A Scoping Review of Suicide Prevention Interventions for Lesbian, Gay, Bisexual, Transgender, Queer, and Other Sexual and Gender Minority Individuals.

Purpose: This scoping review summarizes the literature on suicide-specific psychological interventions among lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) people to synthesize existing findings and support future intervention research and dissemination. Methods: Electronic databases PsycInfo and PubMed were searched for reports of psychological intervention studies with suicide-related outcome data among LGBTQ+ people. A total of 1269 articles were screened, and 19 studies met inclusion criteria (k = 3 examined suicide-specific interventions tailored to LGBTQ+ people, k = 4 examined nontailored suicide-specific interventions, k = 11 examined minority stress- or LGBTQ+ interventions that were not suicide-specific, and k = 1 examined other types of interventions). Results: Synthesis of this literature was made challenging by varied study designs, and features limit confidence in the degree of internal and external validity of the interventions evaluated. The only established suicide-specific intervention examined was Dialectical Behavior Therapy, and minority stress- and LGBTQ-specific interventions rarely targeted suicidal thoughts and behaviors (STBs). Nevertheless, most interventions reviewed demonstrated support for feasibility and/or acceptability. Only five studies tested suicide-related outcome differences between an LGBTQ+ group and a cisgender/heterosexual group. These studies did not find significant differences in STBs, but certain subgroups such as bisexual individuals may exhibit specific treatment disparities. Conclusion: Given the dearth of research, more research examining interventions that may reduce STBs among LGBTQ+ people is critically needed to address this public health issue.

Is adequate dose adequate? An examination of the impact of psychotherapy on posttraumatic stress disorder symptoms utilizing Veterans Health Administration medical records.

Prior studies on individuals with posttraumatic stress disorder (PTSD) defined an adequate dose of psychotherapy as receiving at least nine sessions within a 15-week period. Yet, few studies have examined whether this definition of adequate dose is associated with meaningful change in PTSD symptoms over an extended period. To examine whether an adequate dose of individual or group psychotherapy was associated with PTSD symptom improvement, we identified mental health outpatient visits in the electronic medical record for a cohort of veterans enrolled in Veterans Health Administration (VHA) services (N = 1,649) across 5 years. Using latent growth curve modeling, we estimated the effect of receiving an adequate dose of psychotherapy on the PTSD symptom course. Among the sample, 992 participants (60.16%) received at least one individual therapy session and 506 participants (30.7%) received at least one group therapy session; of those, 226 (22.78%) received an adequate dose of individual therapy and 212 (41.9%) received an adequate dose of group therapy, respectively. An adequate individual therapy dose, but not group therapy dose, was associated with a decrease in PTSD Checklist for DSM-5 (PCL-5) scores over time. This improvement was extremely gradual (average of 1.57 PCL-5 point decrease per year). Adequate dose of psychotherapy, defined as nine sessions of routine psychotherapy over 15 weeks, is associated with minimal symptom change. This suggests that commonly used definitions of adequate dose have minimal clinical utility. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Percutaneous Image Guided Cryoablation of Adrenal Metastases From Renal Cell Carcinoma: A Single Institution Review.

OBJECTIVES: To assess the safety, technical success, disease progression, and survival associated with percutaneous image-guided cryoablation of renal cell carcinoma metastasis (mRCC) in the adrenal gland. METHODS: Retrospective, single-institution review of adult patients undergoing percutaneous cryoablation for adrenal mRCC between the years of 2007-2021. Technical parameters, technical success, safety, and survival were analyzed according to standard criteria. RESULTS: Forty-six patients (39 male; mean age 66 ± 8.8 years) with 57 tumors ablated over 51 sessions with a median hospital length of stay of 1 day (range 0-3 days). Forty-four (96%) had primary of clear cell histology. Aim of ablation was curative intent in 39 of 57 tumors (72%) with local tumor control in the remainder. There were 2 (4%) technical failures and technique efficacy was achieved in 52 out of the remaining 55 (95%). There were no Common Terminology Criteria for Adverse Events' immediate complications and 4 of 51 (8%) delayed complications. Twenty-five of 57 (44%) had disease progression anywhere, away from ablation site. One-, 3-, and 5-year recurrence free survival rates were 100%, 89%, and 89% and overall survival was 98%, 85%, and 71%. Fifty-one of 57 (89%) underwent preprocedural alpha blockade with hypertensive crisis in 27 of 56 (54%) available records, of which there were no adverse outcomes. CONCLUSION: Percutaneous cryoablation of mRCC to the adrenal glands is safe with robust local control, leading to advocacy for its ongoing use in this patient population. Multi-disciplinary management is recommended for successful treatment.

The Efficacy of Hospice-In-Place Care Versus Traditional Inpatient Care.

Introduction: The hospice-in-place program at Vanderbilt University Medical Center (VUMC) is available to patients and families who elect for hospice benefits and are too unstable to be transported for hospice care. The goal of this study was to assess the satisfaction of family members of patients who died while hospitalized at VUMC and received hospice-in-place compared to the families of patients who did not receive hospice care. Methods: Next-of-kin satisfaction was measured through the administration of qualitative interviews and quantitative questionnaires. Semi-structured interviews were audio-recorded, and transcripts were analyzed using an iterative inductive-deductive approach to develop a conceptual framework. Participants were also asked to respond to a 10-question satisfaction questionnaire. Results: Forty participants were enrolled: 20 next-of-kin of patients who received hospice-in-place and 20 next-of-kin of patients who passed without hospice. Factors influencing satisfaction were organized into a conceptual framework with three categories: individual-level factors, systems-level factors, and modifying factors. For the questionnaires, the hospice-in-place group had a mean satisfaction score of 4.54 (0.76) out of five, while the non-hospice group had a mean score of 4.14 (1.00). A comparison of the two groups' responses did not show a statistically significant difference (P = 0.06). Discussion: Quantitative findings of this study showed improved satisfaction but were unable to show a significant difference in satisfaction with hospice-in-place compared to traditional care. Questionnaire results suggest that both types of care yield high satisfaction scores and are successfully supporting patients and families. The conceptual framework also adds to the understanding of end-of-life experiences at VUMC.

Long-term neuropsychological outcomes of deep brain stimulation in early-stage Parkinson's disease.

INTRODUCTION: The pilot trial of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) randomized 30 patients (medication duration 0.5-4 years; without dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or subthalamic nucleus (STN) DBS plus ODT (early DBS + ODT). This study reports long-term neuropsychological outcomes from the early DBS pilot trial. METHODS: This is an extension of an earlier study that examined two-year neuropsychological outcomes in the pilot trial. The primary analysis was conducted on the five-year cohort (n = 28), and a secondary analysis was conducted on the 11-year cohort (n = 12). Linear mixed effects models for each analysis compared overall trend in outcomes for randomization groups. All subjects who completed the 11-year assessment were also pooled to evaluate long-term change from baseline. RESULTS: There were no significant differences between groups in either the five- or 11-year analyses. Across all PD patients who completed the 11-year visit, there was significant decline in Stroop Color and Color-Word and Purdue Pegboard from baseline to 11 years. CONCLUSIONS: Previous significant differences between the groups in phonemic verbal fluency and cognitive processing speed showing more decline for early DBS + ODT subjects one year after baseline diminished as PD progressed. No cognitive domains were worse for early DBS + ODT subjects compared to standard of care subjects. There were shared declines across all subjects on cognitive processing speed and motor control, likely reflecting disease progression. More study is needed to understand the long-term neuropsychological outcomes associated with early DBS in PD.

Teleneurology via tablet technology: an effective low-cost method to increase healthcare accessibility.

INTRODUCTION: Telemedicine is a valuable tool to increase access to health care, especially for patients in rural areas who need to visit a specialist. In place of telemedicine robots, which are costly and complicated, hospitals have implemented successful telemedicine programs using lower-cost tablet technology; opting for tablet technology increases the organizational feasibility of a large-scale telemedicine program. METHODS: Vanderbilt University Medical Center (VUMC), in Nashville, Tennessee, USA, launched its teleneurology network program in 2014 to serve patients in surrounding community hospitals who needed a neurology consult. Consults are conducted using an iPad, including examinations and the secure sharing of images and patient information. This article reports on teleneurology consult data and the results of patient and physician satisfaction surveys. RESULTS: Between February 2014 and November 2021, the VUMC teleneurology network program provided consultations for 14 241 patients with a wide variety of neurological diagnoses presenting to 12 community-based hospitals. Patient and community physician satisfaction surveys showed that 96% of physicians were satisfied with the overall care provided, and 89% of patients reported that the telehealth visits met their medical needs. CONCLUSION: One of the goals of telemedicine programs is to increase access to care. Therefore, it is important that the technology used to implement the program also be accessible in terms of cost and complexity. Tablets are low-cost technology, and their use in telemedicine has been shown to satisfy both physicians and patients with a wide variety of diagnoses.

The development of a rapid patient-derived xenograft model to predict chemotherapeutic drug sensitivity/resistance in malignant glial tumors.

BACKGROUND: High-grade gliomas (HGG) are aggressive brain tumors associated with short median patient survival and limited response to therapies, driving the need to develop tools to improve patient outcomes. Patient-derived xenograft (PDX) models, such as mouse PDX, have emerged as potential Avatar platforms for personalized oncology approaches, but the difficulty for some human grafts to grow successfully and the long time required for mice to develop tumors preclude their use for HGG. METHODS: We used a rapid and efficient ex-ovo chicken embryo chorioallantoic membrane (CAM) culture system to evaluate the efficacy of oncologic drug options for HGG patients. RESULTS: Implantation of fresh glioma tissue fragments from 59 of 60 patients, that include difficult-to-grow IDH-mutated samples, successfully established CAM tumor xenografts within 7 days, with a tumor take rate of 98.3%. These xenografts faithfully recapitulate the histological and molecular characteristics of the primary tumor, and the ability of individual fragments to form tumors was predictive of poor patient prognosis. Treatment of drug-sensitive or drug-resistant xenografts indicates that the CAM-glioma assay enables testing tumor sensitivity to temozolomide and carboplatin at doses consistent with those administered to patients. In a proof-of-concept study involving 14 HGG patients, we observed a correlation of 100% between the CAM xenograft response to temozolomide or carboplatin and the clinical response of patients. CONCLUSION: The CAM-glioma model is a fast and reliable assay that has the potential to serve as a complementary model to drug discovery and a real-time Avatar platform to predict the best treatment for HGG patients.

Short Message Service Reminder Nudge for Parents and Influenza Vaccination Uptake in Children and Adolescents With Special Risk Medical Conditions: The Flutext-4U Randomized Clinical Trial.

Importance: Children with chronic medical conditions are at increased risk of severe influenza. Uptake of influenza vaccination in children and adolescents with these identified special risk medical conditions (SRMCs) is suboptimal. Objective: To assess the effectiveness of Flutext-4U, a parent short message service (SMS) reminder nudge intervention, in increasing influenza immunization in children and adolescents with SRMCs. Design, Setting, and Participants: This randomized clinical trial was conducted at a tertiary pediatric hospital in Adelaide, South Australia, from April 15 to September 30, 2021. Children and adolescents aged 6 months to younger than 18 years with SRMCs and a subspecialist outpatient appointment over a 5-month period during the Australian seasonal influenza vaccination season (April-August 2021) were eligible to participate. Follow-up was until September 30, 2021. Interventions: Participants were randomly assigned (1:1 ratio) to control: clinician nudges (hospital vaccine availability, ease of access, and recommendation from hospital subspecialists) or SMS intervention (control conditions plus an additional SMS reminder nudge to parents), with randomization stratified by age group (<5 years, 5-14 years, or >14 to <18 years). Main Outcomes and Measures: The primary outcome was influenza vaccination, as confirmed by the Australian Immunisation Register. Results: A total of 600 participants (intervention group: 298 [49.7%]; mean [SD] age, 11.5 [4.6] years; 162 female participants [54.4%]; control group: 302 [50.3%]; mean [SD] age, 11.4 [4.7] years; 155 female participants [51.3%]) were included. Influenza vaccination was 38.6% (113 of 293) in the SMS intervention group compared with 26.2% (79 of 302) in the control group (adjusted odds ratio [aOR], 1.79; 95% CI, 1.27-2.55; P = .001). Time to vaccine receipt was significantly lower among SMS participants (adjusted hazard ratio, 1.67; 95% CI, 1.25-2.22; P < .001). For participants randomly assigned by June 15, a significantly greater proportion receiving the SMS intervention were vaccinated during the optimal delivery period April to June 30 (SMS group: 40.0% [76 of 190] vs 25.4% [50 of 197]; aOR, 1.97; 95% CI, 1.28-3.06; P = .002). Conclusions and Relevance: Results of this randomized clinical trial suggest that an additional SMS reminder nudge for parents delivered in the tertiary care hospital setting to children and adolescents with SMRCs resulted in higher influenza vaccine uptake compared with clinician nudges alone. Trial Registration: ANZCTR Identifier: ACTRN12621000463875.

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease.

OBJECTIVE: The deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5-4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial. MATERIALS AND METHODS: Attempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures. RESULTS: Twelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson's Disease Rating Scale [UPDRS]-IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; pinteraction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire-39 (PDQ-39), and levodopa equivalent daily dose (LEDD). CONCLUSIONS: Eleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016). CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00282152.

"The role of PTSD symptom severity and relationship functioning in male and female veterans' mental health service use": Correction.

Reports an error in "The role of PTSD symptom severity and relationship functioning in male and female veterans' mental health service use" by Kelly L. Harper, Dawne Vogt, Annie Fox, Yael I. Nillni and Tara Galovski (Psychological Trauma: Theory, Research, Practice, and Policy, Advanced Online Publication, Sep 29, 2022, np). In the original article, the second affiliation of Dawne Vogt was changed from "MGH Institute of Health Professionals, Boston, Massachusetts, United States" to "Department of Psychiatry, Boston University School of Medicine." In addition, the following sentence was deleted from the author note: "The study was funded by the National Center for PTSD." All versions of this article have been corrected. (The following abstract of the original article appeared in record 2023-05302-001). OBJECTIVE: Previous research has shown that difficulties in intimate relationships promote mental health treatment seeking for male veterans, but findings for female veterans have been mixed. The current study sought to further evaluate whether intimate relationship functioning is a motivator for mental health treatment seeking for male and female veterans and examine the impact of different types of trauma exposure on this association. METHOD: Using data from a longitudinal study, we examined whether intimate relationship functioning mediated the association between posttraumatic stress disorder (PTSD) symptom severity and mental health service use (0 = no mental health services, 1 = any mental health services) in male and female veterans (N = 1,200). We used multiple groups path analysis to examine whether intimate relationship functioning mediated the association between PTSD symptom severity and mental health service use for male and female veterans. RESULTS: For male veterans, greater PTSD symptom severity was related to poorer intimate relationship functioning, which in turn explained increased likelihood of mental health service use (R² = .18). This mediation effect was not significant for female veterans. CONCLUSIONS: Our findings suggest that targeting intimate relationship functioning in treatment for male veterans may be beneficial because difficulties in these relationships appear to be a motivating factor for treatment seeking. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A bottom-up approach to developing a unified trauma-minority stress model for transgender and gender diverse people.

OBJECTIVE: Transgender and gender diverse (TGD) people are at heightened risk of both Criterion A trauma exposure and other bias-related minority stressors (e.g., discrimination, rejection). In the absence of a unified trauma-minority stress theory, it remains unclear how to best conceptualize psychopathology for people who experience both trauma and minority stress. METHOD: Using a participant-driven q-sort methodology and network analytic approach, we analyzed card sort data from 18 TGD people and 16 providers with expertise in TGD care to derive thematic networks of trauma and minority stress experiences, as they connected to transdiagnostic symptoms (e.g., hyperarousal, avoidance). RESULTS: The TGD participants' resulting network illustrates conceptualizations of identity- and nonidentity-based Criterion A traumas as similar and only related to psychiatric symptoms via the shared connection through other minority stressors. The provider network was more granular, although the general pattern was consistent with TGD participants, demonstrating similar perceptions of how these experiences are associated. CONCLUSIONS: Evidence of inextricable links between trauma and psychiatric symptoms through the conduit of minority stressors lays the groundwork for novel, integrated models of trauma, minority stress, and their transdiagnostic symptom sequelae. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Longitudinal PTSD network structure: measuring PTSD symptom networks over 5 years.

BACKGROUND: Network modeling has been applied in a range of trauma-exposed samples, yet results are limited by an over reliance on cross-sectional data. The current analyses used posttraumatic stress disorder (PTSD) symptom data collected over a 5-year period to estimate a more robust between-subject network and an associated symptom change network. METHODS: A PTSD symptom network is measured in a sample of military veterans across four time points (Ns = 1254, 1231, 1106, 925). The repeated measures permit isolating between-subject associations by limiting the effects of within-subject variability. The result is a highly reliable PTSD symptom network. A symptom slope network depicting covariation of symptom change over time is also estimated. RESULTS: Negative trauma-related emotions had particularly strong associations with the network. Trauma-related amnesia, sleep disturbance, and self-destructive behavior had weaker overall associations with other PTSD symptoms. CONCLUSIONS: PTSD's network structure appears stable over time. There is no single 'most important' node or node cluster. The relevance of self-destructive behavior, sleep disturbance, and trauma-related amnesia to the PTSD construct may deserve additional consideration.

The role of PTSD symptom severity and relationship functioning in male and female veterans' mental health service use.

[Correction Notice: An Erratum for this article was reported online in Psychological Trauma: Theory, Research, Practice, and Policy on Nov 07 2022 (see record 2023-15574-001). In the original article, the second affiliation of Dawne Vogt was changed from "MGH Institute of Health Professionals, Boston, Massachusetts, United States" to "Department of Psychiatry, Boston University School of Medicine." In addition, the following sentence was deleted from the author note: "The study was funded by the National Center for PTSD." All versions of this article have been corrected.] Objective: Previous research has shown that difficulties in intimate relationships promote mental health treatment seeking for male veterans, but findings for female veterans have been mixed. The current study sought to further evaluate whether intimate relationship functioning is a motivator for mental health treatment seeking for male and female veterans and examine the impact of different types of trauma exposure on this association. METHOD: Using data from a longitudinal study, we examined whether intimate relationship functioning mediated the association between posttraumatic stress disorder (PTSD) symptom severity and mental health service use (0 = no mental health services, 1 = any mental health services) in male and female veterans (N = 1,200). We used multiple groups path analysis to examine whether intimate relationship functioning mediated the association between PTSD symptom severity and mental health service use for male and female veterans. RESULTS: For male veterans, greater PTSD symptom severity was related to poorer intimate relationship functioning, which in turn explained increased likelihood of mental health service use (R² = .18). This mediation effect was not significant for female veterans. CONCLUSIONS: Our findings suggest that targeting intimate relationship functioning in treatment for male veterans may be beneficial because difficulties in these relationships appear to be a motivating factor for treatment seeking. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Establishment of a ccRCC patient-derived chick chorioallantoic membrane model for drug testing.

Clear cell renal cell carcinoma (ccRCC) is an aggressive subtype of renal cell carcinoma accounting for the majority of deaths in kidney cancer patients. Advanced ccRCC has a high mortality rate as most patients progress and develop resistance to currently approved targeted therapies, highlighting the ongoing need for adequate drug testing models to develop novel therapies. Current animal models are expensive and time-consuming. In this study, we investigated the use of the chick chorioallantoic membrane (CAM), a rapid and cost-effective model, as a complementary drug testing model for ccRCC. Our results indicated that tumor samples from ccRCC patients can be successfully cultivated on the chick chorioallantoic membrane (CAM) within 7 days while retaining their histopathological characteristics. Furthermore, treatment of ccRCC xenografts with sunitinib, a tyrosine kinase inhibitor used for the treatment of metastatic RCC, allowed us to evaluate differential responses of individual patients. Our results indicate that the CAM model is a complementary in vivo model that allows for rapid and cost-effective evaluation of ccRCC patient response to drug therapy. Therefore, this model has the potential to become a useful platform for preclinical evaluation of new targeted therapies for the treatment of ccRCC.

Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Family-Involved Mental Health Care Among OEF/OIF Veterans With and Without PTSD Using VHA Administrative Records.

Prior research indicates that veterans are interested in including family members in health care and that family-inclusive mental health treatment can improve treatment outcomes. Consequently, the Veterans Health Administration's (VHA) directive requires providers to offer family-inclusive mental health services to veterans. However, the extent to which veterans engage in family-inclusive mental health services at the VHA remains unclear. Using data from a longitudinal registry of male and female veterans with and without posttraumatic stress disorder, we examined the extent to which veterans included family members in their mental health care and predictors of engagement in family-involved therapy visits using VHA administrative records over a 5-year time span. Of the 1,329 veterans who received mental health care during the study, 8.4% received a family therapy visit-the number of visits per veteran ranged from 1 to 34. Results from logistic regressions indicate that relative to White veterans, Black veterans were 61.0% less likely to receive a family-involved therapy visit. Married veterans or veterans living with a partner, and veterans with poor romantic relationship functioning, were more likely to receive a family-involved therapy visit. These findings indicate that only a small percentage of veterans received a family therapy visit across 5 years. Efforts to understand barriers to family-involved therapy visits and strategies to increase engagement in family-involved visits may improve clinical outcomes and promote patient-centered care.

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.

Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion.

Transforming growth factor ß (TGFß) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFß-targeted therapies. The major TGFß downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFß. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFß signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SARA recruitment to EEA1+ endosomes. A motility gene expression study indicated that SMAD3 selectively increased the expression of ITGB2 and VIM, two genes that were found to be implicated in hypoxia-induced cell invasion and associated with tumor progression and metastasis in cohorts of cancer patients. Furthermore, CAM xenograft assays show the significant benefit of selective inhibition of the SMAD3 signaling pathway as opposed to global TGFß inhibition in preventing tumor progression. Overall, these results suggest that fine-tuning of the pro-invasive HDAC6-SARA-SMAD3 axis could be a better strategy towards effective cancer treatments.

Human Lung Tissue Implanted on the Chick Chorioallantoic Membrane as a Novel In Vivo Model of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with no curative pharmacological treatment. Current preclinical models fail to accurately reproduce human pathophysiology and are therefore poor predictors of clinical outcomes. Here, we investigated whether the chick embryo chorioallantoic membrane (CAM) assay supports the implantation of xenografts derived from IPF lung tissue and primary IPF lung fibroblasts and can be used to evaluate the efficacy of antifibrotic drugs. We demonstrate that IPF xenografts maintain their integrity and are perfused with chick embryo blood. Size measurements indicate that the xenografts amplify on the CAM, and Ki67 and pro-collagen type I immunohistochemical staining highlight the presence of proliferative and functional cells in the xenografts. Moreover, the IPF phenotype and immune microenvironment of lung tissues are retained when cultivated on the CAM and the fibroblast xenografts mimic invasive IPF fibroblastic foci. Daily treatments of the xenografts with nintedanib and PBI-4050 significantly reduce their size, fibrosis-associated gene expression, and collagen deposition. Similar effects are found with GLPG1205 and fenofibric acid, two drugs that target the immune microenvironment. Our CAM-IPF model represents the first in vivo model of IPF that uses human lung tissue. This rapid and cost-effective assay could become a valuable tool for predicting the efficacy of antifibrotic drug candidates for IPF.