A xenotransplantation mouse model to study physiology of the mammary gland from large mammals.

Although highly conserved in structure and function, many (patho)physiological processes of the mammary gland vary drastically between mammals, with mechanisms regulating these differences not well understood. Large mammals display variable lactation strategies and mammary cancer incidence, however, research into these variations is often limited to in vitro analysis due to logistical limitations. Validating a model with functional mammary xenografts from cryopreserved tissue fragments would allow for in vivo comparative analysis of mammary glands from large and/or rare mammals and would improve our understanding of postnatal development, lactation, and premalignancy across mammals.

Comparative Analysis of microRNAs that Stratify in vitro Mammary stem and Progenitor Activity Reveals Functionality of Human miR-92b-3p.

Mammary stem/progenitor cells are fundamental for mammary gland development and function. However, much remains to be elucidated regarding their function in mammals beyond the traditionally studied rodents, human, and to a lesser extent, ruminants. Due to the growing appreciation for microRNAs (miRNAs) as regulators of stem cells and their progenitors, we compared miRNA expression in mammary stem/progenitor cells from mammals with varying mammary stem/progenitor activity in vitro, in order to identify miRNA candidates that regulate stem/progenitor self-renewal and function.

Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer.

Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer.

Telehealth delivery of adherence and medication management system improves outcomes in inner-city children with asthma.

Healthcare disparities exist in pediatric asthma in the United States. Children from minority, low-income families in inner-city areas encounter barriers to healthcare, leading to greater rates of poorly controlled asthma and healthcare utilization. Finding an effective way to deliver high-quality healthcare to this underserved population to improve outcomes, reduce morbidity and mortality, and reduce healthcare utilization is of the utmost importance.

A peroxidized omega-3-enriched polyunsaturated diet leads to adipose and metabolic dysfunction.

Consumption of diets that differ in fat type and amount, and sequestration of various fatty acids to tissues and organs likely have effects on overall physiology and metabolic health. However, the contributions of dietary lipids to brain-adipose communication and adipose tissue function are poorly understood. We designed six custom diets that differed only in amount and type of dietary fat, with high or low levels of saturated fatty acids (SFA), omega-6 polyunsaturated fatty acids (n-6 PUFA) or omega-3 (n-3) PUFA.

Methodology, Criteria, and Characterization of Patient-Matched Thyroid Cell Lines and Patient-Derived Tumor Xenografts.

Objective: To investigate the molecular underpinnings of thyroid cancer, preclinical cell line models are crucial; however, ∼40% of these have been proven to be either duplicates of existing thyroid lines or even nonthyroid-derived lines or are not derived from humans at all. Therefore, we set out to establish procedures and guidelines that should proactively avoid these problems, which facilitated the creation of criteria to make valid preclinical models for thyroid cancer research.

Design: Based on our recommendations, we systematically characterized all new cell lines that we generated by a standardized approach that included (1) determination of human origin, (2) exclusion of lymphoma, (3) DNA fingerprinting and histological comparisons to establish linkage to presumed tissue of origin, (4) examining thyroid differentiation by screening two to three thyroid markers, (5) examination of biological behavior (growth rate, tumorigenicity), and (6) presence of common thyroid cancer genetic changes (TP53, BRAF, PTEN, PIK3CA, RAS, TERT promoter, RET/PTC, PAX8/PPARγ, NF1, and EIF1AX).

Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy.

Here we present an innovative computational-based drug discovery strategy, coupled with machine-based learning and functional assessment, for the rational design of novel small molecule inhibitors of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1). Our methods resulted in the discovery of several unique molecules, of which our lead compound SSI-4 demonstrates potent anti-tumor activity, with an excellent pharmacokinetic and toxicology profile. We improve upon key characteristics, including chemoinformatics and absorption/distribution/metabolism/excretion (ADME) toxicity, while driving the IC50 to 0.

Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity.

Background: A complication of diabetes is neuropathy, a condition of sensory axon degeneration that originates in the epidermis. The mechanisms remain unknown but reactive oxygen species (ROS) have been implicated in this condition. In this study, we assessed the role of ROS and a candidate downstream target, MMP-13 in glucose-induced sensory axon degeneration in zebrafish and mice.

Establishing and characterizing patient-derived xenografts using pre-chemotherapy percutaneous biopsy and post-chemotherapy surgical samples from a prospective neoadjuvant breast cancer study.

Background: Patient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response. Most available breast cancer PDXs have been generated in the metastatic setting. However, in the setting of operable breast cancer, PDX models both sensitive and resistant to chemotherapy are needed for drug development and prospective data are lacking regarding the clinical and molecular characteristics associated with PDX take rate in this setting.

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo.

Friedreich's ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor.

Discovery and Characterization of Nonpeptidyl Agonists of the Tissue-Protective Erythropoietin Receptor.

Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy.

Agonists of the tissue-protective erythropoietin receptor in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease affecting more than a million people in the USA alone. While there are effective symptomatic treatments for PD, there is an urgent need for new therapies that slow or halt the progressive death of dopaminergic neurons. Significant progress has been made in understanding the pathophysiology of PD, which has substantially facilitated the discovery efforts to identify novel drugs.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

Introduction: Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.