Faculty Bibliography

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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BACKGROUND:Previous studies have suggested that social media data, along with machine learning algorithms, can be used to generate computational mental health insights. These computational insights have the potential to support clinician-patient communication during psychotherapy consultations. However, how clinicians perceive and envision using computational insights during consultations has been underexplored. OBJECTIVE:The aim of this study is to understand clinician perspectives regarding computational mental health insights from patients' social media activities. We focus on the opportunities and challenges of using these insights during psychotherapy consultations. METHODS:We developed a prototype that can analyze consented patients' Facebook data and visually represent these computational insights. We incorporated the insights into existing clinician-facing assessment tools, the Hamilton Depression Rating Scale and Global Functioning: Social Scale. The design intent is that a clinician will verbally interview a patient (eg, How was your mood in the past week?) while they reviewed relevant insights from the patient's social media activities (eg, number of depression-indicative posts). Using the prototype, we conducted interviews (n=15) and 3 focus groups (n=13) with mental health clinicians: psychiatrists, clinical psychologists, and licensed clinical social workers. The transcribed qualitative data were analyzed using thematic analysis. RESULTS:Clinicians reported that the prototype can support clinician-patient collaboration in agenda-setting, communicating symptoms, and navigating patients' verbal reports. They suggested potential use scenarios, such as reviewing the prototype before consultations and using the prototype when patients missed their consultations. They also speculated potential negative consequences: patients may feel like they are being monitored, which may yield negative effects, and the use of the prototype may increase the workload of clinicians, which is already difficult to manage. Finally, our participants expressed concerns regarding the prototype: they were unsure whether patients' social media accounts represented their actual behaviors; they wanted to learn how and when the machine learning algorithm can fail to meet their expectations of trust; and they were worried about situations where they could not properly respond to the insights, especially emergency situations outside of clinical settings. CONCLUSIONS:Our findings support the touted potential of computational mental health insights from patients' social media account data, especially in the context of psychotherapy consultations. However, sociotechnical issues, such as transparent algorithmic information and institutional support, should be addressed in future endeavors to design implementable and sustainable technology.

Odor perception can both evoke emotional states and be shaped by emotional or hedonic states. The amygdala complex plays an important role in recognition of, and response to, hedonically valenced stimuli, and has strong, reciprocal connectivity with the primary olfactory (piriform) cortex. Here, we used differential odor-threat conditioning in rats to test the role of basolateral amygdala (BLA) input to the piriform cortex in acquisition and expression of learned olfactory threat responses. Using local field potential recordings, we demonstrated that functional connectivity (high gamma band coherence) between the BLA and posterior piriform cortex (pPCX) is enhanced after differential threat conditioning. Optogenetic suppression of activity within the BLA prevents learned threat acquisition, as do lesions of the pPCX prior to threat conditioning (without inducing anosmia), suggesting that both regions are critical for acquisition of learned odor threat responses. However, optogenetic BLA suppression during testing did not impair threat response to the CS+ , but did induce generalization to the CS-. A similar loss of stimulus control and threat generalization was induced by selective optogenetic suppression of BLA input to pPCX. These results suggest an important role for amygdala-sensory cortical connectivity in shaping responses to threatening stimuli.

BACKGROUND:Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine, are limited. This study assessed the reliability and applicability of DSM-based diagnostic criteria for ketamine use disorder. METHODS:Participants who used ecstasy were recruited through the Tri-City Study of Club Drug Use, Abuse, and Dependence in St. Louis, Miami, and Sydney. Those who reported using ketamine (lifetime use >5 times) were included in these analyses (n = 205). Participants were interviewed using the computerized Substance Abuse Module for Club Drugs (CD-SAM) at baseline and 7 days later for the reliability of diagnoses and individual diagnostic criteria. RESULTS:Overall, 29.3% met DSM-5 adopted criteria for ketamine use disorder at Time 1. Moderate to excellent test-retest reliability was observed consistently across study sites for any ketamine use disorder (κ = 0.57, Y = 0.61) and severe ketamine use disorder (κ = 0.62, Y = 0.79). Continued use of ketamine despite knowledge of physical or psychological problems was the most frequently endorsed individual criterion (59.0%), followed by reported withdrawal (30.2%) and physically hazardous use (29.8%). All individual criteria had acceptable reliability estimates (κ ≥ 0.41). CONCLUSIONS:Diagnoses of ketamine use disorder can be reliably evaluated using this fully structured diagnostic instrument's questions and algorithm. Ketamine-related withdrawal among people who use ketamine should be re-evaluated. Considering that after-effects of this dissociative anesthetic can last for many hours, it is important to explore a different timeframe for possible withdrawal effects.

Background PVSRIPO, a novel intratumoral viral immunotherapy, infects cells via CD155, which is widely expressed on solid tumors and antigen-presenting cells (APC). Infection is lethal in malignant cells, but a unique, activating, nonlethal infection of local APCs yields type-I/III interferon (IFN)-dominant inflammation with subsequent anti-tumor T-cell priming and activation resulting in anti-tumor efficacy. In preclinical models, PVSRIPO-dependent inflammation upregulated the PD-1/L1 pathway, and greater anti-tumor response was observed with PVSRIPO + anti-PD-1/L1 (aPD-1/L1). Promising clinical activity with PVSRIPO monotherapy was observed in patients with recurrent glioblastoma and advanced aPD-1- refractory melanoma.1 2 Collectively, these results warrant further clinical investigation of PVSRIPO +/- aPD-1/L1. Methods LUMINOS-103 (NCT04690699) is a phase (Ph) 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO +/- aPD-1/L1 in adults with solid tumors. Trial objectives are to assess the safety and tolerability of PVSRIPO monotherapy in each cohort in Ph 1 and the safety, tolerability, and antitumor efficacy of PVSRIPO + aPD-1/L1 in each cohort in Ph 2. The first two study cohorts include patients with muscle-invasive bladder cancer being treated in the neoadjuvant setting (A) and patients with metastatic bladder cancer being treated in the 1st/2nd line setting (B); these cohorts have been described previously.3 Cohort C includes patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) being treated in the neoadjuvant setting; Cohort D includes patients with recurrent/ metastatic HNSCC with a PD-L1 Combined Positive Score >=1 being treated in the 1st line setting. Eligibility: HNSCC patients must have histologically or cytologically-proven SCC of the oral cavity, oropharynx, hypopharynx, or larynx. All patients must have prior and boosted PV immunization and tumors amenable to injection and biopsy. Key exclusion criteria: Requirement for oxygen supplementation, systemic or intratumoral therapy <=6 months prior to the first dose of study drug, CNS metastases requiring immediate treatment, systemic immunosuppressive medications <=4 weeks prior to the first dose of study drug, and severe active comorbidities. Patients who are HIV+, HBV+ or HCV+ are eligible provided they meet certain criteria. Primary endpoints include safety (all cohorts), tolerability (all cohorts), surgical complication rate (A, C), pathologic treatment effect/response (A, C), and objective response rate (B, D). Secondary endpoints include overall survival (all cohorts), pathologic downstaging and relapse-free survival (A, C), duration of response and progression- free survival (B, D), and assessment of tumor/blood biomarkers (all cohorts)

BACKGROUND:Disability among women of reproductive age is common; many of these women desire children and do not have impaired fertility. OBJECTIVES/OBJECTIVE:To examine the epidemiological literature on perinatal health outcomes among women with physical disabilities. DATA SOURCES/METHODS:We searched Medline and CINAHL for articles published January 2009-April 2020 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. STUDY SELECTION AND DATA EXTRACTION/METHODS:Eligible studies were observational, quantitative, and reported on physical disabilities in association with prenatal, perinatal, postpartum, and/or infant health outcomes. We included studies that grouped physical and non-physical disabilities, such as surveys that queried only about general daily life limitations. We excluded case reports, descriptive studies without comparison groups, and studies conducted in low- or middle-income countries. Data extraction was done using predefined data fields. SYNTHESIS/RESULTS:All authors were involved in screening activities, data extraction, and/or quality assessment (rating and areas for bias). RESULTS:A total of 2650 articles were evaluated, of which sixteen met inclusion criteria (8 cross-sectional studies and 8 retrospective cohort studies). Assessments of disability status and perinatal outcomes widely varied across studies. Studies were rated as poor (n = 8) or fair quality (n = 8). Findings suggested that women with physical disabilities were at risk of several adverse outcomes, including caesarean delivery, infections, preterm complications, and maternal post-delivery hospitalisations, while their infants may be at risk of low birthweight and small-for-gestational age. Women classified as having complex/severe disabilities were often observed to be at higher risk of adverse outcomes compared to women with less severe disabilities. CONCLUSIONS:Research assessing how physical, functional, and medical restrictions influence health outcomes among women with physical disabilities, from preconception through postpartum, is limited. Longitudinal studies with comprehensive data collection that accurately identify women with physical disabilities are critical to understanding their reproductive health risks and outcomes.

Purpose: Although the intrahippocampal kainic acid (IHKA) model has been widely used to simulate temporal lobe epilepsy (TLE) in mice, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent chronic convulsive seizures that are robust in frequency, duration and both sexes can be used.
Method(s): Our methods varied slightly from prior studies. We employed continuous wideband video-EEG from 2 cortical and 2 hippocampal sites to characterize chronic epilepsy outcomes in both sexes and 2 timepoints (2-4 and 10-12wks post-IHKA).
Result(s): Analysis of convulsive seizures at 2-4 and 10-12wks post-IHKA showed a robust frequency (2-4/day on average) and duration (typically 20-30 sec) at each time. Comparison of the 2 timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high-frequency oscillations (HFOs, >250Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally.
Conclusion(s): In summary, our methods produce a model of TLE in mice with robust convulsive seizures, show variable progression, that HFOs are robust also, and that the model has seizures with onset patterns and pathology like human TLE. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression and other topics of broad interest to the epilepsy research community including preclinical drug screening