Canine osteosarcoma in comparative oncology: Molecular mechanisms through to treatment discovery.

Cancer is a leading cause of non-communicable morbidity and mortality throughout the world, similarly, in dogs, the most frequent cause of mortality is tumors. Some types of cancer, including osteosarcoma (OSA), occur at much higher rates in dogs than people. Dogs therefore not only require treatment themselves but can also act as an effective parallel patient population for the human disease equivalent. It should be noted that although there are many similarities between canine and human OSA, there are also key differences and it is important to research and highlight these features. Despite progress using chorioallantoic membrane models, 2D and 3D in vitro models, and rodent OSA models, many more insights into the molecular and cellular mechanisms, drug development, and treatment are being discovered in a variety of canine OSA patient populations

Canine osteosarcoma in comparative oncology: Molecular mechanisms through to treatment discovery

Cancer is a leading cause of non-communicable morbidity and mortality throughout the world, similarly, in dogs, the most frequent cause of mortality is tumors. Some types of cancer, including osteosarcoma (OSA), occur at much higher rates in dogs than people. Dogs therefore not only require treatment themselves but can also act as an effective parallel patient population for the human disease equivalent. It should be noted that although there are many similarities between canine and human OSA, there are also key differences and it is important to research and highlight these features. Despite progress using chorioallantoic membrane models, 2D and 3D in vitro models, and rodent OSA models, many more insights into the molecular and cellular mechanisms, drug development, and treatment are being discovered in a variety of canine OSA patient populations

Evolving DNA repair synthetic lethality targets in cancer

DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, upregulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair targeted investigations culminating in clinically viable precision oncology strategy using PARP inhibitors in breast, ovarian, pancreatic and prostate cancers. Whilst PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense pre-clinical and clinical investigation. Here we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors and other emerging DNA repair inhibitors for synthetic lethality in cancer

Targeting DNA damage repair precision medicine strategies in cancer

DNA repair targeted therapeutics is a promising precision medicine strategy in cancer. The development and clinical use of PARP inhibitors has transformed lives for many patients with BRCA germline deficient breast and ovarian cancer as well as platinum sensitive epithelial ovarian cancers. However, lessons learnt from the clinical use of PARP inhibitors also confirm that not all patients respond either due to intrinsic or acquired resistance. Therefore, the search for additional synthetic lethality approaches is an active area of translational and clinical research. Here, we review the current clinical state of PARP inhibitors and other evolving DNA repair targets including ATM, ATR, WEE1 inhibitors and others in cancer

Impact of COVID-19 on student attainment and pedagogical needs when undertaking independent scientific research

Research is often an essential component of completing a veterinary medicine degree, with universities worldwide aiming to teach students a variety of techniques and general research comprehension and skills. As universities worldwide navigated the COVID-19 pandemic, it was often necessary to move towards distance learning, this was employed for the research module at The University of Nottingham, School of Veterinary Medicine and Science. Following completion of their independent research project, each student cohort was sent a student evaluation of the module questionnaire and quantitative and qualitative analysis was undertaken. In addition, assessment outcomes based on dissertation grade, supervisor grade and overall module score were analysed quantitatively. This was conducted on both the individual cohorts and between the pre- and peri-pandemic groups, ranging from 2017–2018 through to 2021–2022 cohorts. The students received increased dissertation and supervisor grades (by nearly 6%) during the 2021–2022 peri-pandemic cohort, when compared to the pre-pandemic cohorts, but did differ significantly compared to the 2020–2021 cohort. The pre- and peri-pandemic Likert-scale ratings for module organisation and assessment criteria were similar, workload management and the ability to explore concepts and ideas was reduced in the peri-pandemic cohorts, whereas the accessibility to resources was increased in the peri-pandemic students compared to those taught prior to the pandemic. Student feedback can provide essential information when designing and managing research projects and when compared to assessment grades it can help us understand attainment, essential information when providing a quality university level education whilst supporting student welfare following the COVID-19 pandemic

Epidemiology and risk factors of osteosarcoma

Osteosarcoma is a rare tumor diagnosed at any age; however younger age is a common risk factor. In addition, multiple factors are believed to contribute to higher rates of osteosarcoma, particularly race and gender. Although diagnosed worldwide, osteosarcoma is found to be more prevalent in Africa with high numbers of cases reported in Nigeria, Uganda, and Sudan. Additionally, higher rates are detected in African Americans, suggesting a genetic predisposition linked to race. This review focuses on identifying high risk factors of osteosarcoma with an emphasis on sarcoma epidemiology and risk factors in African countries

The Clinicopathological Significance of the Cyclin D1/E1–Cyclin-Dependent Kinase (CDK2/4/6)–Retinoblastoma (RB1/pRB1) Pathway in Epithelial Ovarian Cancers

Cyclin-dependent kinases (CDK2, CDK4, CDK6), cyclin D1, cyclin E1 and phosphorylated retinoblastoma (pRB1) are key regulators of the G1/S cell cycle checkpoint and may influence platinum response in ovarian cancers. CDK2/4/6 inhibitors are emerging targets in ovarian cancer therapeutics. In the current study, we evaluated the prognostic and predictive significance of the CDK2/4/6–cyclin D1/E1–pRB1 axis in clinical ovarian cancers (OC). The CDK2/4/6, cyclin D1/E1 and RB1/pRB1 protein expression were investigated in 300 ovarian cancers and correlated with clinicopathological parameters and patient outcomes. CDK2/4/6, cyclin D1/E1 and RB1 mRNA expression were evaluated in the publicly available ovarian TCGA dataset. We observed nuclear and cytoplasmic staining for CDK2/4/6, cyclins D1/E1 and RB1/pRB1 in OCs with varying percentages. Increased nuclear CDK2 and nuclear cyclin E1 expression was linked with poor progression-free survival (PFS) and a shorter overall survival (OS). Nuclear CDK6 was associated with poor OS. The cytoplasmic expression of CDK4, cyclin D1 and cyclin E1 also has predictive and/or prognostic significance in OCs. In the multivariate analysis, nuclear cyclin E1 was an independent predictor of poor PFS. Tumours with high nuclear cyclin E1/high nuclear CDK2 have a worse PFS and OS. Detailed bioinformatics in the TCGA cohort showed a positive correlation between cyclin E1 and CDK2. We also showed that cyclin-E1-overexpressing tumours are enriched for genes involved in insulin signalling and release. Our data not only identified the prognostic/predictive significance of these key cell cycle regulators but also demonstrate the importance of sub-cellular localisation. CDK2 targeting in cyclin-E1-amplified OCs could be a rational approach

Towards Personalized Management of Ovarian Cancer

Despite advances in surgery and chemotherapy, the overall outcomes for patients with advanced ovarian cancer remain poor. Although initial response rates to platinum-based chemotherapy is about 60–80%, most patients will have recurrence and succumb to the disease. However, a DNA repair–directed precision medicine strategy has recently generated real hope in improving survival. The clinical development of PARP inhibitors has transformed lives for many patients with BRCA germline-deficient and/or platinum-sensitive epithelial ovarian cancers. Antiangiogenic agents and intraperitoneal chemotherapy approaches may also improve outcomes in patients. Moreover, evolving immunotherapeutic opportunities could also positively impact patient outcomes. Here we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in ovarian cancer

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

Molecular characterisation of canine osteosarcoma in high risk breeds

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease-free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor tissue utilising RNA sequencing, validated by qRT-PCR and immunohistochemistry (n = 16). Polymorphic polyglutamine (polyQ) tracts in the androgen receptor (AR/NR3C4) and nuclear receptor coactivator 3 (NCOA3) genes were investigated in control and OSA patients using polymerase chain reaction (PCR), Sanger sequencing and fragment analysis (n = 1019 Rottweilers, 379 Irish Wolfhounds). Our analysis identified 1281 significantly differentially expressed genes (>2 fold change, p < 0.05), specifically 839 lower and 442 elevated gene expression in osteosarcoma (n = 3) samples relative to non-malignant (n = 4) bone. Enriched pathways and gene ontologies were identified, which provide insight into the molecular pathways implicated in canine OSA. Expression of a subset of these genes (SLC2A1, DKK3, MMP3, POSTN, RBP4, ASPN) was validated by qRTPCR and immunohistochemistry (MMP3, DKK3, SLC2A1) respectively. While little variation was found in the NCOA3 polyQ tract, greater variation was present in both polyQ tracts in the AR, but no significant associations in length were made with OSA. The data provides novel insights into the molecular mechanisms of OSA in high risk breeds. This knowledge may inform development of new prevention strategies and treatments for OSA in dogs and supports utilising spontaneous OSA in dogs to improve understanding of the disease in people