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Multicomponent Parenteral Lipid Emulsions Do Not Prevent Liver Injury in Neonatal Pigs With Obstructive Cholestasis
No full textBiliary atresia (BA) is a pediatric liver disease that often necessitates parenteral nutrition (PN) to support growth due to impaired liver function. While soy-based lipid emulsions (SLE) are commonly used in PN, they may contribute to cholestatic liver injury. In contrast, mixed lipid emulsions (MLE) show promise in preventing cholestasis in infants without BA, potentially by restoring bile flow. However, their effectiveness in patients of complete bile duct obstruction, as seen in BA, remains uncertain. To explore the potential benefits of MLE in BA, we utilized a neonatal pig model of bile duct ligation (BDL). Pigs underwent either BDL or sham surgery and were subsequently fed either MLE or SLE via PN, or enterally with formula. The MLE-BDL pigs exhibited significantly greater weight gain compared with those fed SLE or formula enterally. Additionally, MLE-BDL pigs showed higher serum bile acid and γ-glutamyl transferase concentrations compared with SLE-BDL pigs. However, no significant differences in liver injury, assessed by ductular reaction or fibrosis, were observed between MLE- and SLE-BDL pigs. Based on weight gain alone, MLE may be a superior lipid emulsion for use in neonates with obstructive cholestasis
Improving Genetics Equity: Identifying Women Eligible for Genetic Care Services Using Mammography Clinics in Underserved Areas As Screening Hubs
No full textPURPOSE: Fewer than 20% of underserved individuals undergo guideline-concordant hereditary breast and ovarian cancer (HBOC) genetic testing (GT). Our study aimed to determine the proportion of women eligible for HBOC GT using a cancer genetics risk assessment (CGRA) tool at breast cancer (BC) screening clinics in underserved communities and to describe the program\u27s impact.
METHODS: Participants were women who presented for BC screening at The Rose clinics, serving low-income underserved communities in southeast Texas, and completed the CGRA. High-risk individuals received bilingual educational materials and a saliva-based GT kit. Those with a pathogenic variant (PV) or a variant of uncertain significance (VUS) received telegenetic counseling and risk reduction resources.
RESULTS: A total of 501 women completed the CGRA, with 30.1% uninsured. 150 women were identified as eligible for GT, but only 14 (9.9%) completed GT (11 negative, 2 VUS, 1 PV in NF1). GT completion was significantly associated with being White, Native American/Alaskan Native, and Ashkenazi Jewish (P \u3c .05). Hispanic, low-income, and uninsured individuals, or those with fewer relatives with cancer, were as likely to complete GT as others.
CONCLUSIONS: We successfully identified underserved women at high risk of HBOC using CGRA, but the GT completion rate was low. However, the completion rate did not differ by Hispanic ethnicity, income, or insurance status, suggesting that financial navigation by our study coordinator, support from Spanish-language staff at The Rose clinics, and the use of Spanish-language educational materials and translation may have helped overcome some barriers
KAP1 Promotes Gastric Adenocarcinoma Progression by Activating Hippo/YAP1 Signaling via Binding to HNRNPAB
No full textGastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter and reducing H3K27ac levels. Mass spectrometry identified an interaction between KAP1 and HNRNPAB, further modulating YAP1 signaling. Expression of the KRAB domain of ZFP568 without its DNA-binding zinc fingers inhibited both KAP1 and YAP1 expression, significantly reducing colony formation and tumor growth in vivo. Additionally, emerging antisense oligonucleotides (ASOs) targeting KAP1 or YAP1 effectively suppressed mouse tumor progression. These findings establish KAP1 as a critical driver of tumor progression in GAC through YAP1 regulation and HNRNPAB interaction, highlighting its potential therapeutic target. This study advances our understanding and offers a preclinical framework to improve outcomes for GAC
TREM2 Depletion in Pancreatic Cancer Elicits Pathogenic Inflammation and Accelerates Tumor Progression via Enriching IL-1β+ Macrophages
No full textBackground & aims: Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.
Methods: We generated a novel transgenic mouse model (KPPC;Trem2-/-) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was used to identify changes in the tumor immune microenvironment on TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions of TREM2 in macrophages and PDAC development.
Results: Unexpectedly, genetic depletion of TREM2 significantly accelerated spontaneous PDAC progression and shortened the survival of KPPC;Trem2-/- mice. Single-cell analysis revealed that TREM2 depletion enhanced proinflammatory macrophages and exacerbated pathogenic inflammation in PDAC. Specifically, TREM2 functions as a key braking mechanism for the NLRP3/nuclear factor-κB/interleukin (IL)-1β inflammasome pathway, opposing to microbial lipopolysaccharide as the key activator of this pathway. TREM2 deficiency orchestrated with microbial lipopolysaccharide to trigger IL-1β upregulation and pathogenic inflammation, thereby fueling PDAC development. Notably, IL-1β inhibition or microbiome ablation not only reversed the accelerated PDAC progression caused by TREM2 depletion, but also further inhibited PDAC progression in the TREM2-depleted context.
Conclusions: TREM2 depletion accelerates tumor progression by enhancing proinflammatory macrophages and IL-1β-mediated pathogenic inflammation in PDAC. The accelerated tumor progression by TREM2 depletion can be reversed by blocking IL-1β-associated pathogenic inflammation
Therapy, Safety, and Logistics of Preoperative vs Postoperative Stereotactic Radiation Therapy: A Preliminary Analysis of a Randomized Clinical Trial
No full textImportance: Preoperative stereotactic radiation therapy (SRT) vs postoperative SRT logistics and toxic effects provides clinically significant data on management outcomes.
Objective: To determine preoperative SRT logistics and safety profile compared with postoperative in patients with brain metastases.
Design, setting, and participants: This single-institution phase 3 randomized clinical trial included patients 18 years and older and undergoing a planned surgical resection. Patients were required to have an Eastern Cooperative Oncology Group Performance Status score of 2 or greater and be candidates for SRT within 30 days of surgical resection. Patients with radiosensitive histologies (eg, small cell lung cancer and lymphoma), brain metastasis of unknown primary, and/or radiographic evidence of leptomeningeal disease were excluded. Data were collected from December 2018 to August 2023, and data were analyzed from September 2023 to December 2024.
Interventions: Patients were randomized 1:1. Patients randomized to the preoperative SRT cohort underwent SRT (in 1 to 5 fractions) followed by surgical resection within 1 month of radiation therapy. Patients randomized to the postoperative SRT cohort underwent resection followed by postoperative SRT within 1 month of surgery.
Main outcomes and measures: Outcomes reported focus on nonprimary end point analysis of the trial, including comparative toxic effect outcomes of preoperative vs postoperative SRT postprocedural events, feasibility of preoperative SRT, and radiation therapy management.
Results: Of 103 patients, 56 (54.4%) were male, and the median (range) age was 59 (26-83) years. Of 103 patients, 83 (80.6%) completed both radiation and surgery for brain metastases while in the study. Of these, 70 patients (84%) had 1 to 4 brain metastases at enrollment, 11 (13%) had 5 to 10 lesions, and 2 (2%) had more than 10 lesions. In the preoperative stereotactic radiosurgery (SRS)/SRT cohort, 45 (88%) completed both treatments compared with 38 (73%) in the postoperative SRS/SRT arm. There were no statistically significant differences between treatment groups in 30-day postoperative morbidity or postprocedural events. The median (range) time between surgery and SRT was significantly shorter in the preoperative arm (6 [0-24] days) compared with the postoperative arm (22 [12-42] days; P \u3c .001). The median (range) time from randomization to receiving both brain-directed therapies was 10 (4-31) days in the preoperative arm compared with 32.5 (19-55) days for the postoperative arm (P \u3c .001).
Conclusions and relevance: In this randomized clinical trial, preoperative SRT had comparable safety to postoperative SRT and resulted in shorter time to treatment completion, potentially facilitating expedited care.
Trial registration: ClinicalTrials.gov Identifier: NCT03741673
NLRP3 Inflammasome Activation Expands the Immunosuppressive Myeloid Stroma and Antagonizes the Therapeutic Benefit of STING Activation in Glioblastoma
No full textGlioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects of this innate immune combination on the GBM tumor immune landscape. We find that STING activation does not prime pro-IL-1β expression for activated NLRP3 inflammasome secretion. In subcutaneous GL261 GBM, we show that NLRP3 activation expands the immunosuppressive myeloid stroma primarily via granulocytic MDSC recruitment and antagonizes the benefit of STING activation. In brain GL261, we find that NLRP3 activation expands granulocytic MDSCs but does not antagonize the therapeutic benefit of STING activation. Finally, we report that mesenchymal subtype GBM tumors have elevated neutrophil, IL-1β, and NLRP3 gene expression, a setting where our data suggest that NLRP3 activation could counteract STING agonists.
Significance: NLRP3 inflammasome signaling, which suppresses antitumor immunity in some cancers, has been observed in GBM tissues. NLRP3 activation in GBM induces granulocyte-dependent tumor immunosuppression and antagonizes the therapeutic efficacy of STING activation
Blunted CD40-Responsive Enhancer Activation in CREBBP-Mutant Lymphomas Can Be Restored by Enforced CD4 T-Cell Engagement
No full textThe CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor (TF), thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of TF or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear TF abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. Therefore, we provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects
Protocol To Analyze tRNA and rRNA Processing Using Biotin-Labeled Probes
No full textMature tRNAs and rRNAs are derived from larger precursor transcripts through intricate endo- and exonuclease processing steps. Here, we present a protocol to analyze rRNA and tRNA processing using total RNA extracted from human cells. We describe steps for separating RNA by denaturing electrophoresis, followed by northern blotting. We detail procedures for detecting pre-rRNA intermediates or specific tRNA species using biotin-labeled probes imaged via fluorescence or chemiluminescence. This non-radioactive, high-sensitivity assay enables the investigation of rRNA and tRNA expression dynamics. For complete details on the use and execution of this protocol, please refer to Hwang et al
Human Pain Neuroscience and the Next Generation of Pain Therapeutics
No full textThe recent approval of suzetrigine for acute pain treatment highlights both the success of targeting peripheral sensory neurons for pain management and the potential of developing new pain therapies primarily in human-based systems. To realize this transformative potential, further research into somatosensation and pain neuroimmunology in human systems is essential
Leveraging Observational and RCT Data for Understanding Interventions’ efficacy: Applications in Progressive and Acute Neurological Diseases
No full textThe advancement of drug repurposing for progressive and acute neurological diseases is hampered by the limitations of randomized clinical trials (RCTs) and observational data. This dissertation presents a comprehensive framework to integrate data-driven insights from multiple sources, including observational studies, RCTs, and synthetic data generation, to overcome these challenges.
The first study focuses on estimating treatment effects on the population level, which investigates the effects of routine and high-dose influenza vaccines on the risk of Alzheimer’s Disease and Related Dementias (ADRD) through a trial emulation framework applied to health claims data, addressing biases inherent in observational studies. The second study develops an interpretable framework for estimating heterogeneous treatment effects, enabling the identification of responsive subgroups from failed clinical trials and supporting personalized therapeutic strategies. Lastly, the third study introduces a novel generative approach leveraging Large Language Models (LLMs) and causal graphs for synthesizing high-quality tabular data in low-data regimes, addressing the challenges of small sample sizes and enhancing the robustness of clinical insights.
By bridging gaps between data availability, treatment effect estimation, and personalized medicine, this dissertation contributes to advancing the precision of drug repurposing strategies for complex neurological conditions. Future work will extend the proposed frameworks to broader clinical domains, further validating their efficacy and applicability