Jean-François Pelletier

Global methylation profiling in serous ovarian cancer is indicative for distinct aberrant DNA methylation signatures associated with tumor aggressiveness and disease progression

OBJECTIVE To characterize at high resolution the DNA methylation changes which occur in the genome of serous epithelial ovarian cancer (EOC) in association with tumor aggressiveness. METHODS Methylated DNA immunoprecipitation in combination with CpG island-tiling arrays was used to compare the methylation profiles of five borderline, five grade 1/stage III/IV, five grade 3/stage I and five grade 3/stage III/IV serous EOC tumors, to those of five normal human ovarian tissue samples. RESULTS We found widespread DNA hypermethylation that occurs even in low-malignant potential (borderline) tumors and which predominantly includes key developmental/homeobox genes. Contrary to DNA hypermethylation, significant DNA hypomethylation was observed only in grade 3 serous EOC tumors. The latter observation was further confirmed when comparing the DNA methylation profiles of primary cell cultures derived from matched tumor samples obtained prior to, and following chemotherapy treatment from two serous EOC patients with advanced disease. To our knowledge this is the first report that has shown the presence of massive DNA hypomethylation in advanced serous EOC, associated with tumor malignancy and disease progression. CONCLUSIONS Our data raise the concern that demethylating drugs that are currently being used in advanced EOC disease (representing the majority of serous EOC cases) might have adverse effects due to activation of oncogenes and prometastatic genes. Understanding the relative roles of hypomethylation and hypermethylation in cancer could have clear implications on the therapeutic use of agents targeting the DNA methylation machinery.

Citizenship: A Response to the Marginalization of People with Mental Illnesses

The juncture of citizenship and marginalized groups is particularly dramatic when those groups include people who are doubly or triply challenged by homelessness and criminal justice histories. We discuss core themes in the literature on citizenship followed by a review of two of our citizenship research projects: a randomized controlled trial that tested intervention and a community-based participatory research study to develop an individual outcome measurement of citizenship. We then discuss lessons learned from this research, with implications for theory and practice on citizenship in regard to marginalized groups.

No personalization without participation: on the active contribution of psychiatric patients to the development of a mobile application for mental health

BackgroundDespite the increasing pervasiveness of mobile computational technologies, knowledge about psychiatric patients’ preferences regarding the design and utility of mobile applications is very poor. This paper reports on a pilot-study that involved 120 psychiatric patients in the development of a mobile application (app) that is being used for data entry into the Signature Project data bank at the Institut universitaire en santé mentale de Montréal (IUSMM), Canada. Participants were invited to comment on the ‘look and feel’ of the Signature App. Their input also extended the procedures for data collection. These suggestions may contribute to increased mental health literacy and empowerment of persons with mental illness receiving services at the IUSMM.MethodsParticipants were recruited to fill out a questionnaire on a tablet computer while waiting at the Emergency Room (ER, n = 40), Psychotic Disorders outpatient clinic (n = 40) or Anxiety and Mood Disorders outpatient clinic (n = 40) of IUSMM. Nine patients from each of these sub-groups participated in a focus group to review the results and to discuss how the design and use of the Signature App could be improved to better meet the needs of patients.ResultsThis study (n = 120) indicated that psychiatric patients are clearly capable of using a tablet computer to fill out questionnaires for quantitative data entry, and that they enjoyed this experience. Results from the focus groups (n = 27) highlight that the app could also be used by patients to communicate some personal and contextual qualitative information. This would support a holistic and person-centered approach, especially at the ER where people acutely need to describe their recent history and receive emotional support.ConclusionsThis pilot-study has confirmed the necessity of involving patients not only in the testing of a new mobile application, but also as active contributors in the entire research and development process of a person-centered information and communication technology infrastructure. The input of participants was essential in designing the Signature Project computational procedure and making use of the app a positive and empowering experience. Participants also gave critical feedback remarks that went beyond the initial scope of the pilot-study, for example they suggested the addition of a client-clinician component.

Strategies to Fight Stigma toward People with Mental Disorders: Perspectives from Different Stakeholders

This study aims to provide a more complete and exhaustive perspective on the whole range of potential strategies to fight stigma by considering the perspectives of different stakeholders. Delegates to a Canadian conference were invited to participate in a survey that focused on stigma, from which the responses to the following question were analyzed: tell us briefly what you do to reduce prejudice and stigma toward people with a diagnosis of mental disorder? From 253 participants, 15 categories of strategies to fight stigma were identified from the verbatim (e.g., sharing/encouraging disclosure). These categories fell under six main themes: education, contact, protestation, person centered, working on recovery and social inclusion, and reflexive consciousness. The occurrence of these themes was different among stakeholders (clinical, organizational, and experiential knowledge). For example, people with mental disorders (experiential knowledge) often mentioned contact and person centered strategies, while mental health professionals (clinical knowledge) preferred education and working on recovery and social inclusion strategies. The results from this study highlight the need to pay more attention to the concept of disclosure of mental disorders in the process for de-stigmatization. Future studies are needed to assess the impact of the emerging strategies to fight stigma in the community.

Citizenship and Recovery for Everyone: A Global Model of Public Mental Health

A systematic review of the literature on health promotion as conveyed by the Ottawa Charter for Health Promotion yielded two major findings: health promotion and recovery in mental health have many values and features in common, and health promotion and recovery in mental health do not refer very much to one another. A global model of public mental health is therefore needed to bring recovery and health promotion together, to clarify the boundaries of mental health promotion and to promote citizenship for everyone. Inspired and adapted from the ecological approach initially developed on the basis of health promotion programs, the model introduced here addresses mainly the issue of recovery, which has been neglected recently in the literature on both public health and mental health promotion. It advocates the idea that recovery can explicitly be related to mental health promotion through the Ottawa Charter for health promotion. Many issues and sub-issues are addressed, and the global model suggests keeping track of various activities unfolding at five levels, with examples of citizen psychiatry. The uniqueness and additional contribution of this model to already existing literature are that the supranational level is a key component of an approach that would truly be global.

Citizenship and recovery: two intertwined concepts for civic-recovery

BackgroundValidation of the psychometric properties of a new measure of citizenship was required for a research project in the province of Quebec, Canada. This study was meant to study the interplay between recovery- and citizenship-oriented supportive employment. As recovery and citizenship were expected to be two related concepts, convergent validity between the Citizenship Measure (CM) and the Recovery Assessment Scale (RAS) was tested.MethodsStudy objectives were to: 1) conduct exploratory factor analyses on the CM and confirmatory factor analysis on the RAS tools (construct validity), 2) calculate Cronbach’s alphas for each dimension emerging from objective 1 (reliability), and 3) calculate correlations between all dimensions from both tools (convergent validity). Data were collected from 174 individuals with serious mental illness, working in social firms. Serious mental illnesses include major depression, schizophrenia, bipolar disorder, obsessive compulsive disorder, panic disorder, post traumatic stress disorder and borderline personality disorder.ResultsFive factors emerged from the exploratory factor analysis of the CM, with good reliability. Confirmatory factor analyses showed that the short and the long versions of the RAS present satisfactory results. Finally, the correlation matrix indicated that all dimensions from both tools are significantly correlated, thus confirming their convergent validity.ConclusionsThis study confirms the validity and reliability of two tools, CM and RAS. These tools can be used in combination to assess citizenship and recovery, both of which may be combined in the new concept of civic-recovery.

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Ovarian cancer (OVCA) and cervical cancer (CECA) are lethal gynecological malignancies. Cisplatin (CDDP) and platinum derivatives are first line chemotherapeutics and their resistance impedes successful treatment. Understanding the molecular dysregulation underlying chemoresistance is important in developing rational therapeutic strategies. We have established that Protein Phosphatase Magnesium‐dependent 1 D (PPM1D) confers CDDP resistance in gynecological cancer cells by deactivating p53. However, whether CDDP regulates intra‐cellular PPM1D localization and whether this regulation is different between chemosensitive and chemoresistant cancer cells is unknown. Moreover, whether Akt regulates PPM1D in the context of CDDP resistance has not been studied. To illustrate the role of PPM1D in gynecological cancer cell chemoresistance and its regulation by Akt we have demonstrated that: (a) CDDP induced PPM1D down‐regulation through proteasomal degradation in sensitive CECA cells; (b) CDDP induced PPM1D nuclear localization in resistant CECA cells, and nuclear exclusion in sensitive CECA cells and OVCA xenografts; (c) Over‐expression of active Akt in sensitive CECA cells stabilized PPM1D content through inhibition of CDDP‐induced PPM1D down‐regulation; (d) Inhibition of Akt activity in resistant OVCA cells leads to decreased PPM1D stability and CDDP‐induced down‐regulation in resistant CECA cells; and (e) PPM1D is highly expressed in human ovarian tumor subtypes and in a tissue microarray panel of human ovarian tumors. In conclusion, we have established that PPM1D plays an important role in promoting CDDP resistance and as a novel downstream target of Akt, PPM1D mediates its action in conferring CDDP resistance in gynecological cancer cells.

The Global Model of Public Mental Health through the WHO QualityRights project

Purpose – The purpose of this paper is to update the Global Model of Public Mental Health (GMPMH) in light of the WHO QualityRights project. Design/methodology/approach – Being able to refer to international conventions and human rights standards is a key component of a genuine global approach that is supportive of individuals and communities in their quest for recovery and full citizenship. The GMPMH was inspired by the ecological approach in health promotion programs, adding to that approach the individuals as agents of mental health policies and legislation transformation. The GMPMH integrates recovery- and citizenship-oriented psychiatric practices through the Ottawa Charter for Health Promotion (WHO, 1986). Findings – Updating the GMPMH through the WHO QualityRights Toolkit highlights the need for a new form of governance body, namely the Civic Forum, which is inclusive of local communities and persons in recovery. People with mental health disabilities, intellectual disabilities, and substance use conditions can be “included in the community” (UN Convention on the Rights of Persons with Disabilities, Article 19) only if the community is informed and welcoming, for instance through a Civic Forum and its organizing Local Council of Mental Health. Research limitations/implications – Transition from social marginalization to full citizenship represents a daunting challenge in public mental health care. An approach that focuses primarily on individuals is not sufficient in creating access to valued roles those individuals will be able to occupy in community settings. Instead, public intervention and debate are required to promote and monitor the bond of citizenship that connects people to their communities. Originality/value – The GMPMH is the result of a conceptual cross-breeding between recovery and health promotion (WHO, 1986). The GMPMH is an offspring of the ecological approach in health promotion programs, adding to that approach individuals as agents of mental health transformation. It refers to international conventions and human rights standards as a central component of a genuine global approach. A community-based participatory research design is well suited, which includes a Civic Forum for local communities to become involved and supportive of service users in their quality and human rights assessments.

Virtual reality therapy for refractory auditory verbal hallucinations in schizophrenia: A pilot clinical trial

Schizophrenia is a chronic and severe mental illness that poses significant challenges. While many pharmacological and psychosocial interventions are available, many treatment-resistant schizophrenia patients continue to suffer from persistent psychotic symptoms, notably auditory verbal hallucinations (AVH), which are highly disabling. This unmet clinical need requires new innovative treatment options. Recently, a psychological therapy using computerized technology has shown large therapeutic effects on AVH severity by enabling patients to engage in a dialogue with a computerized representation of their voices. These very promising results have been extended by our team using immersive virtual reality (VR). Our study was a 7-week phase-II, randomized, partial cross-over trial. Nineteen schizophrenia patients with refractory AVH were recruited and randomly allocated to either VR-assisted therapy (VRT) or treatment-as-usual (TAU). The group allocated to TAU consisted of antipsychotic treatment and usual meetings with clinicians. The TAU group then received a delayed 7weeks of VRT. A follow-up was ensured 3months after the last VRT therapy session. Changes in psychiatric symptoms, before and after TAU or VRT, were assessed using a linear mixed-effects model. Our findings showed that VRT produced significant improvements in AVH severity, depressive symptoms and quality of life that lasted at the 3-month follow-up period. Consistent with previous research, our results suggest that VRT might be efficacious in reducing AVH related distress. The therapeutic effects of VRT on the distress associated with the voices were particularly prominent (d=1.2). VRT is a highly novel and promising intervention for refractory AVH in schizophrenia.

Psychometric characteristics of the “General Oral Health Assessment Index (GOHAI) » in a French representative sample of patients with schizophrenia

BackgroundThe “General Oral Health Assessment Index” (GOHAI) was widely used in clinical or epidemiological studies worldwide, as it was available for use in different languages. Therefore, the aim of this study was to evaluate the psychometric characteristics of the GOHAI in a representative sample of patients with schizophrenia.MethodsA total of 90 schizophrenic patients (in-patients and out-patients) were recruited from the participants of the “buccodor study” (NCT02167724) between March and September 2015. They were selected using a random stratified sampling method according to their age, sex, or residential area (urban/rural area). GOHAI validity (construct, predictive, concurrent and known group validity) and internal consistency (reliability) were tested. Test-retest reliability was evaluated in 32 subjects.ResultsThe mean age was 47.34 (SD = 12.17). Internal consistency indicated excellent agreement, with a Cronbach’s α