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Wnt signaling pathways have been extensively studied in the context of several diseases, including cancer, coronary artery disease, and age-related disorders. β-Catenin plays a central role in the most studied Wnt pathways, the Wnt/β-catenin signaling pathway, commonly referred to as the canonical Wnt signaling pathway. β-catenin is a substrate of glycogen synthase kinase 3β (GSK-3β), and the phosphorylated β-catenin by GSK-3β can be degraded by the proteasome through ubiquitination. Thus, GSK-3β inhibitors have become a widely used chemical biology tool to study the canonical Wnt signaling pathway. Among the varied GSK-3β inhibitors, a compound known as CHIR-99021 is one of the most widely used. Although these inhibitors contribute greatly to our understanding of the canonical Wnt pathway, certain pitfalls associated with such an approach may have been overlooked. In many published studies, micromolar concentrations of CHIR-99021 are used to activate the canonical Wnt pathway. Although CHIR-99021 is a specific GSK-3β inhibitor, it specifically inhibits the kinase at the nanomolar level. Therefore, caution is required when micromolar levels of CHIR-99021 are used for the purpose of activating the canonical Wnt signaling pathway.

Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44+/CD24-, ALDH activity, or by tumor sphere formation. In vivo, upregulation of EMP2 promoted tumor growth, whereas knockdown reduced the ALDHhigh CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1α, a transcription factor previously shown to regulate the self-renewal of ALDHhigh CSCs. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSCs, reducing the ALDH+ population and blocking their tumor-initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor-initiating cells, providing a rationale for the continued development of EMP2-targeting agents.

PurposePathologic corneal neovascularization is a major cause of blindness worldwide, and treatment options are currently limited. VEGF is one of the critical mediators of corneal neovascularization but current anti-VEGF therapies have produced limited results in the cornea. Thus, additional therapeutic agents are needed to enhance the antiangiogenic arsenal. Our group previously demonstrated epithelial membrane protein-2 (EMP2) involvement in pathologic angiogenesis in multiple cancer models including breast cancer and glioblastoma. In this paper, we investigate the efficacy of anti-EMP2 immunotherapy in the prevention of corneal neovascularization.MethodsAn in vivo murine cornea alkali burn model was used to study pathologic neovascularization. A unilateral corneal burn was induced using NaOH, and subconjunctival injection of either anti-EMP2 antibody, control antibody, or sterile saline was performed after corneal burn. Neovascularization was clinically scored at 7 days postalkali burn, and eyes were enucleated for histologic analysis and immunostaining including VEGF, CD31, and CD34 expression.ResultsAnti-EMP2 antibody, compared to control antibody or vehicle, significantly reduced neovascularization as measured by clinical score and central cornea thickness, as well as by histologic reduction of neovascularization, decreased CD34 staining, and decreased CD31 staining. Incubation of corneal limbal cells in vitro with anti-EMP2 blocking antibody significantly decreased EMP2 expression, VEGF expression and secretion, and cell migration.ConclusionsThis work demonstrates the effectiveness of EMP2 as a novel target in pathologic corneal neovascularization in an animal model and supports additional investigation into EMP2 antibody blockade as a potential new therapeutic option.

AbstractPoor adherence to medication treatment in those with serious mental illness is common. Typical solutions and consequences in Western, formal psychiatric care settings often involve coercive measures such as involuntary hospital admissions and treatment, and out-patient commitments, with serious infringements on civil liberty. We examine the relatively unfamiliar, controversial and under-explored area of using financial incentive (FI) to enhance medication adherence in this population through a comprehensive scoping literature review, focusing on the ethical aspects of this practice. From nineteen qualified papers, we identified seven key themes of ethical “concerns,” and opposing arguments on whether FI is: (1) itself a form of coercion affecting autonomy; (2) leading to erosion of a proper consent process; (3) causing indirect and unintended harm; (4) worsening multiple levels of stigma related to mental illness; (5) associated with loss of intrinsic motivation of treatment; (6) associated with misuse of the fund itself; and (7) potentially leading to negative impact on therapeutic relationships. The ethics review shows a moderate receptivity to the use of FI in some specific and individualized circumstances; exceptions for those with poor insight and lacking treatment capacity are particularly relevant in order to avoid other forms of coercion. Additional highlights of the review include the optimal amount, duration, scope, and target population of the FI, and need for rigorous attention to psychoeducation, process, therapeutic relationships, stigma, and not lose sight of ultimately aiming to improve on patients’ insight, autonomy, quality of life and intrinsic motivation in this controversial approach. [ABSTRACT FROM AUTHOR]

Beyond the challenges of diagnosis, complexity measurement in clients with mental illness is an important but under-recognized area. Accurate and appropriate psychiatric diagnoses are essential, and further complexity measurements could contribute to improving patient understanding, referral, and service matching and coordination, outcome evaluation, and system-level care planning. Myriad conceptualizations, frameworks, and definitions of patient complexity exist, which are operationalized by a variety of complexity measuring tools. A limited number of these tools are developed for people with mental illness, and they differ in the extent to which they capture clinical, psychosocial, economic, and environmental domains. Guided by the PRISMA Extension for Scoping Reviews, this review evaluates the tools best suited for different mental health settings. The search found 5345 articles published until November 2023 and screened 14 qualified papers and corresponding tools. For each of these, detailed data on their use of psychiatric diagnostic categories, definition of complexity, primary aim and purpose, context of use and settings for their validation, best target populations, historical references, extent of biopsychosocial information inclusion, database and input technology required, and performance assessments were extracted, analyzed, and presented for comparisons. Two tools—the INTERMED, a clinician-scored and multiple healthcare data-sourced tool, and the VCAT, a computer-based instrument that utilizes healthcare databases to generate a comprehensive picture of complexity—are exemplary among the tools reviewed. Information on these limited but suitable tools related to their unique characteristics and utilities, and specialized recommendations for their use in mental health settings could contribute to improved patient care. [ABSTRACT FROM AUTHOR]

Objective: In Canada and elsewhere, making treatment decisions for a person with serious mental illness (SMI) who was found incapable for treatment decisions via a substitute decision maker (SDM) is the norm. This practice is often called into question from a rights-based perspective. The literature on the views of affected individuals is limited. We explore the experiences of adults with SMI who have had SDMs to gain more in-depth understanding. Method: We conducted semistructured interviews with 11 consumers of psychiatric services who have had experiences with SDM (range 1–12 years) at an urban hospital in Toronto, Canada. Results: Thematic analysis showed five main themes and related subthemes, including: (1) strong dissatisfaction with and rejection of the SDM's role and purpose; (2) pervasive sense of stigma associated with having a SDM; (3) ongoing struggles to gain autonomy; (4) mixed changes in relationship with and views about SDM; and (5) views on how to improve SDM process. Conclusion and Implications for Practice: Our study highlights substantial dissatisfaction with the current SDM system and approaches among adults with SMI who have had SDMs. Issues of stigma and struggles to regain autonomy are prevalent. We discuss the personal, clinical, and social-legal contexts in which they occur, particularly in light of the United Nations' Convention on the Rights of Persons with Disabilities that calls for replacing SDMs with supported decision making. Rights-based approaches to care carry substantial practice implications and call for thoughtful change management. Impact and Implications: This study of consumers with severe mental illness who have been appointed a substitute decision maker for their psychiatric treatment decisions found mostly negative experiences, typically worsened relationships, a sense of stigmatization, and a strong wish to regain decisional autonomy. The findings could inform reexamination and improvement in this area as promoted by the United Nations Convention for the Rights of Persons with Disability. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Community Mental Health is the property of Canadian Periodical for Community Studies Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Using an online survey distributed to members of the provincial organization that represents the 88 Assertive Community Treatment (ACT) and Flexible ACT teams in Ontario, Canada, this descriptive study relied on the unique vantage points and observations of the front-line community psychiatry workers who maintained contact with patients through outreach and telecommunication during the height of COVID-19. The patients who suffer from serious mental illness (SMI) were uniquely affected by COVID-19 due to the changes, reduction or shut down of many essential clinical and community support services. Thematic and quantitative analyses of the workers' observations highlighted 6 main areas of note, including significant social isolation and loneliness, clinical course deterioration and life disruption, increased hospital and ER use, police and legal contacts, and substance abuse and related deaths. There were also encouraging signs of positive adaptations in terms of independence and resilience. Reflections of these impacts and potential ameliorating approaches are further discussed. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Community Mental Health is the property of Canadian Periodical for Community Studies Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)