Biology subjects

Finlay, J. B.

Publications and source records attributed to Finlay, J. B..

4 recordsLinked to original sources

bioRxiv2023

Antigen presentation by tumor-associated macrophages mediates progenitor to terminal exhaustion transition in GBM and other solid tumors

Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAM) - not tumor cells - were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to PD-1 immunotherapy. Thus, targeting TAM - T cell interactions may further license checkpoint blockade responses.

immunology↗

bioRxiv2022

Deconstructing olfactory epithelium developmental pathways in esthesioneuroblastoma

ImportanceEsthesioneuroblastoma (ENB) is a rare tumor arising from the olfactory cleft region of the nasal cavity. Due to the low incidence of this tumor, as well as an absence of established reagents such as cell lines or murine models, understanding the mechanisms driving ENB pathobiology has been challenging. ObjectiveHere, we sought to apply advances from research on the human olfactory epithelial neurogenic niche, along with new biocomputational approaches, to better understand the cellular and molecular factors in low and high grade ENB and how specific transcriptomic markers may predict prognosis. Design, Setting, and ParticipantsThis was a retrospective biocomputational analysis utilizing human ENB and normal olfactory mucosal tissue and clinical outcomes data. The setting was a large academic medical center. Participants were selected based on available datasets, and included ENB patients across all four tumor grades, and patients with normal olfactory mucosa. Main Outcomes and MeasuresOutcomes include deconvolution analysis, differential gene expression analysis, overall survival, and immunohistochemistry. A machine learning model was used to predict cell-type proportion signatures in ENB, and Kaplan-Meier curves with associated log-rank tests were used to estimate differences in overall survival. ResultsWe analyzed a total of 19 ENB samples (9 low grade I/II, 10 high grade III/IV) with available bulk RNA-Sequencing and survival data, along with 10 samples from normal olfactory mucosa (3 bulk RNA-Sequencing, 7 single cell RNA-Sequencing). The bulk RNA-Sequencing deconvolution model identified a significant increase in globose basal cell (GBC) and CD8 T cell identities in high grade tumors (GBC from approximately 0% to 8%, CD8 T cell from 0.7% to 2.2%), and significant decreases in mature neuronal, Bowmans gland, and olfactory ensheathing programs, in high grade tumors (mature neuronal from 3.7% to approximately 0%, Bowmans gland from 18.6% to 10.5%, olfactory ensheathing from 3.4% to 1.1%). Trajectory analysis identified potential regulatory pathways in proliferative ENB cells, including PRC2. Survival analysis guided by gene expression in bulk RNA-Sequencing data identified favorable prognostic markers such as SOX9, S100B, and PLP1 expression. Conclusions and RelevanceOur analyses provide a basis for additional translational research on ENB management, as well as identification of potential new prognostic markers.

cancer biology↗

bioRxiv2022

Persistent post-COVID-19 smell loss is associated with inflammatory infiltration and altered olfactory epithelial gene expression

Most human subjects infected by SARS-CoV-2 report an acute alteration in their sense of smell, and more than 25% of COVID patients report lasting olfactory dysfunction. While animal studies and human autopsy tissues have suggested mechanisms underlying acute loss of smell, the pathophysiology that underlies persistent smell loss remains unclear. Here we combine objective measurements of smell loss in patients suffering from post-acute sequelae of SARS-CoV-2 infection (PASC) with single cell sequencing and histology of the olfactory epithelium (OE). This approach reveals that the OE of patients with persistent smell loss harbors a diffuse infiltrate of T cells expressing interferon-gamma; gene expression in sustentacular cells appears to reflect a response to inflammatory signaling, which is accompanied by a reduction in the number of olfactory sensory neurons relative to support cells. These data identify a persistent epithelial inflammatory process associated with PASC, and suggests mechanisms through which this T cell-mediated inflammation alters the sense of smell.

neuroscience↗

bioRxiv2022

Pharmacokinetics of Sustained-Release Buprenorphine and Extended-Release Buprenorphine in Mice with Surgical Catheterization

The Guide for the Care and Use of Laboratory Animals strongly encourages the use of pharmaceutical grade chemicals and analgesics. The extra-label use of sustained-release buprenorphine (SRB) is commonly administered to rodents to mitigate moderate-to-severe pain. An FDA-indexed buprenorphine formulation, known as extended-release buprenorphine (XRB), has recently become available and is currently the only pharmaceutical grade slow-release buprenorphine approved for use in mice and rats. However, no studies have directly compared the pharmacokinetic (PK) parameters and therapeutic efficacy of SRB and XRB in surgically catheterized mice. Thus, we compared the plasma buprenorphine concentrations and PK parameters of SRB and XRB in mice after surgical catheterization. We hypothesized that mice treated with SRB or XRB would have circulating buprenorphine concentrations exceeding the therapeutic threshold for up to 72-hours post-operatively. Male and female C57Bl/6J mice were anesthetized, treated with either SRB (1 mg/kg, SC, once) or XRB (3.25 mg/kg, SC, once) and underwent surgical catheterization. At 6, 24, 48, and 72 h after SRB or XRB administration, arterial blood samples were collected. Post-operative weight loss was similar between groups with a decline of 11.7 {+/-} 1.6 and 12.3 {+/-} 0.7% in males and 7.6 {+/-} 2.2 and 8.1 {+/-} 1.1% (mean {+/-} SEM) in females treated with SRB and XRB, respectively. Both SRB and XRB maintained circulating buprenorphine concentrations above the therapeutic level of 1.0 ng/mL for 72 h after administration. XRB buprenorphine concentrations were significantly greater (3-4-fold) than SRB concentrations at 6, 24, and 48 h, commensurate with the increase dose concentration of XRB to SRB. These results support the use of either SRB or XRB for the alleviation of postoperative pain in mice. The new availability of FDA-indexed XRB increases the options for safe and effective pharmaceutical grade analgesia in rodents.

pharmacology and toxicology↗