Citations

Abstract The interactions between transcription factors (TFs) and the target genes could provide a basis for constructing gene regulatory networks (GRNs) for mechanistic understanding of various biological complex processes. From gene expression data, particularly single-cell transcriptomic data containing rich cell-to-cell variations, it is highly desirable to infer TF–gene interactions (TGIs) using deep learning technologies. Numerous models or software including deep learning–based algorithms have been designed to identify transcriptional regulatory relationships between TFs and the downstream genes. However, these methods do not significantly improve predictions of TGIs due to some limitations regarding constructing underlying interactive structures linking regulatory components. In this study, we introduce a deep learning framework, DeepTGI, that encodes gene expression profiles from single-cell and/or bulk transcriptomic data and predicts TGIs with high accuracy. Our approach could fuse the features extracted from Auto-encoder with self-attention mechanism and other networks and could transform multihead attention modules to define representative features. By comparing it with other models or methods, DeepTGI exhibits its superiority to identify more potential TGIs and to reconstruct the GRNs and, therefore, could provide broader perspectives for discovery of more biological meaningful TGIs and for understanding transcriptional gene regulatory mechanisms.

Abstract Ataxia Telangiectasia–mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.

Abstract Background An escape room is a cooperative game that has been adapted into medical education and major academic conferences. Methods We describe the design, development, and implementation of an educational ID-themed escape room activity entitled “Out-BREAK!” at an international conference, IDWeek 2023. An anonymous survey was conducted to collect demographic data, assess participant satisfaction with the escape room puzzles, and gauge participant interest in game-based learning. Results Thirty escape room sessions were held over 3 days and included 201 participants. Escape room survey respondents (n = 132) were younger and more likely to be trainees compared with in-person IDWeek attendants. Among 131 responses, all respondents enjoyed the experience and would recommend the escape room activity to friends. Survey respondents enjoyed the puzzle solving (93%), medical content (92%), and team building (79%) components. Only 35% of the respondents had ever previously participated in game-based learning; 95% thought the escape room was a valuable teaching method. Among the 72 survey respondents involved in medical education, almost all (90%) said they were interested in incorporating escape rooms into medical education. Conclusions The Out-BREAK! escape room at IDWeek 2023 was successfully implemented and well received. Despite only a third of participants having prior experience with game-based learning, almost all respondents perceived the escape room to be an effective teaching method.

Abstract Background: Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) to pancreatic ductal adenocarcinoma (PDAC) risk at over 20 genomic loci. The Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium are currently expanding on previous GWAS studies for PDAC from ∼9,000 cases and ∼12,000 controls to ∼36,000 cases and ∼800,000 controls in individuals of European and Asian ancestry. This ongoing GWAS phase is estimated to detect up to 50 new risk signals. Post-GWAS studies aim to fine-map and functionally assess risk variants in disease-relevant cell types and contexts to identify target genes and underlying mechanisms of risk. Massively parallel reporter assays (MPRAs) are a powerful method of assessing allele-specific gene regulatory effects. Integrating sequences into the genome using lentiviruses (Lenti-MPRA) enables the capture of variant function in the context of the native cellular chromatin. An added benefit is that Lenti-MPRAs can be used for difficult to transfect cells such as primary cells, that often reflect the disease relevant cell types. Methods: We have used a lentiviral MPRA to test 228 fine-mapped SNPs at the chr5p15.33 multi-cancer risk locus in PDAC cell lines (MIA PaCa-2, PANC-1) and the normal-derived ductal pancreas (HPDE) cell line. Additionally, we have optimized the transduction of large MPRA libraries into primary pancreas cells. Tunicamycin was used to induce ER stress in cell lines and primary cells, assessing downstream gene expression using RT-qPCR. Results: Our pilot MPRA demonstrated high reproducibility in PDAC cell lines (r2=0.93-0.97, MIA PaCa-2, PANC-1 cells) and normal-derived pancreatic ductal cells (r2=0.68-0.86, HPDE cells). We identified 33 SNPs out of 228 with significant allele-specific transcriptional activity in PDAC cell lines and 5 in HPDE cells (FDR ≤0.05). An additional 6-15% of variants exhibited significant allele-specific transcriptional activity when in the frames of the SNP-centered tested oligos were shifted left or right. We demonstrate the inducibility of ER-stress with tunicamycin treatment over 24 hours in cells lines and primary pancreatic cells. Additionally, we observed increased expression of CLPTM1IL at the chr5p15.33 locus after tunicamycin treatment over 24 hours in cell lines and primary pancreatic cells, suggesting ER-stress and inflammation may influence gene expression at this locus. Conclusions: Lentiviral MPRA assays in commonly used PDAC cell lines have demonstrated good reproducibility. The optimization studies and preliminary work in primary pancreatic cells provide a solid foundation for the next steps of assessing all GWAS loci in ER stress, an important disease relevant condition. Citation Format: Minal B Patel, Aidan O'Brien, Jun Zhong, Irene Collins, Jason W Hoskins, Stephen J Chanock, Samuel O Antwi, Rachel Z Stolzenberg-Solomon, Alison P Klein, Brian M Wolpin, Sara Lindström, H. Efsun Arda, Kevin M Brown, Katelyn E Connelly, Laufey T Amundadottir, Meagan Jezek. The functional characterization of pancreatic ductal adenocarcinoma GWAS risk variants in primary pancreatic cells – A pilot study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A018.

Abstract Outcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Abstract Although the functions of tyrosine phosphatases in T‐cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4 + T‐cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8 + T‐cell homeostasis and effector functions. Our results demonstrate that T‐cell intrinsic PP2A Cα is critically required for CD8 + T‐cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα–deficient CD8 + T cells exhibit reduced proliferation and survival. CD8 + T‐cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8 + T‐cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8 + T‐cell homeostasis and effector functions.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135