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Aberrant
Terms modified by Aberrant Selected AbstractsGenomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosisHISTOPATHOLOGY, Issue 6 2010Maria S Tretiakova Tretiakova M S, Shabani-Rad M T, Guggisberg K, Hart J, Anders R A & Gao Z-h (2010) Histopathology,56, 683,693 Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis Aims:, To compare the expression of genes involved in p53, Wnt/,-catenin, and retinoblastoma (Rb) 1 pathways between cirrhosis-associated hepatocellular carcinoma (HCC-C) and hepatocellular carcinoma arising in non-cirrhotic liver (HCC-NC). Methods and results:, The gene expression profile was analysed using oligo-DNA arrays, and then validated at protein level in a tissue microarray using immunohistochemistry. Compared with their background non-neoplastic liver tissue, HCC-C showed a significantly higher rate of p53, ,-catenin (protein only) and cyclin D1 expression, whereas HCC-NC showed a significantly higher rate of p21Waf1/cip1 and p27Kip1 expression. HCC-C had a significantly higher rate of p53 expression and a significantly lower rate of p21waf1/cip1 expression than HCC-NC. There was no statistically significant association between the expression of genetic markers and tumour histological grade, underlying aetiology, or lymphovascular invasion. Aberrant ,-catenin expression was more commonly seen in single tumours in comparison with multiple tumours. Increased p16INK4 and p21waf1/cip1 expression was more commonly observed in large-sized tumours (>50 mm) than small-sized tumours. Conclusions:, Alteration of the p53 pathway plays a more important role in the pathogenesis of HCC-C, whereas alterations in cell cycle regulators p21waf1/cip1 and p27Kip1 play a more important role in the pathogenesis of HCC-NC. [source] Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activityINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Katharine H. Wrighton Abstract The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S- and G2 arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity. © 2004 Wiley-Liss, Inc. [source] Prognostic significance of ,-catenin and topoisomerase II, in de novo acute myeloid leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2009Chih-Cheng Chen The Wnt/,-catenin signaling is important for controlling self-renewal of hematopoietic stem cells and its constitutive activation has recently been documented in a significant proportion of acute myeloid leukemia (AML) cases. Topoisomerase II, (Topo II,) is a marker of cell proliferation and a crucial target for anthracycline cytotoxicity, the mainstay of management employed in AML. We retrospectively investigated the prognostic roles of ,-catenin and topo II, in a cohort of 59 patients with newly diagnosed AML by immunohistochemistry. Aberrant ,-catenin expression was demonstrated in 13 patients (22%), and it was more likely to occur in those with unfavorable karyotypes. Advanced age and poor performance status adversely influenced the achievement of complete remission, while neither aberrant ,-catenin expression nor enhanced topo II, activity did. On multivariate survival analysis, four factors independently predicted a shortened overall survival: aberrant ,-catenin expression, high topo II, activity, poor-risk cytogenetics, and presence of at least one comorbidity factor. Our results suggest that both ,-catenin and topo II, independently predicted an adverse prognosis and might serve as new markers for risk stratification in AML patients. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Myosin-mediated cytoskeleton contraction and Rho GTPases regulate laminin-5 matrix assemblyCYTOSKELETON, Issue 2 2004Gregory W. deHart Abstract Laminin-5 is a major structural element of epithelial tissue basement membranes. In the matrix of cultured epithelial cells, laminin-5 is arranged into intricate patterns. Here we tested a hypothesis that myosin II-mediated actin contraction is necessary for the proper assembly of a laminin-5 matrix by cultured SCC12 epithelial cells. To do so, the cells were treated with ML-7, a myosin II light chain kinase inhibitor, or Y-27632, an inhibitor of Rho-kinase (ROCK), both of which block actomyosin contraction. Under these conditions, laminin-5 shows an aberrant localization in dense patches at the cell periphery. Since ROCK activity is regulated by the small GTPase Rho, this suggests that members of the Rho family of GTPases may also be important for laminin-5 matrix assembly by SCC12 cells. We confirmed this hypothesis since SCC12 cells expressing mutant proteins that inhibit RhoA, Rac, and Cdc42 assemble the same aberrant laminin-5 protein arrays as drug-treated cells. We have also evaluated the organization of the laminin-5 receptors ,3,1 and ,6,4 integrin and hemidesmosome proteins in ML-7- and Y-27632-treated cells or in cells in which RhoA, Rac, and Cdc42 activity were inhibited. In all instances, ,3,1 and ,6,4 integrin heterodimers, as well as hemidesmosome proteins, localize precisely with laminin-5 in the matrix of the cells. In summary, our results provide evidence that myosin II-mediated actin contraction and the activity of Rho GTPases are necessary for the proper organization of a laminin-5 matrix and localization of hemidesmosome protein arrays in epithelial cells. Cell Motil. Cytoskeleton 57:107,117, 2004. © 2004 Wiley-Liss, Inc. [source] The neuroanatomy and neuroendocrinology of fragile X syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2004David Hessl Abstract Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene,brain,behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic,pituitary,adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population. MRDD Research Reviews 2004;10:17,24. © 2004 Wiley-Liss, Inc. [source] New reproductive anomalies in fruitless -mutant Drosophila males: Extreme lengthening of mating durations and infertility correlated with defective serotonergic innervation of reproductive organsDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2001Gyunghee Lee Abstract Several features of male reproductive behavior are under the neural control of fruitless (fru) in Drosophila melanogaster. This gene is known to influence courtship steps prior to mating, due to the absence of attempted copulation in the behavioral repertoire of most types of fru -mutant males. However, certain combinations of fru mutations allow for fertility. By analyzing such matings and their consequences, we uncovered two striking defects: mating times up to four times the normal average duration of copulation; and frequent infertility, regardless of the time of mating by a given transheterozygous fru -mutant male. The lengthened copulation times may be connected with fru -induced defects in the formation of a male-specific abdominal muscle. Production of sperm and certain seminal fluid proteins are normal in these fru mutants. However, analysis of postmating qualities of females that copulated with transheterozygous mutants strongly implied defects in the ability of these males to transfer sperm and seminal fluids. Such abnormalities may be associated with certain serotonergic neurons in the abdominal ganglion in which production of 5HT is regulated by fru. These cells send processes to contractile muscles of the male's internal sex organs; such projection patterns are aberrant in the semifertile fru mutants. Therefore, the reproductive functions regulated by fruitless are expanded in their scope, encompassing not only the earliest stages of courtship behavior along with almost all subsequent steps in the behavioral sequence, but also more than one component of the culminating events. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 121,149, 2001 [source] Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivoENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2001Cynthia R. Giver Abstract Accumulation of genetic damage in long-lived cell populations with proliferative capacity is implicated in tumorigenesis. Hematopoietic stem cells (hsc) maintain lifetime hematopoiesis, and recent studies demonstrate that hsc in leukemic patients are cytogenetically aberrant. We postulated that exposure to agents associated with increased leukemia risk would induce genomic changes in cells in the hsc compartment. Aneusomy involving chromosomes 2 and 11 in sorted hsc (Lin,c-kit+Sca-1+) and maturing lymphoid and myeloid cells from mice that received topical doses of benzene (bz) or trichloroethylene (TCE) was quantified using fluorescence in situ hybridization. Six days after bz or TCE exposure, aneuploid cells in the hsc compartment increase four- to eightfold in a dose- and schedule-independent manner. Aneuploid lymphoid and myeloid cells from bz- and TCE-treated mice approximate controls, except after repeated benzene exposures. Aneuploid cells are more frequent in the hsc compartment than in mature hematopoietic subpopulations. Hematotoxicity was also quantified in bz- and TCE-exposed hematopoietic subpopulations using two colony-forming assays: CFU-GM (colony-forming units/granulocyte-macrophage progenitors) and CAFC (cobblestone area,forming cells). Data indicate that bz is transiently cytotoxic (,1 week) to hsc subpopulations, and induces more persistent toxicity (>2 weeks) in maturing, committed progenitor subpopulations. TCE is not hematotoxic at the doses applied. In conclusion, we provide direct evidence for induction of aneuploidy in cells in the hsc compartment by topical exposure to bz and TCE. Disruption of genomic integrity and/or toxicity in hsc subpopulations may be one step in leukemic progression. Environ. Mol. Mutagen. 37:185,194, 2001. © 2001 Wiley-Liss, Inc. [source] Distribution and Initiation of Seizure Activity in a Rat Brain with Subcortical Band HeterotopiaEPILEPSIA, Issue 5 2000Zong-Fu Chen Summary: Purpose: Misplaced (heterotopic) cortical neurons are a common feature of developmental epilepsies. To better understand seizure disorders associated with cortical heterotopia, the sites of aberrant discharge activity were investigated in vivo and in vitro in a seizure-prone mutant rat (tish) exhibiting subcortical band heterotopia. Methods: Depth electrode recordings and postmortem assessment of regional c- fos mRNA levels were used to characterize the distribution of aberrant discharge activity during spontaneous seizures in vivo. Electrophysiologic recordings of spontaneous and evoked activity also were performed by using in vitro brain slices from the tish rat treated with proconvulsant drugs (penicillin and 4-aminopyridine). Results: Depth electrode recordings demonstrate that seizure activity begins almost simultaneously in the normotopic and heterotopic areas of the tish neocortex. Spontaneous seizures induce c- fos mRNA in normotopic and heterotopic neocortical areas, and limbic regions. The threshold concentrations of proconvulsant drugs for inducing epileptiform spiking were similar in the normotopic and heterotopic areas of tish brain slices. Manipulations that blocked communication between the normotopic and heterotopic areas of the cortex inhibited spiking in the heterotopic, but not the normotopic, area of the cortex. Conclusions: These findings indicate that aberrant discharge activity occurs in normotopic and heterotopic areas of the neocortex, and in certain limbic regions during spontaneous seizures in the tish rat. Normotopic neurons are more prone to exhibit epileptiform activity than are heterotopic neurons in the tish cortex, and heterotopic neurons are recruited into spiking by activity initiated in normotopic neurons. The findings indicate that seizures in the tish brain primarily involve telencephalic structures, and suggest that normotopic neurons are responsible for initiating seizures in the dysplastic neocortex. [source] Meiosis induced by inactivation of Pat1 kinase proceeds with aberrant nuclear positioning of centromeres in the fission yeast Schizosaccharomyces pombeGENES TO CELLS, Issue 8 2004Yuji Chikashige Nuclear organization of chromosomes proceeds with significant changes during meiosis. In the fission yeast Schizosaccharomyces pombe, centromeres are clustered at the spindle-pole body (SPB) during the mitotic cell cycle; however, during meiotic prophase telomeres become clustered to the SPB and centromeres dissociate from the SPB. We followed the movement of telomeres, centromeres and sister chromatids in living S. pombe cells that were induced to meiosis by inactivation of Pat1 kinase (a key negative regulator of meiosis). Time-course observation in living cells determined the temporal order of DNA synthesis, telomere clustering, centromere separation and meiotic chromosome segregation. When meiosis was induced by Pat1 inactivation at the G1 phase of mitosis, telomeres clustered to the SPB as per normal meiosis, but in most cells the centromeres remained partially associated with the SPB. When meiosis was initiated at the G2 phase by Pat1 inactivation, both telomeres and centromeres retained their mitotic nuclear positions in the majority of cells. These results indicate that the progression of meiosis induced by Pat1 inactivation is aberrant from normal meiosis in some events. As Pat1 inactivation is often useful to induce S. pombe cells synchronously into meiosis, the temporal order of chromosomal events determined here will provide landmarks for the progression of meiosis downstream the Pat1 inactivation. [source] Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1 - SLC12A1 fusion geneGENES, CHROMOSOMES AND CANCER, Issue 6 2010Linda B. C. Bralten We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5,-3, expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes. © 2010 Wiley-Liss, Inc. [source] Isotype class switching and the pathogenenesis of multiple myelomaHEMATOLOGICAL ONCOLOGY, Issue 2 2002J. A. L. Fenton Abstract Translocations at the immunoglobulin heavy chain locus (14q32) are now considered the commonest karyotypic change in multiple myeloma. These translocations are thought to be intimately involved in the pathogenesis of this disease. The heavy chain locus is strongly transcriptionally active in B and plasma cells and transfer of a potential oncogene to 14q32 would result in its dysregulation. Molecular characterization suggests that the majority of these breakpoints cluster in switch regions within the heavy chain locus. Switch regions are normally involved in the regulated process of isotype switching so that in myeloma the rearrangements are believed to be a result of so-called illegitimate (aberrant) switch recombination and are likely to be an early event in myeloma development. A legitimate switch recombination event occurs between two switch regions producing a hybrid switch; this is necessary for class switching to proceed on a productive allele. In this review we describe the process of isotype switching and how illegitimate class switching may be related to the pathogenesis of multiple myeloma. Copyright © 2001 John Wiley & Sons, Ltd. [source] Loss of input from the mossy cells blocks maturation of newly generated granule cellsHIPPOCAMPUS, Issue 7 2007Ana-Isabel Marqués-Marí Abstract The objective of this work is to check whether the input from the mossy cells to the inner molecular layer is necessary for the integration and maturation of the newly generated granule cells of the dentate gyrus (DG) in mice, and if after status epilepticus the sprouting of the mossy fibers can substitute for this projection. Newly generated cells were labeled by administration of 5-bromo-deoxyuridine either before or after pilocarpine administration. The neuronal loss in the hippocampus after administration of pilocarpine combined with scopolamine and diazepam seemed restricted to the hilar mossy cells. The maturation of the granule cells was studied using immunohistochemistry for calretinin and NeuN in combination with detection of 5-bromo-deoxyuridine. The sprouting of the mossy fibers was detected using Timm staining for zinc-rich boutons. In normal conditions, granule cells took about 2 weeks to lose the immature marker calretinin. After the loss of the mossy cells, newly generated granule cells remained expressing calretinin for more than a month, until the sprouting of the mossy fibers substituted for the projection of the mossy cells in the inner molecular layer of the DG. Therefore, a proper pattern of connectivity is necessary for the normal development and integration of newly generated granule cells in the adult brain. In a changed environment they cannot adapt transforming in other cell types; simply they are unable to mature. The sprouting of the mossy fibers, although aberrant and a probable source of epileptic activity, may be important for the correct physiology of the granule cells, restoring a likeness of normality in their connective environment. The survival of granule cells incorporated as mature neurons was increased after pilocarpine when compared with normal conditions. Thus, it is likely that the reorganization of the circuitry after the loss of the mossy cells facilitates the survival and incorporation of the newly generated granule cells. © 2007 Wiley-Liss, Inc. [source] Magnetoencephalographic gamma power reduction in patients with schizophrenia during resting conditionHUMAN BRAIN MAPPING, Issue 10 2009Lindsay Rutter Abstract Objective: The "default network" represents a baseline condition of brain function and is of interest in schizophrenia research because its component brain regions are believed to be aberrant in the disorder. We hypothesized that magnetoencephalographic (MEG) source localization analysis would reveal abnormal resting activity within particular frequency bands in schizophrenia. Experimental Design: Eyes-closed resting state MEG signals were collected for two comparison groups. Patients with schizophrenia (N = 38) were age-gender matched with healthy control subjects (N = 38), and with a group of unmedicated unaffected siblings of patients with schizophrenia (N = 38). To localize 3D-brain regional differences, synthetic aperture magnetometry was calculated across established frequency bands as follows: delta (0.9,4 Hz), theta (4,8 Hz), alpha (8,14 Hz), beta (14,30 Hz), gamma (30,80 Hz), and super-gamma (80,150 Hz). Principle Observations: Patients with schizophrenia showed significantly reduced activation in the gamma frequency band in the posterior region of the medial parietal cortex. As a group, unaffected siblings of schizophrenia patients also showed significantly reduced activation in the gamma bandwidth across similar brain regions. Moreover, using the significant region for the patients and examining the gamma band power gave an odds ratio of 6:1 for reductions of two standard deviations from the mean. This suggests that the measure might be the basis of an intermediate phenotype. Conclusions: MEG resting state analysis adds to the evidence that schizophrenic patients experience this condition very differently than healthy controls. Whether this baseline difference relates to network abnormalities remains to be seen. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [source] Phenotypic consequences of branch point substitutions,HUMAN MUTATION, Issue 8 2006Jana Královi Abstract The branch point sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders, but their phenotypic consequences have been difficult to predict, largely due to a highly degenerate nature of the BPS consensus. Here, we have examined the splicing pattern of nine reporter pre-mRNAs that have previously been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3, splice sites and also activated a cryptic 5, splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonical transcripts was lower for BP transitions than BP transversions. Differential splicing outcome for transitions vs. transversions was abrogated or reduced if introns were truncated to 200 nt or less, suggesting that the nature of the BP residue is less critical for interactions across very short introns. Together, these results improve prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggest that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in Mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing. Hum Mutat 27(8), 803,813, 2006. © 2006 WileyLiss, Inc. [source] Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell,macrophage lineageIMMUNOLOGICAL REVIEWS, Issue 1 2010R. Maarten Egeler Summary:, In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin+ DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research. [source] The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controlsINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 5 2009Frank H. Pierik Summary It is inconclusive whether the feedback mechanisms of the hypothalamus-pituitary-testis (HTP) axis are already established in the first 6 months of life, partly due to the dramatic changes in HPT-axis hormone levels over this period. Moreover, it is unclear whether these hormone levels are aberrant in boys with cryptorchidism or hypospadias, and therefore predictive for future fertility. We studied the regulation mechanisms of the HTP axis, and the effect of age, in boys 1,6 months of age. Secondly, we studied testicular function - as reflected by HPT hormones - in newborns with cryptorchidism or hypospadias. Sera from a population sample of infants with cryptorchidism (n = 43), hypospadias (n = 41) and controls (n = 113) were analyzed for inhibin B, anti-Müllerian hormone (AMH), testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). LH, testosterone, non-shbg-bound testosterone (NSBT), and AHM levels showed significant age-related trends. After age-correction, a negative correlation between FSH and inhibin B was observed (r = ,0.43). The only significant group-differences were lower testosterone and NSBT levels in cryptorchidism cases, with a mean testosterone of 1.8 and 2.6 nmol/L and a mean NSBT of 0.48 and 0.70 nmol/L for cryptorchidism cases and controls, respectively. The higher levels of LH, testosterone, and NSBT in boys born pre-term or with a low birthweight indicate that abnormal prenatal development may determine postnatal testis function. Our results support the hypothesis that the inhibin B , FSH feedback loop is already functional before puberty. The lower testosterone and NSBT levels indicate that disturbed Leydig cell function can already be detected early after birth in cryptorchid boys. [source] Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Christopher M. Heaphy Abstract Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. © 2006 Wiley-Liss, Inc. [source] Transcriptional profiling on chromosome 19p indicated frequent downregulation of ACP5 expression in hepatocellular carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Kathy Y.-Y. Abstract Chromosomal rearrangements unraveled by spectral karyotyping (SKY) indicated frequent chromosome 19 translocations in hepatocellular carcinoma (HCC). In an effort to characterize the aberrant 19 rearrangements in HCC, we performed positional mapping by fluorescence in-situ hybridization (FISH) in 10 HCC cell lines. SKY analysis indicated structural rearrangements of chromosome 19 in 6 cell lines, 4 of which demonstrated recurring 19p translocations with different partner chromosomes. Using fluorescence-labeled BAC probes, physical mapping indicated a breakpoint cluster between 19p13.12 and 19p12. A corresponding transcriptional mapping by cDNA array on 19p suggested the differential expression of a single downregulated gene ACP5 (tartrate-resistant acid phosphatase type 5). Quantitative RT-PCR confirmed the reduced expression of ACP5 and indicated a strong correlation of its repressed expression only in cell lines that contain a 19p rearrangement (p = 0.004). We further examined the expression of ACP5 in a cohort of 82 primary tumors and 74 matching nonmalignant liver tissues. In the primary HCC examined, a reduction of ACP5 transcripts by 2 to as much as 1,000-fold was suggested in 67% of tumors (55/82 cases). When compared to adjacent nonmalignant tissues, 46% of tumors (34/74 cases) demonstrated a lower expression level (p = 0.015). On closer examination, a high significance of ACP5 repression was suggested in the cirrhotic HCC subgroup that was derived from chronic hepatitis B infected patients (55%; 30/54 cases; p = 0.001). Functional examination of ACP5 ectopic expression in HCC cells further demonstrated a significant growth inhibitory effect of ACP5 on tumor cell survival (p < 0.001). In our study, the novel finding of common ACP5 downregulation in HCC may provide basis for further investigations on the role of acid phosphatase in hepatocarcinogenesis. © 2004 Wiley-Liss, Inc. [source] Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activityINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Katharine H. Wrighton Abstract The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S- and G2 arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity. © 2004 Wiley-Liss, Inc. [source] From collagen chemistry towards cell therapy , a personal journeyINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 4 2007Michael E. Grant Summary The Fell,Muir Award requires the recipient to deliver a lecture and a review manuscript which provides a personal overview of significant scientific developments in the field of matrix biology over the period of the recipient's career. In this context, this review considers the collagen family of structural proteins and the advances in biochemical, molecular biological and genetic techniques which led to the elucidation of the structure, synthesis and function of this important group of extracellular matrix constituents. Particular attention is focussed on early research on the identification and assembly of the soluble precursors of collagen types I and II, and the identification of the precursor of basement membrane collagen type IV. In subsequent studies investigating the maintenance of the chick chondrocyte phenotype in culture, the influence of the extracellular milieu was found to influence markedly both cell morphology and collagen gene expression. These studies led to the discovery of collagen type X whose expression is restricted to hypertrophic chondrocytes at sites of endochondral ossification. Such research provided a prelude to investigations of mammalian endochondral ossification which is known to be aberrant in a variety of human chondrodysplasias and is reactivated in bone fracture repair and in osteoarthritis. The cloning of bovine and then human collagen type X genes facilitated studies in relevant human diseases and contributed to the discovery of mutations in the COL10A1 gene in families with metaphyseal chondrodysplasia type Schmid. Clustering of mutations in the C-terminal domain of the type X collagen molecule has now been widely documented and investigations of the pathogenic mechanisms in animal models are beginning to suggest the prospect of novel treatment strategies. [source] A New AcanthocyclopsKiefer, 1927 (Copepoda: Cyclopoida) from Central Mexico with Comments on the Distributionof the Genus in Middle AmericaINTERNATIONAL REVIEW OF HYDROBIOLOGY, Issue 2 2006Nancy Mercado Abstract A new species of AcanthocyclopsKiefer is described from central Mexico. It differs from its congeners by a combination of characters including mainly: 11,13 antennular segments, a spine formula of 3444 and modified setae on legs 2,4. The presence of a compound distal antennular segment is aberrant within the Cyclopoida. The new species seems to be related to Nearctic forms of the vernalis ,robustus clade. Ancestors of this lineage probably reached central Mexico as a result of glaciation events and the new species is a remain of stranded postglacial populations; some of these forms were succesful in colonizing tropical lands. A key for the identification of the species of Acanthocyclops recorded in Mexico is included. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Topology of the Mitochondrial Inner Membrane: Dynamics and Bioenergetic ImplicationsIUBMB LIFE, Issue 3-5 2001Carmen A. Mannella Abstract Electron tomography indicates that the mitochondrial inner membrane is not normally comprised of baffle-like folds as depicted in textbooks. In actuality, this membrane is pleomorphic, with narrow tubular regions connecting the internal compartments (cristae) to each other and to the membrane periphery. The membrane topologies observed in condensed (matrix contracted) and orthodox (matrix expanded) mitochondria cannot be interconverted by passive folding and unfolding. Instead, transitions between these morphological states likely involve membrane fusion and fission. Formation of tubular junctions in the inner membrane appears to be energetically favored, because they form spontaneously in yeast mitochondria following large-amplitude swelling and recontraction. However, aberrant, unattached, vesicular cristae are also observed in these mitochondria, suggesting that formation of cristae junctions depends on factors (such as the distribution of key proteins and/or lipids) that are disrupted during extreme swelling. Computer modeling studies using the "Virtual Cell" program suggest that the shape of the inner membrane can influence mitochondrial function. Simulations indicate that narrow cristae junctions restrict diffusion between intracristal and external compartments, causing depletion of ADP and decreased ATP output inside the cristae. [source] The fellowship of the hobbit: the fauna surrounding Homo floresiensisJOURNAL OF BIOGEOGRAPHY, Issue 6 2010Hanneke J. M. Meijer Abstract The Late Pleistocene Flores fauna shows a pattern observed on many other islands. It is neither aberrant nor exclusive, but the result of non-random selective forces acting upon an impoverished and disharmonic insular fauna. By comparing the Flores vertebrate fauna with other fossil insular biotas, it is apparent that the evolution of Homo floresiensis is part of a general pattern affecting all the inhabitants of Pleistocene Flores. Vertebrate evolution on Flores appears to have been characterized by phylogenetic continuity, low species richness and a disharmonic fauna. All three aspects stem from the isolated position of the island and have resulted in the distinct morphological characteristics of the Flores fauna. Evidence reviewed herein shows that features exhibited by H. floresiensis, such as small stature, a small brain, relatively long arms, robust lower limbs and long feet, are not unique, but are shared by other insular taxa. Therefore, the evolution of H. floresiensis can be explained by existing models of insular evolution and followed evolutionary pathways similar to those of the other terrestrial vertebrates inhabiting Pleistocene Flores. [source] Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell linesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004William F. Holmes Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all- trans -retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N -[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR. © 2004 Wiley-Liss, Inc. [source] Three-dimensional sonography in the prenatal diagnosis of aortic arch abnormalitiesJOURNAL OF CLINICAL ULTRASOUND, Issue 5 2009RDMS, Sifa Turan MD Abstract Purpose To assess the added value of 3-dimensional (3D) echocardiography with spatiotemporal image correlation (STIC) in the diagnosis of aortic arch abnormalities in fetuses with isolated abnormal upper thoracic 3-vessel view (3VV). Method A total of 3,420 women underwent a targeted anatomic survey at 18,22 weeks' gestation in a 1-year period. An isolated abnormal upper thoracic 3VV detected on 2-dimensional (2D) imaging was followed up by conventional 2D echocardiography and 3D fetal echocardiography with STIC. Offline reconstruction by a second operator blinded to the suspected diagnosis was performed. Neonatal echocardiography and MRI with 3D reconstruction were performed to verify the prenatal diagnosis. Result Of the 3,420 patients referred, 4 had an isolated abnormal 3VV (0.09%). A right-sided aortic arch (RAA, n = 3) and double aortic arch (DAA, n = 1) were suspected. In all aortic arch abnormalities, 3D fetal echocardiography and STIC correctly identified RAA with aberrant left subclavian artery in 3 cases and DAA in 1 case with a degree of definition that was equal to the confirmatory postnatal echocardiography and 3D MRI. Conclusion Although the 2D upper 3VV is a powerful screening tool for isolated aortic arch abnormalities, 3D fetal echocardiography with STIC allows an accurate prenatal characterization of the abnormality to a degree that is typically attainable only by post partum imaging. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2009 [source] Benign ectopic thyroid tissue in a cutaneous location: a case report and reviewJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2004Kim Maino Background:, For many years, lateral, aberrant thyroid tissue in adults was a term used almost exclusively for metastatic thyroid carcinoma. However, aberrant, benign ectopic thyroid tissue does occur, and it is most commonly found as a part of the evaluation of endocrine dysfunction. Rarely, aberrant, benign ectopic thyroid presents as a primary mass. Case report:, We present a 35-year-old female who presented for removal of a lifelong posterior lateral neck nodule. Results:, Histologic examination and immunohistochemical studies confirmed the presence of aberrant, benign ectopic thyroid tissue. The patient had no endocrine problems, and she had a normally located and functioning thyroid gland. Conclusions:, This case illustrates that not all aberrant thyroid tissues in adults are malignant or associated with endocrine disorders. This case also illustrates the rare association of ectopic thyroid and a normally located and functioning thyroid gland. In this patient, a somatic mutation in a transcription factor important in thyroid migration could explain these findings. [source] Accounting for Aberrant Test Response Patterns Using Multilevel ModelsJOURNAL OF EDUCATIONAL MEASUREMENT, Issue 3 2007Alexandra Petridou Hypotheses about aberrant test-response behavior and hence invalid person-measurement have hitherto included factors like ability, gender, language, test-anxiety, and motivation, but these have not previously been collectively investigated with real data, or with multilevel models. This study analyzes the effect of these factors on person aberrance using a real mathematics assessment data set under the framework of a two-level (person and classroom) hierarchical model. The results suggest that higher-scoring pupils, and, to a lesser extent, second-language learners are significantly more often aberrant. But more importantly, we find that the classroom makes a significant contribution to person aberrance and conclude that studies that investigate the sources of person aberrance with real data should model the classroom as well as individual levels. [source] Aging and cancer cell biology, 2009AGING CELL, Issue 3 2009Judith Campisi Summary Cancer is an age-related disease in organisms with renewable tissues. A malignant tumor arises in part from genomic damage, which can also drive age-related degeneration. However, cancer differs from many age-related degenerative diseases in that it entails gain-of-function changes that confer new (albeit aberrant) properties on cells, resulting in vigorous cell proliferation and survival. Nonetheless, interventions that delay age-related degeneration , for example, caloric restriction or dampened insulin/IGF-1 signaling , often also delay cancer. How then is the development of cancer linked to aging? The answer to this question is complex, as suggested by recent findings. This Hot Topic review discusses some of these findings, including how genomic damage might alter cellular properties without conferring mutations, and how some genes that regulate lifespan in organisms that lack renewable tissues might affect the development of cancer in mammals. [source] Association of aberrant p53 and p21WAF1 immunoreactivity with the outcome of oral verrucous leukoplakia in TaiwanJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 2 2000Kuo-Wei Chang Abstract: The expression of p53 and p21WAF1 in 53 oral verrucous leukoplakias (OVLs), mostly non-dysplastic lesions, was investigated to ascertain the role of such events in malignant conversion. Immunohistochemical analysis revealed aberrant p53 and p21WAF1 immunoreactivity in 51% (27 cases) and 75% (40 cases), respectively. After an average follow-up period of three and a half years, histopathological examination revealed that 22 (42%) cases had developed oral squamous cell carcinoma (OSCC), 14 (26%) cases had undergone recurrence, and 17 (32%) cases were free of disease. The oncogenic potential of this subset of premalignant lesions warrants attention. A significant difference in the frequency of OSCC progression/recurrence was noted in lesions bearing aberrant immunoreactivity of either p53 (93% vs 42%; P=0.00008) or p21WAF1 (80% vs 32%; P=0.002) in comparison with lesions without immunoreactivity. This study suggested that the aberrant immunoreactivity of p53 and p21WAF1 may represent important alterations of OVL and could affect the outcome of this lesion. [source] Tracheobronchography and angiocardiography of paediatric cardiac patients with airway disordersJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 3 2002YF Cheung Objective: We report our experience in combining tracheobronchography and angiocardiography in the assessment of a selected cohort of paediatric cardiac patients with problematic airway disorders. Methodology: The clinical records of 11 patients who underwent 17 studies at a median age of 5.5 months (range 3 months to 10.8 years) were reviewed. Tracheobronchography and angiocardiography were performed under general anaesthesia using a non-ionic contrast agent. The findings were compared with those of flexible bronchoscopy and magnetic resonance imaging (MRI). Results: Seven patients had cardiac lesions associated with vascular anomalies potentially compressing the airway, while four had no identifiable aberrant or enlarged vessels. All examinations but one were performed without complications. Tracheobronchography demonstrated extrinsic vascular compression with secondary airway malacia in three (27%), intrinsic tracheobronchial stenosis in five (45%), and airway malacia in three patients (27%). Precise measurement of the airway calibre and real-time fluoroscopic monitoring facilitated transcatheter tracheobronchial interventions (six balloon dilations, three stent implantations) in four patients. In conjunction with angiocardiography, cine-tracheobronchography provided detailed information on the spatial relationship between vascular and airway structures in all patients; allowed dynamic assessment of airway malacia; and facilitated preoperative planning in six patients. In contrast, bronchoscopy failed to differentiate malacia from extrinsic compression in four patients (36%), while MRI, performed in six patients, was unsatisfactory in one due to a motion artefact and failed to diagnose airway malacia and extrinsic compression in three patients. Conclusions: Tracheobronchography is relatively safe in paediatric cardiac patients. Combined tracheobronchography and angiocardiography, a less operator-dependent imaging modality compared to bronchoscopy and MRI, delineated the airway and vascular anatomy in detail; facilitated preoperative planning; and permitted transcatheter tracheo-bronchial interventions. The dynamic capability of tracheobronchography supplements that of flexible bronchoscopy and MRI in the diagnosis of airway malacia. [source] | ||||||||||||||||||||||||||||||||||||||||||||||