Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation.

Utilization of data from historical control animals to form virtual control groups (VCGs) is an innovative approach to embody the 3Rs (reduce, refine, and replace use of control animals) principle in research. However, there is no available systematic comparison of statistical performance between concurrent control groups (CCGs) and VCGs in nonrodent safety assessment. The optimal selection criteria and combination of VCGs and CCGs also remain unclear.

Regulated dynamic subcellular GLUT4 localization revealed by proximal proteome mapping in human muscle cells.

Regulation of glucose transport, which is central for control of whole-body metabolism, is determined by the amount of GLUT4 glucose transporter (also known as SLC2A4) in the plasma membrane (PM) of fat and muscle cells. Physiologic signals [such as activated insulin receptor or AMP-activated protein kinase (AMPK)] increase PM GLUT4. Here, we show that the distribution of GLUT4 between the PM and interior of human muscle cells is dynamically maintained, and that AMPK promotes PM redistribution of GLUT4 by regulating exocytosis and endocytosis.

GLUT4 dynamic subcellular localization is controlled by AMP kinase activation as revealed by proximal proteome mapping in human muscle cells.

Regulation of glucose transport into muscle and adipocytes, central for control of whole-body metabolism, is determined by the amount of GLUT4 glucose transporter in the plasma membrane ( ). Physiologic signals (activated insulin receptor or AMP kinase [ ]), acutely increase PM GLUT4 to enhance glucose uptake. Here we show in kinetic studies that intracellular GLUT4 is in equilibrium with the PM in unstimulated cultured human skeletal muscle cells, and that AMPK promotes GLUT4 redistribution to the PM by regulating both exocytosis and endocytosis.

A Novel C-C Chemoattractant Cytokine (Chemokine) Receptor 6 (CCR6) Antagonist (PF-07054894) Distinguishes between Homologous Chemokine Receptors, Increases Basal Circulating CCR6 T Cells, and Ameliorates Interleukin-23-Induced Skin Inflammation.

Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) receptor (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C chemoattractant cytokine (chemokine) receptor (CXCR) 2 in a -arrestin assay panel of 168 G protein-coupled receptors. Inhibition of CCR6-mediated human T cell chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) was insurmountable by CCR6 ligand, C-C motif ligand (CCL) 20.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease.

Clinical utility of a serum biomarker panel in distinguishing prostate cancer from benign prostate hyperplasia.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.

Characterization of cachexia in the human fibrosarcoma HT-1080 mouse tumour model.

Background: Cancer cachexia is a complex metabolic disease with unmet medical need. Although many rodent models are available, none are identical to the human disease. Therefore, the development of new preclinical models that simulate some of the physiological, biochemical, and clinical characteristics of the human disease is valuable.

Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion.

The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions.

Clinical Validation of a Serum Protein Panel (FLNA, FLNB and KRT19) for Diagnosis of Prostate Cancer.

This study reports on the development of a novel serum protein panel of three prostate cancer biomarkers, Filamin A, Filamin B and Keratin-19 (FLNA, FLNB and KRT19) using multivariate models for disease screening and prognosis. ELISA and IPMRM (LC-MS/MS) based assays were developed and analytically validated by quantitative measurements of the biomarkers in serum. Retrospectively collected and clinically annotated serum samples with PSA values and Gleason scores were analyzed from subjects who underwent prostate biopsy, and showed no evidence of cancer with or without indication of prostatic hyperplasia, or had a definitive pathology diagnosis of prostatic adenocarcinoma.

Non-obvious correlations to disease management unraveled by Bayesian artificial intelligence analyses of CMS data.

Objective: Given the availability of extensive digitized healthcare data from medical records, claims and prescription information, it is now possible to use hypothesis-free, data-driven approaches to mine medical databases for novel insight. The goal of this analysis was to demonstrate the use of artificial intelligence based methods such as Bayesian networks to open up opportunities for creation of new knowledge in management of chronic conditions.

Materials And Methods: Hospital level Medicare claims data containing discharge numbers for most common diagnoses were analyzed in a hypothesis-free manner using Bayesian networks learning methodology.

Fosaprepitant for the prevention of nausea and vomiting in patients receiving BEAM or high-dose melphalan before autologous hematopoietic stem cell transplant.

Purpose: To assess the impact of single-dose fosaprepitant on nausea and emesis after BEAM and high-dose melphalan conditioning regimens for autologous hematopoietic stem cell transplantation.

Methods: In a single-center cohort study patients receiving melphalan containing hematopoietic stem cell transplantation regimens who received a one-time dose of 150 mg IV fosaprepitant (n = 56) were compared to a historical control (n = 70).

Results: The primary endpoint of no emesis from melphalan administration through five days afterward was 80% for the fosaprepitant group versus 66% in the control group (p = 0.

Polymorphic Amplified Typing Sequences (PATS) Strain Typing System Accurately Discriminates a Set of Temporally and Spatially Disparate Escherichia coli O157 Isolates Associated with Human Infection.

Polymorphic Amplified Typing Sequences (PATS) is a PCR-based Escherichia coli O157 (O157) strain typing system. Here, we show that PATS compares excellently with Pulsed-Field Gel Electrophoresis (PFGE) in that both methods cluster geographically diverse O157 isolates similarly. Comparative analysis of the results obtained in this simulated "blind" study attests to the discriminating power and applicability of PATS to epidemiological/nosocomial situations.

Polymorphic Amplified Typing Sequences and Pulsed-Field Gel Electrophoresis Yield Comparable Results in the Strain Typing of a Diverse Set of Bovine Escherichia coli O157:H7 Isolates.

Polymorphic amplified typing sequences (PATS), a PCR-based Escherichia coli O157:H7 (O157) strain typing system, targets insertions-deletions and single nucleotide polymorphisms at XbaI and AvrII restriction enzyme sites, respectively, and the virulence genes (stx1, stx2, eae, hlyA) in the O157 genome. In this study, the ability of PATS to discriminate O157 isolates associated with cattle was evaluated. An in-depth comparison of 25 bovine O157 isolates, from different geographic locations across Northwest United States, showed that about 85% of these isolates shared the same dendogram clade by PATS and pulsed-field gel electrophoresis (PFGE), irrespective of the restriction enzyme sites targeted.

Label-free detection of micro-RNA hybridization using surface-enhanced Raman spectroscopy and least-squares analysis.

Label-free surface-enhanced Raman spectroscopy (SERS) detection of nucleic acid hybridization is impeded by poor spectral reproducibility and the fact that the chemical signatures of hybridized and unhybridized sequences are highly similar. To overcome these issues, highly reproducible silver nanorod SERS substrates along with a straightforward least-squares (LS) technique have been employed for the quantitative determination of the relative ratios of the four nucleotide components A, C, G, and T/U before and after hybridization using a clinically relevant micro-RNA sequence.

Racial disparities and barriers to colorectal cancer screening in rural areas.

Introduction: This study examined barriers to colorectal cancer (CRC) screening in people living in rural areas.

Methods: We identified 2 rural counties with high rates of CRC and randomly contacted county residents by telephone using a published listing.

Results: Six hundred thirty-five of the 1839 eligible respondents (34.

Dynamic rastering surface-enhanced Raman scattering (SERS) measurements on silver nanorod substrates.

Surface-enhanced Raman spectra of a thiol-modified biotin derivative on oblique-angle-deposited silver nanorod (AgNR) array substrates were measured using both static and rotating rastering methods. We find that the rotating rastering method has a strong tendency to decrease the point-to-point relative standard deviation (RSD) compared to static measurements as well as decrease the effects of cumulative excitation exposure. The AgNR substrates treated with the modified biotin typically demonstrate intra-substrate RSDs of <10%, with an average RSD of ∼3% when the rastering radius r=1 mm.

The relationship of a diabetes telehealth eye care program to standard eye care and change in diabetes health outcomes.

Several studies suggest that telehealth eye care programs that combine retinal imaging, education, and some care management can improve patient adherence to annual, comprehensive eye examinations and follow-up treatments. Little is known, however, about whether such programs relate to other, more distal outcomes that affect diabetic eye disease, such as blood glucose control. This paper assesses the relationship of participation in a diabetes telehealth eye care program with standard, face-to-face eye care as well as improvements in other diabetes-related health outcomes.

Identification of a protein subset of the anthrax spore immunome in humans immunized with the anthrax vaccine adsorbed preparation.

We identified spore targets of Anthrax Vaccine Adsorbed (AVA)-induced immunity in humans by screening recombinant clones of a previously generated, limited genomic Bacillus anthracis Sterne (pXO1(+), pXO2(-)) expression library of putative spore surface (spore-associated [SA]) proteins with pooled sera from human adults immunized with AVA (immune sera), the anthrax vaccine currently approved for use by humans in the United States. We identified 69 clones that reacted specifically with pooled immune sera but not with pooled sera obtained from the same individuals prior to immunization. Positive clones expressed proteins previously identified as localized on the anthrax spore surface, proteins highly expressed during spore germination, orthologs of proteins of diverse pathogens under investigation as drug targets, and orthologs of proteins contributing to the virulence of both gram-positive and gram-negative pathogens.