A Projection of Washington\u27s Financial Needs

This is a projection of the financial needs of the State of Washington over the next three biennial periods. It is intended to serve the practical need of observing current issues of state appropriations and financing in terms of apparent short-range trends. At the outset, it should be made clear that this effort is highly tentative. At the time of writing, basic data with respect to the trends that influence levels of governmental activity, both locally and statewide, fall far short of a desirable base for an accurate projection. Also, several possibilities for federal action which directly influence state and local outlays remain speculative

The Constitutional Aspects of Washington\u27s Fiscal Crisis

The aim of this paper is to sketch the scope and nature of the current problem, to explore the legal rigidities that dominate it, and to suggest the apparent steps prerequisite to realistic, durable and workable solutions

The Cost of Criminal Justice in West Virginia

The National Commission on Law Observance and Enforcement, generally known as the Wickersham Commission, is popularly associated with prohibition, as critic, protagonist, propagandist, or apologist, depending upon the point of view. The more fundamental aspects of its work have escaped popular attention. The first two reports dealt with the problem of national prohibition. Twelve more were devoted to other phases of crime and its treatment. Here attention is to be devoted to the Report on the Cost of Crime in an effort to determine the economic burden through taxation, private expenditures, and economic loss which results from the necessity of suppressing crime and correcting the criminal in modern society? The tremendous scope of this project is apparent to the most casual observer. Innumerable jurisdictions throughout the states are attempting, each in its own way with varying costs and equally varying success, to eliminate crime. The sheer expense of this effort must be a matter of wide concern. The determination of the cost of the administration of criminal justice reveals little aside from the approximate drain upon economic resources due to the perversity of humanity. It indicates, moreover, little of importance with regard to the absolute or even the comparative effectiveness of the governmental agency which happens to be the object of the expenditure. The infinite variety of conditions, not alone throughout the states, but even among the cities of the same state, makes practically barren any attempt to match against each other the cost elements of different jurisdictions. Such comparisons reveal only resultant conditions, but the causal factors are beclouded with influences beyond the application of statistical methods. To imply in variations of expense definite elements of causation would require that all factors be reduced to a basis of absolute equality. This is not possible. The degree of effectiveness of the discharge of governmental functions must, therefore, be measured in some other way. Cheap government is not necessarily good government, nor is costly government necessarily inefficient. False economy often masquerades as efficiency. The attempt to determine cost is limited to the measurement of what the crime bill of the nation is. Whether to accomplish the desired result it should be more or less than present figures show is quite another matter. The purpose of this paper is to assemble and present the elements of criminal cost which bear upon the State of West Virginia. The present writers co6perated with the directors of the national investigation of the cost of crime in studying conditions in certain municipalities of the State. At this time the results, hardly to be termed conclusions, are presented, together with other pertinent material which has been taken from the extensive national report. At the risk of incurring justifiable criticism for exaggerating the implications of these statistics, it is suggested that further study along these lines may contribute to a better planned and more effective administration of criminal justice in the wider field of social benefit in the State of West Virginia

Synthesis and Functionalization of Azetidine‐Containing Small Macrocyclic Peptides

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle

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

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

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