Rapalogs induce non-apoptotic,autophagy-dependent cell death in HPV-negative TP53 mutant head and neck squamous cell carcinoma

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.     

Exposure to ambient air pollution and the incidence of lung cancer and breast cancer in the Ontario Population Health and Environment Cohort

Lung and female breast cancers are highly prevalent worldwide. Although the association between exposure to ambient fine particulate matter (PM_2.5) and lung cancer has been recognized, there is less evidence for associations with other common air pollutants such as nitrogen dioxide (NO₂) and ozone (O₃). Even less is known about potential associations between these pollutants and breast cancer. We conducted a population-based cohort study to investigate the associations of chronic exposure to PM_2.5, NO₂, O₃ and redox-weighted average of NO₂ and O₃ (O_x) with incident lung and breast cancer, using the Ontario Population Health and Environment Cohort (ONPHEC), which includes all long-term residents aged 35–85 years who lived in Ontario, Canada, 2001–2015. Incident lung and breast cancers were ascertained using the Ontario Cancer Registry. Annual estimates of exposures were assigned to the residential postal codes of subjects for each year during follow-up. We used Cox proportional-hazards models adjusting for personal- and neighborhood-level covariates. Our cohorts for lung and breast cancer analyses included ~4.9 million individuals and ~2.5 million women, respectively. During follow-up, 100,146 incident cases of lung cancer and 91,146 incident cases of breast cancer were diagnosed. The fully adjusted analyses showed positive associations of lung cancer incidence with PM_2.5 (hazard ratio [HR] = 1.02 [95% CI: 1.01–1.05] per 5.3 μg/m³) and NO₂ (HR = 1.05 [95% CI: 1.03–1.07] per 14 ppb). No associations with lung cancer were observed for O₃ or O_x. Relationships between PM_2.5 and NO₂ with lung cancer exhibited a sublinear shape. We did not find compelling evidence linking air pollution to breast cancer.     

Extended thromboprophylaxis in the acutely ill medical patient after hospitalization – a paradigm shift in post-discharge thromboprophylaxis

Venous thromboembolism (VTE) is a significant healthcare burden with approximately 900,000 events annually in the United States, over half of which are healthcare-associated. This number is anticipated to double by 2050. Group prophylaxis strategies confined to the inpatient setting appear to have minimal impact on the reduction of post-discharge VTE in medically ill patients due to shortened lengths of stay and a heterogenous population that includes patients at low risk for VTE. In accordance with current guideline recommendations, very few (<5%) medically ill patients are discharged with extended prophylaxis, which potentially creates a clinical gap for at-risk patients as VTE risk has been shown to persist for up to 90 days. Initial studies of extended thromboprophylaxis in acutely ill medical patients with enoxaparin, rivaroxaban and apixaban showed little to no benefit towards VTE reduction that was consistently outweighed by increased bleeding. The more recent APEX study that compared betrixaban to enoxaparin in an enriched patient population at high-risk for VTE was the first study of extended thromboprophylaxis that showed similar efficacy in VTE prevention without an increase in major bleeding. Based on the APEX results, betrixaban recently gained FDA approval for extended thromboprophylaxis in acutely ill medical patients. Recognition that up to half of medically ill patients are not at sufficient risk to warrant thromboprophylaxis has driven extensive research towards development of scientifically derived and validated VTE risk assessment models intended to identify patients who do not warrant prophylaxis, as well as those at high risk who may derive benefit from extended thromboprophylaxis. This article will review prior and ongoing extended thromboprophylaxis studies, VTE and bleed risk assessment models, incorporation of biomarkers in VTE risk assessment and key issues in the paradigm shift towards individualized VTE prophylaxis in acutely ill medical patients.     

Review of <Emphasis Type="Italic">Landscapes of the Heart</Emphasis>

Using the Pesso Boyden System of Psychomotor (PBSP) treatment model, Grayson’s Landscapes of the Heart: The Working World of a Sex and Relationship Therapist offers those in search of relationship support, an accessible resource. The author uses case examples and concise explanation of theory to convey PBSP’s effectiveness.