Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (k/K > 10 M min). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC of 3.9 μM, representing a significant improvement over our previously reported "hit" NC9.

Background Patients with chronic diseases commonly report fears of illness or symptoms recurring or worsening. These fears have been addressed from an illness-specific perspective (e.g., fear of cancer recurrence), a generic illness perspective (e.g., fear of progression), and a psychiatric perspective (DSM-5 illness anxiety disorder and somatic symptom disorder). The broader concept of health anxiety (HA) can also be applied to patients with a chronic disease. This review was conducted to investigate the conceptual, theoretical, measurementoverlap, and differences between these distinct perspectives. We also aimed to summarize prevalence, course, and correlates of these fears in different chronic illnesses.

Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.

Background Unregulated care providers (UCPs) are at the forefront of direct client care in the community. Their services are required to meet the demand for home-based palliative care from a growing older population, yet understanding of UCPs involvement in care is limited. The study aimed to identify the types and frequencies of tasks performed by UCPs in home-based palliative care to older clients ( > 65 years) and their families and to describe UCPs’ engagement in care, and barriers and facilitators to their work. Methods A mixed method approach was used comprising a quantitative retrospective chart review of UCPs’ tasks ( n = 66), qualitative content analysis of progress notes from clients’ charts ( n = 85), and thematic analyses of in-depth interviews with UCPs ( n = 10). Results A thematic structure was derived from analyses and integration of data from the chart review and interviews. The themes reflect the physical, affective, and relational aspects of UCPs involvement in the care of clients and families at the end of life. The findings indicate that although a significant proportion (63%) of the 13, 558 UCP tasks identified were directed toward meeting clients’ physical care needs, their presence in the home, made UCPs an important source of information on the client’s condition; observing and appraising the situation. Further, the nature of their work and frequent interactions with clients and families also presented opportunities for UCPs to provide emotional support; a role UCPs felt was integral to their work. Conclusions The study highlights the challenging nature of palliative care to older clients and their families whose needs are often complicated, situated within the unique environment of home care where supervision of UCPs is at a distance. Challenges and facilitators to UCPs’ work in this context are discussed with recommendations to support UCPs in their roles.

Evidence-based practices facilitate the effective delivery of psychological services, yet research on the implementation of evidence-based practices in psychosocial oncology (PSO) is scarce. Responding to this gap, we interviewed a diverse sample of 16 directors of Canadian psychosocial oncology services about (a) how evidence-based practices in psychosocial oncology are being implemented in clinical care and how the service quality is monitored and (b) what are barriers and facilitators to evidence-based practice in psychosocial oncology services? Responses were grouped according to three main themes emerging from the data: screening for distress and referral to PSO services, delivery of evidence-based PSO services, and monitoring of PSO services. Our findings highlight facilitators and barriers to evidence-based practice in psychosocial oncology, which were related to the political, social, economic, and geographic contexts. The stepped care model was identified as a science-informed approach to improve the cost-effectiveness of triage systems and treatment delivery while facilitating more equitable access to services. Other facilitators included electronic screening and referral systems as well as protected time for clinicians to communicate more within their teams and participate in knowledge exchange. High caseloads presented a major barrier to acquiring and implementing evidence-based practices. Recommen–dations include increased support for evidence-based onboarding and continued training as well as for data collection regarding service needs, quality, and quantity to inform service monitoring and advocacy for more financial resources. Our findings are relevant to healthcare decision makers, implementation researchers, as well as service directors and practitioners providing psychosocial oncology care.