Case Western Reserve University

About: Case Western Reserve University is a education organization based out in Cleveland, Ohio, United States. It is known for research contribution in the topics: Population & Health care. The organization has 54617 authors who have published 106568 publications receiving 5071613 citations. The organization is also known as: Case & Case Western.

Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers

Abstract: Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer. Previ- ously however, we demonstrated that in many sporadic MSI colon cancers hMLH1 and all other DNA mismatch repair genes are wild type. To investigate this class of tumors further, we examined a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI- positive malignant tumors. In five of six such cases we found that hMLH1 protein was absent, even though hMLH1-coding sequences were wild type. In each such case, absence of hMLH1 protein was associated with the methylation of the hMLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expres- sion of the absent hMLH1 protein. Moreover, in single cell clones, hMLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of hMLH1 additionally accounted for the silencing of both maternal and paternal tumor hMLH1 alleles, both of which could be reactivated by 5-azacytidine. In summary, substantial numbers of human MSI cancers appear to arise by hMLH1 silencing via an epigenetic mechanism that can inactivate both of the hMLH1 alleles. Promoter methyl- ation is intimately associated with this epigenetic silencing mechanism.

Differential roles of microglia and monocytes in the inflamed central nervous system.

Abstract: In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Improved Survival Rates With Increased Neurodevelopmental Disability for Extremely Low Birth Weight Infants in the 1990s

Abstract: Background. Advances in perinatal care have resulted in increased survival rates for extremely low birth weight children. We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods, before and after the introduction of surfactant therapy in 1990. Methods. Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I (1982–1989) (mean body weight: 762 g; mean gestational age: 25.8 weeks) and 682 during period II (1990–1998) (mean body weight: 756 g; mean gestational age: 25.5 weeks). Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses, with adjustment for gestational age. Results. Survival rates increased from 49% during period I to 67% during period II. Neonatal morbidity rates also increased during period II, including rates of sepsis (from 37% to 51%), periventricular leukomalacia (from 2% to 7%), and chronic lung disease, defined as oxygen dependence at 36 weeks of corrected age (from 32% to 43%). Rates of severe cranial ultrasound abnormalities were similar (22% vs 22%). Among children monitored, the rate of neurologic abnormalities, including cerebral palsy, increased from 16% during period I to 25% during period II and the rate of deafness increased from 3% to 7%. The overall rate of neurodevelopmental impairment (major neurosensory abnormality and/or Bayley Mental Developmental Index score of Conclusions. The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment. Prospective parents of extremely low birth weight infants should be advised of this substantial risk, to facilitate decision-making in the delivery room.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management

Abstract: Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

Control of mucin-type O-glycosylation: A classification of the polypeptide GalNAc-transferase gene family

Abstract: Glycosylation of proteins is an essential process in all eukaryotes and a great diversity in types of protein glycosylation exists in animals, plants and microorganisms. Mucin-type O-glycosylation, consisting of glycans attached via O-linked N-acetylgalactosamine (GalNAc) to serine and threonine residues, is one of the most abundant forms of protein glycosylation in animals. Although most protein glycosylation is controlled by one or two genes encoding the enzymes responsible for the initiation of glycosylation, i.e. the step where the first glycan is attached to the relevant amino acid residue in the protein, mucin-type O-glycosylation is controlled by a large family of up to 20 homologous genes encoding UDP-GalNAc:polypeptide GalNAc-transferases (GalNAc-Ts) (EC 2.4.1.41). Therefore, mucin-type O-glycosylation has the greatest potential for differential regulation in cells and tissues. The GalNAc-T family is the largest glycosyltransferase enzyme family covering a single known glycosidic linkage and it is highly conserved throughout animal evolution, although absent in bacteria, yeast and plants. Emerging studies have shown that the large number of genes (GALNTs) in the GalNAc-T family do not provide full functional redundancy and single GalNAc-T genes have been shown to be important in both animals and human. Here, we present an overview of the GalNAc-T gene family in animals and propose a classification of the genes into subfamilies, which appear to be conserved in evolution structurally as well as functionally.