Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity.

The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. The goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed B7-H3; whereas, levels were undetectable on normal dog tissues. Both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little anti-tumor activity was generated by B7-H3 CAR T cells; whereas, B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.

Preliminary Efficacy of a Digital Intervention for Adolescent Depression: Randomized Controlled Trial.

BACKGROUND: Adolescent depression is a significant public health concern; however, access to effective mental health care is limited. Digital therapeutics (DTx) can improve access to evidence-based interventions; however, their efficacy in adolescents is sparsely documented. OBJECTIVE: This study aims to examine the efficacy of a mobile app DTx versus an active control as an adjunct treatment for adolescent depression symptoms. METHODS: An internet-based open-label randomized control trial was conducted nationwide with a partial crossover design, and 168 adolescents aged 13 to 21 years with symptoms of depression were recruited between November 2020 and September 2021. Participants were randomized (1:1) to the cognitive behavioral therapy-based treatment app (Spark) or to a psychoeducational control app (control), which they would use for a duration of 5 weeks. The primary outcome was a between-group (Spark vs control) difference in the change in depression symptoms from baseline to postintervention, as measured by the Patient Health Questionnaire-8 (PHQ-8) using a linear mixed-effects analysis. The PHQ-8 ranges from 0 to 24, with scores of 5 to 9 indicating mild depression symptoms, scores of 10 to 14 indicating moderate symptoms, scores of 15 to 19 indicating moderately severe symptoms, and scores of 20 to 24 indicating severe symptoms. A minimal clinically important difference (5-point reduction between baseline and postintervention) in the Spark arm and group differences in remission and treatment response rates based on the PHQ-8 at postintervention were also investigated. RESULTS: A total of 160 participants were randomized, 80 in the Spark arm (mean age 16.89, SD 2.5 y) and 80 in the control arm (mean age 16.79, SD 2.59 y). Data from 121 participants (Spark: n=63; control: n=58) with moderate to severe (PHQ-8≥10) symptoms at baseline were included in the primary analyses following a modified intention-to-treat principle. A linear mixed-effect analysis revealed a nonsignificant difference between the study arms in depression symptom change over the intervention period. The Spark arm met a minimal clinically important difference threshold (mean -5.08, 95% CI -6.72 to -3.42). The remission rate in the Spark arm was significantly higher than that in the control arm (11/63, 17% vs 2/58, 3%; χ21=6.2; P=.01; false discovery rate-adjusted P=.03). The treatment response rates were not significantly different between the study arms (P=.07; false discovery rate-adjusted P=.16). Post hoc analyses including participants with mild to severe (PHQ-8 score ≥5) symptoms at baseline revealed promising evidence that Spark is effective in those with mild to severe symptoms. CONCLUSIONS: There is initial evidence that a self-guided, cognitive behavioral therapy-based DTx intervention may effectively treat mild to severe depression symptoms in adolescents. DTx may improve access to mental health care for adolescents or serve as an important adjunct to the standard of care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04524598; https://clinicaltrials.gov/study/NCT04524598.

Single cell RNA-sequencing of Ewing sarcoma tumors demonstrates transcriptional heterogeneity and clonal evolution.

Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single cell RNA-sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and surrounding tumor microenvironment (TME). Copy-number analysis identified subclonal evolution within patients even prior to treatment. Primary tumor samples demonstrate a heterogenous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and EWS targets. We also were able to identify the composition of the TME and molecularly dissect the transcriptional profile of circulating tumor cells in peripheral blood at the time of diagnosis.

Self-Guided Digital Intervention for Depression in Adolescents: Feasibility and Preliminary Efficacy Study.

BACKGROUND: Depression in adolescents is a large and growing problem; however, access to effective mental health care continues to be a challenge. Digitally based interventions may serve to bridge this access gap for adolescents in need of care. Digital interventions that deliver components of cognitive behavioral therapy (CBT) have been shown to reduce symptoms of depression, and virtual reality (VR) may be a promising adjunctive component. However, research on these types of treatments in adolescents and young adults is limited. OBJECTIVE: This study aims to evaluate the feasibility, acceptability, and preliminary efficacy of Spark (v1.0), a 5-week, self-guided, CBT-based digital program using a mobile app and VR experiences to target symptoms of depression in adolescents. METHODS: A single-arm, open-label study of the Spark program was conducted with a community sample of 30 adolescents and young adults aged 12 to 21 years with self-reported moderate to severe depression symptoms. Participants completed a weekly depression assessment (Patient Health Questionnaire-8) in the app during the 5-week intervention period as well as web-based baseline, postintervention, and 1-month follow-up self-report assessments. The participants also completed a qualitative postintervention interview. For participants aged <18 years, caregivers completed assessments at baseline and postintervention time points. Feasibility outcomes included recruitment rate (the proportion of participants who enrolled in the study divided by the total number of participants screened for eligibility) and retention rate (the proportion of participants who completed postintervention assessments divided by the total number of participants who received the intervention). Acceptability outcomes included engagement with the program and quantitative and qualitative feedback about the program. Preliminary efficacy was evaluated based on the Patient Health Questionnaire-8. RESULTS: The study recruitment (31/66, 47%) and retention (29/30, 97%) rates were high. Participants provided higher ratings for the ease of use of the Spark program (8.76 out of 10) and their enjoyment of both the mobile app (7.00 out of 10) and VR components (7.48 out of 10) of the program, whereas they provided lower ratings for the program's ability to improve mood (4.38 out of 10) or fit into their daily routines (5.69 out of 10). We observed a clinically and statistically significant reduction in depression scores at postintervention (mean difference 5.36; P<.001) and 1-month follow-up (mean difference 6.44; P<.001) time points. CONCLUSIONS: The Spark program was found to be a feasible and acceptable way to deliver a self-guided CBT-focused intervention to adolescents and young adults with symptoms of depression. Preliminary data also indicated that the Spark program reduced the symptoms of depression in adolescents and young adults. Future studies should evaluate the efficacy of this intervention in an adequately powered randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04165681; https://classic.clinicaltrials.gov/ct2/show/NCT04165681.

Assessing the Efficacy and Safety of a Digital Therapeutic for Symptoms of Depression in Adolescents: Protocol for a Randomized Controlled Trial.

BACKGROUND: Depression is a serious, prevalent, recurrent, and undertreated disorder in adolescents. Low levels of treatment seeking and treatment adherence in this age group, combined with a growing national crisis in access to mental health care, have increased efforts to identify effective treatment alternatives for this demographic. Digital health interventions for mental illness can provide cost-effective, engaging, and accessible means of delivering psychotherapy to adolescents. OBJECTIVE: This protocol describes a virtual randomized controlled trial designed to evaluate the efficacy and safety of a self-guided, mobile app-based implementation of behavioral activation therapy, SparkRx, for the adjunct treatment of symptoms of depression in adolescents. METHODS: Participants are recruited directly through web-based and print advertisements. Following eligibility screening and consenting, participants are randomly assigned to a treatment arm (SparkRx) or a control arm (assessment-enhanced usual care) for 5 weeks. The primary efficacy outcome, total score on the 8-item Patient Health Questionnaire (PHQ-8), is assessed at the end of the 5-week intervention period. Additional participant-reported outcomes are assessed at baseline, the postintervention time point, and 1-month follow-up. The safety of the intervention is assessed by participant report (and legal guardian report, if the participant is younger than 18 years) and by patterns of symptom deterioration on the PHQ-8, as part of a larger clinical safety monitoring protocol. The primary efficacy outcome, total PHQ-8 score at the postintervention time point, will be compared between SparkRx and enhanced usual care arms using mixed effect modeling, with baseline PHQ-8 and current antidepressant medication status included as covariates. Secondary efficacy outcomes, including the proportion of participants exhibiting treatment response, remission, and minimal clinically significant improvement (all derived from total PHQ-8 scores), will be compared between groups using chi-square tests. Symptom severity at 1-month follow-up will also be compared between arms. Planned subgroup analyses will examine the robustness of treatment effects to differences in baseline symptom severity (PHQ-8 score <15 or ≥ 15) and age (younger than 18 years and older than 18 years). The primary safety outcome, the number of psychiatric serious adverse events, will be compared between trial arms using the Fisher exact test. All other adverse events will be presented descriptively. RESULTS: As of May 2023, enrollment into the study has concluded; 223 participants were randomized. The analysis of the efficacy and safety data is expected to be completed by Fall 2023. CONCLUSIONS: We hypothesize that the results of this trial will support the efficacy and safety of SparkRx in attenuating symptoms of depression in adolescents. Positive results would more broadly support the prospect of using accessible, scientifically validated, digital therapeutics in the adjunct treatment of mental health disorders in this age range. TRIAL REGISTRATION: ClinicalTrials.gov NCT05462652; https://clinicaltrials.gov/study/NCT05462652. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48740.

A CBT-based mobile intervention as an adjunct treatment for adolescents with symptoms of depression: a virtual randomized controlled feasibility trial.

Background: High rates of adolescent depression demand for more effective, accessible treatment options. A virtual randomized controlled trial was used to assess the feasibility and acceptability of a 5-week, self-guided, cognitive behavioral therapy (CBT)-based mobile application, Spark, compared to a psychoeducational mobile application (Active Control) as an adjunct treatment for adolescents with depression during the COVID-19 pandemic. Methods: A community sample aged 13-21, with self-reported symptoms of depression, was recruited nationwide. Participants were randomly assigned to use either Spark or Active Control (NSpark = 35; NActive Control = 25). Questionnaires, including the PHQ-8 measuring depression symptoms, completed before, during, and immediately following completion of the intervention, evaluated depressive symptoms, usability, engagement, and participant safety. App engagement data were also analyzed. Results: 60 eligible adolescents (female = 47) were enrolled in 2 months. 35.6% of those expressing interest were consented and all enrolled. Study retention was high (85%). Spark users rated the app as usable (System Usability Scalemean = 80.67) and engaging (User Engagement Scale-Short Formmean = 3.62). Median daily use was 29%, and 23% completed all levels. There was a significant negative relationship between behavioral activations completed and change in PHQ-8. Efficacy analyses revealed a significant main effect of time, F = 40.60, p < .001, associated with decreased PHQ-8 scores over time. There was no significant Group × Time interaction (F = 0.13, p = .72) though the numeric decrease in PHQ-8 was greater for Spark (4.69 vs. 3.56). No serious adverse events or adverse device effects were reported for Spark users. Two serious adverse events reported in the Active Control group were addressed per our safety protocol. Conclusion: Recruitment, enrollment, and retention rates demonstrated study feasibility by being comparable or better than other mental health apps. Spark was highly acceptable relative to published norms. The study's novel safety protocol efficiently detected and managed adverse events. The lack of significant difference in depression symptom reduction between Spark and Active Control may be explained by study design and study design factors. Procedures established during this feasibility study will be leveraged for subsequent powered clinical trials evaluating app efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04524598.

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.

Meaningful engagement: A crossfunctional framework for digital therapeutics.

Digital mental health interventions, or digital therapeutics, have the potential to transform the field of mental health. They provide the opportunity for increased accessibility, reduced stigma, and daily integration with patient's lives. However, as the burgeoning field continues to expand, there is a growing concern regarding the level and type of engagement users have with these technologies. Unlike many traditional technology products that have optimized their user experience to maximize the amount of time users spend within the product, such engagement within a digital therapeutic is not sufficient if users are not experiencing an improvement in clinical outcomes. In fact, a primary challenge within digital therapeutics is user engagement. Digital therapeutics are only effective if users sufficiently engage with them and, we argue, only if users meaningfully engage with the product. Therefore, we propose a 4-step framework to assess meaningful engagement within digital therapeutics: (1) Define the measure of value (2) Operationalize meaningful engagement for your digital therapeutic (3) Implement solutions to increase meaningful engagement (4) Iteratively evaluate the solution's impact on meaningful engagement and clinical outcomes. We provide recommendations to the common challenges associated with each step. We specifically emphasize a cross-functional approach to assessing meaningful engagement and use an adolescent-focused example throughout to further highlight developmental considerations one should consider depending on their target users.

SAHA Enhances Differentiation of CD34+CD45+ Hematopoietic Stem and Progenitor Cells from Pluripotent Stem Cells Concomitant with an Increase in Hemogenic Endothelium.

Epigenetic modification is an important process during hematopoietic cell differentiation. Histone deacetylase (HDAC) inhibitors have previously been shown to enhance expansion of umbilical cord blood-derived hematopoietic stem cells (HSCs). However, the effect of HDAC inhibitors on pluripotent stem cells (PSCs) in this context is less understood. For years, investigators have considered PSC-derived natural killer (NK) and T-cell therapies. These "off-the-shelf" cellular therapies are now entering the clinic. However, the in vitro commitment of PSCs to the hematopoietic lineage is inefficient and represents a major bottleneck. We investigated whether HDAC inhibitors (HDACi) influence human PSC differentiation into CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), focusing on hemogenic endothelium (HE). Pluripotent stem cells cultured in the presence of HDACi showed a 2-5 times increase in HSPCs. Concurrent with this, HDACi-treated PSCs increased expression of 7 transcription factors (HOXA5, HOXA9, HOXA10, RUNX1, ERG, SPI1, and LCOR) recently shown to convert HE to HSPCs. ChIP-qPCR showed that SAHA upregulated acetylated-H3 at the promoter region of the above key genes. SAHA-treated human PSC-derived CD34+CD45+ cells showed primary engraftment in immunodeficient mice, but not serial transplantation. We further demonstrate that SAHA-derived HSPCs could differentiate into functional NK cells in vitro. The addition of SAHA is an easy and effective approach to overcoming the bottleneck in the transition from PSC to HSPCs for "off-the-shelf" cellular immunotherapy.

Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling.

Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34+CD117+α4ß7+Lin-) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34+CD117+α4ß7+Lin-CD48-CD52+ and CD34+CD117+α4ß7+Lin-CD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4ß7+Lin-CD48+CD52+ subset and give rise to ILC1s, ILC2s, and NCR+ ILC3s, whereas CD34+CD117+α4ß7+Lin-CD48+CD52- ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. In addition, CD48-expressing CD34+CD117+α4ß7+Lin- precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.

Effective connectivity between Broca's area and amygdala as a mechanism of top-down control in worry.

Individuals higher in trait worry exhibit increased activation in Broca's area during inhibitory processing tasks. To identify whether such activity represents an adaptive mechanism supporting top-down control, functional and effective connectivity of Broca's area were investigated during a task of inhibitory control. fMRI data obtained from 106 participants performing an emotion-word Stroop task were examined using psychophysiological interaction and Granger Causality (GC) analyses. Findings revealed greater directed connectivity from Broca's to amygdala in the presence of emotional distraction. Furthermore, a predictive relationship was observed between worry and the asymmetry in effective connectivity, with worriers exhibiting greater directed connectivity from Broca's to amygdala. When performing the task, worriers with greater GC directional asymmetry were more accurate than worriers with less asymmetry. Present findings indicate that individuals with elevated trait worry employ a mechanism of top-down control in which communication from Broca's to amygdala fosters successful compensation for interference effects.

Prolactin Acts on Myeloid Progenitors to Modulate SMAD7 Expression and Enhance Hematopoietic Stem Cell Differentiation into the NK Cell Lineage.

Numerous cell types modulate hematopoiesis through soluble and membrane bound molecules. Whether developing hematopoietic progenitors of a particular lineage modulate the differentiation of other hematopoietic lineages is largely unknown. Here we aimed to investigate the influence of myeloid progenitors on CD34+ cell differentiation into CD56+ innate lymphocytes. Sorted CD34+ cells cultured in the presence of stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (FLT3L) give rise to numerous cell types, including progenitors that expressed the prolactin receptor (PRLR). These CD34+PRLR+ myeloid-lineage progenitors were derived from granulocyte monocyte precursors (GMPs) and could develop into granulocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Moreover, CD34+PRLR+ myeloid progenitors lacked lymphoid developmental potential, but when stimulated with prolactin (PRL) they increased the differentiation of other CD34+ cell populations into the NK lineage in a non-contact dependent manner. Both mRNA and protein analyses show that PRL increased mothers against decapentaplegic homolog 7 (SMAD7) in CD34+PRLR+ myeloid cells, which reduced the production of transforming growth factor beta 1 (TGF-ß1), a cytokine known to inhibit CD56+ cell development. Thus, we uncover an axis whereby CD34+PRLR+ GMPs inhibit CD56+ lineage development through TGF-ß1 production and PRL stimulation leads to SMAD7 activation, repression of TGF-ß1, resulting in CD56+ cell development.

Haematopoiesis, or Blood Poetry.

"It was just a few small red dots," I would recount to innumerable sympathetic nurses. They-the dots, not nurses-clustered together on my son's smooth slim neck. I stroked them as I dressed him after the bath. My inner hypochondriac was oddly quiet. Larry, my son, was well, throwing himself through the world with speed, joy, and curiosity. The next day I took him casually to our general practitioner to get these curious freckles checked. Then everything started to tilt. How do I weave it all together? In a string of Facebook posts? In a small impersonal room opposite a stranger while I sip a glass of water? In a series of dark jokes with my husband in the kitchen late at night? In snatches of awkward conversation with friends? In dreams from which I wake gasping? By scouring the sentences of authors and archives? From the discoveries of Paul Ehrlich to the scattered words of Emily Dickinson to the constant mechanical chugging of the IV pump, this interdisciplinary essay delves into the medical and cultural history of blood and bone marrow to tell an acutely personal story.

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.

BACKGROUND: The use of next-generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long-term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. METHODS: Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. RESULTS: We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI-MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB-ALK, CIC-LEUTX, FGFR2-KIAA159, and MN1-CXXC5 and detail their morphological features. CONCLUSIONS: Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

Targetable molecular alterations in congenital glioblastoma.

INTRODUCTION: Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. METHODS: Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. RESULTS: Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. CONCLUSIONS: Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.

Reward anticipation and punishment anticipation are instantiated in the brain via opponent mechanisms.

fMRI investigations have examined the extent to which reward and punishment motivation are associated with common or opponent neural systems, but such investigations have been limited by confounding variables and methodological constraints. The present study aimed to address limitations of earlier approaches and more comprehensively evaluate the extent to which neural activation associated with reward and punishment motivation reflects opponent or shared systems. Participants completed a modified monetary incentive delay task, which involved the presentation of a cue followed by a target to which participants were required to make a speeded button press. Using a factorial design, cues indicated whether monetary reward and/or loss (i.e., cues signaled probability of reward, punishment, both, or neither) could be expected depending upon response speed. Neural analyses evaluated evidence of (a) directionally opposing effects by testing for regions of differential activation for reward and punishment anticipation, (b) mutual inhibition by testing for interactive effects of reward and punishment anticipation within a factorial design, and (c) opposing effects on shared outputs via a psychophysiological interaction analysis. Evidence supporting all three criteria for opponent systems was obtained. Collectively, present findings support conceptualizing reward and punishment motivation as opponent forces influencing brain and behavior and indicate that shared activation does not suggest the operation of a common neural mechanism instantiating reward and punishment motivation.

Transient Expression of GATA3 in Hematopoietic Stem Cells Facilitates Helper Innate Lymphoid Cell Differentiation.

Helper Innate lymphoid cells (ILCs) are tissue resident lymphocytes that play a critical role in a number of biological processes. Several transcription factors are required for the differentiation of hematopoietic stem cells (HSCs) into ILCs. Recent studies demonstrate GATA3 as a transcriptional regulator that plays an essential role in ILC development. We aimed to modulate the differentiation of human cord blood-derived CD34+ cells into ILCs by transient and ectopic expression of mRNA encoding transcription factors known to be important for ILC lineage differentiation, including GATA3, TOX, NFIL3, ID2, and RORγt. Using this experimental protocol, only GATA3 significantly modulated HSCs to differentiate into helper ILCs. Transient overexpression of GATA3 drove the emergence of CD34+α4ß7+ early ILC progenitors during the first few days of culture. These ILC progenitors further acquired IL-7Rα and CD117 to give rise to immediate ILC precursors. In support of these findings, analysis of the genes induced by GATA3 in HSCs showed an upregulation of those associated with ILC development. Moreover, we show GATA3 also acts on more committed progenitors and significantly shifts the differentiation of progenitors away from the ILC1/NK lineage to the ILC2 and ILC3 lineage. In summary, transient overexpression of GATA3 mRNA in CD34+ HSCs enhances the differentiation of HSCs into the helper ILC lineages, at the expense of NK cell development.

Measuring the Impact of Academic Cancer Network Development on Clinical Integration, Quality of Care, and Patient Satisfaction.

PURPOSE: Many US academic centers have acquired community practices to expand their clinical care and research footprint. The objective of this assessment was to determine whether the acquisition and integration of community oncology practices by Yale/Smilow Cancer Hospital improved outcomes in quality of care, disease team integration, clinical trial accrual, and patient satisfaction at network practice sites. METHODS: We evaluated quality of care by testing the hypothesis that core Quality Oncology Practice Initiative measures at network sites that were acquired in 2012 were significantly different after their 2016 integration into the network. Clinical and research integration were measured using the number of tumor board case presentations and total accruals in clinical trials. We used Press-Ganey scores to measure patient satisfaction pre- and postintegration. RESULTS: Mean Quality Oncology Practice Initiative scores at Smilow Care Centers were significantly higher in 2016 than in 2012 for core measures related to improvement in tumor staging ( z = 1.33; P < .05), signed consent and documentation plans for antineoplastic treatment ( z = 2.69; P < .01; and z = 2.36; P < .05, respectively), and appropriately quantifying and addressing pain during office visits ( z = 2.95; P < .05; and z = 3.1; P < .01, respectively). A total of 493 cases were presented by care center physicians at the tumor board in 2017 compared with 45 presented in 2013. Compared with 2012, Smilow Care Center clinical trial accrual increased from 25 to 170 patients in 2017. Last, patient satisfaction has remained at greater than the 90th percentile pre- and postintegration. CONCLUSION: The process of integration facilitates the ability to standardize cancer practice and provides a platform for quality improvement.

Misunderstanding RDoC.

Mental illness is fundamentally mental, by definition about psychological rather than biological phenomena, but biological phenomena play key roles in understanding, preventing, and treating mental illness. The Research Domain Criteria initiative (RDoC) of the US National Institute of Mental Health is an unusually ambitious effort to foster integration of psychological and biological science in the service of psychopathology research. Some key features and common misunderstandings of RDoC are discussed here.