirus immediate early P35 protein is well known for its anti-apoptotic as well as anti-oxidant properties. Mechanism of action of P35 involves inhibition of a vast range of initiator to executioner class of caspases. In addition, P35's role in inhibiting oxidant-induced mitochondrial damage, primarily in the apoptotic pathway, has also been extensively investigated. Elucidation of P35's functions during regulation of programmed cell death (PCD) has led to a renewed focus on exploiting this basic knowledge for clinical and other related applications. This review outlines specific biochemical and genetic pathways where P35 intervenes and regulates rate-limiting steps in the apoptotic signaling cascade. Research efforts are underway to utilize P35 as an agent in regulating apoptosis and under certain circumstances, also explore the therapeutic potential of its anti-oxidant features. One of the major outcomes of recent studies include significantly improved effectiveness of cytochrome P450 directed enzyme pro-drug delivery tools when used in conjunction with P35, which may help in alleviating drug resistance in tumor cells and simultaneously prolonging the cytotoxic effects of anti-cancer drugs. Moreover, applied research carried out recently in the fields of diabetes, ischemia-induced neuronal cell death, experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), inflammatory arthritis, cardiovascular and ocular disorders illustrate P35's utilization across diverse therapeutic areas and will certainly make it an attractive biomolecule for the discovery research. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] DATE analysis: A general theory of biological change applied to microarray dataBIOTECHNOLOGY PROGRESS, Issue 5 2009David Rasnick Abstract In contrast to conventional data mining, which searches for specific subsets of genes (extensive variables) to correlate with specific phenotypes, DATE analysis correlates intensive state variables calculated from the same datasets. At the heart of DATE analysis are two biological equations of state not dependent on genetic pathways. This result distinguishes DATE analysis from other bioinformatics approaches. The dimensionless state variable F quantifies the relative overall cellular activity of test cells compared to well-chosen reference cells. The variable ,i is the fold-change in the expression of the ith gene of test cells relative to reference. It is the fraction , of the genome undergoing differential expression,not the magnitude ,,that controls biological change. The state variable , is equivalent to the control strength of metabolic control analysis. For tractability, DATE analysis assumes a linear system of enzyme-connected networks and exploits the small average contribution of each cellular component. This approach was validated by reproducible values of the state variables F, RNA index, and , calculated from random subsets of transcript microarray data. Using published microarray data, F, RNA index, and , were correlated with: (1) the blood-feeding cycle of the malaria parasite, (2) embryonic development of the fruit fly, (3) temperature adaptation of Killifish, (4) exponential growth of cultured S. pneumoniae, and (5) human cancers. DATE analysis was applied to aCGH data from the great apes. A good example of the power of DATE analysis is its application to genomically unstable cancers, which have been refractory to data mining strategies. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source] Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: An overview of the current conceptsBIRTH DEFECTS RESEARCH, Issue 9 2009Janine F. Felix Abstract Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) are severe congenital anomalies. Although recent years have brought significant improvement in clinical treatment, our understanding of the etiology of these defects is lagging. Many genes and genetic pathways have been implicated in the development of EA/TEF, but only a few genes have been shown to be involved in humans, in animals, or in both. Extrapolating data from animal models to humans is not always straightforward. Environmental factors may also carry a risk, but the mechanisms are yet to be elucidated. This review gives an overview of the current state of knowledge about both genetic and environmental risk factors in the etiology of EA/TEF. Birth Defects Research (Part A) 2009. © 2009 Wiley-Liss, Inc. [source] Diversity of genome profiles in malignant lymphomaCANCER SCIENCE, Issue 3 2010Masao Seto (Cancer Sci 2010; 101: 573,578) Characteristic chromosome translocations are associated with specific disease entities, and are known to play a pivotal role in lymphoma development. Chromosome translocation alone, however, is not sufficient to produce tumors. Factors including the microenvironment and epigenetic and genetic alterations other than chromosome translocations have been shown to play a role in lymphoma development. Follicular lymphoma cells proliferate in close contact with follicular dendritic cells. Mucosa-associated lymphoid tissue (MALT) lymphoma cells proliferate at the marginal zone area of reactive follicles which are formed by preceding chronic inflammation. The importance of genetic alterations other than chromosome translocation has been recognized since the introduction of array comparative genomic hybridization (array CGH). Variations in the genomic profile among patients with the same disease entity have been found by array CGH analyses. These variations indicate that multiple genetic pathways leading to the development of lymphomas may exist and hence result in the variable clinicopathological features observed. [source] Genetic alterations and signaling pathways in the evolution of gliomasCANCER SCIENCE, Issue 12 2009Hiroko Ohgaki Gliomas are the most common primary brain tumors. They account for more than 70% of all neoplasms of the central nervous system and vary considerably in morphology, location, genetic alterations, and response to therapy. Most frequent and malignant are glioblastomas. The vast majority (>90%) develops rapidly after a short clinical history and without evidence of a less malignant precursor lesion (primary or de novo glioblastoma). Secondary glioblastomas develop more slowly through progression from low-grade or anaplastic astrocytoma. These glioblastoma subtypes constitute distinct disease entities that affect patients of different age, develop through distinct genetic pathways, show different RNA and protein expression profiles, and may differ in their response to radio- and chemotherapy. Recently, isocitrate dehydrogenase 1 (IDH1) mutations have been identified as a very early and frequent genetic alteration in the pathway to secondary glioblastomas as well as that in oligodendroglial tumors, providing the first evidence that low-grade astrocytomas and oligodendrogliomas may share common cells of origin. In contrast, primary glioblastomas very rarely contain IDH1 mutations, suggesting that primary and secondary glioblastomas may originate from different progenitor cells, despite the fact that they are histologically largely indistinguishable. In this review, we summarize the current status of genetic alterations and signaling pathways operative in the evolution of astrocytic and oligodendroglial tumors. (Cancer Sci 2009; 100 2235,2241) [source] Isolation of Differentiated Squamous and Undifferentiated Spindle Carcinoma Cell Lines with Differing Metastatic Potential from a 4-Nitroquinoline N-Oxide-induced Tongue Carcinoma in a F344 RatCANCER SCIENCE, Issue 12 2000Shinichi Takeuchi One differentiated squamous cell carcinoma (SCC) cell line (RSC3-E2) and two undifferentiated tumor cell lines (RSC3-LM and RSC3-E2R) with different metastatic potential were established from a 4-nitroquinoline N-oxide (4NQO)-induced differentiated SCC in F344 rat tongue. The RSC3-E2 subline was isolated from a parental cell line (RSC3-P) by single cell cloning in vitro, whereas the RSC3-LM subline was isolated from a lung metastatic focus after subcutaneous (s.c.) injection of RSC3-P cells. The RSC3-E2R cell line was isolated from a lung metastatic focus following s.c. injection of RSC3-E2 cells after X-irradiation in vitro. The RSC3-E2 cell line is keratinpositive and grows as a keratinizing tumor in nude mice, whereas RSC3-LM and RSC3-E2R cells are keratin-negative, vimentin-positive and form undifferentiated tumors. When s.c. injected into nude mice, the RSC3-E2 cell line proved to be non-metastatic, while the RSC3-LM cell line was metastatic by both hematogenous and lymphogenous routes, and the RSC3-E2R cell line was metastatic only hematogenously. In vitro relative growth rates and in vitro invasion activity of these cell lines were in the order RSC3-LM>RSC3-E2R>RSC3-E2. Chromosome analysis revealed two peaks with modal chromosome numbers of 83 and 78 for RSC3-P cells and single peaks at 83, 78 and 56 for RSC3-LM, RSC3-E2 and RSC3-E2R cell lines, respectively. Common structural abnormalities on chromosome 11 were shared by all cell lines. Mutation analysis of the p53 gene using a yeast functional assay demonstrated RSC3-LM cell line to have a point mutation at codon 269, whereas RSC3-E2 and RSC3-E2R had double mutations at codons 106 and 170 on each allele. These results suggest that the two undifferentiated RSC3-LM and RSC3-E2R tumor cell lines with different metastatic potential were generated from differentiated SCC cells via different genetic pathways as a consequence of tumor progression in vivo and in vitro, respectively. These cell lines should provide a useful model for understanding mechanisms of hematogenous and lymphogenous metastasis, as well as tumor progression of oral SCCs. [source] | |||||||||||||