GalNAc-conjugated siRNA targeting the DNAJB1-PRKACA fusion junction in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer caused by a dominant recurrent fusion of the heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). Current therapies such as chemotherapy and radiation have limited efficacy, and new treatment options are needed urgently. We have previously shown that FLC tumors are dependent on the fusion kinase DNAJB1::PRKACA, making the oncokinase an ideal drug target. mRNA degrading modalities such as antisense oligonucleotides or small interfering RNAs (siRNAs) provide an opportunity to specifically target the fusion junction. Here, we identify a potent and specific siRNA that inhibits DNAJB1::PRKACA expression. We found expression of the asialoglycoprotein receptor in FLC to be maintained at sufficient levels to effectively deliver siRNA conjugated to the GalNAc ligand. We observe productive uptake and siRNA activity in FLC patient-derived xenografts (PDX) models in vitro and in vivo. Knockdown of DNAJB1::PRKACA results in durable growth inhibition of FLC PDX in vivo with no detectable toxicities. Our results suggest that this approach could be a treatment option for FLC patients.

Effect of the DASH diet on the sodium-chloride cotransporter and aquaporin-2 in urinary extracellular vesicles.

The dietary approach to stop hypertension (DASH) diet combines the antihypertensive effect of a low sodium and high potassium diet. In particular, the potassium component of the diet acts as a switch in the distal convoluted tubule to reduce sodium reabsorption, similar to a diuretic but without the side effects. Previous trials to understand the mechanism of the DASH diet were based on animal models and did not characterize changes in human ion channel protein abundance. More recently, protein cargo of urinary extracellular vesicles (uEVs) has been shown to mirror tissue content and physiological changes within the kidney. We designed an inpatient open label nutritional study transitioning hypertensive volunteers from an American style diet to DASH diet to examine physiological changes in adults with stage 1 hypertension otherwise untreated (Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group. N Engl J Med 344: 3-10, 2001). Urine samples from this study were used for proteomic characterization of a large range of pure uEVs (small to large) to reveal kidney epithelium changes in response to the DASH diet. These samples were collected from nine volunteers at three time points, and mass spectrometry identified 1,800 proteins from all 27 samples. We demonstrated an increase in total SLC12A3 [sodium-chloride cotransporter (NCC)] abundance and a decrease in aquaporin-2 (AQP2) in uEVs with this mass spectrometry analysis, immunoblotting revealed a significant increase in the proportion of activated (phosphorylated) NCC to total NCC and a decrease in AQP2 from day 5 to day 11. This data demonstrates that the human kidney's response to nutritional interventions may be captured noninvasively by uEV protein abundance changes. Future studies need to confirm these findings in a larger cohort and focus on which factor drove the changes in NCC and AQP2, to which degree NCC and AQP2 contributed to the antihypertensive effect and address if some uEVs function also as a waste pathway for functionally inactive proteins rather than mirroring protein changes.NEW & NOTEWORTHY Numerous studies link DASH diet to lower blood pressure, but its mechanism is unclear. Urinary extracellular vesicles (uEVs) offer noninvasive insights, potentially replacing tissue sampling. Transitioning to DASH diet alters kidney transporters in our stage 1 hypertension cohort: AQP2 decreases, NCC increases in uEVs. This aligns with increased urine volume, reduced sodium reabsorption, and blood pressure decline. Our data highlight uEV protein changes as diet markers, suggesting some uEVs may function as waste pathways. We analyzed larger EVs alongside small EVs, and NCC in immunoblots across its molecular weight range.

Elevated ad libitum alcohol consumption following continuous theta burst stimulation to the left-dorsolateral prefrontal cortex is partially mediated by changes in craving.

Previous research indicates that following alcohol intoxication, activity in prefrontal cortices is reduced, linking to changes in associated cognitive processes, such as inhibitory control, attentional bias (AB), and craving. While these changes have been implicated in alcohol consumption behaviour, it has yet to be fully illuminated how these frontal regions and cognitive processes interact to govern alcohol consumption behaviour. The current preregistered study applied continuous theta burst transcranial magnetic stimulation (cTBS) to examine directly these relationships while removing the wider pharmacological effects of alcohol. A mixed design was implemented, with cTBS stimulation to right and left dorsolateral prefrontal cortex (DLPFC), the medial orbital frontal cortex (mOFC) and Vertex, with measures of inhibitory control, AB, and craving taken both pre- and post-stimulation. Ad libitum consumption was measured using a bogus taste task. Results suggest that rDLPFC stimulation impaired inhibitory control but did not significantly increase ad libitum consumption. However, lDLPFC stimulation heightened craving and increased consumption, with findings indicating that changes in craving partially mediated the relationship between cTBS stimulation of prefrontal regions and ad libitum consumption. Medial OFC stimulation and AB findings were inconclusive. Overall, results implicate the left DLPFC in the regulation of craving, which appears to be a prepotent cognitive mechanism by which alcohol consumption is driven and maintained.

Implementing DASH-aligned Congregate Meals and Self-Measured Blood Pressure in two senior centers: An open label study.

BACKGROUND AND AIMS: Cardiovascular Disease (CVD) poses significant health risks for seniors, especially among low-income and minority communities. Senior centers offer multiple services. We tested whether implementing two evidence-based interventions- DASH-aligned meals provided through an existing congregate meal program, and support for home Self-Measured Blood Pressure (SMBP) monitoring-lowers blood pressure among participants at two senior centers serving low-income, racially diverse communities. METHODS AND RESULTS: Open-label study, enrolling clients aged ≥60, eating ≥4 meals/week at two NYC senior centers. Participants received DASH-aligned congregate meals, and training in nutrition, BP management education, and personal SMBP device. Co-Primary outcomes: a) change in systolic BP measured by independent health professionals, and b) change in percent with "controlled BP" (Eighth Joint National Committee (JNC-8) Guidelines), at Month 1 compared to Baseline. SECONDARY OUTCOMES: Changes in BP at Months 3 and 5/6 (last measure). We enrolled 94 participants; COVID closures interrupted implementation mid-study. Mean systolic BP at Month-1 changed by -4.41 mmHg (n = 61 p = 0.07) compared to Baseline. Participants with controlled BP increased (15.7%) at Month 1. Change in mean BP at Month 1 was significantly correlated with BMI (p = 0.02), age (p = 0.04), and baseline BP (p < 0.001). Mean systolic SMBP changed by -6.9 mmHg (p = 0.004) at Months 5/6. CONCLUSIONS: Implementing an evidence-based multi-component BP-lowering intervention within existing congregate meal programs at senior centers serving minority and low-income communities is feasible, and early findings show promising evidence of effectiveness. This approach to cardiovascular risk reduction should be further tested for widespread adoption and impact. Registered on ClinicalTrials.gov NCT03993808 (June 21st, 2019).

The Effects of Placebo and Moderate Dose Alcohol on Attentional Bias, Inhibitory Control and Subjective Craving.

AIMS: Previous research indicates that acute alcohol intoxication and placebo can inhibit people's control over consumption behaviour and heighten attentional bias (AB) towards alcohol-related stimuli and craving. We designed a study to disentangle anticipated from pharmacological effects of alcohol in order to gain a clearer view of their relative contributions to alcohol consumption. METHODS: In a within-participants design (moderate alcohol dose, placebo and control), and over a minimum 2-week period, participants completed a battery of questionnaires and cognitive tasks, followed by a bogus taste task to measure ad libitum consumption. RESULTS: Both alcohol preload and placebo resulted in cognitive and psychological changes, including impaired inhibitory control, heightened AB and craving. However, ad libitum consumption only increased following alcohol and not placebo. Furthermore, inhibitory control impairments did not mediate the relationship between initial intoxication and ad libitum consumption, and findings indicate that increases in craving may mediate this association. CONCLUSION: Psychological processes such as craving may be more important in driving consummatory behaviour relative to transient changes in cognitive processes, such as inhibitory control.

Emotion and liking: how director emotional expression and knowledge of (dis)liking may impact adults' ability to follow the instructions of an ignorant speaker.

BACKGROUND: Theory of mind (ToM), the ability to understand that others have different knowledge and beliefs to ourselves, has been the subject of extensive research which suggests that we are not always efficient at taking another's perspective, known as visual perspective taking (VPT). This has been studied extensively and a growing literature has explored the individual-level factors that may affect perspective taking (e.g. empathy and group membership). However, while emotion and (dis)liking are key aspects within everyday social interaction, research has not hitherto explored how these factors may impact ToM. METHOD: A total of 164 participants took part in a modified director task (31 males (19%), M age = 20.65, SD age = 5.34), exploring how correct object selection may be impacted by another's emotion (director facial emotion; neutral × happy × sad) and knowledge of their (dis)likes (i.e. director likes specific objects). RESULT: When the director liked the target object or disliked the competitor object, accuracy rates were increased relative to when he disliked the target object or liked the competitor object. When the emotion shown by the director was incongruent with their stated (dis)liking of an object (e.g. happy when he disliked an object), accuracy rates were also increased. None of these effects were significant in the analysis of response time. These findings suggest that knowledge of liking may impact ToM use, as can emotional incongruency, perhaps by increasing the saliency of perspective differences between participant and director. CONCLUSION: As well as contributing further to our understanding of real-life social interactions, these findings may have implications for ToM research, where it appears that more consideration of the target/director's characteristics may be prudent.

Visual and auditory contextual cues differentially influence alcohol-related inhibitory control. / Los estímulos contextuales visuales y auditivos impactan de manera diferenciada el control inhibitorio relacionado con el alcohol.

Representing a more immersive testing environment, the current study exposed individuals to both alcohol-related visual and auditory cues to assess their respective impact on alcohol-related inhibitory control. It examined further whether individual variation in alcohol consumption and trait effortful control may predict inhibitory control performance. Twenty-five U.K. university students (Mage = 23.08, SD = 8.26) completed an anti-saccade eye-tracking task and were instructed to look towards (pro) or directly away (anti) from alcohol-related and neutral visual stimuli. Short alcohol-related sound cues (bar audio) were played on 50% of trials and were compared with responses where no sounds were played. Findings indicate that participants launched more incorrect saccades towards alcohol-related visual stimuli on anti-saccade trials, and responded quicker to alcohol on pro-saccade trials. Alcohol-related audio cues reduced latencies for both pro- and anti-saccade trials and reduced anti-saccade error rates to alcohol-related visual stimuli. Controlling for trait effortful control and problem alcohol consumption removed these effects. These findings suggest that alcohol-related visual cues may be associated with reduced inhibitory control, evidenced by increased errors and faster response latencies. The presentation of alcohol-related auditory cues, however, appears to enhance performance accuracy. It is postulated that auditory cues may re-contextualise visual stimuli into a more familiar setting that reduces their saliency and lessens their attentional pull.

Con el objetivo de crear un entorno de evaluación más ajustado a la realidad, en este estudio se expuso a los participantes a estímulos visuales y auditivos relacionados con el alcohol para evaluar su impacto en el control inhibitorio relacionado con el alcohol. Además, se examinó si las diferencias individuales en el consumo de alcohol y el rasgo autorregulación predecían el rendimiento del control inhibitorio. Veinticinco estudiantes universitarios del Reino Unido (edad media = 23,08 años; SD = 8,26) llevaron a cabo una tarea anti-sacádica de seguimiento ocular, en la que se les pedía que miraran hacia (pro), o directamente en la dirección contraria (anti), estímulos visuales tanto relacionados con el alcohol como neutros. Además, en el 50% de los ensayos se reprodujeron estímulos auditivos breves relacionados con el alcohol (sonido de bar), y las respuestas se compararon con las que se producían en la ausencia de sonidos. Los resultados indican que los participantes dirigieron más movimientos sacádicos incorrectos hacia los estímulos visuales relacionados con el alcohol en los ensayos anti-sacádicos, y que respondieron más rápido al alcohol en los ensayos pro-sacádicos. Los estímulos auditivos relacionados con el alcohol redujeron la latencia de respuesta tanto para los ensayos pro- como anti-sacádicos, y redujeron la tasa de errores anti-sacádicos en los estímulos relacionados con el alcohol. Sin embargo, estos efectos se eliminaron al controlar el rasgo autorregulación y el consumo problemático de alcohol. Estos resultados sugieren que los estímulos visuales relacionados con el alcohol pueden estar asociados con una reducción del control inhibitorio, lo cual se pone de manifiesto en el aumento de errores y en unas latencias de respuesta más rápidas. Sin embargo, la presentación de estímulos auditivos relacionados con el alcohol parece aumentar la precisión en la tarea. Se propone que los estímulos auditivos pueden recontextualizar los estímulos visuales en un contexto más familiar que reduce su prominencia y disminuye su capacidad de captar la atención.

Stimulation of the dorsolateral prefrontal cortex impacts conflict resolution in Level-1 visual perspective taking.

Theory of mind is the ability to understand others' beliefs, mental states, and knowledge. Perspective-taking is a key part of this capacity, and while previous research has suggested that calculating another's perspective is relatively straightforward, executive function is required to resolve the conflict between the self and that other perspective. Previous studies have shown that theory of mind is selectively impaired by transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC). However, it has been hitherto unclear as to which specific aspect of perspective-taking is impacted. The current study administered rTMS (N = 31 adult participants) to the DLPFC (active condition) and vertex (control condition) in a within-subjects design. Participants completed a L1 VPT task after each stimulation session, and focus (relative performance on self-perspective trials compared with other perspective trials) and conflict indices (relative ability to resolve competing self/other perspectives) were calculated. Results showed that stimulation of the DLPFC selectively impaired the conflict index, suggesting that the DLPFC may be causally related with the resolution of conflict between self and other perspectives, and that self-other interference may rely on domain-general processes.

Continuous Theta Burst Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex Impairs Inhibitory Control and Increases Alcohol Consumption.

Previous research indicates that alcohol intoxication impairs inhibitory control and that the right dorsolateral prefrontal cortex (rDLPFC) is a functional brain region important for exercising control over thoughts and behaviour. At the same time, the extent to which changes in inhibitory control following initial intoxication mediate subsequent drinking behaviours has not been elucidated fully. Ascertaining the extent to which inhibitory control impairments drive alcohol consumption, we applied continuous theta burst transcranial magnetic stimulation (rDLPFC cTBS vs. control) to isolate how inhibitory control impairments (measured using the Stop-Signal task) shape ad libitum alcohol consumption in a pseudo taste test. Twenty participants (13 males) took part in a within-participants design; their age ranged between 18 and 27 years (M = 20.95, SD = 2.74). Results indicate that following rDLPFC cTBS participants' inhibitory control was impaired, and ad libitum consumption increased. The relationship between stimulation and consumption did not appear to be mediated by inhibitory control in the present study. Overall, findings suggest that applying TMS to the rDLPFC may inhibit neural activity and increase alcohol consumption. Future research with greater power is recommended to determine the extent to which inhibitory control is the primary mechanism by which the rDLPFC exerts influence over alcohol consumption, and the degree to which other cognitive processes may play a role.

Perfect for a Gin and Tonic: How Context Drives Consumption Within a Modified Bogus Taste Test.

AIM: To implement a modified bogus taste test (BTT) and to examine the interactive effects of environmental and social contexts on levels of 'alcohol' consumption. METHOD: University students (Study 1 n = 38, Study 2 n = 80), recruited via opportunity sampling, completed a modified BTT under the pretence of assessing garnish preference for gin and tonic. All participants were tested alone or as part of an existing friendship group. In Study 1 participants were in a laboratory setting but were exposed to different contextual cues (alcohol-related or neutral) by way of posters displayed on the walls. In Study 2, participants assessed the drinks in either a pub or a library setting. RESULTS: In Study 1 participants tested in a group consumed significantly more when exposed to pub-related stimuli in contrast to those who were exposed to library-related stimuli. Participants who were alone and exposed to library-related cues consumed significantly more than those in a group and exposed to these cues. In Study 2, as in Study 1, participants tested in a group condition consumed significantly more of what they believed to be alcohol when in the pub compared to those who were tested in the library. Higher group consumption was also evident in the library condition, although the size of this difference was not as large as in the pub testing condition. CONCLUSION: In the absence of any pharmacological effects of alcohol, social and environmental context have an interactive impact on shaping consumption.

The Decoy Effect Within Alcohol Purchasing Decisions.

BACKGROUND: The decoy effect is the phenomenon where the introduction of a third choice to a decision dyad changes the distribution of preferences between options. OBJECTIVES: Examine whether this effect exists in alcohol purchasing decisions and whether testing context impacts this. METHOD: Fifty-two participants tested in either a bar or library context and were asked to choose one of a series of beer and water deals presented for timed intervals. In some cases, two options were presented (with similar attractiveness) and in other cases a third, less preferable, decoy option was added. RESULTS: A basic decoy effect in both alcohol and water purchasing decisions. Specifically, there were reductions in the selection of both the original options when the decoy was added into choice dyads. A significant interaction demonstrated in the bar context there was a significant difference such that there was a slight increase in participants selecting the most cost effective option when the decoy was added, and a simultaneous decrease in those choosing the moderately cost effective option. There were no such differences observed in the library condition. CONCLUSION: The same product may be perceived differently across contexts and, as such, consumers in a pub environment may be particularly vulnerable to the decoy effect.

Fluorescent logic systems for sensing and molecular computation: structure-activity relationships in edge-detection.

Molecular logic-based computation continues to throw up new applications in sensing and switching, the newest of which is the edge detection of objects. The scope of this phenomenon is mapped out by the use of structure-activity relationships, where several structures of the molecules and of the objects are examined. The different angles and curvatures of the objects are followed with good fidelity in the visualized edges, even when the objects are in reverse video.

The work and social adjustment scale: reliability, sensitivity and value.

OBJECTIVE: To investigate the psychometric properties of the Work and Social Adjustment Scale (WSAS) as an outcome measure for the Improving Access to Psychological Therapy programme, assessing its value as an addition to the Patient Health (PHQ-9) and Generalised Anxiety Disorder questionnaires (GAD-7). Little research has investigated these properties to date. METHODS: Reliability and responsiveness to change were assessed using data from 4,835 patients. Principal components analysis was used to determine whether the WSAS measures a factor distinct from the PHQ-9 and GAD-7. RESULTS: The WSAS measures a distinct social functioning factor, has high internal reliability, and is sensitive to treatment effects. CONCLUSIONS: The WSAS, PHQ-9 and GAD-7 perform comparably on measures of reliability and sensitivity. The WSAS also measures a distinct social functioning component suggesting it has potential as an additional outcome measure.

Factor structure of the alcohol expectancies questionnaire among adolescents in rural Ghana.

INTRODUCTION: Children's early experiences with alcohol inform the development of alcohol-related beliefs which are known to predict alcohol consumption during the critical stage of adolescence. Yet, there has been considerably less research into these alcohol-related cognitions in low- and middle-income countries (LMIC) and existing measures of these beliefs are highly reflective of Western contexts, which may not be fully appropriate for use in LMICs. The aim is to ascertain the construct validity of the Alcohol Expectancies Questionnaire (AEQ) in a non-Western sample. METHODS: A cross-sectional diagnostic accuracy study involving 500 adolescents aged 10 to 18 years randomly selected from the database of the Navrongo Health and Demographic Surveillance System. Participants were administered the locally back translated version of the 34-item AEQ. Confirmatory factor analysis using the lavaan package in R was conducted to generate indices for the factor structure of the AEQ. RESULTS: Confirmatory factor analyses showed that while groupings of positive and negative expectancies were similar to those observed when expectancies have been assessed previously in Western studies, these formed a single 'alcohol expectancy' factor. Questions relating to positive tension reduction and negative physical expectancies showed inconsistent responses in this study. DISCUSSION AND CONCLUSIONS: Commonly used tools for the assessment of alcohol expectancies may not be suitable for use in Ghana, possibly owing to their development and validation in Western contexts. These findings have implications for the assessment of alcohol-related beliefs in LMIC settings and begin to map out a research agenda to develop more contextually and culturally attune alcohol assessments.

Empowering the Participant Voice (EPV): Design and implementation of collaborative infrastructure to collect research participant experience feedback at scale.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

Affect and alcohol consumption: An ecological momentary assessment study during national lockdown.

Coronavirus disease (COVID-19)-related lockdown provided an opportunity to examine the relationship between affect and alcohol consumption in a historically unique context. To shed light on mixed findings regarding the interplay between affective states and alcohol consumption, the present study examined how affective states and affect fluctuations impact drinking during confinement of people to their homes. It also examined the extent to which the social context moderated the affect-consumption relationship. Having preregistered study protocols, methods, and hypotheses, 87 U.K. participants (34% male, Mage = 29.33) used their smartphones to respond to thrice daily prompts, recording their affective states, alcohol consumption, and social context over 1 week. Multilevel modeling suggested that being with someone (vs. alone) was associated with increased alcohol consumption. Increased drinking on the previous day was associated with increased next day negative affect, and the number of household occupants was associated with decreased negative affect. Preconsumption affect was not associated with subsequent drinking. These findings point to a complex relationship between alcohol consumption, social context, and negative affect. The opportunity to interact with others during lockdown was generally associated with decreased negative affect in the moment. However, the presence of others was associated with increased consumption which, in turn, predicted elevated next-day negative affect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

UK alcohol consumption during the COVID-19 pandemic: The role of drinking motives, employment and subjective mental health.

Background Previous investigations suggest that the COVID-19 pandemic effects on alcohol consumption were heterogenous and may vary as a function of structural and psychological factors. Research examining mediating or moderating factors implicated in pandemic-occasioned changes in drinking have also tended to use single-study cross-sectional designs and convenience samples. AIMS: First, to explore structural (changed employment or unemployment) and psychological (subjective mental health and drinking motives) correlates of consumption reported during the COVID-19 pandemic using a UK nationally representative (quota sampled) dataset. Second, to determine whether population-level differences in drinking during the COVID-19 pandemic (versus pre-pandemic levels) could be attributable to drinking motives. METHOD: Data collected from samples of UK adults before and during the pandemic were obtained and analysed: Step1 carried out structural equation modelling (SEM) to explore data gathered during a period of social restrictions after the UK's first COVID-19-related lockdown (27 August-15 September, 2020; n = 3,798). It assessed whether drinking motives (enhancement, social, conformity, coping), employment and the perceived impact of the pandemic on subjective mental health may explain between-person differences in self-reported alcohol consumption. Step 2 multigroup SEM evaluated data gathered pre-pandemic (2018; n = 7,902) in concert with the pandemic data from step 1, to test the theory that population-level differences in alcohol consumption are attributable to variances in drinking motives. RESULTS: Analyses of the 2020 dataset detected both direct and indirect effects of subjective mental health, drinking motives, and employment matters (e.g., having been furloughed) on alcohol use. Findings from a multigroup SEM were consistent with the theory that drinking motives explain not only individual differences in alcohol use at both time points, but also population-level increases in use during the pandemic. CONCLUSION: This work highlights socioeconomic and employment considerations when seeking to understand COVID-19-related drinking. It also indicates that drinking motives may be particularly important in explaining the apparent trend of heightened drinking during the pandemic. Limitations related to causal inference are discussed.

Developing a simple risk metric for the effect of sport-related concussion and physical pain on mental health.

Risk factors associated with depression in athletes include biological sex, physical pain, and history of sport-related concussion (SRC). Due to the well-documented benefits of sport and physical activity on mental health, athletes and non-athletes were recruited to assess any differences. Beyond this, athletes were also grouped by sport-type (contact/non-contact sports) due to the increased prevalence of pain and SRC in contact sports. To our knowledge, there has been no research on how these factors influence the likelihood of depression. In the current study, 144 participants completed a short survey on the above factors and the Center for Epidemiological Studies Depression Scale. Sixty-two of these reported a history of concussion. Logistic regression revealed all the above predictors to be significantly associated with the depression scale. Individuals that had previously sustained SRC, were experiencing greater physical pain and females were more likely to display poor mental health. However, we provide further evidence for the benefits of engaging in sport and physical activity as those that took part in sport were less likely to report depression. Therefore, this study provides a simple risk metric whereby sportspeople can make a better informed choice of their sporting participation, making their own cost/reward judgement.

Oncogenic Addiction of Fibrolamellar Hepatocellular Carcinoma to the Fusion Kinase DNAJB1-PRKACA.

PURPOSE: Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression. EXPERIMENTAL DESIGN: We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX). RESULTS: We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA. CONCLUSIONS: Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.