Longitudinal Assessment of Growth in Hypoplastic Left Heart Syndrome: Results From the Single Ventricle Reconstruction Trial

Background: We sought to characterize growth between birth and age 3 years in infants with hypoplastic left heart syndrome who underwent the Norwood procedure. Methods and Results: We performed a secondary analysis using the Single Ventricle Reconstruction Trial database after excluding patients 2 SD below normal). Failure to find consistent risk factors supports the strategy of tailoring nutritional therapies to patient‐ and stage‐specific targets. Clinical Trial Registration URL: http://clinicaltrials.gov/. Unique identifier: NCT00115934

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes

<div><p>Type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with functional beta cell loss due to ongoing inflammation. Despite shared similarities, T1D is an autoimmune disease with evidence of autoantibody production, as well as a role for exocrine pancreas involvement. Our hypothesis is that differential protein expression occurs in disease stratified pancreas tissues and regulated proteins from endocrine and exocrine tissues are potential markers of disease and potential therapeutic targets. The study objective was to identify novel proteins that distinguish the pancreas from donors with T1D from the pancreas from patients with T2D, or autoantibody positive non-diabetic donors. Detailed quantitative comprehensive proteomic analysis was applied to snap frozen human pancreatic tissue lysates from organ donors without diabetes, with T1D-associated autoantibodies in the absence of diabetes, with T1D, or with T2D. These disease-stratified human pancreas tissues contain exocrine and endocrine tissues (with dysfunctional islets) in the same microenvironment. The expression profiles of several of the proteins were further verified by western blot. We identified protein panels that are significantly and uniquely upregulated in the three disease-stratified pancreas tissues compared to non-disease control tissues. These proteins are involved in inflammation, metabolic regulation, and autoimmunity, all of which are pathways linked to, and likely involved in, T1 and T2 diabetes pathogenesis. Several new proteins were differentially upregulated in prediabetic, T1D, and T2D pancreas. The results identify proteins that could serve as novel prognostic, diagnostic, and therapeutic tools to preserve functional islet mass in Type 1 Diabetes.</p></div

Obesity adversely affects survival in pancreatic cancer patients

Background: Higher body-mass index (BMI) has been implicated as a risk factor for developing pancreatic cancer, but its effect on survival has not been thoroughly investigated. The authors assessed the association of BMI with survival in a sample of pancreatic cancer patients and used epidemiologic and clinical information to understand the contribution of diabetes and hyperglycemia. Methods: A survival analysis using Cox proportional hazards by usual adult BMI was performed on 1861 unselected patients with pancreatic adenocarcinoma; analyses were adjusted for covariates that included clinical stage, age, and sex. Secondary analyses incorporated self-reported diabetes and fasting blood glucose in the survival model. RESULTS: BMI as a continuous variable was inversely associated with survival from pancreatic adenocarcinoma (hazard ratio [HR], 1.019 for each increased unit of BMI [kg/m2], P \u3c.001) after adjustment for age, stage, and sex. In analysis by National Institutes of Health BMI category, BMIs of 30 to 34.99 kg/m2 (HR, 1.14; 95% confidence interval [CI], 0.98-1.33), 35 to 39.99 kg/m2 (HR 1.32, 95% CI 1.08-1.62), and ≥40 (HR 1.60, 95% CI 1.26-2.04) were associated with decreased survival compared with normal BMI of 18.5 to 24.99 kg/m 2 (overall trend test P \u3c.001). Fasting blood glucose and diabetes did not affect the results. CONCLUSIONS: Higher BMI is associated with decreased survival in pancreatic cancer. Although the mechanism of this association remains undetermined, diabetes and hyperglycemia do not appear to account for the observed association. © 2010 American Cancer Society

Functional categories and biological processes of all the proteins that are identified in ND, AAb+, T1D and T2D cases.

<p>Functional categories and biological processes of all the proteins that are identified in ND, AAb+, T1D and T2D cases.</p

Validation of differentially upregulated of specific proteins in pancreas tissue lysates.

<p>Normalized total protein lysates from pooled normal, Aab+, T1D and T2D samples were subjected Western blot analysis to detect for REGIIIα/γ (Panel A), Olfactomedin 4 (Panel B), and ENPP1 (Panel C),, . GAPDH detection was included as a loading control. ImageJ analysis was used to confirm the expression of the three proteins after normalization using GAPDH values. The bar graphs represent data from triplicate analyses.</p

(A) Venn diagram comparison of uniquely upregulated proteins in AAb+, T1D and T2D cases compared to ND.

<p>The cut-off for the threshold fold change differences were ≥ 2.0 for upregulation with p- values < 0.05. <b>(B).</b> Ingenuity pathway analysis showing top interaction network for uniquely upregulated proteins in AAb+ cases. Those highlighted with red color are upregulated genes and those with green are downregulated genes. The names of these genes are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135663#pone.0135663.s018" target="_blank">S8 Table</a>.</p

(A) Ingenuity pathway analysis showing top interaction network for differentially regulated proteins in AAb+ cases.

<p>Those highlighted with red color are upregulated genes and those with green are downregulated genes. The names of these genes are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135663#pone.0135663.s017" target="_blank">S7 Table</a>. (<b>B).</b> Ingenuity pathway analysis depicting the activated transcription factor KDM5B) in AAb+ cases when compared to controls. This leads to the inhibition of FHL1, IARS2, ARL6IP5, PSIP1 and PRPS1.</p