Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

Context: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED).

Objective: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED.

Design: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials.

In cancer, all roads lead to NADPH.

Cancer cells require increased levels of NADPH for increased nucleotide synthesis and for protection from ROS. Recent studies show that increased NADPH is generated in several ways. Activated AKT phosphorylates NAD kinase (NADK), increasing its activity.

Temporal trends in intake and outcome data for animal shelter and rescue facilities in Colorado from 2000 through 2015.

OBJECTIVE To measure temporal trends in animal shelter and rescue intakes and outcomes for dogs and cats in Colorado from 2000 through 2015 and compare trends from 2008 through 2015 with previously reported trends from 2000 through 2007. DESIGN Serial cross-sectional study. SAMPLE 76 animal shelter and rescue facilities with annual intake and outcome data consistently reported to the state of Colorado from 2000 through 2015.

A Randomized Controlled Trial of Animal-Assisted Therapy as an Adjunct to Intensive Family Preservation Services.

Method: Families referred by Child Protective Services ( M = 6 years ± 4; M = 32 years ± 8.26) were individually randomized to experimental ( n = 14) or control ( n = 14) intervention. Family functioning outcomes were measured using the North Carolina Family Assessment Scale for Reunification.

The relations among animal abuse, psychological disorders, and crime: Implications for forensic assessment.

The confluence of developments in the assessment of animal abuse, the evolution of psychiatric nosology for the diagnosis of conduct disorder, legislative changes involving crimes against non-human animals, and the recent inclusion of crimes against animals in the FBI's National Incident-Based Reporting System, highlights the critical need for examining the forensic dimensions of animal abuse cases. We provide an overview of the research literature on these topics in the hope that forensic evaluators will have an evidence-based framework for assessing cases they encounter that include perpetration of violence against animals.

Race and ethnicity are not primary determinants in utilizing veterinary services in underserved communities in the United States.

A retrospective database analysis (2011-2015) evaluated associations between race and ethnicity and veterinary service utilization by sampling 83,260 companion animals whose guardians (owners) self-identified as White, Black, or Latino/a from 39 Humane Society of the United States Pets for Life (PFL) sites across the United States. Controlling for socioeconomic status, the percentage of nonhuman animals sterilized through PFL whose owners were Latino/a or Black was substantially higher than in previously reported findings. While Latinos/as had the highest mean number of days from first contact with the program to consent, they also had the highest percentage of owners accepting the voucher during initial contact.

NAD+ Kinase as a Therapeutic Target in Cancer.

NAD kinase (NADK) catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide phosphate (NADP) using ATP as the phosphate donor. NADP is then reduced to NADPH by dehydrogenases, in particular glucose-6-phosphate dehydrogenase and the malic enzymes. NADPH functions as an important cofactor in a variety of metabolic and biosynthetic pathways.

Functional annotation of rare gene aberration drivers of pancreatic cancer.

As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy.

NAD(+) kinase (NADK) is the only known cytosolic enzyme that converts NAD(+) to NADP(+), which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS.

Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development.

Rapidly proliferating tumors attempt to meet the demands for nucleotide biosynthesis by upregulating folate pathways that provide the building blocks for pyrimidine and purine biosynthesis. In particular, the key role of mitochondrial folate enzymes in providing formate for de novo purine synthesis and for providing the one-carbon moiety for thymidylate synthesis has been recognized in recent studies. We have shown a significant correlation between the upregulation of the mitochondrial folate enzymes, high proliferation rates, and sensitivity to the folate antagonist methotrexate (MTX).

Quantification of folate metabolism using transient metabolic flux analysis.

Background: Systematic quantitative methodologies are needed to understand the heterogeneity of cell metabolism across cell types in normal physiology, disease, and treatment. Metabolic flux analysis (MFA) can be used to infer steady state fluxes, but it does not apply for transient dynamics. Kinetic flux profiling (KFP) can be used in the context of transient dynamics, and it is the current gold standard.

Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination.

Purpose: To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).

Methods: CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.

Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts.

Purpose: To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.

Methods: H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later.

The metabolic demands of cancer cells are coupled to their size and protein synthesis rates.

Background: Although cells require nutrients to proliferate, most nutrient exchange rates of the NCI60 panel of cancer cell lines correlate poorly with their proliferation rate. Here, we provide evidence indicating that this inconsistency is rooted in the variability of cell size.

Results: We integrate previously reported data characterizing genome copy number variations, gene expression, protein expression and exchange fluxes with our own measurements of cell size and protein content in the NCI60 panel of cell lines.

Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs.

Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin's lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses.

Overexpression of the mitochondrial folate and glycine-serine pathway: a new determinant of methotrexate selectivity in tumors.

Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to methotrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate.

Association of quarterly average achieved hematocrit with mortality in dialysis patients: a time-dependent comorbidity-adjusted model.

Background: Recent publications suggest that increased mortality is associated with high hematocrit targets in erythropoietin-stimulating agent-treated patients with chronic kidney disease. We aim to further inform the debate about optimal hematocrit targets, advancing the hypothesis that the current hematocrit target may not optimize the survival of patients with end-stage renal disease.

Study Design: Cross-sectional observational study.

Case-mix adjustment for an expanded renal prospective payment system.

Medicare is considering an expansion of the bundle of dialysis-related services to be paid on a prospective basis. Exploratory models were developed to assess the potential limitations of case-mix adjustment for such an expansion. A broad set of patient characteristics explained 11.

Understanding the basic case-mix adjustment for the composite rate.

In April 2005, Medicare began adjusting payments to dialysis providers for composite-rate services for a limited set of patient characteristics, including age, body surface area, and low body mass index. We present analyses intended to help the end-stage renal disease community understand the empirical reasons behind the new composite-rate basic case-mix adjustment. The U-shaped relationship between age and composite-rate cost that is reflected in the basic case-mix adjustment has generated significant discussion within the end-stage renal disease community.

Is case-mix adjustment necessary for an expanded dialysis bundle?

Congress has required CMS to expand the Medicare outpatient prospective payment system (PPS) for dialysis services to include as many drugs and diagnostic procedures provided to end stage renal disease (ESRD) patients as possible. One important implementation question is whether dialysis facility case mix should be reflected in payment. We use fiscal year (FY) 2000 cost report and patient billing and clinical data to determine the relationship between costs and case mix, as represented by several patient demographic, diagnostic, and clinical characteristics.

Characteristics of primary care physicians and their practices associated with mammography rates for older women.

Background: Mammography screening rates are below national recommendations for older women. Understanding the relation between the characteristics of primary care physicians (PCPs) and mammography rates for older women can help to target screening improvement efforts.

Methods: Subjects were 2527 PCPs practicing in Michigan between 1997 and 1998.

Personalized targeted mailing increases mammography among long-term noncompliant medicare beneficiaries: a randomized trial.

Objectives: The study purpose was to increase mammography screening among older women by identifying female Medicare beneficiaries without a recent mammogram and assesses the cost-effectiveness of a personalized targeted mailing encouraging them to have a mammogram.

Methods: A randomized paired controlled trial included 1229 pairs of women matched on zip code, race, and urban or rural county. Postintervention mammography claims were measured from November 1997 through December 1998.

5-Year mammography rates and associated factors for older women.

Background: Major national interventions occurred in the early and mid-1990s to increase mammography screening rates among older women. The current study examined mammography utilization by older women during this period. Relation between mammography utilization and demographic measures and health care-related factors also were examined.