A fibroblast-dependent TGFß1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Biopsies from untreated patients showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzle-like receptor protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision cut lung slices (PCLS) from non-diseased donors, we found TGFß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature Krt5+ basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

Phage Immunoprecipitation-Sequencing Reveals CDHR5 Autoantibodies in Select Patients With Interstitial Lung Disease.

OBJECTIVE: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. METHODS: We use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP-Seq. We next developed a radio-labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort. RESULTS: PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free-survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD. CONCLUSION: We used PhIP-Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5-IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

The Impact of Community Engagement in the Design and Implementation of the Flint Registry.

BACKGROUND: The Flint water crisis (FWC) was a public health tragedy caused by crumbling infrastructure, subverted democracy, and indifference toward a predominantly poor and Black community that resulted in lead-in-water exposure, Legionnaires' disease, and emotional and health-related trauma. Through the cooperation of community partners, the Flint Registry (FR) was conceived to track long-term health and improve public health via service connections. OBJECTIVES: This study sought to share the FR's community-partnered, multi-tiered engagement strategy and determine the efficacy of this strategy to engage the community and reach Flint residents. METHODS: Community engagement and impact were measured by collecting and describing feedback from the community engagement strategies and by comparing the demographics of the enrollees recruited through community-engaged recruitment (CER) and non-CER methods. Enroll-ees indicated how they heard about the FR; CER involved direct interaction with a community member. RESULTS: Community engagement strategies incorporated approximately 1,200 people and 7 funded organizations, impacting 22 key areas of FR design and implementation. More than 50% of enrollees heard about the FR through CER methods. They were, on average, more likely to be younger, female, Black/African American, and living outside of Flint during the FWC. CONCLUSIONS: Community engagement elevated voices of those impacted by the FWC. CER methods were as effective as non-CER methods. Although there were no differences in screened measures of social vulnerability, there were in age, gender, and race. CER methods may increase participation and build trust in populations which historically are hesitant to participate in public health efforts.

Making sense of artificial intelligence and large language models-including ChatGPT-in pediatric hematology/oncology.

ChatGPT and other artificial intelligence (AI) systems have captivated the attention of healthcare providers and researchers for their potential to improve care processes and outcomes. While these technologies hold promise to automate processes, increase efficiency, and reduce cognitive burden, their use also carries risks. In this commentary, we review basic concepts of AI, outline some of the capabilities and limitations of currently available tools, discuss current and future applications in pediatric hematology/oncology, and provide an evaluation and implementation framework that can be used by pediatric hematologist/oncologists considering the use of AI in clinical practice.

Extracting Electronic Health Record Neuroblastoma Treatment Data With High Fidelity Using the REDCap Clinical Data Interoperability Services Module.

PURPOSE: Although the International Neuroblastoma Risk Group Data Commons (INRGdc) has enabled seminal large cohort studies, the research is limited by the lack of real-world, electronic health record (EHR) treatment data. To address this limitation, we evaluated the feasibility of extracting treatment data directly from EHRs using the REDCap Clinical Data Interoperability Services (CDIS) module for future submission to the INRGdc. METHODS: Patients enrolled on the Children's Oncology Group neuroblastoma biology study ANBL00B1 (ClinicalTrials.gov identifier: NCT00904241) who received care at the University of Chicago (UChicago) or the Vanderbilt University Medical Center (VUMC) after the go-live dates for the Fast Healthcare Interoperability Resources (FHIR)-compliant EHRs were identified. Antineoplastic drug orders were extracted using the CDIS module. To validate the CDIS output, antineoplastic agents extracted through FHIR were compared with those queried through EHR relational databases (UChicago's Clinical Research Data Warehouse and VUMC's Epic Clarity database) and manual chart review. RESULTS: The analytic cohort consisted of 41 patients at UChicago and 32 VUMC patients. Antineoplastic drug orders were identified in the extracted EHR records of 39 (95.1%) UChicago patients and 26 (81.3%) VUMC patients. Manual chart review confirmed that patients with missing (n = 8) or discontinued (n = 1) orders in the CDIS output did not receive antineoplastic agents during the timeframe of the study. More than 99% of the antineoplastic drug orders in the EHR relational databases were identified in the corresponding CDIS output. CONCLUSION: Our results demonstrate the feasibility of extracting EHR treatment data with high fidelity using HL7-FHIR via REDCap CDIS for future submission to the INRGdc.

The Immunogenomic Landscape of Peripheral High-Dose IL-2 Pharmacodynamics in Patients with Metastatic Renal Cell Carcinoma: A Benchmark for Next-Generation IL-2-Based Immunotherapies.

High-dose (HD) IL-2 was the first immuno-oncology agent approved for treating advanced renal cell carcinoma and metastatic melanoma, but its use was limited because of substantial toxicities. Multiple next-generation IL-2 agents are being developed to improve tolerability. However, a knowledge gap still exists for the genomic markers that define the target pharmacology for HD IL-2 itself. In this retrospective observational study, we collected PBMC samples from 23 patients with metastatic renal cell carcinoma who were treated with HD IL-2 between 2009 and 2015. We previously reported the results of flow cytometry analyses. In this study, we report the results of our RNA-sequencing immunogenomic survey, which was performed on bulk PBMC samples from immediately before (day 1), during (day 3), and after treatment (day 5) in cycle 1 and/or cycle 2 of the first course of HD IL-2. As part of a detailed analysis of immunogenomic response to HD IL-2 treatment, we analyzed the changes in individual genes and immune gene signatures. By day 3, most lymphoid cell types had transiently decreased, whereas myeloid transcripts increased. Although most genes and/or signatures generally returned to pretreatment expression levels by day 5, certain ones representative of B cell, NK cell, and T cell proliferation and effector functions continued to increase, along with B cell (but not T cell) oligoclonal expansion. Regulatory T cells progressively expanded during and after treatment. They showed strong negative correlation with myeloid effector cells. This detailed RNA-sequencing immunogenomic survey of IL-2 pharmacology complements results of prior flow cytometry analyses. These data provide valuable pharmacological context for assessing PBMC gene expression data from patients dosed with IL-2-related compounds that are currently in development.

Acta non verba.

It is with a great deal of gratitude that Kirk D. Strosahl and Patricia J. Robinson accept the Don Bloch Award. Thirty-five years ago, when they embarked on their mission to improve healthcare, they never imagined that this recognition would come their way. Now that it has, they want to take about 1,000 words to share their views on health and their understanding of important barriers to improving healthcare services, and offer four practical strategies to consider as we do your part. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Saccharomyces Cerevisiae as a Model Organism for Retrospective Impedance Biodosimetry.

ABSTRACT: Previous studies have shown that measuring changes in electrical impedance that follow radiation-induced suppression of metabolic activity in irradiated yeast cells can be used to determine radiation dose. The current work investigates the radiation response of Saccharomyces cerevisiae cells by using metabolic activity of cells as a damage indicator. Impedance biodosimetry was examined as a method to evaluate the radiation response of yeast cells. Active lab-grade dry yeast cells were used as the biological material as these samples are simple to handle and have a long shelf-life. A novel dosimeter design has been developed with a strict fabrication method and measurement procedure to ensure reproducible measurements are possible. Prepared yeast samples were irradiated to doses from 0.5 to 8 Gy using a 137Cs source, and a dose response curve was developed that showed a linear relationship of dose with changes in impedance measurements. Fading of the impedance signal was also investigated, and it was shown that there was no noticeable fading of the impedance signal over a period of 7 mo. Finally, the lowest detectable limit measured using this methodology was determined to be 300 mGy. This work presents an alternative retrospective dosimetry technique that can be used at a high scale and low cost following large-scale radiological accidents.

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.

Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

An open-source platform for pediatric cancer data exploration: a report from Data for the Common Good.

Objective: The Pediatric Cancer Data Commons (PCDC)-a project of Data for the Common Good-houses clinical pediatric oncology data and utilizes the open-source Gen3 platform. To meet the needs of end users, the PCDC development team expanded the out-of-box functionality and developed additional custom features that should be useful to any group developing similar data commons. Materials and Methods: Modifications of the PCDC data portal software were implemented to facilitate desired functionality. Results: Newly developed functionality includes updates to authorization methods, expansion of filtering capabilities, and addition of data analysis functions. Discussion: We describe the process by which custom functionalities were developed. Features are open source and available to be implemented and adapted to suit needs of data portals that utilize the Gen3 platform. Conclusion: Data portals are indispensable tools for facilitating data sharing. Open-source infrastructure facilitates a modular and collaborative approach for meeting needs of end users and stakeholders.

Targeted Enrollment in Pediatric Oncology Trials: A Vision for Just-in-Time Matching.

@PedsDataCommons shares vision for automated clinical trials matching in pediatric oncology.

Magnetically localized and wash-free fluorescent immuno-assay: From a research platform (MLFIA) to a multiplexed POC system (MagIA).

Sexually transmitted infections (STI) remain one of the world's public health priorities: Nearly 400 million people are infected not only in emerging, but also in western countries. HIV, HBV and HCV share common infection pathways; thus these 3 diseases are recommended to be tested at the same time. However, this combined approach is currently mainly available in laboratories, and seldomly at the Point-of-care (POC). Consequently, there is a need for a STI screening POC platform with laboratory-like performance. Such a platform should be autonomous and portable and enable multiplexed screening from capillary blood. The previously developed and introduced MLFIA (Magnetically Localized and wash-free Fluorescent Immuno-Assay) technology has the potential to address these needs, as the MLFIA 18-chamber microfluidic cartridge and the MLFIA Analyzer were previously characterized and evaluated with plasma and serum from patients infected with HIV, Hepatitis B (Hep B) or C (Hep C). Here, we present the efforts to transfer this research platform (MLFIA) to a fully integrated multi-analysis solution (MagIA). First, we present the design changes of the consumable enabling to perform multiple assays in parallel, a fast filling of the cartridge with patient samples, and a homogeneous reagent/sample incubation. Second, we describe the development a piezoelectric actuator integrated into the Analyzer: this mixing module allows for an automated, fully integrated and portable workflow, with homogeneous in-situ mixing capabilities. The obtained MagIA platform was further characterized and validated for immunoassays (LOD, cartridge stability over time), using various biological models including OVA and IgG. We discuss the performances of the MLFIA and MagIA platforms for the detection of HIV / Hep B / Hep C using results from 102 patient plasma samples. Lastly, we assessed the compatibility of the MagIA platform with veinous and capillary blood samples as a final step towards its POC validation.

Explaining racial and ethnic disparities in antiretroviral therapy adherence and viral suppression among U.S. men who have sex with men.

OBJECTIVE: To identify factors - including social determinants of health (SDOH) - that explain racial/ethnic disparities in antiretroviral therapy (ART) adherence and sustained viral suppression (SVS) among U.S. men who have sex with men (MSM) with HIV. DESIGN: We used weighted data from 2017-2021 cycles of the Medical Monitoring Project. METHODS: Among MSM taking ART, we calculated prevalence differences (PDs) with 95% confidence intervals (CIs) of ART adherence (100% ART adherence, past 30 days) and SVS (all viral loads in past 12 months <200 copies/ml or undetectable) for Black MSM (BMSM) and Hispanic/Latino MSM (HMSM) compared with White MSM (WMSM). Using forward stepwise selection, we calculated adjusted PDs with 95% CIs to examine if controlling for selected variables reduced PDs. RESULTS: After adjusting for age, any unmet service need, federal poverty level (FPL), food insecurity, homelessness, time since HIV diagnosis, gap in health coverage, and education, the BMSM/WMSM PD for ART adherence reduced from -16.9 to -8.2 (51.5%). For SVS, the BMSM/WMSM PD reduced from -8.3 to -3.6 (56.6%) after adjusting for ART adherence, age, homelessness, food insecurity, gap in health coverage, FPL, any unmet service need, time since diagnosis, and ER visit(s). The HMSM/WMSM PD for ART adherence reduced from -9.3 to -2.9 (68.8%) after adjusting for age and FPL. The unadjusted HMSM/WMSM PD for SVS was not statistically significant. CONCLUSIONS: Adjusting for SDOH and other factors greatly reduced racial/ethnic disparities in ART adherence and SVS. Addressing these factors - particularly among BMSM - could substantially improve health equity among MSM with HIV.

Accelerating pediatric Hodgkin lymphoma research: the Hodgkin Lymphoma Data Collaboration (NODAL).

Data commons have proven to be an indispensable avenue for advancing pediatric cancer research by serving as unified information technology platforms that, when coupled with data standards, facilitate data sharing. The Pediatric Cancer Data Commons, the flagship project of Data for the Common Good (D4CG), collaborates with disease-based consortia to facilitate development of clinical data standards, harmonization and pooling of clinical data from disparate sources, establishment of governance structure, and sharing of clinical data. In the interest of international collaboration, researchers developed the Hodgkin Lymphoma Data Collaboration and forged a relationship with the Pediatric Cancer Data Commons to establish a data commons for pediatric Hodgkin lymphoma. Herein, we describe the progress made in the formation of Hodgkin Lymphoma Data Collaboration and foundational goals to advance pediatric Hodgkin lymphoma research.

Inequities Along the Human Immunodeficiency Virus (HIV) Pre-exposure Prophylaxis Services Continuum for Black Women in the United States, 2015-2020.

OBJECTIVE: To estimate the number of women who received human immunodeficiency virus (HIV) and sexually transmitted infection (STI) testing and HIV pre-exposure prophylaxis (PrEP) services by race and ethnicity in seven THRIVE (Targeted Highly Effective Interventions to Reverse the HIV Epidemic)-funded jurisdictions and to estimate associations of age and syphilis and gonorrhea diagnoses with receipt of HIV PrEP services. METHODS: We analyzed data collected from 2015 to 2020 in Birmingham, Alabama; Baltimore City, Maryland; Washington, DC, New Orleans, Louisiana; Brooklyn, New York; Philadelphia, Pennsylvania; and Hampton Roads, Virginia. We compared Black women and women of additional racial and ethnic groups by age, HIV status at enrollment, receipt of STI testing and test positivity, and steps in the PrEP continuum (screened, eligible, referred, linked, and prescribed). We also examined the association of age, syphilis, or gonorrhea with the following steps in the PrEP continuum: screened, referred, linked, and prescribed. RESULTS: Black women made up 69.2% (8,758/12,647) of women served in THRIVE. Compared with non-Black women, Black women were more likely to have a positive test result for syphilis (3.3% vs 2.1%), gonorrhea (4.9% vs 3.5%), chlamydia (5.1% vs 1.9%), or more than one STI (1.4% vs 0.3%). Among women with negative HIV test results or unknown HIV status, Black women were more likely to be screened for PrEP eligibility (88.4% vs 64.9%). Among Black women, the proportion screened for PrEP was higher among those diagnosed with syphilis (97.3%) or gonorrhea (100%) than among those without an STI (88.1% and 87.8%, respectively). Among 219 Black women who presented with syphilis, only 10 (4.6%) were prescribed PrEP; among 407 with gonorrhea, only 11 (2.7%) were prescribed PrEP. CONCLUSION: Although most Black women seeking services received STI testing, the proportion of Black women who were eligible for PrEP and prescribed PrEP was low. To achieve national HIV-prevention goals, it is imperative that Black women have access to PrEP information and services.

Development of a Video-Delivered Serial Drama Designed to Reduce Community Homophobia and HIV Stigma, Decrease Sexual Risk Behavior, and Increase HIV Testing Among Black Youth.

This article describes the development of a video serial drama intervention that was designed to address factors that influence HIV in the United States among Black youth. These include HIV testing, sexual behaviors not protected by condoms, negative attitudes towards sexual minorities, and HIV stigma. Behavior-change principles (social learning theory and education-entertainment) and input from members of the priority audience formed the basis of this 27-episode (3 minutes each) drama for dissemination on multiple platforms, including in public spaces or privately online. The developmental process, specifically involving members of the population of interest and use of behavioral theory, enriched the narrative elements and likely ensured intervention acceptability, enhancing effectiveness. Public health practitioners and prevention programmers may want to consider using this intervention and/or the narrative communication approach when intervening to change behavior.

Protocol to visualize ion channel trafficking in acutely isolated rodent neurons using live-cell immunocytochemistry.

Here, we present a protocol for live-cell immunocytochemistry to demonstrate reversible translocation of ion channels to the neuronal cell surface. We describe steps for cell preparation and isolation, experimental treatment, antibody binding prior to fixation, specific pipetting techniques, troubleshooting, and expected outcomes of correct use of the protocol. This protocol will be useful to study regulated translocation of ion channels and other membrane proteins. For complete details on the use and execution of this protocol, please refer to Haan et al.1.