AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin

AbstractThe Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1

The Progression of Serious Mental Disorders to Mortality in Primary Care

Serious mental disorders (schizophrenia, bipolar disorder and major depressive disorder (MDD)) have been associated with an excess risk of mortality. However, most datasets used to study these associations have been limited by small sample sizes, use of specialized clinical samples, and few covariates recorded, thereby impeding proper assessments of mortality risks. Electronic medical records databases such as The Health Improvement Network (THIN) directly address these limitations by offering a large primary care population for study, with inclusion of numerous clinically-relevant covariate data over a long follow-up period. To date, THIN has not been used to study mortality in serious mental illness. As such, this thesis had the following objectives: i) estimate annual prevalence of serious mental illness; ii) determine the covariate-adjusted and unadjusted risk of all-cause mortality in serious mental illness and iii) demonstrate the feasibility of using THIN to study the excess mortality associated with serious mental illness. THIN was used to define schizophrenia, bipolar disorder and MDD cohorts between the years of 1986-2012, where annual prevalence estimates in 2012 were 0.23%, 0.26% and 9.49% respectively. Survival analyses adjusted for important covariates revealed that in the schizophrenia cohort (n=6,056), the risk of all-cause mortality was more than double (HR=2.36, 95%CI: 1.83 – 3.04) the risk in the referent cohort (n=6,137,760). Similarly, patients with bipolar disorder (n=9,425) were found to have twice the risk of all-cause mortality (HR=2.00, 95%CI: 1.70-2.34) compared to the referent cohort (n=6,131,373). Patients with MDD (n=405,866) were also found to have a significantly greater risk of all-cause mortality (HR=1.28, 95%CI: 1.21-1.36) compared to the referent cohort (n=5,337,098). Annual prevalence estimates for schizophrenia and MDD were similar to previous reports, but estimates were lower for bipolar disorder, possibly due to issues in correctly identifying these patients in primary care. This study was the first to confirm the excess mortality associated with serious mental disorders using THIN, highlighting that studying mortality among patients with serious mental illness is feasible in THIN. As such, the work presented in this thesis can pave the way for future research using THIN to improve the health of patients with serious mental disorders

Ustekinumab for the treatment of recalcitrant pyoderma gangrenosum: A case report

Pyoderma gangrenosum is an ulcerating disease associated with a high degree of morbidity and mortality. Currently, little is known about the pathophysiology of pyoderma gangrenosum, though it has been linked to increased levels of inflammatory cytokines including interleukin-23. As pyoderma gangrenosum is a rare disease, evidence for pyoderma gangrenosum treatment is dependent on reporting of cases with successful therapies. Here, we describe a case of pyoderma gangrenosum developing on the lateral leg of a medically complex 47-year-old male already on chronic immunosuppressive therapy, who achieved successful wound healing with the use of ustekinumab, a monoclonal antibody targeting inhibition of interleukin-12 and interleukin-23. This case lends further evidence for the role of interleukin-23 in the pathogenesis of recalcitrant pyoderma gangrenosum and also suggests that healthcare providers may consider a trial of ustekinumab in pyoderma gangrenosum that has failed previous topical treatments or systemic immunosuppression

Passion for driving and aggressive driving behavior: A look at their relationship

The purpose of the present research was to investigate the relationship between passion for driving and aggressive driving behavior in 3 studies. Study 1 examined the association between passion and aggressive driving behavior in a sample of undergraduate students. Results showed that an obsessive passion for driving was associated with aggressive driving behavior, while harmonious passion was not. Study 2 replicated these results with an ecologically valid sample of community-dwelling drivers. Finally, Study 3 replicated the results obtained in Studies 1 and 2 in a laboratory setting using a driving simulator under controlled frustrating driving situations with judges' assessment of aggressive driving behavior. Study 3 also showed that the emotion of anger mediated the obsessive-passion/aggressive-driving-behavior relationship

Passion for driving and aggressive driving behavior : A look at their relationship

The purpose of the present research was to investigate the relationship between passion for driving and aggressive driving behavior in 3 studies. Study 1 examined the association between passion and aggressive driving behavior in a sample of undergraduate students. Results showed that an obsessive passion for driving was associated with aggressive driving behavior, while harmonious passion was not. Study 2 replicated these results with an ecologically valid sample of communitydwelling drivers. Finally, Study 3 replicated the results obtained in Studies 1 and 2 in a laboratory setting using a driving simulator under controlled frustrating driving situations with judges’ assessment of aggressive driving behavior. Study 3 also showed that the emotion of anger mediated the obsessive-passion/aggressivedriving- behavior relationship

On the dynamic relationships between contextual (or general) and situational (or state) motivation toward exercise and physical activity: A longitudinal test of the top-down and bottom-up hypothesis

The present research sought to test key postulates of the Hierarchical Model of Intrinsic and Extrinsic Motivation (HMIEM, Vallerand, 1997) in two different physical activity settings. Specifically, the top‐down and the recursive (bottom‐up) effects were tested with adult participants (n = 89) in a fitness center as well as with high school students (n = 168) in physical activity classes. Study 1 further assessed the positive consequences resulting from a self‐determined situational motivation while Study 2 tested the impact of the perceived motivational climate on students’ situational motivation. Two short‐term longitudinal designs (with three measurement times in Study 1 and five measurement times in Study 2) were used. These models enabled the investigation of the interplay between the contextual and the situational levels of the motivational hierarchy over time. Overall, the results of Study 1 and Study 2 supported the postulates of the HMIEM (Vallerand, 1997). Furthermore, the results of Study 1 showed that self‐determined situational motivation predicted positive outcome variables (i.e., positive emotions and concentration) while the results of Study 2 showed the significant relationship between a perceived mastery climate and self‐determined situational motivation. The present findings allow us to hypothesize the existence of a dynamic process through which changes in contextual self‐determined motivation may take place over time

The impact of depression and antidepressant usage on primary biliary cholangitis clinical outcomes.

Depression is prevalent in primary biliary cholangitis (PBC) patients. Our aims were to examine the effects of depression and antidepressants on hepatic outcomes of PBC patients.We used the UK Health Improvement Network database to identify PBC patients between 1974 and 2007. Our primary outcome was one of three clinical events: decompensated cirrhosis, liver transplantation and death. We assessed depression and each class of antidepressant medication in adjusted multivariate Cox proportional hazards models to identify independent predictors of outcomes. In a sensitivity analysis, the study population was restricted to PBC patients using ursodeoxycholic acid (UDCA).We identified 1,177 PBC patients during our study period. In our cohort, 86 patients (7.3%) had a depression diagnosis prior to PBC diagnosis, while 79 patients (6.7%) had a depression diagnosis after PBC diagnosis. Ten-year incidence of mortality, decompensated cirrhosis, and liver transplantation were 13.4%, 6.6%, and 2.0%, respectively. In our adjusted models, depression status was not a predictor of poor outcomes. After studying all classes of antidepressants, using the atypical antidepressant mirtazapine after PBC diagnosis was significantly protective (Adjusted HR 0.23: 95% CI 0.07-0.72) against poor liver outcomes (decompensation, liver transplant, mortality), which remained statistically significant in patients using UCDA (HR 0.21: 95% CI 0.05-0.83).In our study, depression was not associated with poor clinical outcomes. However, using the antidepressant mirtazapine was associated with decreased mortality, decompensated cirrhosis and liver transplantation in PBC patients. These findings support further assessment of mirtazapine as a potential treatment for PBC patients

Public health interventions slowed but did not halt the spread of COVID-19 in India

The government of India implemented social distancing interventions to contain the COVID-19 epidemic. However, effects of these interventions on epidemic dynamics are yet to be understood. Rates of laboratory-confirmed COVID-19 infections per day and effective reproduction number (Rt ) were estimated for 7 periods (Pre-lockdown, Lockdown Phases 1 to 4 and Unlock 1-2) according to nationally implemented interventions with phased relaxation. Adoption of these interventions was estimated using Google mobility data. Estimates at the national level and for 12 Indian states most affected by COVID-19 are presented. Daily case rates ranged from 0·03 to 285.60/10 million people across 7 discrete periods in India. From 18 May to 31 July 2020, the NCT of Delhi had the highest case rate (999/10 million people/day), whereas Madhya Pradesh had the lowest (49/10 million/day). Average Rt was 1.99 (95% CI 1.93-2.06) and 1.39 (95% CI 1.38-1.40) for the entirety of India during the period from 22 March 2020 to 17 May 2020 and from 18 May 2020 to 31 July 2020, respectively. Median mobility in India decreased in all contact domains during the period from 22 March 2020 to 17 May 2020, with the lowest being 21% in retail/recreation, except home which increased to 129% compared to the 100% baseline value. Median mobility in the 'Grocery and Pharmacy' returned to levels observed before 22 March 2020 in Unlock 1 and 2 and the enhanced mobility in the Pharmacy sector needs to be investigated. The Indian government imposed strict contact mitigation, followed by a phased relaxation, which slowed the spread of COVID-19 epidemic progression in India. The identified daily COVID-19 case rates and Rt will aid national and state governments in formulating ongoing COVID-19 containment plans. Furthermore, these findings may inform COVID-19 public health policy in developing countries with similar settings to India

Meta-analysis and adjusted estimation of COVID-19 case fatality risk in India and its association with the underlying comorbidities

Management of coronavirus disease 2019 (COVID-19) in India is a top government priority. However, there is a lack of COVID-19 adjusted case fatality risk (aCFR) estimates and information on states with high aCFR. Data on COVID-19 cases and deaths in the first pandemic wave and 17 state-specific geodemographic, socio-economic, health and comorbidity-related factors were collected. State-specific aCFRs were estimated, using a 13-day lag for fatality. To estimate country-level aCFR in the first wave, state estimates were meta-analysed based on inverse-variance weighting and aCFR as either a fixed- or random-effect. Multiple correspondence analyses, followed by univariable logistic regression, were conducted to understand the association between aCFR and geodemographic, health and social indicators. Based on health indicators, states likely to report a higher aCFR were identified. Using random- and fixed-effects models, cumulative aCFRs in the first pandemic wave on 27 July 2020 in India were 1.42% (95% CI 1.19%–1.70%) and 2.97% (95% CI 2.94%–3.00%), respectively. At the end of the first wave, as of 15 February 2021, a cumulative aCFR of 1.18% (95% CI 0.99%–1.41%) using random and 1.64% (95% CI 1.64%–1.65%) using fixed-effects models was estimated. Based on high heterogeneity among states, we inferred that the random-effects model likely provided more accurate estimates of the aCFR for India. The aCFR was grouped with the incidence of diabetes, hypertension, cardiovascular diseases and acute respiratory infections in the first and second dimensions of multiple correspondence analyses. Univariable logistic regression confirmed associations between the aCFR and the proportion of urban population, and between aCFR and the number of persons diagnosed with diabetes, hypertension, cardiovascular diseases and stroke per 10,000 population that had visited NCD (Non-communicable disease) clinics. Incidence of pneumonia was also associated with COVID-19 aCFR. Based on predictor variables, we categorised 10, 17 and one Indian state(s) expected to have a high, medium and low aCFR risk, respectively. The current study demonstrated the value of using meta-analysis to estimate aCFR. To decrease COVID-19 associated fatalities, states estimated to have a high aCFR must take steps to reduce co-morbidities