141 research outputs found
Acidity Studies of Deuterated Acids and Bases Commonly Used as Buffers in NMR Studies
Structure based drug development is currently considered to be an important strategy for drug discovery. This strategy requires that critical knowledge of the three dimensional binding site on receptor molecules be known. NMR studies are frequently employed to ascertain important structural data on individual proteins as well as complexes of proteins with ligands. Deuterium labeled acids and bases are frequently used as buffers in deuterium oxide solutions for NMR studies on the structural conformations of bioactive molecules. Since pH is an important factor in any study of the conformational and stereochemical aspects of biologically active molecules, deuterated buffers are an essential part of the NMR experiments. However, the ionization constant for deuterium oxide (1.95 x 1015) is significantly different from that of water. Therefore, a pH comparison of deuterium-labeled acids and bases in deuterium oxide with nondeuterated aqueous acids and bases was conducted. Titration curve comparisons for deuterated and nondeuterated hydrochloric acid, acetic acid, sodium formate, and TRIS (tris[hydroxymethyl] amino methane) are described. Also, the average pKas of deuterated and non-deuterated acetic acid, formic acid, and TRIS are compared
Preparation of Novel Hydroxyethyl Amine Isosteres as Potential Cathepsin D Inhibitors
Cathepsin D is a lysosomal aspartic protease found in all mammalian cells and is considered to be one of the main catabolic proteinases. Cathepsin D has been suggested to play a role in the metastatic potential of several types of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer, and ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D inactivity, such as the HIV-1 aspartyl protease. We have undertaken the design, via computer molecular modeling, and the synthesis of (hydroxyethyl) amine isostere inhibitors, which are similar to potent inhibitors of the aspartyl HIV-1 protease. We now report the preparation of six compounds that contain novel hydroxyethyl isosteres with cyclic tertiary amines
Co-polymers of Furan with Pyrrole or Thiophene: A Synthetic Study
The use of conductive polymers as a substitute for metallic conductors and semiconductors has attracted much attention in the literature. In particular, aromatic heterocyclic polymers constitute an important class since they possess chemical and electrical stability in both the oxidized (doped) and neutral (undoped) state. Doping a polymer allows one to vary its electrical, mechanical, optical, and thermal properties. The properties of these polymers are promising for their many technological uses such as antistatic coatings, solar cells, and electronic devises. Polyfuran is among the least common heterocyclic polymers. Polyfuran has been reported to be much less stable that either polypyrrole or polythiophene. The preparation of co-polymers of polyfuran with two percent pyrrole or thiophene is reported. The polymers are characterized by *HNMR, IR, and ESR spectroscopy, and the electrical conductivity of the doped and un-doped synthetic polyfuran and co-polymers is provided
Synthesis and Evaluation of New Cathepsin D Inhibitors
Cathepsin D, a lysosomal aspartic protease, has been suggested to play a role in the metastatic potential of several types of cancer A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer, and ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases, such as cathepsin D and the HIV1 aspartyl protease. Also cathepsin D has recently been associated with the development of Alzheimer\u27s disease. Specific proteinase inhibitors, useful in investigations of the mechanisms and pathways of intracellular protein degradation, could lead to the development of therapeutic agents for treatment of many types of carcinomas as well as Alzheimer\u27s disease. The design and the synthesis of (hydroxyethyl)amine isostere inhibitors with the cyclic tertiary amines is described. The IC-50 and apparent Ki values for several cathepsin D inhibitors are reported
The First Hour of Extra-galactic Data of the Sloan Digital Sky Survey Spectroscopic Commissioning: The Coma Cluster
On 26 May 1999, one of the Sloan Digital Sky Survey (SDSS) fiber-fed
spectrographs saw astronomical first light. This was followed by the first
spectroscopic commissioning run during the dark period of June 1999. We present
here the first hour of extra-galactic spectroscopy taken during these early
commissioning stages: an observation of the Coma cluster of galaxies. Our data
samples the Southern part of this cluster, out to a radius of 1.5degrees and
thus fully covers the NGC 4839 group. We outline in this paper the main
characteristics of the SDSS spectroscopic systems and provide redshifts and
spectral classifications for 196 Coma galaxies, of which 45 redshifts are new.
For the 151 galaxies in common with the literature, we find excellent agreement
between our redshift determinations and the published values. As part of our
analysis, we have investigated four different spectral classification
algorithms: spectral line strengths, a principal component decomposition, a
wavelet analysis and the fitting of spectral synthesis models to the data. We
find that a significant fraction (25%) of our observed Coma galaxies show signs
of recent star-formation activity and that the velocity dispersion of these
active galaxies (emission-line and post-starburst galaxies) is 30% larger than
the absorption-line galaxies. We also find no active galaxies within the
central (projected) 200 h-1 Kpc of the cluster. The spatial distribution of our
Coma active galaxies is consistent with that found at higher redshift for the
CNOC1 cluster survey. Beyond the core region, the fraction of bright active
galaxies appears to rise slowly out to the virial radius and are randomly
distributed within the cluster with no apparent correlation with the potential
merger of the NGC 4839 group. [ABRIDGED]Comment: Accepted in AJ, 65 pages, 20 figures, 5 table
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images
of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL
maps are derived through computational staining using a convolutional neural network trained to
classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and
correlation with overall survival. TIL map structural patterns were grouped using standard
histopathological parameters. These patterns are enriched in particular T cell subpopulations
derived from molecular measures. TIL densities and spatial structure were differentially enriched
among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial
infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic
patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for
the TCGA image archives with insights into the tumor-immune microenvironment
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