Medicine and Health Sciences Commons^™

Targeted Apoptotic Effects Of Thymoquinone And Tamoxifen On Xiap Mediated Akt Regulation In Breast Cancer, Shashi Rajput, B. N. P. Kumar, Siddik Sarkar, Subhasis Das, Belal Azab, Prasanna K. Santhekadur, Swadesh K. Das, Luni Emdad, Devanand Sarkar, Paul B. Fisher, Mahitosh Mandal

Human and Molecular Genetics Publications

X-linked inhibitor of apoptosis protein (XIAP) is constitutively expressed endogenous inhibitor of apoptosis, exhibit its antiapoptotic effect by inactivating key caspases such as caspase-3, caspase-7 and caspase-9 and also play pivotal role in rendering cancer chemoresistance. Our studies showed the coadministration of TQ and TAM resulting in a substantial increase in breast cancer cell apoptosis and marked inhibition of cell growth both in vitro and in vivo. Anti-angiogenic and anti-invasive potential of TQ and TAM was assessed through in vitro studies. This novel combinatorial regimen leads to regulation of multiple cell signaling targets including inactivation of Akt and XIAP degradation. …

Otx But Not Mitf Transcription Factors Are Required For Zebrafish Retinal Pigment Epithelium Development, Brandon M. Lane, James A. Lister

Human and Molecular Genetics Publications

Otx and Mitf transcription factors have been implicated in the development of the retinal pigmented epithelium (RPE), but the relationship between these factors and their specific roles in the development of the RPE have not been fully defined. The role of the three Otx transcription factors (Otx1a, Otx1b, and Otx2) and two Mitf transcription factors (Mitfa and Mitfb) in the development of the zebrafish RPE was explored in these experiments. The loss of Otx activity through morpholino knockdown produced variable eye defects, ranging from delayed RPE pigmentation to severe coloboma, depending on the combination of Otx factors that were targeted. …

A First-Generation Multi-Functional Cytokine For Simultaneous Optical Tracking And Tumor Therapy, Shawn Hingtgen, Randa Kasmieh, Elizabeth Elbayly, Irina Nesterenko, Jose-Luiz Figueiredo, Rupesh Dash, Devanand Sarkar, David Hall, Dima Kozakov, Sandor Vajda, Paul B. Fisher, Khalid Shah

Human and Molecular Genetics Publications

Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant …

Genetic Dissection Of Acute Ethanol Responsive Gene Networks In Prefrontal Cortex: Functional And Mechanistic Implications, Aaron R. Wolen, Charles A. Phillips, Michael A. Langston, Alex H. Putman, Paul J. Vorster, Nathan A. Bruce, Timothy P. York, Robert W. Williams, Michael F. Miles

Human and Molecular Genetics Publications

Background

Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol.

Results

Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted …

A Duplication Cnv That Conveys Traits Reciprocal To Metabolic Syndrome And Protects Against Diet-Induced Obesity In Mice And Men, Melanie Lacaria, Pradip Saha, Lorraine Potocki, Weimin Bi, Jiong Yan, Santhosh Girirajan, Brooke Burns, Sarah H. Elsea, Katherina Walz, Lawrence Chan, James R. Lupski, Wenli Gu

Human and Molecular Genetics Publications

The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion,Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype …

Combinatorial Effect Of Non-Steroidal Anti-Inflammatory Drugs And Nf-Κb Inhibitors In Ovarian Cancer Therapy, Luiz F. Zerbini, Rodrigo E. Tamura, Ricardo G. Correa, Akos Czibere, Jason Coideiro, Manoj Bhasin, Fernando M. Simabuco, Yihong Wang, Xuesong Gu, Linglin Li, Devanand Sarkar, Jin-Rong Zhou, Paul B. Fisher, Towia A. Libermann

Human and Molecular Genetics Publications

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor …

Comprehensive Gene-Based Association Study Of A Chromosome 20 Linked Region Implicates Novel Risk Loci For Depressive Symptoms In Psychotic Illness, T. Bernard Bigdeli, Brion S. Maher, Zhongming Zhao, Edwin J. C. G. Van Den Oord, Dawn L. Thiselton, Jingchun Sun, Bradley T. Webb, Richard L. Amdur, Brandon Wormley, Francis A. O'Neill, Dermot Walsh, Brien P. Riley, Kenneth S. Kendler, Ayman H. Fanous

Human and Molecular Genetics Publications

Background

Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.

Methods

We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted …

Racial Differences In Genetic And Environmental Risk To Preterm Birth, Timothy P. York, Jerome F. Strauss Iii, Michael C. Neale, Lindon J. Eaves

Human and Molecular Genetics Publications

Preterm birth is more prevalent in African Americans than European Americans and contributes to 3.4 times more African American infant deaths. Models of social inequity do not appreciably account for this marked disparity and molecular genetic studies have yet to characterize whether allelic differences that exist between races contribute to this gap. In this study, biometrical genetic models are applied to a large mixed-race sample consisting of 733,339 births to measure the extent that heritable factors and environmental exposures predict the timing of birth and explain differences between racial groups. Although we expected significant differences in mean gestational age between …

Development Of A Syngeneic Mouse Model Of Epithelial Ovarian Cancer, Bridget A. Quinn, Fang Xiao, Laura Bickel, Lainie Martin, Xiang Hua, Andres Klein-Szanto, Denise C. Connolly

Human and Molecular Genetics Publications

Background

Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies.

Methods

Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no …

Apoptotic Engulfment Pathway And Schizophrenia, Xiangning Chen, Cuie Sun, Qi Chen, F. Anthony O'Neill, Dermot Walsh, Ayman H. Fanous, Kodavali V. Chowdari, Vishwajit L. Nimgaonkar, Adrian Scott, Sibylle G. Schwab, Dieter B. Wildenauer, Ronglin Che, Wei Tang, Yongyong Shi, Lin He, Xiong-Jian Luo, Bing Su, Todd L. Edwards, Zhongming Zhao, Kenneth S. Kendler

Human and Molecular Genetics Publications

Background

Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease.

Methodology/Principal Findings

Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and …

Clinical Findings In Four Children With Biotinidase Deficiency Detected Through A Statewide Neonatal Screening Program, Barry Wolf, Gregory S. Heard, Linda G. Jefferson, Virginia K. Proud, Walter E. Nance, Karen A. Weissbecker

Human and Molecular Genetics Publications

Four children with biotinidase deficiency were identified during the first year of a neonatal screening program for this disease in the Commonwealth of Virginia. Two unrelated probands were identified among the 81,243 newborn infants who were screened. In addition, two siblings of one of these infants were found to be affected. Both probands had mild neurologic symptoms at two and four months, respectively, and the two older children had more severe neurologic abnormalities, cutaneous findings, and developmental delay at two and three years of age. However, none of the affected children had acute metabolic decompensation. Previous studies have shown that …

Discordant Expression Of Fetal Hydantoin Syndrome In Heteropaternal Dizygotic Twins, Mary C. Phelan , B.S., John M. Pellock , M.D., Walter E. Nance , M.D., Ph.D.

Human and Molecular Genetics Publications

No abstract provided.

Systemic Membrane Defect In The Proximal Muscular Dystrophies, Nathan A. Pickard , Ph.D., Hanns-Dieter Gruemer , M.D., Harland L. Verrill , Ph.D., Edward R. Isaacs , M.D., Meinhard Robinow , M.D., Walter E. Nance , M.D., Ph.D., Edwin C. Myers , M.D., Barbara Goldsmith , B.S.

Human and Molecular Genetics Publications

Abstract

We studied lymphocyte capping in 61 patients with Duchenne, Becker, limb-girdle, facioscapulohumeral and congenital muscular dystrophies. All showed a markedly diminished percentage of capped cells when compared with 86 normal controls, providing support for previous evidence that an alteration in membrane fluidity may be a common pathogenic feature in several genetically distinct forms of proximal muscular dystrophy.

Heterozygous carriers of Duchenne muscular dystrophy showed diminished capping that was indistinguishable from that of afflicted males and was often present even when serum enzyme levels were normal. Studies in 25 families with 16 suspected sporadic cases indicated that no more than …