The Molecular 'Myc-anisms' Behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics.

MYC, a well-studied proto-oncogene that is overexpressed in >20% of tumors across all cancers, is classically known as "undruggable" due to its crucial roles in cell processes and its lack of a drug binding pocket. Four decades of research and creativity led to the discovery of a myriad of indirect (and now some direct!) therapeutic strategies targeting Myc. This review explores the various mechanisms in which Myc promotes cancer and highlights five key therapeutic approaches to disrupt Myc, including transcription, Myc-Max dimerization, protein stability, cell cycle regulation, and metabolism, in order to develop more specific Myc-directed therapies.

Transplacental Antibody Transfer of Respiratory Syncytial Virus Specific IgG in Non-Human Primate Mother-Infant Pairs.

One approach to protect new-borns against respiratory syncytial virus (RSV) is to vaccinate pregnant women in the last trimester of pregnancy. The boosting of circulating antibodies which can be transferred to the foetus would offer immune protection against the virus and ultimately the disease. Since non-human primates (NHPs) have similar reproductive anatomy, physiology, and antibody architecture and kinetics to humans, we utilized this preclinical species to evaluate maternal immunization (MI) using an RSV F subunit vaccine. Three species of NHPs known for their ability to be infected with human RSV in experimental challenge studies were tested for RSV-specific antibodies. African green monkeys had the highest overall antibody levels of the old-world monkeys evaluated and they gave birth to offspring with anti-RSV titers that were proportional to their mother. These higher overall antibody levels are associated with greater durability found in their offspring. Immunization of RSV seropositive AGMs during late pregnancy boosts RSV titers, which consequentially results in significantly higher titers in the vaccinated new-borns compared to the new-borns of unvaccinated mothers. These findings, accomplished in small treatment group sizes, demonstrate a model that provides an efficient, resource sparing and translatable preclinical in vivo system for evaluating vaccine candidates for maternal immunization.

miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling.

Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.

'That just breaks my heart': Moral Concerns of Direct Care Workers Providing Palliative Care in LTC Homes.

ABSTRACTThe literature on ethics in health care that explores the moral concerns of care providers typically focuses on registered health professionals and ethical dilemmas in acute and primary care. Far less attention has been paid to the long-term care (LTC) environment and non-registered, direct care workers. To address this gap, this research examined the moral concerns of personal support workers (PSWs) who provide direct care to residents. Data were collected during a 5-year participatory action research project to formalize palliative care programs in LTC homes. Eleven focus groups explored PSWs' experiences providing palliative care in LTC homes, their challenges and learning needs (n = 45). In-depth secondary analysis of these focus groups found that PSWs experienced moral dilemmas. Two main moral dilemmas were ensuring that residents don't die alone; and providing the appropriate care based on residents' wishes. Their organizational constraints coalesced around policies, hierarchy, time, and balancing residents' needs.

WA22†"it's hard to watch people die for a living": embedding the palliative approach into the organisational culture of long term care homes using participatory action research.

BACKGROUND: Long term care homes (LTC) in Canada have become a major location of death with 20% or more residents dying each year. Given the increasing age and frailty of residents, this is soon expected to increase to 40%. LTC has struggled to incorporate care of the dying into their day to day practice and culture because death is often absent from formalised policy and protocols. AIM: This workshop will share resources created during a 5 year participatory action research project in Ontario, Canada that aimed to improve the quality of life of people who were dying in long term care homes. METHODS: Through staff participation and empowerment, a process of organisational capacity development was undertaken. An extensive needs assessment was followed by creating an interprofessional palliative care resource team within each home. This team assessed the assets and gaps in their home and guided development of education, policy and clinical practices to address needs. Community partners with expertise in palliative care were engaged to support staff. RESULTS: A framework for palliative care in LTC integrates the palliative approach into the residents' journey from admission to death. Resources for organisational change were developed and organised into a toolkit that is unique to the LTC setting and context, and can be accessed at www.palliativealliance.ca CONCLUSION: The Quality Palliative Care in Long term Care Toolkit is the first of its kind in Canada. The toolkit can guide LTC management and staff through a process of culture change to incorporate a palliative approach to care.