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1.
Sci Immunol ; 8(87): eadf6717, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37713508

ABSTRACT

Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR-Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.


Subject(s)
Basic-Leucine Zipper Transcription Factors , Gene Regulatory Networks , Head and Neck Neoplasms , Humans , Autoimmune Diseases , Basic-Leucine Zipper Transcription Factors/genetics , Head and Neck Neoplasms/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , T-Lymphocytes, Regulatory
4.
Am J Med Qual ; 36(4): 215-220, 2021.
Article in English | MEDLINE | ID: mdl-32812436

ABSTRACT

Intensive care units (ICUs) lack both standardized performance indicators to better understand the effectiveness of interventions and uniform platforms to present these indicators. The goal of this study was to identify ICU metrics meaningful to stakeholders to help guide the development of a local visualization dashboard. Individual ICU directors were interviewed to collate their input on metrics important to their units. These qualitative data were used to develop a dashboard draft, after which the authors surveyed 20 stakeholders from different hospital departments for feedback on its content and structure. The varied survey results reinforced the inherent difficulties of adapting previously developed measurement tools while also selecting ICU performance measures that are simultaneously widely accepted yet relevant to local practice. These results also call attention to the importance of interdisciplinary input in quality dashboard development, thereby enabling more successful implementation and utilization for ICU quality improvement.


Subject(s)
Critical Care , Quality Improvement , Benchmarking , Feedback , Humans , Intensive Care Units
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