Biology subjects

Lloyd, P.

Publications and source records attributed to Lloyd, P..

4 recordsLinked to original sources

bioRxiv2025

Identification and Characterization of PLUTO-201, a Novel Long Non-Coding RNA Associated with Poor Outcomes in Prostate Cancer

Background: Despite extensive investigation, the factors promoting aggressive prostate cancer are poorly understood. In particular, despite a few prominent examples, the role of long non-coding RNAs (lncRNAs) is largely unknown. Methods: We performed a comprehensive analysis of whole-genome transcriptome data to identify differential expression across 1,567 patients with prostate cancer, then correlated differential expression with risk of metastatic recurrence. We characterized the lncRNA most associated with metastasis in vitro and in vivo to investigate the mechanism by which it promotes aggressive prostate cancer. Results: We have identified a novel lncRNA, Prostate Cancer Associated hnRNPK Interacting Transcript (PCAHIT), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that overexpression/knockdown of PCAHIT in pre-clinical models of prostate cancer modulates proliferation rates and markers of an aggressive phenotype through regulation of steroid biosynthesis and expression of the MHC class I complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. We further find that the heterogeneous nuclear ribonucleoprotein hnRNPK directly binds PCAHIT and is indispensable for its activity. Conclusions: Overall, our findings indicate that PCAHIT is a driver of aggressive prostate cancer phenotypes and poor clinical outcomes through suppression of the immune response and increased androgen-independent cancer growth. PCAHIT is a potential biomarker of aggressive disease.

cancer biology↗

bioRxiv2021

A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

BackgroundPersistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, evoking protective spike antibody responses, conceived in 2020, are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. MethodsUsing a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC Class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 x 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms, viral load, chest radiographs, sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. ResultsVaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. ConclusionsWe demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA Class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in non-human primates. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/441228v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c0730aorg.highwire.dtl.DTLVardef@c0bff7org.highwire.dtl.DTLVardef@7b1ea6org.highwire.dtl.DTLVardef@11950a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors' CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design

The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.

immunology↗

bioRxiv2019

Metabolic rate is negatively linked to adult survival but does not explain latitudinal differences in songbirds

Survival rates vary dramatically among species and predictably across latitudes, but causes of this variation are unclear. The rate of living hypothesis posits that physiological damage from metabolism causes species with faster metabolic rates to exhibit lower survival rates. However, whether increased survival commonly observed in tropical and south temperate latitudes is associated with slower metabolic rate remains unclear. We compared metabolic rates and annual survival rates across 46 species that we measured, and 147 species from literature data across northern, southern, and tropical latitudes. High metabolic rates were associated with lower survival but latitude had substantial direct effects on survival independent of metabolism. The inability of metabolic rate to explain latitudinal variation in survival suggests 1) that species may evolve physiological mechanisms that mitigate physiological damage from cellular metabolism, and 2) a larger role of extrinsic environmental, rather than intrinsic metabolic, causes of latitudinal differences in mortality.

evolutionary biology↗