Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model.

EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated toxin.

Expression and high levels of insertional polymorphism of an endogenous gammaretrovirus lineage in dogs.

Despite the absence of a confirmed exogenously replicating retrovirus in Canis lupus familiaris (C. familiaris), past retroviral infections are evident in the genomes of living animals via the presence of endogenous retroviruses (ERVs). Although gammaretrovirus-like transcripts and enzyme activities were previously reported to be present in canine leukemias and lymphomas, those findings were not further explored.

Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma.

A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma.

Bioapplications of Magnetic Nanowires: Barcodes, Biocomposites, Heaters.

Magnetic nanowires (MNWs) can have their moments reversed via several mechanisms that are controlled using the composition, length, diameter, and density of nanowires in arrays as-synthesized or as individual nanoparticles in assays or gels. This tailoring of magnetic reversal leads to unique properties that can be used as a signature for reading out the type of MNW for applications as nano-barcodes. When synthesized inside track-etched polycarbonate membranes, the resulting MNW-embedded membranes can be used as biocompatible bandaids for detection without contact or optical sighting.

Increased risk of cancer in dogs and humans: a consequence of recent extension of lifespan beyond evolutionarily-determined limitations?

Cancer is among the most common causes of death for dogs (and cats) and humans in the developed world, even though it is uncommon in wildlife and other domestic animals. We provide a rationale for this observation based on recent advances in our understanding of the evolutionary basis of cancer. Over the course of evolutionary time, species have acquired and fine-tuned adaptive cancer protective mechanisms that are intrinsically related to their energy demands, reproductive strategies, and expected lifespan.

Evaluation of coated platelets, a subset of highly procoagulant platelets, in healthy dogs and dogs with neoplasia.

Objective: To determine if dogs with neoplasia produce more coated platelets, a subpopulation of activated platelets generated by dual stimulation with thrombin and convulxin, a glycoprotein VI agonist, than healthy control dogs.

Animals: Client-owned dogs diagnosed with lymphoma (n = 19) or solid tumors (14) and healthy control dogs (14).

Procedures: Platelets were stimulated ex vivo with thrombin and convulxin.

Targeted sequencing of candidate gene regions for myelofibrosis in dogs.

Background: Myelofibrosis often lacks an identifiable cause in dogs. In humans, most primary myelofibrosis cases develop secondary to driver mutations in JAK2, CALR, or MPL.

Objectives: To determine the prevalence of variants in JAK2, CALR, or MPL candidate regions in dogs with myelofibrosis and in healthy dogs.

Examination of IgG Fc Receptor CD16A and CD64 Expression by Canine Leukocytes and Their ADCC Activity in Engineered NK Cells.

Human natural killer (NK) cells can target tumor cells in an antigen-specific manner by the recognition of cell bound antibodies. This process induces antibody-dependent cell-mediated cytotoxicity (ADCC) and is exclusively mediated by the low affinity IgG Fc receptor CD16A (FcγRIIIA). Exploiting ADCC by NK cells is a major area of emphasis for advancing cancer immunotherapies.

Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning.

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools.

Extracellular Vesicles Secreted by Tumor Cells Promote the Generation of Suppressive Monocytes.

Monocytes are among the first cells to infiltrate the tumor microenvironment. The conversion of monocytes to suppressor cells in the tumor microenvironment is crucial in evasion of the immune response and tumor maintenance. Tumor cells may secrete products that promote the conversion of monocytes to suppressor cells.

Retrospective evaluation of thrombocytopenia and tumor stage as prognostic indicators in dogs with splenic hemangiosarcoma.

Objective: To identify physical examination and perioperative CBC variables in dogs with splenic hemangiosarcoma (HSA) that could aid in predicting progression-free interval (PFI) and overall survival time (OST) in affected dogs.

Animals: 70 client-owned dogs with splenic HSA treated with splenectomy and chemotherapy between September 2004 and October 2016.

Procedures: A retrospective search of the University of Minnesota Veterinary Medical Center medical records database was performed to identify dogs with splenic HSA treated with splenectomy and with evidence in the medical records of intent to treat with chemotherapy.

Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions.

Sporadic angiosarcomas are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic angiosarcomas. In this study, we leveraged RNA-sequencing data from 13 human angiosarcomas and 76 spontaneous canine hemangiosarcomas to identify fusion genes associated with spontaneous vascular malignancies.

Ectodomain shedding by ADAM17 (a disintegrin and metalloproteinase 17) in canine neutrophils.

ADAM17 is a transmembrane protease expressed by most cells in humans and mice that cleaves cell surface substrates primarily in a cis manner, a process referred to as ectodomain shedding. ADAM17 has numerous substrates and plays a broad role in various physiological processes, including as a key regulator of inflammation. At this time, little is known about ADAM17 expression and function in dogs.

Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma.

Osteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor protein p53 (TP53) is nearly universal other high frequency mutations or structural variations have not been identified.

Isolation of Cancer-Derived Exosomes Using a Variety of Magnetic Nanostructures: From FeO Nanoparticles to Ni Nanowires.

Isolating and analyzing tumor-derived exosomes (TEX) can provide important information about the state of a tumor, facilitating early diagnosis and prognosis. Since current isolation methods are mostly laborious and expensive, we propose herein a fast and cost-effective method based on a magnetic nanoplatform to isolate TEX. In this work, we have tested our method using three magnetic nanostructures: (i) Ni magnetic nanowires (MNWs) (1500 × 40 nm), (ii) FeO nanorods (NRs) (41 × 7 nm), and (iii) FeO cube-octahedral magnetosomes (MGs) (45 nm) obtained from magnetotactic bacteria.

Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors.

Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target.

Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer.

Background: Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations.

S100A4 mRNA-protein relationship uncovered by measurement noise reduction.

Intrinsic biological fluctuation and/or measurement error can obscure the association of gene expression patterns between RNA and protein levels. Appropriate normalization of reverse-transcription quantitative PCR (RT-qPCR) data can reduce technical noise in transcript measurement, thus uncovering such relationships. The accuracy of gene expression measurement is often challenged in the context of cancer due to the genetic instability and "splicing weakness" involved.

Impact of repeated cycles of EGF bispecific angiotoxin (eBAT) administered at a reduced interval from doxorubicin chemotherapy in dogs with splenic haemangiosarcoma.

We previously reported that eBAT, an EGF-targeted angiotoxin, was safe and it improved the overall survival for dogs with splenic haemangiosarcoma when added to the standard of care in a single cycle of three administrations in the minimal residual disease setting. Our objective for the SRCBST-2 trial was to assess whether increased dosing through multiple cycles of eBAT would be well tolerated and would further enhance the benefits of eBAT. Eligibility was expanded to dogs with stage 3 haemangiosarcoma, provided that gross lesions could be surgically excised.

Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression.