Faculty Bibliography

BACKGROUND:Climate change has important implications for the health and futures of children and young people, yet they have little power to limit its harm, making them vulnerable to climate anxiety. This is the first large-scale investigation of climate anxiety in children and young people globally and its relationship with perceived government response. METHODS:We surveyed 10 000 children and young people (aged 16-25 years) in ten countries (Australia, Brazil, Finland, France, India, Nigeria, Philippines, Portugal, the UK, and the USA; 1000 participants per country). Invitations to complete the survey were sent via the platform Kantar between May 18 and June 7, 2021. Data were collected on participants' thoughts and feelings about climate change, and government responses to climate change. Descriptive statistics were calculated for each aspect of climate anxiety, and Pearson's correlation analysis was done to evaluate whether climate-related distress, functioning, and negative beliefs about climate change were linked to thoughts and feelings about government response. FINDINGS/RESULTS:Respondents across all countries were worried about climate change (59% were very or extremely worried and 84% were at least moderately worried). More than 50% reported each of the following emotions: sad, anxious, angry, powerless, helpless, and guilty. More than 45% of respondents said their feelings about climate change negatively affected their daily life and functioning, and many reported a high number of negative thoughts about climate change (eg, 75% said that they think the future is frightening and 83% said that they think people have failed to take care of the planet). Respondents rated governmental responses to climate change negatively and reported greater feelings of betrayal than of reassurance. Climate anxiety and distress were correlated with perceived inadequate government response and associated feelings of betrayal. INTERPRETATION/CONCLUSIONS:Climate anxiety and dissatisfaction with government responses are widespread in children and young people in countries across the world and impact their daily functioning. A perceived failure by governments to respond to the climate crisis is associated with increased distress. There is an urgent need for further research into the emotional impact of climate change on children and young people and for governments to validate their distress by taking urgent action on climate change. FUNDING/BACKGROUND:AVAAZ.

BACKGROUND:Emotion regulation develops through bidirectional affective communication. AIM:To investigate the role of maternal interactive behavior in predicting infant affect among preterm versus full-term infants. STUDY DESIGN:The association between maternal interactive behavior (contingent, attention seeking, watching) and infant affect during a modified Still Face (SF) paradigm in a sample of 22 preterm and 28 full term infants (3 ½ - 4 ½ months old) was investigated. METHODS:Maternal behavior and infant affect were coded in one second intervals. RESULTS:Maternal contingent interaction was positively correlated with positive infant affect (p < 0.001 for Play; p < 0.001 for Reunion#1; p < 0.01 for Reunion#2, respectively), with a stronger association during the second reunion for preterm infants (p < 0.001). In the preterm sample but not in the full-term sample, attention seeking maternal interaction at Play (baseline), Reunion#1, and Reunion#2 were all positively correlated with negative infant affect at Still Face#2. Maternal watching was negatively associated with positive infant affect for the full sample for both Reunion episodes (p < 0.05). Full term infants' negative affect increased from baseline to the first SF episode and then plateaued, whereas preterm infants demonstrated greater negative affect and less recovery throughout. Mothers of full-term infants showed increased contingent responding after the first SF stressor, while mothers of preterm infants did not (p < 0.05). CONCLUSIONS:Preterm infants may be more susceptible to both positive and negative maternal behaviors and mothers of full-term infants may be more responsive to infants' increased distress. Relationship-focused interventions addressing maternal behaviors may enhance positive emotionality and improve self-regulation in medically at-risk infants.

Last year, we wrote to you of our dedication and vision for this journal "to be antiracist at every level," outlining the following 6 initiatives "to reshape the Journal to pursue this vision:" (1) Issuing a Call for Papers "on racism and its impacts on child development and children's mental health;" (2) updating our Guide for Authors "to emphasize that we will evaluate articles submitted to the Journal on whether their study designs and discussions consider and address human diversity in the context of their research questions and hypotheses; (3) assembling a special collection of "Journal articles on bias, bigotry, racism, and mental health disparities;" (4) accelerating "our efforts to make our editorial board inclusive and representative of our community of scientists and practitioners as well as the communities we all serve;" (5) engaging in "continuing education and dialogue as an Editorial Board that will include antiracism training;" and (6) critically examining "our editorial and peer review process to ensure it is antiracist.¹ In this Editors' Note, we write to update you on our progress.

OBJECTIVE:Our objectives were to assess in perinatal women: the most effective methods used to meet social support needs during COVID-19, the impact of COVID-19 on self-reported social support levels, and how perceived change in social support related to distress, depression, and mental health. DESIGN/METHODS:One-time survey administered from April to August 2020 SETTING: Online PARTICIPANTS: Pregnant and postpartum women with infants less than 6 months of age MEASUREMENT AND FINDINGS: Participants indicated the methods they used to meet social support needs during COVID-19. They self-rated their social support level pre- and during pandemic and their distress, depressive symptoms, and mental health changes on a Likert scale. Out of 1142 participants, the most effective methods for obtaining social support during the pandemic were virtual means (e.g. video call) and interaction with friends. There was a significant difference in distribution of self-reported levels of social support before and during the pandemic, with more respondents reporting a decrease in support. Decreases in social support were associated with higher distress levels, higher levels of depressive symptoms, and poorer mental health. KEY CONCLUSIONS/CONCLUSIONS:Perinatal women reported decreased social support during the COVID-19 pandemic which was associated with poorer mental health. Using virtual means of social support and support provided by friends had the largest positive effect on perceived social support levels. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:Interventions using virtual support means from friends may be helpful to improve social support and mental health in this population.

In response to the COVID-19 pandemic, research institutions across the globe have modified their operations in ways that have limited or eliminated the amount of permissible in-person research interaction. In order to prevent the loss of important developmentally-timed data during the pandemic, researchers have quickly pivoted and developed innovative methods for remote assessment of research participants. In this manuscript, we describe methods developed for remote assessment of a parent child cohort with a focus on examining the perinatal environment, behavioral and biological indicators of child neurobehavioral development, parent-child interaction, as well as parent and child mental and physical health. We include recommendations relevant to adapting in-laboratory assessments for remote data collection and conclude with a description of the successful dissemination of the methods to eight research sites across the United States, each of whom are involved in Phase 1 of the HEALthy Brain and Child Development (HBCD) Study. These remote methods were born out of pandemic-related necessity; however, they have much wider applicability and may offer advantages over in-laboratory neurodevelopmental assessments.

Introduction: Peripheral T-cell lymphomas (PTCLs) include heterogeneous entities of rare and aggressive neoplasms. The improved understanding of the biological/molecular mechanisms driving T-cell transformation and tumor maintenance has powerfully propelled new therapeutic programs. However, despite this progress, PTCLs remain an unmet medical need. Recurrent aberrations and the deregulated activation of distinct signaling pathways have been mapped and linked to selective subtypes. The JAK/STAT signaling pathway's deregulated activation plays a pathogenetic role in PTCL, including ALCL subtypes. STATs regulate the differentiation/phenotype, survival and cell-growth, metabolism, and drug resistance of T-cell lymphomas as well as host immunosuppressive microenvironments. Although many drugs' discovery programs were launched, a plethora of compounds has failed.
Method(s): We have discovered heterobifunctional molecules by an iterative medicinal chemistry SAR campaign that potently and selectively degrade STAT3 in a proteasome-dependent manner. Conventional PTCL cell lines and Patient Derived Tumor Xenograft (PDTX) and/or derived cell lines (PDTX-CL), carrying either WT- or mutated-STAT3, were exposed to increasing amounts (50nM5microM) of STAT3-degraders. Proteins and mRNA transcripts (2144hrs) were assessed by deep-proteomics and paired-end RNA sequencing, combined with WB/flow cytometry and qRT-PCR. Cell-titer-glo, cell titer blue, Annexin-V and S-cell cycle analyses were used as readouts. Chromatin accessibility, STAT3 DNA binding, 3D chromosomal architecture reorganization and 5-hmC profiling were assessed by ATACseq, CHIPseq and Hi-C and H3K27ac Hi-CHIP and mass-spectrometry. Drug testing/discovery combinations (96-well-plate) were performed using a semi-automated flow-cytometry. A battery of PTCL PDTX models were tested in pre-clinical trials.
Result(s): Treatment of ALK+ ALCL (SU-DHL1) led to the rapid (~6hrs.) and profound down-regulation of STAT3 followed by the loss of canonical STAT3-regulated proteins (SOCS3, MYC, Granzyme B, GAS1, and IL2RA), without appreciable changes for other STAT family members (STAT1, STAT5b). In vitro, cytoplasmic, nuclear, and mitochondrial STAT3 downregulation was maintained up to 144 hrs. Loss of STAT3 in ALK+/- ALCL and BIA-ALCL cells was associated with major transcriptional changes (7116-10615 and 15114 DEGs in ALK- and ALK+ ALCL, respectively), underscoring public/shared as well as private time-dependent signatures. Main down-regulated pathways included JAK-STAT, MAPK, NF-kB, PI3K, TGFb, and TNFa. Comparison of STAT3 shRNA (ALK+ ALCL) and STAT3 degrader (ALK-/ALK+ ALCL) signatures demonstrated a substantial and concordant gene modulation (24hrs) among all models with the highest overlaps between ALK+ ALCL (Figure 3). To identify direct STAT3 gene targets, we analyzed CHIPseq peaks and predicted bindings sites, demonstrating that canonical genes, i.e., SOCS3, Granzyme B, GAS1, IL2RA, STAT3, and CD30, were significantly downregulated. Conversely, CD58, CD274, and MCH-I/II were upregulated at late time points. By mapping the STAT3 binding sites in ALK+ and ALK- ALCL, we have identified 1077 and 2763 STAT3 peaks within promoter/5'-/3'- and distant intergenic regions, corresponding to both coding and non-coding genes. Therapeutically, in vitro treatments led to cell cycle arrest and profound growth inhibition, and over time increased cell death of PTCL cells, including ALCL. Accordingly, growth inhibition of ALCL xenograft and PDTX tumors was also achieved (Figure 2). To identify drugs that could synergize withSTAT3-degrader activity, we tested a compound library (40) targeting pro-tumorigenic PTCL pathways as well as FDA-approved compounds. Ongoing studies are in progress.
Conclusion(s): We have discovered selective STAT3 degraders which control PTCL growth. STAT3 degraders are powerful tools to define the STAT3 pathogenetic mechanisms and dissect genes/pathways to be targeted for T-cell lymphoma eradication. These data provide additional rationale for testing STAT3 degraders in the clinic for the treatment of aggressive malignancies including PTCL/ALCL. [Formula presented] Disclosures: Yang: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Elemento: Owkin: Consultancy, Other: Current equity holder; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Eli Lilly: Research Funding; Janssen: Research Funding; Champions Oncology: Consultancy; Freenome: Consultancy, Other: Current equity holder in a privately-held company; One Three Biotech: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding. Horwitz: Affimed: Research Funding; Aileron: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. DeSavi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.
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