Biomedical subjects

John Bell

Publications and source records attributed to John Bell.

3 recordsLinked to original sources

PubMed2026

The SARS-CoV-2 Integrated Genomic Epidemiology Database (IGED): Linking viral genomes with patient-level metadata to advance statewide genomic surveillance in California.

In July 2021, the California Code of Regulations Title 17 required all laboratories performing SARS‑CoV‑2 whole genome sequencing (WGS) to report their sequencing results to the California Department of Public Health (CDPH). These viral genomic data and patient metadata were compiled into the Integrated Genomic Epidemiology Database (IGED). Linking anonymized viral sequences with patient‑level information enabled monitoring of infectiousness, pathogenicity, transmission dynamics, evolution, and vaccine evasion among emerging SARS‑CoV‑2 lineages. Laboratories performing SARS-CoV-2 WGS transmitted sequencing results to CDPH through Electronic Laboratory Reporting (ELR) and non-ELR pathways. CDPH applied uniform reporting requirements but allowed flexibility in specific data formats to accommodate diverse data systems. To preserve data quality and interoperability across heterogeneous sources, CDPH implemented standardization, validation, and deduplication protocols. Snowflake, a cloud‑based data storage and analytics platform, and Posit Connect, a cloud deployment and automation platform, supported the management, processing, and integration of data within the IGED. The IGED established links between SARS‑CoV‑2 WGS data and epidemiologic metadata for 801,418 sequences, representing 81.7% of all sequences reported in California. Lineages reported to the IGED showed strong concordance with lineage proportions in GISAID. Sequences reported to the IGED had average turnaround times longer than one month, and the majority of sequencing was performed in Southern California and Los Angeles. The IGED enhanced genomic surveillance through predictive modeling and monitoring concerning evolutionary trends such as recombination and saltations in persistent infections. Development of the IGED highlighted the need for standardized data requirements, sustained funding for sequencing, incentives for data submission, and interdisciplinary collaboration to build an effective genomic surveillance system. This framework for linking genomic and epidemiologic data has not only generated critical insights for SARS‑CoV‑2 but also provided the foundation for CDPH and other public health organizations to develop similar IGED‑like systems for other priority pathogens as genomic surveillance expands.

Journal Article↗

PubMed2026

GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.

Animals↗

PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗