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Du L.,Harold mmons Comprehensive Cancer Center | Pertsemlidis A.,Harold mmons Comprehensive Cancer Center | Pertsemlidis A.,Eugene rmott Center for Human Growth and Development | Pertsemlidis A.,Southwestern Medical Center
Journal of Molecular Cell Biology | Year: 2011

Although cancer and neurodegenerative disease are two distinct pathological disorders, emerging evidence indicates that these two types of disease share common mechanisms of genetic and molecular abnormalities. Recent studies show that individual microRNAs (miRNAs) could be involved in the pathology of both diseases, indicating that the mechanisms of these two seemingly dichotomous diseases converge in the dysregulation of gene expression at the post-transcriptional level. Given the increasing evidence showing that miRNA-based therapeutic strategies that modulate the activity of one or more miRNAs are potentially effective for a wide range of pathological conditions, the involvement of miRNAs in the common pathways of leading both diseases suggests a bright future for developing common therapeutic approaches for both diseases. Moreover, the miRNAs that are dysregulated in both diseases may hold promise as uniquely informative diagnostic markers. Here, we review recent studies on the miRNAs that have been implicated in both cancer and neurodegenerative diseases. © 2011 The Author. Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Garcia-Rodriguez J.,Southwestern Medical Center | Mendiratta S.,Southwestern Medical Center | White M.A.,Southwestern Medical Center | Xie X.-S.,Eugene rmott Center for Human Growth and Development | De Brabander J.K.,Southwestern Medical Center
Bioorganic and Medicinal Chemistry Letters | Year: 2015

An efficient total synthesis of the potent V-ATPase inhibitor saliphenylhalamide (SaliPhe), a synthetic variant of the natural product salicylihalamide A (SaliA), has been accomplished aimed at facilitating the development of SaliPhe as an anticancer and antiviral agent. This new approach enabled facile access to derivatives for structure-activity relationship studies, leading to simplified analogs that maintain SaliPhe's biological properties. These studies will provide a solid foundation for the continued evaluation of SaliPhe and analogs as potential anticancer and antiviral agents. © 2015 Elsevier Ltd.

Yan Z.,University of Texas Southwestern Medical Center | Yan Z.,Childrens Medical Center Dallas | Wang L.,University of Texas Southwestern Medical Center | Wang L.,Childrens Medical Center Dallas | And 8 more authors.
International Journal of Surgical Pathology | Year: 2014

Background. Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract is associated with high mortality in immunosuppressed patients. However, few studies have correlated blood CMV load with GI histopathological findings. Furthermore, there have been few studies determining the clinical significance of isolated CMV infection. Design. Cases were selected for the diagnosis of GI CMV infection by searching the information system of a tertiary hospital. The electronic medical record was reviewed for each case to determine blood viral load, clinicopathological features at the time of diagnosis and clinical outcomes after discharge. Results. In all, 30 patients with CMV-positive intestinal biopsies confirmed by immunohistochemistry (IHC) were identified. All were immunosuppressed. CMV inclusions were also recognized by hematoxylin and eosin stain in 27% of the cases, and the remaining cases were identified by IHC alone. CMV blood load was only positive in 17% of the cases; 8 cases had only isolated CMV-infected cells (0.1-0.5 IHC count/high-power field), with the following outcomes: worsening symptoms that responded to antiviral therapy (n = 5); clinical improvement without treatment (n = 1); death without treatment (n = 2). Conclusions. CMV infection of the intestines is clinically significant but will not always present with classic viral cytopathic changes. IHC should be considered in any case where there is a clinical suspicion for CMV infection. Identification of isolated CMV infection by IHC should be considered clinically significant. Current blood viral load tests have poor sensitivity in detecting CMV intestinal infection. Future studies will investigate the predictive value of positive peripheral blood viral load in patients with intestinal symptoms. © The Author(s) 2013.

Sant D.W.,Arup | Margraf R.L.,Arup | Stevenson D.A.,Stanford University | Stevenson D.A.,University of Utah | And 12 more authors.
Journal of Medical Genetics | Year: 2015

Background: Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the 'second hit' mutation remains unclear. Methods: Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline ( peripheral blood). Results: A germline NF1 splice site mutation (c.61- 2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown. Conclusions: Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.

Kappei D.,TU Dresden | Kappei D.,Max Planck Institute of Molecular Cell Biology and Genetics | Butter F.,Max Planck Institute of Biochemistry | Benda C.,Max Planck Institute of Biochemistry | And 15 more authors.
EMBO Journal | Year: 2013

Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the telomerase complex to telomeres through a not yet fully understood mechanism. Factors promoting telomerase-telomere interaction are expected to directly bind telomeres and physically interact with the telomerase complex. In search for such a factor we carried out a SILAC-based DNA-protein interaction screen and identified HMBOX1, hereafter referred to as homeobox telomere-binding protein 1 (HOT1). HOT1 directly and specifically binds double-stranded telomere repeats, with the in vivo association correlating with binding to actively processed telomeres. Depletion and overexpression experiments classify HOT1 as a positive regulator of telomere length. Furthermore, immunoprecipitation and cell fractionation analyses show that HOT1 associates with the active telomerase complex and promotes chromatin association of telomerase. Collectively, these findings suggest that HOT1 supports telomerase-dependent telomere elongation.

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