Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression.

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Evidence-Based Health Communication in Practice: Driving Funding, Research, and Training Through the University of Texas at Austin Center for Health Communication.

Academic centers play a vital role in advancing knowledge, driving innovation, and fostering collaboration. The University of Texas at Austin Center for Health Communication was established in 2014 with the mission to improve public health through evidence-based communication research and practice. In this article, we reflect on the center history, explain our practice-oriented funding structure, and showcase examples of public health campaigns informed by theory and data, as well as professional-oriented educational programs. We also discuss the academic and community impact of our research, education, and practice and the benefits and challenges associated with this practice-led funding model. Although there are other approaches to operating academic centers, we hope the lessons we have learned can be of help to other centers dedicated to health communication research and practice.

A cross-sectional survey of viral hepatitis education within pharmacy curricula in the United States.

BACKGROUND: The Viral Hepatitis National Strategic Plan emphasizes the importance of a collaborative provider workforce trained in hepatitis prevention and treatment to eliminate viral hepatitis in the United States by 2030. Although pharmacists play a key role in hepatitis management, literature lacks documentation of the amount of viral hepatitis education provided to pharmacy students. AIM: Our study goal was to describe viral hepatitis education provided at United States pharmacy schools. METHOD: In this cross-sectional survey study, investigators developed a 19-item Qualtrics questionnaire, sent questionnaire links to curricula content experts at 140 accredited pharmacy colleges/schools in May-June 2022, and allotted 28 days for completion. Questions assessed the viral hepatitis instruction provided to students and hepatitis instructors' training/experience. We used descriptive statistics for analysis. RESULTS: Forty-eight pharmacy institutions across 29 states/territories responded; 44% had 50-99 students/class, and 58% used lecture and discussion to provide required hepatitis education. Students received more lecture (average = 3.4 h, range 0.8-1.6 h/hepatitis topic) than discussion (average = 1.7 h, range 0.6-0.9 h/hepatitis topic), with the most time spent on hepatitis C, followed by hepatitis B virus. Respondents reported 93% of their instructors had post-graduate training/certifications and 67% worked in clinical settings with hepatitis patients. CONCLUSION: Survey results demonstrate variability in hepatitis education across United States pharmacy curricula. Data offer stakeholders in hepatitis elimination efforts knowledge about the viral hepatitis education provided to Doctor of Pharmacy students. Future directions include consideration of implementation of minimum hepatitis education standards to further support work toward national hepatitis elimination.

Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression.

Immunotherapy with CAR T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons (CSE) present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify CSE targets, we analyzed 1,532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We found 2,933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n=148) or the alternatively spliced (AS) isoform (n=9) level. Expression of selected AS targets, including the EDB domain of FN1 (EDB), and gene targets, such as COL11A1, were validated in pediatric PDX tumors. We generated CAR T cells specific to EDB or COL11A1 and demonstrated that COL11A1-CAR T-cells have potent antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Cdc42 activity in the trailing edge is required for persistent directional migration of keratinocytes.

Fibroblasts migrate discontinuously by generating transient leading-edge protrusions and irregular, abrupt retractions of a narrow trailing edge. In contrast, keratinocytes migrate persistently and directionally via a single, stable, broad protrusion paired with a stable trailing-edge. The Rho GTPases Rac1, Cdc42 and RhoA are key regulators of cell protrusions and retractions. However, how these molecules mediate cell-type specific migration modes is still poorly understood. In fibroblasts, all three Rho proteins are active at the leading edge, suggesting short-range coordination of protrusive Rac1 and Cdc42 signals with RhoA retraction signals. Here, we show that Cdc42 was surprisingly active in the trailing-edge of migrating keratinocytes. Elevated Cdc42 activity colocalized with the effectors MRCK and N-WASP suggesting that Cdc42 controls both myosin activation and actin polymerization in the back. Indeed, Cdc42 was required to maintain the highly dynamic contractile acto-myosin retrograde flow at the trailing edge of keratinocytes, and its depletion induced ectopic protrusions in the back, leading to decreased migration directionality. These findings suggest that Cdc42 is required to stabilize the dynamic cytoskeletal polarization in keratinocytes, to enable persistent, directional migration.

Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.

The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.

Direct investigation of cell contraction signal networks by light-based perturbation methods.

Cell contraction plays an important role in many physiological and pathophysiological processes. This includes functions in skeletal, heart, and smooth muscle cells, which lead to highly coordinated contractions of multicellular assemblies, and functions in non-muscle cells, which are often highly localized in subcellular regions and transient in time. While the regulatory processes that control cell contraction in muscle cells are well understood, much less is known about cell contraction in non-muscle cells. In this review, we focus on the mechanisms that control cell contraction in space and time in non-muscle cells, and how they can be investigated by light-based methods. The review particularly focusses on signal networks and cytoskeletal components that together control subcellular contraction patterns to perform functions on the level of cells and tissues, such as directional migration and multicellular rearrangements during development. Key features of light-based methods that enable highly local and fast perturbations are highlighted, and how experimental strategies can capitalize on these features to uncover causal relationships in the complex signal networks that control cell contraction.

An extensive ß1-adrenergic receptor gene signaling network regulates molecular remodeling in dilated cardiomyopathies.

We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a ß1-adrenergic receptor-linked (ß1-AR-linked) gene signaling network (ß1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member ß1-GSN was identified by mRNA expression in transgenic mice overexpressing human ß1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of ß1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major ß1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of ß1-GSN members. We conclude that an extensive 430-member gene network downstream from the ß1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.

[Psychotherapy in disorders of intellectual development-Current evidence and practical implementation]. / Psychotherapie bei Störungen der Intelligenzentwicklung ­ aktuelle Evidenz und praktische Umsetzung.

People with a disorder of intellectual development (German draft of the ICD-11, which came into force on 1 January 2022) suffer more frequently from mental illnesses. According to the international treatment guidelines multimodal approaches should include not only psychopharmacological treatment, but also disorder-specific psychotherapeutic methods. These psychotherapeutic interventions have to be adapted to the communicative and cognitive abilities (performance diagnostics with IQ tests) as well as the emotional developmental stage (developmental diagnostics, e.g., with the scale of emotional development, short version, SED-S 2; [1]). To ensure this, the rules of simple language should be observed and when appropriate relatives or caregivers should be involved in the therapeutic process. The effectiveness of cognitive behavioral therapy has received most scientific attention, especially for affective disorders. Posttraumatic stress disorders can be validly treated with eye movement desensitization and reprocessing (EMDR). There is also good evidence for exposure therapy with reinforcement in the treatment of anxiety disorders.

Correction: Desires for Individual- and Interpersonal-Level Patient Portal Use for HIV Prevention Among Urban Sexual Minority Men: Cross-sectional Study.

[This corrects the article DOI: 10.2196/43550.].

Desires for Individual- and Interpersonal-Level Patient Portal Use for HIV Prevention Among Urban Sexual Minority Men: Cross-sectional Study.

BACKGROUND: Gay, bisexual, and other sexual minority men have expressed the acceptability of patient portals as tools for supporting HIV prevention behaviors, including facilitating disclosure of HIV and other sexually transmitted infection (STI/HIV) laboratory test results to sex partners. However, these studies, in which Black or African American sexual minority men were undersampled, failed to determine the relationship of reported history of discussing HIV results with sex partners and anticipated willingness to disclose web-based STI/HIV test results using a patient portal. OBJECTIVE: Among a sample of predominantly Black sexual minority men, this study aimed to (1) determine preferences for patient portal use for HIV prevention and (2) test the associations between reported history of discussing HIV results and anticipated willingness to disclose web-based STI/HIV test results with most recent main and nonmain partners using patient portals. METHODS: Data come from audio-computer self-assisted interview survey data collected during the 3-month visit of a longitudinal cohort study. Univariate analysis assessed patient portal preferences by measuring the valuation rankings of several portal features. Multiple Poisson regression models with robust error variance determined the associations between history of discussing HIV results and willingness to disclose those results using web-based portals by partner type, and to examine criterion validity of the enhancing dyadic communication (EDC) scale to anticipated willingness. RESULTS: Of the 245 participants, 71% (n=174) were Black and 22% (n=53) were White. Most participants indicated a willingness to share web-based STI/HIV test results with their most recent main partner. Slightly fewer, nonetheless a majority, indicated a willingness to share web-based test results with their most recent nonmain partner. All but 2 patient portal features were valued as high or moderately high priority by >80% of participants. Specifically, tools to help manage HIV (n=183, 75%) and information about pre- and postexposure prophylaxis (both 71%, n=173 and n=175, respectively) were the top-valuated features to include in patient portals for HIV prevention. Discussing HIV test results was significantly associated with increased prevalence of willingness to disclose web-based test results with main (adjusted prevalence ratio [aPR] 1.46, 95% CI 1.21-1.75) and nonmain partners (aPR 1.54, 95% CI 1.23-1.93). CONCLUSIONS: Our findings indicate what features Black sexual minority men envision may be included in the patient portal's design to optimize HIV prevention, further supporting the criterion validity of the EDC scale. Efforts should be made to support Black sexual minority men's willingness to disclose STI/HIV testing history and status with partners overall as it is associated significantly with a willingness to disclose testing results digitally via patient portals. Future studies should consider discussion behaviors regarding past HIV test results with partners when tailoring interventions that leverage patient portals in disclosure events.

Addressing mental health needs of NCAA student-athletes of colour: foundational concepts from the NCAA Summit on Diverse Student-Athlete Mental Health and Well-Being.

We sought to identify concepts that may facilitate National Collegiate Athletic Association efforts to assist member institutions in addressing the mental health needs of student-athletes of colour. A two-step process was followed to generate and refine concepts, guided by Delphi methodology. First, a scoping review was conducted, including original peer-reviewed research articles that quantified or qualitatively described determinant(s) of racial or ethnic differences in athlete mental health or mental healthcare. Next, a multiday virtual meeting was facilitated to review the results of the scoping review, discuss lived experiences and generate potential concepts. Participants included a racially and ethnically diverse group of student-athletes, medical and mental health professionals, athletics administrators, diversity, equity and inclusion experts, health educators and representatives from leading organisations involved in athlete mental health. Through the consensus process, participants identified 42 concepts that member institutions might consider implementing on their campuses. Concepts were largely focused on organisational policies and practices such as staffing diversity and inclusion, expanded options for clinical support (ie, identity-relevant support groups) and within-organisation accountability. Concepts related to specific areas for stakeholder education were also identified. Institutions have the potential to play an important role in supporting the mental well being of student-athletes of colour, and the present concepts can help inform institutional action. While concepts proposed are believed to be broadly relevant across athletics settings, they would need to be further considered and tailored to reflect setting-specific organisational structures, resources and needs.

Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination.

SARS CoV-2 enters host cells via its Spike protein moiety binding to the essential cardiac enzyme angiotensin-converting enzyme (ACE) 2, followed by internalization. COVID-19 mRNA vaccines are RNA sequences that are translated into Spike protein, which follows the same ACE2-binding route as the intact virion. In model systems, isolated Spike protein can produce cell damage and altered gene expression, and myocardial injury or myocarditis can occur during COVID-19 or after mRNA vaccination. We investigated 7 COVID-19 and 6 post-mRNA vaccination patients with myocardial injury and found nearly identical alterations in gene expression that would predispose to inflammation, coagulopathy, and myocardial dysfunction.

Enacted Sexual Minority Stigma, Psychological Distress, and Sexual and Drug Risk Behaviors Among Urban Men Who Have Sex with Men (MSM).

Urban Black men who have sex with men (MSM) bear a disproportionate burden of HIV and syphilis in the U.S. Experiences of enacted sexual minority stigma and psychological distress among these men may be associated with HIV/STI sexual and drug risk behaviors. The objective was to determine the associations between enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. In an urban prospective cohort study, survey measures assessed past 3-month exposure to enacted sexual minority stigma, psychological distress, and sexual and drug risk behaviors. Multivariable logistic regression models were utilized for hypothesis testing. The Black MSM (N = 140) reported the following: 22.1% experiences of enacted sexual minority stigma, 39% high levels of psychological distress, 48.6% > 1 sex partner, 8.6% transactional sex, and 6% injection drug use (IDU). In models adjusted for age and education, enacted sexual minority stigma significantly increased the odds of reporting > 1 sex partner, transactional sex, and IDU. Adjusting additionally for homelessness, the association between enacted sexual minority stigma and transactional sex remained significant. Adding psychological distress to this model showed a significant association between psychological distress and transactional sex, while the association was no longer significant for transactional sex. These findings highlight some of the complex psycho-social relationships that may be associated with sexual and drug risk behaviors among Black MSM placing them at increased risk for HIV and syphilis.

RESUMEN: Hombres urbanos de raza Negra que tienen sexo con hombres (HSH) sobrellevan una carga desproporcionada de VIH y sífilis en los EE.UU. Experiencias de estigma efectivo de minoría sexual y angustia psicológica entre estos hombres pudiese ser asociado con conductas sexuales de riesgo VIH/ITS y drogas. El objetivo era determinar las asociaciones entre un estigma efectivo de minoría sexual, angustia psicológica, y comportamientos sexuales y de riesgo de drogas. En un estudio de cohortes prospectivo urbano, las medidas de la encuesta evaluada en los últimos tres meses de exposición al estigma efectivo, angustia psicológica, y sus conductas sexuales y comportamientos riesgoso de drogas. Modelos de regresión logística multivariante se utilizaron para la prueba de hipótesis. Los HSH de raza negra (N = 140) reportaron lo siguiente: 22.1% experiencias de estigma efectivo, 39% niveles altos de angustia psicológica, 48.6% y > 1 pareja sexual, 8.6% sexo transaccional, y 6% uso de drogas inyectables (UDI). En modelos ajustados a edad y educación, un estigma efectivo de minoría sexual aumentó de manera significante las probabilidades de reportar y > 1 pareja sexual, sexo transaccional, y UDI. Ajustando adicionalmente para personas sin vivienda, la asociación entre estigma efectivo de minoría sexual y sexo transaccional permaneció significante. La adición de angustia psicológica al modelo mostró una asociación significativa entre angustia psicológica y sexo transaccional, mientras que la asociación ya no era significativa para el sexo transaccional. Estos resultados destacan algunas de las complejas relaciones psicosociales que pudiesen estar asociadas con conductas sexuales y de riesgo de drogas entre HSH de raza negra, poniéndolos a mayor riesgo de contraer VIH y sífilis.

Talking About Prescription Opioid Misuse: The Effect of Family Communication Patterns and Messages Advocating Direct and Indirect Communication.

Families play an important role in addressing substance misuse and addiction. Extant literature suggests patterns of communication within families influence the ways in which they engage loved ones who may be misusing substances like prescription opioids. However, little is known regarding how strategic health messages about family communication influence individuals' intentions to engage in conversations about substance misuse. Applying a normative approach, we conducted a (2 × 2) between-participants experiment examining whether messages advocating indirect (versus direct) communication are more effective for individuals (n = 613) who describe their family as having a low (versus high) conversation orientation. Univariate analysis of variance tests show match effects for message attitudes and message elaboration. For intentions to talk with a loved one about the risks of OUD, there was only evidence of a matching effect between the message advocating indirect communication with low conversation audiences. Both message types were equally effective at influencing intentions for high conversation participants. These findings suggest message designers should consider the kinds of communication behaviors and actions advocated in appeals targeting family members. Messages that are inclusive of the conversation dynamics of particular audiences may have greater effect. In particular, for low conversation audiences, messages advocating an indirect approach may be more effective at motivating intentions to engage someone who is misusing opioids.

Medin co-aggregates with vascular amyloid-ß in Alzheimer's disease.

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-ß precursor protein (APP) transgenic mice and in patients with Alzheimer's disease that medin co-localizes with vascular amyloid-ß deposits, and that in mice, medin deficiency reduces vascular amyloid-ß deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-ß burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer's disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-ß to promote its aggregation, as medin forms heterologous fibrils with amyloid-ß, affects amyloid-ß fibril structure, and cross-seeds amyloid-ß aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-ß deposition in the blood vessels of the brain.

Chemical activation of commodity plastics for patterned electroless deposition of robust metallic films.

A general approach to increase the adhesion of metal films to commodity plastic substrates using a metal-chelating polymer, polyethyleneimine, in conjunction with patterned electroless deposition is described. This general fabrication method is compatible with a diverse array of plastics and metals with properties applicable to flexible electronic circuits and electrochemical cells.

Sexually Transmitted Infection Transmission Dynamics During the Coronavirus Disease 2019 (COVID-19) Pandemic Among Urban Gay, Bisexual, and Other Men Who Have Sex With Men.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) mitigation measures on sexually transmitted infection (STI) transmission and racial disparities remains unknown. Our objectives were to compare sex and drug risk behaviors, access to sexual health services, and STI positivity overall and by race during the COVID-19 pandemic compared with pre-pandemic among urban sexual minority men (MSM). METHODS: Sexually active MSM aged 18-45 years were administered a behavioral survey and STI testing every 3-months. Participants who completed at least 1 during-pandemic (April 2020-December 2020) and 1 pre-pandemic study visit (before 13 March 2020) that occurred less than 6 months apart were included. Regression models were used to compare during- and pre-pandemic visit outcomes. RESULTS: Overall, among 231 MSM, reports of more than 3 sex partners declined(pandemic-1: adjusted prevalence ratio 0.68; 95% confidence interval: .54-.86; pandemic-2: 0.65, .51-.84; pandemic-3: 0.57, .43-.75), substance use decreased (pandemic-1: 0.75, .61-.75; pandemic-2: 0.62, .50-.78; pandemic-3: 0.61, .47-.80), and human immunodeficiency virus/preexposure prophylaxis care engagement (pandemic-1: 1.20, 1.07-1.34; pandemic-2: 1.24, 1.11-1.39; pandemic-3: 1.30, 1.16-1.47) increased. STI testing decreased (pandemic-1: 0.68, .57-.81; pandemic-2: 0.78, .67-.92), then rebounded (pandemic-3: 1.01, .87-1.18). Nei-ther Chlamydia (pandemic-2: 1.62, .75-3.46; pandemic-3: 1.13, .24-1.27) nor gonorrhea (pandemic-2: 0.87, .46 1.62; pandemic-3: 0.56, .24-1.27) positivity significantly changed during vs pre-pandemic. Trends were mostly similar among Black vs. non-Black MSM. CONCLUSIONS: We observed sustained decreases in STI risk behaviors but minimal change in STI positivity during compared with pre-pandemic. Our findings underscore the need for novel STI prevention strategies that can be delivered without in-person interactions.