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Proceedings of the 2015 National Toxicology Program Satellite Symposium.

The 2015 Annual National Toxicology Program Satellite Symposium, entitled &quot;Pathology Potpourri&quot; was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to present and discuss diagnostic pathology challenges or nomenclature issues. Because of the combined meeting, both laboratory and domestic animal cases were presented. This article presents summaries of the speakers’ talks, including challenging diagnostic cases or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included hepatocellular lesions, a proposed harmonized diagnostic approach to rat cardiomyopathy, crop milk in a bird, avian feeding accoutrement, heat exchanger in a tuna, metastasis of a tobacco carcinogen-induced pulmonary carcinoma, neurocytoma in a rat, pituicytoma in a rat, rodent mammary gland whole mounts, dog and rat alveolar macrophage ultrastructure, dog and rat pulmonary phospholipidosis, alveolar macrophage aggregation in a dog, degenerating yeast in a cat liver aspirate, myeloid leukemia in lymph node aspirates from a dog,Trypanosoma cruziin a dog, solanum toxicity in a cow, bovine astrovirus, malignant microglial tumor, and nomenclature challenges from the Special Senses International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Group.
© The Author(s) 2016.

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Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates.

THIOMAB drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.
Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.
An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.
Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence.

Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC withoutJAK2amplification. Detection ofJAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates ofJAK2amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available,JAK2amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines withJAK2copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore,JAK2amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors.
Copyright © 2016, American Association for the Advancement of Science.

A Selective V(1A) Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock.

Selective vasopressin V(1A) receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V(1A) receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model.
Randomized animal study.
University hospital animal research laboratory.
Forty-six adult female sheep.
Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 μg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours.
In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals.
In this clinically relevant model, selepressin, a selective V(1A) receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides.

Cancerous cells have an acutely increased demand for energy, leading to increased levels of human glucose transporter 1 (hGLUT1). This up-regulation suggests hGLUT1 as a target for therapeutic inhibitors addressing a multitude of cancer types. Here, we present three inhibitor-bound, inward-open structures of WT-hGLUT1 crystallized with three different inhibitors: cytochalasin B, a nine-membered bicyclic ring fused to a 14-membered macrocycle, which has been described extensively in the literature of hGLUTs, and two previously undescribed Phe amide-derived inhibitors. Despite very different chemical backbones, all three compounds bind in the central cavity of the inward-open state of hGLUT1, and all binding sites overlap the glucose-binding site. The inhibitory action of the compounds was determined for hGLUT family members, hGLUT1-4, using cell-based assays, and compared with homology models for these hGLUT members. This comparison uncovered a probable basis for the observed differences in inhibition between family members. We pinpoint regions of the hGLUT proteins that can be targeted to achieve isoform selectivity, and show that these same regions are used for inhibitors with very distinct structural backbones. The inhibitor cocomplex structures of hGLUT1 provide an important structural insight for the design of more selective inhibitors for hGLUTs and hGLUT1 in particular.