A proposal for comprehensive biobank research laws to promote translational medicine in Indiana

Predictive Health Ethics Research (PredictER), funded by a grant from the Richard M. Fairbanks Foundation, Inc. Indianapolis

Cwatset Isomorphism and its Consequences

We explore the consequences of cwatset isomorphism (there are a finite number of non-isomorphic cwatsets of each order) and consider parallels between the theory of groups and the theory of cwatsets (cwatsets of prime order are cyclic but direct sums of isomorphic cwatsets aren\u27t necessarily isomorphic)

Report from the PredictER Expert Panel Meeting, November 2, 2007

On November 2, 2007, the Indiana University Center for Bioethics convened an expert panel on predictive health research (PHR) as part of the Center’s Program in Predictive Health Ethics Research (http://www.bioethics.iu.edu/predicter.asp) which is supported by a grant from the Richard M. Fairbanks Foundation. The goal of this meeting was to identify the major obstacles and opportunities for engaging the community in PHR. PredictER intends to use the results of this meeting as a first step toward more fully engaging the Indianapolis community in discussions about PHR.Richard M. Fairbanks Foundatio

Telomere Lengths, Pulmonary Fibrosis and Telomerase (<i>TERT</i>) Mutations

Background: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations.Methods and Findings: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively.Conclusions: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a “telomeropathy” caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.</p

Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations

mutations. mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point

Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses

ABSTRACTHelicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori-infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses