Molecular Abnormalities (molecular + abnormality)

Distribution by Scientific Domains


Selected Abstracts


Molecular abnormalities of T-cells in systemic lupus erythematosus

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 4 2006
Tsutomu TAKEUCHI
Abstract Substantial evidence supports that T-cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). To explore the molecular basis of the defective function of SLE T-cells, we focused on the signal transduction system via T-cell antigen receptor (TCR) in peripheral blood T-cells from SLE patients. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR , chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR , chain, including spliced variants lacking exon 7 and with a short 3,-UTR, were detected in SLE T-cells. Although attenuated expression of the TCR , chain is also observed in patients with cancers, infections, and other autoimmune diseases, sustained attenuation of TCR , expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR , defects in SLE. [source]


Mechanisms of Epileptogenesis in Tuberous Sclerosis Complex and Related Malformations of Cortical Development with Abnormal Glioneuronal Proliferation

EPILEPSIA, Issue 1 2008
Michael Wong
Summary Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders. [source]


Insights into Serotonin Signaling Mechanisms Associated with Canine Degenerative Mitral Valve Disease

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2010
M.A. Oyama
Little is known about the molecular abnormalities associated with canine degenerative mitral valve disease (DMVD). The pathology of DMVD involves the differentiation and activation of the normally quiescent mitral valvular interstitial cell (VIC) into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in affected the valve tissue. In both humans and experimental animal models, increased serotonin (5-hydroxytryptamine, 5HT) signaling can induce VIC differentiation and myxomatous valve damage. In canine DMVD, numerous lines of evidence suggest that 5HT and related molecules such as transforming growth factor-, play a critical role in the pathogenesis of this disease. A variety of investigative techniques, including gene expression, immunohistochemistry, protein blotting, and cell culture, shed light on the potential role of 5HT in the differentiation of VIC, elaboration of myxomatous extracellular matrix components, and activation of mitogen-activated protein kinase pathways. These studies help support a hypothesis that 5HT and its related pathways serve as an important stimulus in canine DMVD. This review describes the pathological characteristics of canine DMVD, the organization and role of the 5HT pathway in valve tissue, involvement of 5HT in human and experimental models of valve disease, avenues of evidence that suggest a role for 5HT in naturally occurring DMVD, and finally, a overarching hypothesis describing a potential role for 5HT in canine DMVD. [source]


Decreased Triadin and Increased Calstabin2 Expression in Great Danes with Dilated Cardiomyopathy

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2009
M.A. Oyama
Background: Dilated cardiomyopathy (DCM) is a common cardiac disease of Great Dane dogs, yet very little is known about the underlying molecular abnormalities that contribute to disease. Objective: Discover a set of genes that are differentially expressed in Great Dane dogs with DCM as a way to identify candidate genes for further study as well as to better understand the molecular abnormalities that underlie the disease. Animals: Three Great Dane dogs with end-stage DCM and 3 large breed control dogs. Methods: Prospective study. Transcriptional activity of 42,869 canine DNA sequences was determined with a canine-specific oligonucleotide microarray. Genome expression patterns of left ventricular tissue samples from affected Great Dane dogs were evaluated by measuring the relative amount of complementary RNA hybridization to the microarray probes and comparing it with expression from large breed dogs with noncardiac disease. Results: Three hundred and twenty-three transcripts were differentially expressed (,2-fold change). The transcript with the greatest degree of upregulation (+61.3-fold) was calstabin2 (FKBP12.6), whereas the transcript with the greatest degree of downregulation (,9.07-fold) was triadin. Calstabin2 and triadin are both regulatory components of the cardiac ryanodine receptor (RyR2) and are critical to normal intracellular Ca2+ release and excitation-contraction coupling. Conclusion and clinical importance: Great Dane dogs with DCM demonstrate abnormal calstabin2 and triadin expression. These changes likely affect Ca2+ flux within cardiac cells and may contribute to the pathophysiology of disease. Microarray-based analysis identifies calstabin2, triadin, and RyR2 function as targets of future study. [source]


Classifying the medulloblastoma: insights from morphology and molecular genetics

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2002
D. Ellison
Significant advances in the treatment of the medulloblastoma (MB) have been made in the last 30 years, reducing mortality by 2-fold. Further improvements in the cure rate require an increased understanding of the biology of MBs, and this will translate into refinements in their classification. Scrutiny of the cytological variation found among MBs has recently led to the concept of the anaplastic MB, which overlaps the large-cell variant and appears to share its poor prognosis. In contrast, the MB with extensive nodularity, a distinctive nodular/desmoplastic variant occurring in infants, has a better outcome than most MBs in these young patients. Building on cytogenetic studies that have drawn attention to abnormalities on chromosome 17 in over a third of MBs, research shows non-random losses on chromosomes 8, 9, 10, 11 and 16, and gains on chromosomes 1, 7 and 9. Overexpression of ErbB2 receptors and losses on chromosome 17p have been proposed as independent indicators of aggressive behaviour, while high TrkC receptor expression indicates a favourable outcome. There is a strong association between anaplastic/large-cell tumours and MYC amplification, which has previously been linked with aggressive disease, but associations between abnormalities on chromosome 17 and anaplastic/large-cell MBs and between abnormalities in the shh/PTCH pathway and the desmoplastic variant are more controversial. Classification of the MB histopathologically and according to profiles of molecular abnormalities will help both to rationalize approaches to therapy, increasing the cure rate and reducing long-term side-effects, and to suggest novel treatments. [source]


Differential expression of specific microRNA and their targets in acute myeloid leukemia,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010
Giuseppe Cammarata
Acute myeloid leukemia (AML) the most common acute leukemia in adults is characterized by various cytogenetic and molecular abnormalities. However, the genetic etiology of the disease is not yet fully understood. MicroRNAs (miRNA) are small noncoding RNAs which regulate the expression of target mRNAs both at transcriptional and translational level. In recent years, miRNAs have been identified as a novel mechanism in gene regulation, which show variable expression during myeloid differentiation. We studied miRNA expression of leukemic blasts of 29 cases of newly diagnosed and genetically defined AML using quantitative reverse transcription polymerase chain reaction (RT-PCR) for 365 human miRNA. We showed that miRNA expression profiling reveals distinctive miRNA signatures that correlate with cytogenetic and molecular subtypes of AML. Specific miRNAs with consolidated role on cell proliferation and differentiation such as miR-155, miR-221, let-7, miR-126 and miR-196b appear to be associated with particular subtypes. We observed a significant differentially expressed miRNA profile that characterizes two subgroups of AML with different mechanism of leukemogenesis: core binding factor (CBF) and cytogenetically normal AML with mutations in the genes of NPM1 and FLT3- ITD. We demonstrated, for the first time, the inverse correlation of expression levels between miRNA and their targets in specific AML genetic groups. We suggest that miRNA deregulation may act as complementary hit in the multisteps mechanism of leukemogenesis offering new therapeutic strategies. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source]


Proteomic profiling for cancer progression: Differential display analysis for the expression of intracellular proteins between regressive and progressive cancer cell lines

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2005
Eiko Hayashi
Abstract Tumor development and progression consist of a series of complex processes involving multiple changes in gene expression (Paolo et al. Physiol. Rev., 1993, 73, 161,195; Lance et al. Cell., 1991, 64, 327,336). Tumor cells acquire an invasive and metastatic phenotype that is the main cause of death for cancer patients. Therefore, for early diagnosis and effective therapeutic intervention, we need to detect the alterations associated with transition from benign to malignant tumor cells on a molecular basis. To unravel alterations concerned with tumor progression, the proteomic approach has attracted great attention because it can identify qualitative and quantitative changes in protein composition, including post-translational modifications. In this study, we performed proteomic differential display analysis for the expression of intracellular proteins in the regressive cancer cell line QR-32 and the inflammatory cell-promoting progressive cancer cell line QRsP-11 of murine fibrosarcoma by two-dimensional gel electrophoresis and mass spectrometry using an Agilent 1100 LC/MSD Trap XCT. We found 11,protein spots whose expression was different between QR-32 and QRsP-11 cells and identified nine proteins, seven of which, calreticulin precursor, tropomyosin,1 , chain, annexin,A5, heat shock protein (HSP)90-,, HSP90-,, PEBP, and Prx,II, were over-expressed, and two, Anp32e and HDGF, which were down-regulated. The results suggest an important complementary role for proteomics in identification of molecular abnormalities in tumor progression. [source]


Gastrointestinal stromal tumors (GISTs): a review

APMIS, Issue 2 2009
SONJA E. STEIGEN
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms in the gastrointestinal tract, which, over the last 10 years, have emerged from a poorly understood neoplasm to a well-defined tumor entity exhibiting particular molecular abnormalities and for which promising novel treatment modalities have been developed. GISTs probably arise from the precursor cell of the interstitial cell of Cajal, express KIT tyrosine kinase in most of the cases and harbor mutations of importance for individualized treatment. The molecular targets for therapeutic interventions are not only of importance for the treatment of GIST patients but also useful for in the development of novel drug modalities and new strategies in basic cancer therapy. [source]


Photoageing shows histological features of chronic skin inflammation without clinical and molecular abnormalities

BRITISH JOURNAL OF DERMATOLOGY, Issue 4 2003
S. Bosset
Summary Background Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis. Mast cells and macrophages, which are found in higher numbers in photoaged skin, have been implicated in this process. Objectives To analyse the phenotype of haematopoietic-derived infiltrating cells in photodamaged skin. Methods Chronically sun-exposed (preauricular) and control sun-protected (postauricular) skin was recovered from eight healthy subjects undergoing cosmetic surgery (facial lifting). Results Histological analysis showed that sun-exposed skin harboured more infiltrating mononuclear cells than sun-protected skin. Cellular infiltrates were found at the periphery of areas of elastolysis around hair follicles in sun-exposed sites, whereas they were found in the interfollicular dermis around blood vessels and around hair follicles in sun-protected samples. Immunohistochemical analysis revealed an increased number of mast cells, macrophages and CD4+ CD45RO+ T cells in sun-exposed dermis as well as a higher number of CD1a+ dendritic cells in sun-exposed epidermis, compared with the sun-protected samples. Thus photoageing displays histological features of chronic skin inflammation. However, no molecular sign of inflammation was observed and we even found a decreased expression of interleukin-1, mRNA in sun-exposed compared with sun-protected sites. Furthermore, the patients' skin looked normal and did not display any clinical inflammation. Conclusions Collectively, these data show that chronic ultraviolet irradiation induces alterations of innate immune cells which are recruited in sun-exposed skin without being activated. [source]


Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO

BRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006
F. Kuchenbauer
Abstract AML1-ETO collaborates with further genetic abnormalities to induce acute myeloid leukaemia (AML). We analysed 99 patients with an AML1-ETO rearrangement for additional aberrations. Frequent genetic abnormalities were, loss of a sex chromosome (56/99, 56·5%) and del(9)(q22) (24/99, 24·2%). The most frequent molecular aberrations were mutations of KITD816 (3/23, 13%) and NRAS (8/89, 8·9%). Further molecular abnormalities were FLT3 mutations (3/87, 3·4%), AML1 (1/26, 3·8%) and PU1 (1/14, 7·1%). MLL-PTD, KRAS and CEBPA mutations were not found. These clinical findings support the model that AML1-ETO collaborates with other genetic alterations, such as mutations of receptor tyrosine kinases, to induce AML. [source]


Molecularly targeted therapy for hepatocellular carcinoma

CANCER SCIENCE, Issue 1 2009
Shinji Tanaka
Accumulated understanding of the molecular pathways regulating cancer progression has led to the development of novel targeted therapies. Hepatocellular carcinoma (HCC) remains a highly lethal disease that is resistant to conventional cytotoxic chemotherapy and radiotherapy. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. A recent clinical trial revealed an oral multikinase inhibitor, sorafenib, as the first agent that has demonstrated improved overall survival in patients with advanced HCC. The present review summarizes molecular abnormalities of HCC with a focus on clinical studies, and current status as well as problems of the targeted strategies for HCC. (Cancer Sci 2009; 100: 1,8) [source]


Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese

JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2000
Shu-Chun Lin
Abstract: To determine the alterations of the p16/MTS1 gene in oral squamous cell carcinoma (OSCC), we examined in Taiwanese patients the mutation, deletion and methylation of p16/MTS1 in primary OSCCs associated mostly with betel quid (BQ)/tobacco use. Among 110 tumors undergoing mutational analyses, seven (6%) showed mutations in exon 2 or the intron 1/exon 2 splice site. All but one mutation disrupted the encoded proteins. Base transitions represented the vast majority (6/7) of the mutations identified in BQ/tobacco consuming subjects. It was noted that 15/56 (27%) tumors examined by restriction fragment methylation analysis revealed a significant level of methylation in different loci of exon 1 as compared with the respective non-cancerous tissue. Mutation of p16/MTS1 was exclusively identified in carcinomas of buccal mucosa, whereas methylation of the p16/MTS1 promoter region occurred preferentially in carcinomas of the tongue (54%) rather than at other sites (22%). Homozygous deletion was not found in 56 paired samples examined, nor was hemizygous deletion indicated in 12 informative cases. The results indicated aberrant methylation and mutation as the molecular abnormality of p16/MTS1 in the OSCC from Taiwanese. [source]