Machine learning models predict PTSD severity and functional impairment: A personalized medicine approach for uncovering complex associations among heterogeneous symptom profiles.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric illness, experienced by approximately 10% of the population. Heterogeneous presentations that include heightened dissociation, comorbid anxiety and depression, and emotion dysregulation contribute to the severity of PTSD, in turn, creating barriers to recovery. There is an urgent need to use data-driven approaches to better characterize complex psychiatric presentations with the aim of improving treatment outcomes. We sought to determine if machine learning models could predict PTSD-related illness in a real-world treatment-seeking population using self-report clinical data. METHOD: Secondary clinical data from 2017 to 2019 included pretreatment measures such as trauma-related symptoms, other mental health symptoms, functional impairment, and demographic information from adults admitted to an inpatient unit for PTSD in Canada (n = 393). We trained two nonlinear machine learning models (extremely randomized trees) to identify predictors of (a) PTSD symptom severity and (b) functional impairment. We assessed model performance based on predictions in novel subsets of patients. RESULTS: Approximately 43% of the variance in PTSD symptom severity (R²avg = .43, R²median = .44, p = .001) was predicted by symptoms of anxiety, dissociation, depression, negative trauma-related beliefs about others, and emotion dysregulation. In addition, 32% of the variance in functional impairment scores (R²avg = .32, R²median = .33, p = .001) was predicted by anxiety, PTSD symptom severity, cognitive dysfunction, dissociation, and depressive symptoms. CONCLUSIONS: Our results reinforce that dissociation, cooccurring anxiety and depressive symptoms, maladaptive trauma appraisals, cognitive dysfunction, and emotion dysregulation are critical targets for trauma-related interventions. Machine learning models can inform personalized medicine approaches to maximize trauma recovery in real-world inpatient populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dissociative symptoms predict severe illness presentation in Canadian public safety personnel with presumptive post-traumatic stress disorder (PTSD).

Background: Post-traumatic stress disorder affects 9% of individuals across their lifetime and increases nearly fourfold to 35% in Canadian public safety personnel (PSP). On-the-job experiences of PSP frequently meet criteria for traumatic events, making these individuals highly vulnerable to exposures of trauma and the negative consequences of PTSD. Few studies have reported on the clinical characteristics of Canadian samples of PSP and even fewer have examined the dissociative subtype of PTSD, which is associated with more severe, chronic traumatic experiences, and worse outcomes. Objective: This study aimed to characterize dissociative symptoms, PTSD symptom severity, and other clinical variables among Canadian PSP with presumptive PTSD. Methods: We sampled current and past PSP in Canada from both inpatient and outpatient populations (N = 50) that were enrolled in a psychological intervention. Only baseline testing data (prior to any intervention) were analysed in this study, such as PTSD symptom severity, dissociative symptoms, emotion dysregulation, and functional impairment. Results: In our sample, 24.4% self-reported elevated levels of dissociation, specifically symptoms of depersonalization and derealization. Depersonalization and derealization symptoms were associated with more severe PTSD symptoms, greater emotion dysregulation, and functional impairment. Conclusions: Nearly a quarter of this sample of Canadian PSP reported experiencing elevated levels of PTSD-related dissociation (depersonalization and derealization). These high levels of depersonalization and derealization were consistently positively associated with greater illness severity across clinical measures. It is imperative that dissociative symptoms be better recognized in patient populations that are exposed to chronic traumatic events such as PSP, so that treatment interventions can be designed to target a more severe illness presentation.

Antecedentes: El trastorno de estrés postraumático afecta al 9% de los individuos a lo largo de su vida y se incrementa casi cuatro veces hasta el 35% en el personal de seguridad pública canadiense (PSP). Las experiencias en el trabajo de los PSP cumplen con frecuencia los criterios de eventos traumáticos, lo que hace que estos individuos sean muy vulnerables a la exposición al trauma y a las consecuencias negativas del TEPT. Pocos estudios han informado sobre las características clínicas de las muestras canadienses de PSP y aún menos han examinado el subtipo disociativo del TEPT, que se asocia con experiencias traumáticas más graves y crónicas, y con peores resultados.Objetivo: Este estudio tenía como objetivo caracterizar los síntomas disociativos, la gravedad de los síntomas del TEPT y otras variables clínicas entre los PSP canadienses con presunto TEPT.Métodos: Tomamos una muestra de PSP actuales y pasados en Canadá de poblaciones de pacientes hospitalizados y ambulatorios (N = 50) que se inscribieron en una intervención psicológica. En este estudio sólo se analizaron los datos de las pruebas de referencia (antes de cualquier intervención), como la gravedad de los síntomas del TEPT, los síntomas disociativos, la desregulación de las emociones y el deterioro funcional.Resultados: En nuestra muestra, el 24,4% auto-reportó niveles elevados de disociación, específicamente síntomas de despersonalización y des-realización. Los síntomas de despersonalización y des-realización se asociaron con síntomas de TEPT más graves, mayor desregulación de la emoción y deterioro funcional.Conclusiones: Casi una cuarta parte de esta muestra de PSP canadiense reportó experimentar niveles elevados de disociación relacionada con el TEPT (despersonalización y des-realización). Estos niveles elevados de despersonalización y des-realización se asociaron positivamente de forma consistente con una mayor gravedad de la enfermedad en las medidas clínicas. Es imperativo que se reconozcan mejor los síntomas disociativos en las poblaciones de pacientes que están expuestos a eventos traumáticos crónicos como el PSP, para que las intervenciones de tratamiento puedan ser diseñadas para dirigirse a una presentación de la enfermedad más severa.

Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells.

BACKGROUND: Nucleostemin is a nucleolus residing GTPase that is considered to be an important cancer stem/progenitor cell marker protein due to its high expression levels in breast cancer stem cells and its role in tumor-initiation of human mammary tumor cells. It has been proposed that nucleostemin may represent a valuable therapeutic target for breast cancer; however, to date evidence supporting the cellular mechanism has not been elucidated. RESULTS: Expression of exogenous HER2, a member of the EGF receptor gene family, in the human MCF-10AT preneoplastic mammary epithelial cell line formed a new breast cancer cell line, 10AT-Her2, which is highly enriched in cells with stem/progenitor cell-like character. 10AT-Her2 cells display a CD44+/CD24-/low phenotype with high levels of the cancer stem/progenitor cell marker proteins nucleostemin, and active aldehyde dehydrogenase-1. The overall expression pattern of HER2 protein and the stem/progenitor cell marker proteins in the 10AT-Her2 cell population is similar to that of the luminal HER2+ SKBR3 human breast cancer cell line, whereas, both MCF-7 and MDA-MB-231 cells display reduced levels of nucleostemin and no detectable expression of ALDH-1. Importantly, in contrast to the other well-established human breast cancer cell lines, 10AT-Her2 cells efficiently form tumorspheres in suspension cultures and initiate tumor xenograft formation in athymic mice at low cell numbers. Furthermore, 10AT-Her2 cells are highly sensitive to the anti-proliferative apoptotic effects of indole-3-carbinol (I3C), a natural anti-cancer indolecarbinol from cruciferous vegetables of the Brassica genus such as broccoli and cabbage. I3C promotes the interaction of nucleostemin with MDM2 (Murine Double Mutant 2), an inhibitor of the p53 tumor suppressor, and disrupts the MDM2 interaction with p53. I3C also induced nucleostemin to sequester MDM2 in a nucleolus compartment, thereby freeing p53 to mediate its apoptotic activity. siRNA knockdown of nucleostemin functionally documented that nucleostemin is required for I3C to trigger its cellular anti-proliferative responses, inhibit tumorsphere formation, and disrupt MDM2-p53 protein-protein interactions. Furthermore, expression of an I3C-resistant form of elastase, the only known target protein for I3C, prevented I3C anti-proliferative responses in cells and in tumor xenografts in vivo, as well as disrupt the I3C stimulated nucleostemin-MDM2 interactions. CONCLUSIONS: Our results provide the first evidence that a natural anti-cancer compound mediates its cellular and in vivo tumor anti-proliferative responses by selectively stimulating cellular interactions of the stem/progenitor cell marker nucleostemin with MDM2, which frees p53 to trigger its apoptotic response. Furthermore, our study provides a new mechanistic template that can be potentially exploited for the development of cancer stem/progenitor cell targeted therapeutic strategies.

Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes.

Artemisinin, a sesquiterpene phytolactone derived from Artemisia annua, is a potent antimalarial compound with promising anticancer properties, although the mechanism of its anticancer signaling is not well understood. Artemisinin inhibited proliferation and induced a strong G1 cell cycle arrest of cultured MCF7 cells, an estrogen-responsive human breast cancer cell line that represents an early-stage cancer phenotype, and effectively inhibited the in-vivo growth of MCF7 cell-derived tumors from xenografts in athymic nude mice. Artemisinin also induced a growth arrest of tumorigenic human breast cancer cell lines with preneoplastic and late stage cancer phenotypes, but failed to arrest the growth of a nontumorigenic human mammary cell line. Concurrent with the cell cycle arrest of MCF7 cells, artemisinin selectively downregulated the transcript and protein levels of the CDK2 and CDK4 cyclin-dependent kinases, cyclin E, cyclin D1, and the E2F1 transcription factor. Analysis of CDK2 promoter-luciferase reporter constructs showed that the artemisinin ablation of CDK2 gene expression was accounted for by the loss of CDK2 promoter activity. Chromatin immunoprecipitation revealed that artemisinin inhibited E2F1 interactions with the endogenous MCF7 cell CDK2 and cyclin E promoters. Moreover, constitutive expression of exogenous E2F1 prevented the artemisinin-induced cell cycle arrest and downregulation of CDK2 and cyclin E gene expression. Taken together, our results demonstrate that the artemisinin disruption of E2F1 transcription factor expression mediates the cell cycle arrest of human breast cancer cells and represents a critical transcriptional pathway by which artemisinin controls human reproductive cancer cell growth.