Insights into Mechanisms of Chronic Neurodegeneration

Rona Barron - ORCID: 0000-0003-4512-9177 https://orcid.org/0000-0003-4512-9177Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.https://doi.org/10.3390/ijms1701008217pubpub

Immunohistochemical Characterisation of GLUT1, MMP3 and NRF2 in Osteosarcoma.

Osteosarcoma (OSA) is an aggressive bone malignancy. Unlike many other malignancies, OSA outcomes have not improved in recent decades. One challenge to the development of better diagnostic and therapeutic methods for OSA has been the lack of well characterized experimental model systems. Spontaneous OSA in dogs provides a good model for the disease seen in people and also remains an important veterinary clinical challenge. We recently used RNA sequencing and qRT-PCR to provide a detailed molecular characterization of OSA relative to non-malignant bone in dogs. We identified differential mRNA expression of the solute carrier family 2 member 1 (SLC2A1/GLUT1), matrix metallopeptidase 3 (MMP3) and nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2) genes in canine OSA tissue in comparison to paired non-tumor tissue. Our present work characterizes protein expression of GLUT1, MMP3 and NRF2 using immunohistochemistry. As these proteins affect key processes such as Wnt activation, heme biosynthesis, glucose transport, understanding their expression and the enriched pathways and gene ontologies enables us to further understand the potential molecular pathways and mechanisms involved in OSA. This study further supports spontaneous OSA in dogs as a model system to inform the development of new methods to diagnose and treat OSA in both dogs and people

Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration

Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread and distribution is restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein seeds were observed widespread throughout the brain accumulating in all brain regions examined irrespective of neurodegeneration. Importantly neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion infected brains, a 11 novel homeostatic response in all regions and an innate immune response restricted to sites of 12 neurodegeneration. Therefore accumulation of misfolded prion protein alone does not define targeting 13 of neurodegeneration which instead results only when misfolded prion protein accompanies a specific 14 innate immune response

Side Effects of Medical Cancer Therapy in Genitourinary Malignancies

Genitourinary cancers represent 12.8% of cancer in both sexes and 21.5% in men, accounting for 7% of cancer deaths in both sexes and 10.5% in men. The systemic treatment of prostate cancer and renal cell carcinoma does not rely on chemotherapy, with the exception of taxane docetaxel and cabazitaxel. Prostate cancer is primarily treated by androgen deprivation, by surgical castration or LHRH analogs, or by androgen receptor pathway inhibitor enzalutamide and abiraterone acetate. Renal cell carcinoma is nowadays treated with agents targeting survival and angiogenesis pathways, including tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, axitinib, and pazopanib; anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab; mammalian target of rapamycin (mTOR) inhibitors temsirolimus and everolimus; and oral inhibitor of tyrosine kinases MET, VEGFR, AXL, cabozantinib. Most recently, immune checkpoint inhibitors have made their way to genitourinary cancers, revolutionizing the treatment of urothelial cancers and renal cell carcinoma. Hormone therapies and targeted therapies don’t eradicate prostate cancer and renal cell carcinoma but rather switch them to a more chronic state. This means that these treatments are prescribed chronically for an extended period of time. In such conditions, even the least bothersome side effect may profoundly alter the quality of life of patients. Ultimately, this is a threat to compliance and then to the efficacy of these treatments. In addition, many of the side effects of these drugs often overlap with common chronic illnesses such as diabetes, hypertension, hypercholesterolemia, heart failure, and osteoporosis. An exhaustive knowledge of these side effects, proper monitoring, and in-depth education of patients are key elements to secure the efficacy of these treatments