Web Services Technology Infrastructure

Web Services using eXtensible Markup Language (XML) based standards are becoming the new archetype for enabling business to business collaborations. This paper describes the conceptual architecture and semantics of constructing and consuming Web Services. It describes how Web Services fit into the enterprise application environment. It discusses Web Services security. Finally, it outlines the flaws of Web Services in their current state

Performance budgeting: Its rise and fall

Among various budgeting theories and practices at the federal level, performance budgeting has played an important role with its long developmental history. Performance budgeting was short-lived as it was replaced by program budgeting in the early 1960s. Looking at the period between the first decade of the twentieth century and the mid-1960s, the present paper seeks to investigate two major questions to which budgetary literature has given short shrift: 1) What forces led to the emergence of performance budgeting and its earlier forms?, and 2) Why did the budgeting practice fall into disfavor at the federal level shortly after a prolonged period to get institutionalized? The paper's investigation of the first question reveals three major factors that gave rise to performance budgeting and its forerunners: the rise of scientific management by Frederick Taylor, increasing public pressure on the government's role and practices, and the expansion of government responsibilities. Three principal opposing forces attributed to the long gestation of performance budgeting and its premature decline are its inherent weaknesses and limitations, the legislature's hostility to it, and the rapid rise of a new budgeting practice

Patient-Level Omics Data Analysis Identifies Gene-Specific Survival Associations for a PD-1/PD-L1 Network in Pleural Mesothelioma

Immune checkpoint blockade targeting PDCD1 (PD-1) or CD274 (PD-L1) has demonstrated efficacy and interest across multiple cancers. However, the exact determinants of the response and cancer-specific molecular features remain unclear. A recent pan-cancer study identified a PDCD1/CD274-related immunotherapy network of 40 genes that had differential patient survival associations across multiple cancers. However, the survival relevance of this network in mesothelioma could not be assessed due to a lack of available survival data for the mesothelioma study included. Mesothelioma, a rare cancer that most commonly arises in the pleural membranes around the lung, does have immune checkpoint blockade as an approved treatment strategy, yet questions over its efficacy remain. RNA-seq data from 87 pleural mesothelioma patients were interrogated on cBioPortal to assess the role of the PDCD1/CD274 network identified in a previous study, in addition to identifying repurposed drugs that may have therapeutic efficacy. Extensive literature searches were conducted to identify known information from the literature around the genes shown to impact patient survival (CCR5, GATD3A/GATD3, CXCR6, GZMA, and TBC1D10C). The same literature validation was performed for putative repurposed drugs that were identified as potential immunotherapeutic adjuvants in the context of mesothelioma (disulfiram, terfenadine, maraviroc, clioquinol, chloroxine, and oxyphenbutazone). Only disulfiram returned a specifically focused research article based on the literature search. This article demonstrated cytotoxicity in a panel of five human MPM cell lines of mixed histology (epithelioid, biphasic, and sarcomatoid). There was little information on the remaining five drugs, yet the clear preclinical efficacy of disulfiram validates the methodology used herein and prompts further exploration of the remaining drugs in mesothelioma. This study ultimately sheds light on novel preclinical information of genes related to PDCD1/CD274 in mesothelioma, as well as identifying putative drugs that may have therapeutic efficacy either independently or as an immunotherapeutic adjuvant

Molecular Mechanisms of PD-1 and PD-L1 Activity on a Pan-Cancer Basis: A Bioinformatic Exploratory Study

Immune checkpoint blockade targeting PD-1 (PDCD1)/PD-L1 (CD274) is increasingly used for multiple cancers. However, efficacy and adverse-related events vary significantly. This bioinformatic study interrogated molecular differences pertaining to PDCD1/CD274 and their correlated genes on a pan-cancer basis to identify differences between cancer types. Patient RNA-seq data from fifteen cancer types were accessed on cBioPortal to determine the role of PDCD1/CD274 in patient survival and to identify positively and negatively correlated genes, which were also assessed for clinical relevance. Genes correlating with PDCD1/CD274 across multiple cancers were taken forward for drug repurposing via DRUGSURV and microRNA analysis using miRDB and miRabel. MicroRNAs were also screened for clinical relevance using OncomiR. Forty genes were consistently correlated with PDCD1/CD274 across multiple cancers, with the cancers themselves exhibiting a differential role for the correlated genes in terms of patient survival. Esophageal and renal cancers in particular stood out in this regard as having a unique survival profile. Forty-nine putative microRNAs were identified as being linked to the PDCD1/CD274 network, which were taken forward and further assessed for clinical relevance using OncomiR and previously published literature. One hundred and thirty significant survival associations for 46 microRNAs across fourteen groups of cancers were identified. Finally, a total of 23 putative repurposed drugs targeting multiple components of the PDCD1/CD274 network were identified, which may represent immunotherapeutic adjuvants. Taken together, these results shed light on the varying PDCD1/CD274 networks between individual cancers and signpost a need for more cancer-specific investigations and treatments

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01–restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker

Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space

The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL; https://anvilproject.org) was developed to address a widespread community need for a unified computing environment for genomics data storage, management, and analysis. In this perspective, we present AnVIL, describe its ecosystem and interoperability with other platforms, and highlight how this platform and associated initiatives contribute to improved genomic data sharing efforts. The AnVIL is a federated cloud platform designed to manage and store genomics and related data, enable population-scale analysis, and facilitate collaboration through the sharing of data, code, and analysis results. By inverting the traditional model of data sharing, the AnVIL eliminates the need for data movement while also adding security measures for active threat detection and monitoring and provides scalable, shared computing resources for any researcher. We describe the core data management and analysis components of the AnVIL, which currently consists of Terra, Gen3, Galaxy, RStudio/Bioconductor, Dockstore, and Jupyter, and describe several flagship genomics datasets available within the AnVIL. We continue to extend and innovate the AnVIL ecosystem by implementing new capabilities, including mechanisms for interoperability and responsible data sharing, while streamlining access management. The AnVIL opens many new opportunities for analysis, collaboration, and data sharing that are needed to drive research and to make discoveries through the joint analysis of hundreds of thousands to millions of genomes along with associated clinical and molecular data types

Patient-Level Omics Data Analysis Identifies Gene-Specific Survival Associations for a PD-1/PD-L1 Network in Pleural Mesothelioma

Immune checkpoint blockade targeting PDCD1 (PD-1) or CD274 (PD-L1) has demonstrated efficacy and interest across multiple cancers. However, the exact determinants of the response and cancer-specific molecular features remain unclear. A recent pan-cancer study identified a PDCD1/CD274-related immunotherapy network of 40 genes that had differential patient survival associations across multiple cancers. However, the survival relevance of this network in mesothelioma could not be assessed due to a lack of available survival data for the mesothelioma study included. Mesothelioma, a rare cancer that most commonly arises in the pleural membranes around the lung, does have immune checkpoint blockade as an approved treatment strategy, yet questions over its efficacy remain. RNA-seq data from 87 pleural mesothelioma patients were interrogated on cBioPortal to assess the role of the PDCD1/CD274 network identified in a previous study, in addition to identifying repurposed drugs that may have therapeutic efficacy. Extensive literature searches were conducted to identify known information from the literature around the genes shown to impact patient survival (CCR5, GATD3A/GATD3, CXCR6, GZMA, and TBC1D10C). The same literature validation was performed for putative repurposed drugs that were identified as potential immunotherapeutic adjuvants in the context of mesothelioma (disulfiram, terfenadine, maraviroc, clioquinol, chloroxine, and oxyphenbutazone). Only disulfiram returned a specifically focused research article based on the literature search. This article demonstrated cytotoxicity in a panel of five human MPM cell lines of mixed histology (epithelioid, biphasic, and sarcomatoid). There was little information on the remaining five drugs, yet the clear preclinical efficacy of disulfiram validates the methodology used herein and prompts further exploration of the remaining drugs in mesothelioma. This study ultimately sheds light on novel preclinical information of genes related to PDCD1/CD274 in mesothelioma, as well as identifying putative drugs that may have therapeutic efficacy either independently or as an immunotherapeutic adjuvant