Like all organisms on the planet, environmental microbes are subject to the forces of molecular evolution. Metagenomic sequencing provides a means to access the DNA sequence of uncultured microbes. By combining DNA sequencing of microbial communities with evolutionary modeling and phylogenetic analysis we might obtain new insights into microbiology and also provide a basis for practical tools such as forensic pathogen detection.In this work we present an approach to leverage phylogenetic analysis of metagenomic sequence data to conduct several types of analysis. First, we present a method to conduct phylogeny-driven Bayesian hypothesis tests for the presence of an organism in a sample. Second, we present a means to compare community structure across a collection of many samples and develop direct associations between the abundance of certain organisms and sample metadata. Third, we apply new tools to analyze the phylogenetic diversity of microbial communities and again demonstrate how this can be associated to sample metadata.These analyses are implemented in an open source software pipeline called PhyloSift. As a pipeline, PhyloSift incorporates several other programs including LAST, HMMER, and pplacer to automate phylogenetic analysis of protein coding and RNA sequences in metagenomic datasets generated by modern sequencing platforms (e.g., Illumina, 454).
Serious leukostasis-related complications are relatively uncommon in childhood ALL and most occur at presentation. Their incidence increases in proportion to the leukocyte count. A large subset of cases can be managed successfully without cytoreduction. Cytoreduction may be considered for patients with leukocyte counts >400 x 10(9)/L or patients who have complications at presentation.
Background-Anaplastic large cell lymphoma (ALCL) is characterized by advanced disease at presentation (70-80% of pediatric cases) and accounts for 10-15% of all childhood lymphomas. Treatment strategies for pediatric ALCL vary from short pulse B-NHL chemotherapy to prolonged leukemia like therapy. The optimal treatment strategy is unknown.
Summary. Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin‐like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T‐cell‐depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T‐cell alloreactivity. We investigated the relative significance of NK‐cell and T‐cell alloreactivity in 105 paediatric patients who received a minimally T‐cell‐depleted human leucocyte antigen‐non‐identical BM transplantation. Donor NK‐cell incompatibility did not improve patient outcome [engraftment, graft‐versus‐host disease (GVHD), relapse or overall survival]. In contrast, donor T‐cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T‐cell alloreactivity dominated that of NK cells in minimally T‐cell‐depleted grafts.
Selective
immunoproteasome inhibition is a promising approach for treating
autoimmune disorders, but optimal proteolytic active site subunit
inhibition profiles remain unknown. We reveal here our design of peptide
epoxyketone-based selective low molecular mass polypeptide-7 (LMP7)
and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit
inhibitors. Utilizing these and our previously disclosed low molecular
mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement
of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent
cytokine expression inhibition and in vivo efficacy in an inflammatory
disease model. These and additional findings toward optimized solubility
led the design and selection of KZR-616 disclosed here and presently
in clinical trials for treatment of rheumatic disease.
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().
Summary
Anaplastic large cell lymphoma (ALCL) comprises 10–15% of childhood non‐Hodgkin lymphomas (NHL). Systemic ALCL is highly associated with anaplastic lymphoma kinase (ALK) gene translocations with over‐expression of ALK protein. We studied ALK rearrangements using fluorescence in situ hybridisation (FISH) and ALK immunohistochemical staining in 43 paediatric systemic ALCLs. FISH (performed on 35 cases) identified a translocation in 29 cases (83%). Immunohistochemistry identified ALK over‐expression in 42/43 cases (97%) with the single ALK‐negative case demonstrating an ALK rearrangement by FISH, indicating 100% incidence of ALK translocations.
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