Application of combined omics platforms to accelerate biomedical discovery in diabesity

Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large-scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions. This report discusses how various types of omics data can be integrated to shed light on the changes in metabolism that occur in obesity and diabetes

Ronald V. Dellums v. George Bush (D.D.C. 1990): Memorandum Amicus Curiae of Law Professors

This joint memorandum is submitted to the court hearing Dellums v. Bush. This amicus brief advocates that the President may not order American armed forces to make war without consultation with and approval by Congress. The brief also argues that the case is justiciable

\u3cem\u3eRonald V. Dellums v. George Bush\u3c/em\u3e (D.D.C. 1990): Memorandum \u3cem\u3eAmicus Curiae\u3c/em\u3e of Law Professors

This joint memorandum is submitted to the court hearing Dellums v. Bush. This amicus brief advocates that the President may not order American armed forces to make war without consultation with and approval by Congress. The brief also argues that the case is justiciable

Clinical Trial Design and Development Work Group within the Quantitative Imaging Network

The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging. As a validation platform, the Group led a multireader study to test a semi-automated positron emission tomography quantification software. Clinical translation of QI tools cannot be possible without a continuing dialogue with clinical users. This article also highlights the outreach activities extended to cooperative groups and other organizations that promote the use of QI tools to support clinical decisions

Pediatric lung transplantation: The years 1985 to 1992 and the clinical trial of FK 506

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplantation program, which began in 1982. Twenty pediatric patients (age range 3 to 18 years) have had heart-lung (n = 11), double lung (n = 8), and single lung (n = 1) transplantation procedures. The causes of end-stage lung disease were primary pulmonary hypertension (n = 7), congenital heart disease (n = 5), cystic fibrosis (n = 4), pulmonary arteriovenous malformation (n = 2), graft- versus-host disease (n = 1), and desquamative interstitial pneumonitis (n = 1). Four (20%) patients had thoracic surgical procedures before the transplantation operation. The survival was 80% at a mean follow-up of 2 years. Immunosuppressive drugs included cyclosporine (n = 9) or FK 506 (n = 11) based therapy with azathioprine and steroids. Children were followed up by means of spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection was 1.4 at 30 days, 0.5 at 30 to 90 days, and 1.4 at more than 90 days, and the first treated rejection episode occurred on average 28 days after the operation. Obliterative bronchiolitis developed in four (25%) of 16 patients surviving more than 100 days. Results of pulmonary function tests have remained good in almost all recipients. The greatest infectious risk was that of cytomegalovirus: one death and one case of pneumonia. Posttransplantation lymphoproliferative disease was diagnosed in two (12.5%) patients; both recovered. The most common complications were hypertension (25%) and postoperative bleeding (15%). Early results indicate that lung transplantation is a most promising therapy for children with severe vascular and parenchymal lung disease

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies

The Vein Patterning 1 (VEP1) Gene Family Laterally Spread through an Ecological Network

Lateral gene transfer (LGT) is a major evolutionary mechanism in prokaryotes. Knowledge about LGT— particularly, multicellular— eukaryotes has only recently started to accumulate. A widespread assumption sees the gene as the unit of LGT, largely because little is yet known about how LGT chances are affected by structural/functional features at the subgenic level. Here we trace the evolutionary trajectory of VEin Patterning 1, a novel gene family known to be essential for plant development and defense. At the subgenic level VEP1 encodes a dinucleotide-binding Rossmann-fold domain, in common with members of the short-chain dehydrogenase/reductase (SDR) protein family. We found: i) VEP1 likely originated in an aerobic, mesophilic and chemoorganotrophic α-proteobacterium, and was laterally propagated through nets of ecological interactions, including multiple LGTs between phylogenetically distant green plant/fungi-associated bacteria, and five independent LGTs to eukaryotes. Of these latest five transfers, three are ancient LGTs, implicating an ancestral fungus, the last common ancestor of land plants and an ancestral trebouxiophyte green alga, and two are recent LGTs to modern embryophytes. ii) VEP1's rampant LGT behavior was enabled by the robustness and broad utility of the dinucleotide-binding Rossmann-fold, which provided a platform for the evolution of two unprecedented departures from the canonical SDR catalytic triad. iii) The fate of VEP1 in eukaryotes has been different in different lineages, being ubiquitous and highly conserved in land plants, whereas fungi underwent multiple losses. And iv) VEP1-harboring bacteria include non-phytopathogenic and phytopathogenic symbionts which are non-randomly distributed with respect to the type of harbored VEP1 gene. Our findings suggest that VEP1 may have been instrumental for the evolutionary transition of green plants to land, and point to a LGT-mediated ‘Trojan Horse’ mechanism for the evolution of bacterial pathogenesis against plants. VEP1 may serve as tool for revealing microbial interactions in plant/fungi-associated environments