Medical Genetics Commons^™

Long-Term Survival After Multidisciplinary Management Of Resected Pancreatic Adenocarcinoma, Matthew H G Katz, Huamin Wang, Jason B Fleming, Charlotte C Sun, Rosa F Hwang, Robert A Wolff, Gauri Varadhachary, James L Abbruzzese, Christopher H Crane, Sunil Krishnan, Jean-Nicolas Vauthey, Eddie K Abdalla, Jeffrey E Lee, Peter W T Pisters, Douglas B Evans

Faculty, Staff and Student Publications

INTRODUCTION: Actual 5-year survival rates of 10-18% have been reported for patients with resected pancreatic adenocarcinoma (PC), but the use of multimodality therapy was uncommon in these series. We evaluated long-term survival and patterns of recurrence in patients treated for PC with contemporary staging and multimodality therapy.

METHODS: We analyzed 329 consecutive patients with PC evaluated between 1990 and 2002 who underwent resection. Each received a multidisciplinary evaluation and a standard operative approach. Pre- or postoperative chemotherapy and/or chemoradiation were routine. Surgical specimens of 5-year survivors were re-reviewed. A multivariate model of factors associated with long-term survival was constructed.

RESULTS: …

Revealing Genes Associated With Vitellogenesis In The Liver Of The Zebrafish (Danio Rerio) By Transcriptome Profiling., Liraz Levi, Irena Pekarski, Ellen Gutman, Paolo Fortina, Terry Hyslop, Jakob Biran, Berta Levavi-Sivan, Esther Lubzens

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: In oviparous vertebrates, including fish, vitellogenesis consists of highly regulated pathways involving 17beta-estradiol (E2). Previous studies focused on a relatively small number of hepatic expressed genes during vitellogenesis. This study aims to identify hepatic genes involved in vitellogenesis and regulated by E2, by using zebrafish microarray gene expression profiling, and to provide information on functional distinctive genes expressed in the liver of a vitellogenic female, using zebrafish as a model fish. RESULTS: Genes associated with vitellogenesis were revealed by the following paired t-tests (SAM) comparisons: a) two-month old vitellogenic (Vit2) females were compared with non-vitellogenic (NV) females, showing 825 …

Beta3 Integrin Haplotype Influences Gene Regulation And Plasma Von Willebrand Factor Activity, Katie E. Payne, Paul F. Bray, Peter J. Grant, Angela M. Carter

Department of Medicine Faculty Papers

The Leu33Pro polymorphism of the gene encoding beta(3) integrin (ITGB3) is associated with acute coronary syndromes and influences platelet aggregation. Three common promoter polymorphisms have also been identified. The aims of this study were to (1) investigate the influence of the ITGB3 -400C/A, -425A/C and -468G/A promoter polymorphisms on reporter gene expression and nuclear protein binding and (2) determine genotype and haplotype associations with platelet alpha(IIb)beta(3) receptor density. Promoter haplotypes were introduced into an ITGB3 promoter-pGL3 construct by site directed mutagenesis and luciferase reporter gene expression analysed in HEL and HMEC-1 cells. Binding of nuclear proteins was assessed by electrophoretic …

Multiple Forms Of Atypical Rearrangements Generating Supernumerary Derivative Chromosome 15., Nicholas J Wang, Alexander S Parokonny, Karen N Thatcher, Jennette Driscoll, Barbara M Malone, Naghmeh Dorrani, Marian Sigman, Janine M Lasalle, N Carolyn Schanen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders1. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the …

Let-7 Expression Defines Two Differentiation Stages Of Cancer, Scott Shell, Sun-Mi Park, Amir Reza Radjabi, Robert Schickel, Emily Kistner, David Jewell

Dartmouth Scholarship

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined …

Cystic Lymphangioma Of The Pancreas, Madhusudhan R. Sanaka, Thomas E. Kowalski

Department of Medicine Faculty Papers

A case report.

A Drosophila Deg/Enac Channel Subunit Is Required For Male Response To Female Pheromones, Heping Lin, Kevin J. Mann, Elena Starostina, Ronald D. Kinser, Claudio W. Pikielny

Dartmouth Scholarship

Odorants and pheromones as well as sweet- and bitter-tasting small molecules are perceived through activation of G protein-coupled chemosensory receptors. In contrast, gustatory detection of salty and sour tastes may involve direct gating of sodium channels of the DEG/ENaC family by sodium and hydrogen ions, respectively. We have found that ppk25, a Drosophila melanogaster gene encoding a DEG/ENaC channel subunit, is expressed at highest levels in the male appendages responsible for gustatory and olfactory detection of female pheromones: the legs, wings, and antennae. Mutations in the ppk25 gene reduce or even abolish male courtship response to females in the dark, …

A Critical Role For The Programmed Death Ligand 1 In Fetomaternal Tolerance, Indira Guleria, Arezou Khosroshahi, Mohammed Javeed Ansari, Antje Habicht, Miyuki Azuma, Hideo Yagita, Randolph J. Noelle

Dartmouth Scholarship

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell

Genetic Polymorphisms Of The Interleukin-1 Gene And Early Marginal Bone Loss Around Endosseous Dental Implants, Hitomi Shimpuku, Yasuhiro Nosaka, Tatsuya Kawamura, Yoichi Tachi, Mitsuko Shinohara, Kiyoshi Ohura

Faculty, Staff and Student Publications

Dental implant surgery commonly proceeds in two stages. It is generally accepted that bone loss around implants does not occur at stage-II surgery because implants do not receive mechanical loading. However, early marginal bone loss around implants occasionally does occur during the healing period. Genetic polymorphisms in the interleukin-1 (IL-1) gene have been reported to be important for bone homeostasis and susceptibility to bone disease. We therefore investigated whether the idiopathic early marginal bone loss around implants is related to polymorphisms in the IL-1 gene. We performed a case-control study. Patients demonstrating marginal bone loss around implants at stage-II surgery …

Aneuploidy Frequencies In Semen Fractions From Ten Oligoasthenoteratozoospermic Patients Donating Sperm For Intracytoplasmic Sperm Injection, Jerome Pfeffer, Myung-Geol Pang, Stanton F. Hoegerman, Christopher J. Osgood, M. W. Stacey, Jacob Mayer, Sergio Oehninger, William G. Kearns

Biological Sciences Faculty Publications

Objective: To determine aneuploidy frequencies in pellet and swim-up semen fractions from 10 infertile men with severe oligoasthenoteratozoospermia (OAT) who were donating sperm for intracytoplasmic sperm injection and to determine whether the swim-up isolation method would successfully separate aneuploid from haploid sperm.

Design: Prospective study.

Setting: Infertility clinic and molecular genetics laboratory.

Patient(s): Ten patients with severe OAT.

Intervention(s): Cytogenetic analyses by fluorescence in situ hybridization to determine aneuploidy frequencies for chromosomes 1, 13, 18, 21, X, and Y in sperm from swim-up and pellet fractions.

Main Outcome Measure(s): Gametic aneuploidy was scored in sperm fractions separated by the swim-up …

Stent Placement Compared With Balloon Angioplasty For Obstructed Coronary Bypass Grafts. Saphenous Vein De Novo Trial Investigators., M P Savage, J S Douglas, D L Fischman, C J Pepine, S B King, J A Werner, S R Bailey, P A Overlie, S H Fenton, J A Brinker, M B Leon, S Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Treatment of stenosis in saphenous-vein grafts after coronary-artery bypass surgery is a difficult challenge. The purpose of this study was to compare the effects of stent placement with those of balloon angioplasty on clinical and angiographic outcomes in patients with obstructive disease of saphenous-vein grafts.

METHODS: A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later.

RESULTS: As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate …

Disruption Of The Cbfa2 Gene Causes Necrosis And Hemorrhaging In The Central Nervous System And Blocks Definitive Hematopoiesis., Qing Wang, Terryl Stacy, Michael M Binder, Miguel Marin-Padilla, Arlene H. Sharpe, Nancy A. Speck

Dartmouth Scholarship

The CBFA2 (AML1) gene encodes a DNA-binding subunit of the heterodimeric core-binding factor. The CBFA2 gene is disrupted by the (8;21), (3;21), and (12;21) chromosomal translocations associated with leukemias and myelodysplasias in humans. Mice lacking a CBF alpha 2 protein capable of binding DNA die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS), at the nerve/CNS interfaces of cranial and spinal nerves, and in somitic/intersomitic regions along the presumptive spinal cord. Hemorrhaging is preceded by symmetric, bilateral necrosis in these regions. Definitive erythropoiesis and myelopoiesis do not occur in Cbfa2-deficient embryos, and disruption …

A Requirement For Bone Morphogenetic Protein-7 During Development Of The Mammalian Kidney And Eye., Andrew T. Dudley, K. M. Lyons, E. J. Robertson

Journal Articles: Genetics, Cell Biology & Anatomy

BMP-7/OP-1, a member of the transforming growth factor-beta (TGF-beta) family of secreted growth factors, is expressed during mouse embryogenesis in a pattern suggesting potential roles in a variety of inductive tissue interactions. The present study demonstrates that mice lacking BMP-7 display severe defects confined to the developing kidney and eye. Surprisingly, the early inductive tissue interactions responsible for establishing both organs appear largely unaffected. However, the absence of BMP-7 disrupts the subsequent cellular interactions required for their continued growth and development. Consequently, homozygous mutant animals exhibit renal dysplasia and anophthalmia at birth. Overall, these findings identify BMP-7 as an essential …

A Randomized Comparison Of Coronary-Stent Placement And Balloon Angioplasty In The Treatment Of Coronary Artery Disease. Stent Restenosis Study Investigators., David L. Fischman, Martin B. Leon, Donald S. Baim, Richard A. Schatz, Michael P. Savage, Ian Penn, Katherine Detre, Lisa Veltri, Donald Ricci, Masakiyo Nobuyoshi, Michael Cleman, Richard Heuser, David Almond, Paul S. Teirstein, R. David Fish, Antonio Colombo, Jeffrey Brinker, Jeffrey Moses, Alex Shaknovich, John Hirshfeld, Stephen Bailey, Stephen Ellis, Randal Rake, Sheldon Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes.

METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.

RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who …

Parentage Analysis With Genetic Markers In Natural Populations I The Expected Proportion Of Offspring With Unambiguous Paternity, R Chakraborty, T R Meagher, P E Smouse

Faculty, Staff and Student Publications

Recent studies indicate that polymorphic genetic markers are potentially helpful in resolving genealogical relationships among individuals in a natural population. Genetic data provide opportunities for paternity exclusion when genotypic incompatibilities are observed among individuals, and the present investigation examines the resolving power of genetic markers in unambiguous positive determination of paternity. Under the assumption that the mother for each offspring in a population is unambiguously known, an analytical expression for the fraction of males excluded from paternity is derived for the case where males and females may be derived from two different gene pools. This theoretical formulation can also be …

Genetics And Epidemiology Of Gallbladder Disease In New World Native Peoples, K M Weiss, R E Ferrell, C L Hanis, P N Styne

Faculty, Staff and Student Publications

Native peoples of the New World, including Amerindians and admixed Latin Americans such as Mexican-Americans, are highly susceptible to diseases of the gallbladder. These include cholesterol cholelithiasis (gallstones) and its complications, as well as cancer of the gallbladder. Although there is clearly some necessary dietary or other environmental risk factor involved, the pattern of disease prevalence is geographically associated with the distribution of genes of aboriginal Amerindian origin, and levels of risk generally correspond to the degree of Amerindian admixture. This pattern differs from that generally associated with Westernization, which suggests a gene-environment interaction, and that within an admixed population …

Genetically Controlled Variation Of “Acid” Beta-Galactosidase Detected In Rattus Norvegicus By Isoelectric Focusing, T C Douglas, K A Kimmel, P E Dawson

Faculty, Staff and Student Publications

Two genetically variant forms of rat "acid" beta-galactosidase were found to differ in isoelectric point and pH dependence, but not in thermostability or sensitivity to inhibition by p-mercuribenzoate (PMB). The results of two backcrosses and an intercross indicated that the isoelectric focusing phenotypes are controlled by two codominant alleles at a single autosomal locus, for which we propose the name Glb-1. No significant linkage between Glb-1 and albino (LG I), brown (LG II), or hooded (LG VI) was observed. Strain-specific differences in total levels of kidney beta-galactosidase were detected, but it is not yet known whether the variation is controlled …

Three Linked Enzyme Loci In Fishes: Implications In The Evolution Of Vertebrate Chromosomes, D C Morizot, D A Wright, M J Siciliano

Faculty, Staff and Student Publications

A three-point linkage group comprised of loci coding for adenosine deaminase (ADA), glucose-6-phosphate dehydrogenase (G6PDH), and 6-phospho-gluconate dehydrogenase (6PGD) is described in fish of the genus Xiphophorus (Poeciliidae). The alleles at loci in this group were shown to assort independently from the alleles at three other loci--isocitrate dehydrogenase 1 and 2, and glyceraldehyde-3-phosphate dehydrogenase 1. Alleles at the latter three loci also assort independently from each other. Data were obtained by observing the segregation of electrophoretically variant alleles in reciprocal backcross hybrids derived from crosses between either X. helleri guentheri or X. h. strigatus and X. maculatus. The linkage component …