A Non-Canonical Hippo Pathway Represses the Expression of ΔNp63.

The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cell carcinomas, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in MCF10A mammary epithelial cells as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for p63 repression. This suggests that regulation of p63 expression occurs by a noncanonical version of the Hippo pathway. We identified similarly regulated genes, suggesting the broader importance of this pathway. Interestingly, lowering p63 expression lead to increased YAP protein levels, indicating crosstalk of the YAP/TAZ-independent and -dependent branches of the Hippo pathway. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.

A non-canonical Hippo pathway represses the expression of ΔNp63.

The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, the protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in the MCF10A mammary epithelial cell line as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases in a manner that is independent of p53. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for repression of p63. This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. We additionally identified additional genes that were similarly regulated suggesting the broader importance of this pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased YAP protein levels, thereby constituting a feedback loop. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells. One Sentence Summary: Regulation of p63 expression occurs by a non-canonical version of the Hippo pathway in mammary epithelial, breast carcinoma and head and neck squamous carcinoma cells.

Characterizing Health Care Delays and Interruptions in the United States During the COVID-19 Pandemic: Internet-Based, Cross-sectional Survey Study.

BACKGROUND: The COVID-19 pandemic has broader geographic spread and potentially longer lasting effects than those of previous disasters. Necessary preventive precautions for the transmission of COVID-19 has resulted in delays for in-person health care services, especially at the outset of the pandemic. OBJECTIVE: Among a US sample, we examined the rates of delays (defined as cancellations and postponements) in health care at the outset of the pandemic and characterized the reasons for such delays. METHODS: As part of an internet-based survey that was distributed on social media in April 2020, we asked a US-based convenience sample of 2570 participants about delays in their health care resulting from the COVID-19 pandemic. Participant demographics and self-reported worries about general health and the COVID-19 pandemic were explored as potent determinants of health care delays. In addition to all delays, we focused on the following three main types of delays, which were the primary outcomes in this study: dental, preventive, and diagnostic care delays. For each outcome, we used bivariate statistical tests (t tests and chi-square tests) and multiple logistic regression models to determine which factors were associated with health care delays. RESULTS: The top reported barrier to receiving health care was the fear of SARS-CoV-2 infection (126/374, 33.6%). Almost half (1227/2570, 47.7%) of the participants reported experiencing health care delays. Among those who experienced health care delays and further clarified the type of delay they experienced (921/1227, 75.1%), the top three reported types of care that were affected by delays included dental (351/921, 38.1%), preventive (269/921, 29.2%), and diagnostic (151/921, 16.4%) care. The logistic regression models showed that age (P<.001), gender identity (P<.001), education (P=.007), and self-reported worry about general health (P<.001) were significantly associated with experiencing health care delays. Self-reported worry about general health was negatively related to experiencing delays in dental care. However, this predictor was positively associated with delays in diagnostic testing based on the logistic regression model. Additionally, age was positively associated with delays in diagnostic testing. No factors remained significant in the multiple logistic regression for delays in preventive care, and although there was trend between race and delays (people of color experienced fewer delays than White participants), it was not significant (P=.06). CONCLUSIONS: The lessons learned from the initial surge of COVID-19 cases can inform systemic mitigation strategies for potential future disruptions. This study addresses the demand side of health care delays by exploring the determinants of such delays. More research on health care delays during the pandemic is needed, including research on their short- and long-term impacts on patient-level outcomes such as mortality, morbidity, mental health, people's quality of life, and the experience of pain.

Addressing the critical need for long-term mental health data during the COVID-19 pandemic: Changes in mental health from April to September 2020.

Despite the large amounts of research currently being conducted and the high number of editorials warning about the potential mental health impacts, there is a stunning lack of longitudinal mental health data on the effects of the pandemic. Yet, the pandemic may have sizable long-term impacts on psychological distress and health behaviors-these effects may be long-lasting and may disproportionately affect some demographic groups more than others. Data came from a longitudinal international study of the impacts of the COVID-19 pandemic on adults' psychological distress and wellbeing (N = 1567). We found high rates of depression (55% were diagnosable with probable depression at baseline), anxiety (65%), and risk for PTSD (51%). More than one-third of participants who reported that they drank alcohol indicated that their drinking had increased since the start of the pandemic. Over time, depressive symptoms and suicidal thoughts and behaviors increased significantly, but acute stress symptoms decreased. Specific demographic groups (people of color and sexual and gender minorities) appeared to be at high risk of distress across analyses. Our findings suggest high rates of depression, anxiety, acute stress, and other signs of distress like isolation, hopelessness, and use of substances to cope-even at five-month follow-up. Our findings suggest a need to prioritize availability of, and access to, mental health care during both the pandemic and the recovery.