YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

Mental health service use by elderly patients with bipolar disorder and unipolar major depression.

Symptoms, functioning, and mental health service use were compared in older out-patients with bipolar disorder and unipolar depression. Bipolar outpatients (n = 37, mean age = 69.7) had higher total symptom severity and positive symptom scores, more impaired community-living skills, and earlier age at onset of illness than patients with unipolar depression (n = 85, mean age = 70.9). Bipolar elderly patients used almost four times the total amount of mental health services and were four times more likely to have had a psychiatric hospitalization over the previous 6 months. These findings underscore the need for effective services for elderly patients with bipolar disorder, who account for a minority of patients with affective disorders, but use a disproportionate amount of costly services.

Substance use disorder in hospitalized severely mentally ill psychiatric patients: prevalence, correlates, and subgroups.

The prevalence and demographic and clinical correlates of lifetime substance use disorders were examined in a cohort of 325 recently hospitalized psychiatric patients (53% schizophrenia or schizoaffective disorder). Alcohol use was the most common type of substance use disorder, followed by cannabis and cocaine use. Univariate analyses indicated that gender (male), age (younger), education (less), history of time in jail, conduct disorder symptoms, and antisocial personality disorder symptoms were predictive of substance use disorders. Lifetime cannabis use disorder was uniquely predicted by marital status (never married) and fewer psychiatric hospitalizations during the previous 6 months. Optimal classification tree analysis, an exploratory, nonlinear method of identifying patient subgroups, was successful in predicting 74 percent to 86 percent of the alcohol, cannabis, and cocaine use disorders. The implications of this method for identifying specific patient subgroups and service needs are discussed.

Conduct disorder, antisocial personality disorder and substance use disorders in schizophrenia and major affective disorders.

OBJECTIVE: To examine the relationships between childhood conduct disorder (CD), antisocial personality disorder (ASPD) and substance use disorders (substance abuse or substance dependence) in psychiatric patients with severe mental illness. METHOD: Substance use-related problems on screening instruments, lifetime and recent prevalence of substance use disorders, and family history of substance use disorder were evaluated in four groups of 293 patients with mainly schizophrenia-spectrum and major affective disorders: No ASPD/CD, CD Only, Adult ASPD Only, Full ASPD. RESULTS: Full ASPD was strongly related to all measures of substance use problems and disorders, as well as fathers' history of substance use disorder. The odds ratios for Full ASPD and substance use disorders ranged between 3.96 (lifetime cannabis use disorder) to 11.35 (recent cocaine use disorder). To a lesser extent, patients with CD Only or Adult ASPD Only were also at increased risk for having substance use disorders compared to the No ASPD/CD patients. CONCLUSIONS: Childhood CD and adult ASPD represent significant risk factors for substance use disorders in patients with schizophrenia-spectrum and major affective disorders. Considering other research indicating that CD and ASPD have a higher prevalence in patients with severe mental illness, the present findings suggest that CD and ASPD could reflect a common factor that independently increases patients' vulnerability to both psychiatric and substance use disorders.

Antisocial personality disorder, conduct disorder, and substance abuse in schizophrenia.

The validity of subtypes based on antisocial personality disorder (APD) or childhood conduct disorder without adult APD (CD only) in patients with schizophrenia (or schizoaffective disorder) and a substance use disorder (abuse or dependence) was examined. APD patients scored lower on personality measures related to socialization and higher on antisocial behavior, psychopathy, and aggression. APD patients also reported higher rates of aggression and legal problems. APD, and to a lesser extent CD only, was associated with more severe psychiatric symptoms, an earlier age of onset of substance abuse, more severe symptoms of substance abuse, and a stronger family history of substance abuse and psychiatric hospitalization. The findings suggest that schizophrenia patients with APD represent a high-risk subgroup vulnerable to more severe substance abuse, psychiatric impairment, aggression, and legal problems.

A comparative study of elderly patients with schizophrenia and bipolar disorder in nursing homes and the community.

This study compared the functioning of 188 elderly schizophrenic and bipolar disorder patients living in nursing homes and the community. Residential status and diagnostic groups were compared on measures of symptomatology, cognitive impairment, functional impairment, and behavior problems. In general, the diagnostic groups differed in symptoms, while most differences in living setting were related to cognition, functioning, and behavior. Nursing home status was significantly associated with more severe overall symptom ratings, worse cognitive impairment, greater functional impairment, more aggressive behaviors, and marital status of having never married. Self-care skills, community living skills, and marital status were most uniquely predictive of nursing home residence. However, cognitive deficits were strongly predictive of both self-care and community living skills, explaining approximately half of the variance in these variables. The implications of these findings for the treatment of elderly patients with schizophrenia and other severe mental illnesses are discussed.