Biology subjects

Young, C. A.

Publications and source records attributed to Young, C. A..

6 recordsLinked to original sources

bioRxiv2026

Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment

177Lu-PSMA-617 (PluvictoTM, Lu-177 RLT) is an FDA-approved targeted radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC), but its durability of response to this singular approach poses a challenge to the field. Chimeric antigen receptor (CAR) T cell therapy has revolutionized clinical practice for hematological malignancies, but its clinical development for solid tumors, including mCRPC, has been encumbered by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Here, we evaluate the therapeutic combination of Lu-177 RLT and PSCA-CAR T cells to overcome these barriers. In human xenograft and mouse syngeneic prostate cancer models with homogeneous or heterogeneous antigen expression, the sequential administration of Lu-177 RLT, cyclophosphamide (Cy), and PSCA-CAR T cells improves tumor control and prolongs survival compared to monotherapies. Mechanistically, Lu-177 RLT alone or with Cy remodels the TME by promoting pro-inflammatory myeloid responses and activating endogenous T cells, while enhancing CAR T cell activation and effector function. We additionally evaluated 225Ac-PSMA-617 RLT as an emerging approach in combination with CAR T cells and observed anti-tumor responses, supporting its potential as an alternative RLT partner. These findings support RLT as an immune priming strategy to enhance CAR T cell therapy and provide a rationale for clinical translation of this combination in mCRPC. One Sentence SummaryCombining 177Lu-PSMA-617 radioligand therapy with PSCA-CAR T cells improves tumor control and survival in prostate cancer models by overcoming the antigen heterogeneity and reshaping the immunosuppressive tumor microenvironment.

cancer biology↗

bioRxiv2023

Progenitors influence patterning of the sensory epithelium.

During embryonic development Wnt signaling has been shown to influence proliferation and sensory formation in the cochlea. How the dual nature of Wnt signaling is coordinated is unknown. In this study, we define a novel role for a Wnt regulated gene, Mybl2, which was already known to be important for proliferation, in influencing patterning and determining the size of the sensory epithelium in the murine cochlea. Using a quantitative spatial analysis approach and analyzing Mybl2 loss-of-function cochleas, we show that Mybl2 simultaneously specifies the progenitor niche and the size of the sensory domain, and influences the positioning of the medial sensory domain boundary via Jag1 regulation during the mid-gestational stages. Mybl2 conditional knockout resulted in a decrease of proliferation within the progenitor niche. During the late embryonic stages, conditional knockout of Mybl2 produced a wider sensory epithelium across the radial axis with an increase in ectopic inner hair cell formation. These data suggest that Mybl2-positive progenitors play a role in boundary formation and patterning the sensory epithelium. Summary StatementMybl2 is a Wnt-regulated gene encoding a transcription factor that is expressed in the cochlear progenitor niche and influences the boundary formation between the niche and the sensory domain during mid-cochlear developmental stages, thereby impacting the size of the sensory epithelium.

developmental biology↗

bioRxiv2021

Spatial and temporal expression of PORCN is highly dynamic in the developing mouse cochlea.

The mammalian organ of Corti is a highly specialized sensory organ of the cochlea with a fine-grained pattern that is essential for auditory function. The sensory epithelium, the organ of Corti consists of a single row of inner hair cells and three rows of outer hair cells that are intercalated by support cells in a mosaic pattern. Previous studies show that the Wnt pathway regulates proliferation, promotes medial compartment formation in the cochlea, differentiation of the mechanosensory hair cells and axon guidance of Type II afferent neurons. WNT ligand expressions are highly dynamic throughout development but are insufficient to explain the roles of the Wnt pathway. We address a potential way for how WNTs specify the medial compartment by characterizing the expression of Porcupine (PORCN), an O-acyltransferase that is required for WNT secretion. We show PORCN expression across embryonic ages (E)12.5 - E14.5, E16.5, and postnatal day (P)1. Our results showed enriched PORCN in the medial domains during early stages of development, indicating that WNTs have a stronger influence on patterning of the medial compartment. PORCN was rapidly downregulated after E14.5, following the onset of sensory cell differentiation; residual expression remained in some hair cells and supporting cells. On E14.5 and E16.5, we also examined the spatial expression of Gsk3{beta}, an inhibitor of canonical Wnt signaling to determine its potential role in radial patterning of the cochlea. Gsk3{beta} was broadly expressed across the radial axis of the epithelium; therefore, unlikely to control WNT-mediated medial specification. In conclusion, the spatial expression of PORCN enriches WNT secretion from the medial domains of the cochlea to influence the specification of cell fates in the medial sensory domain. HighlightsO_LIWnt ligands are broadly expressed during cochlear development. C_LIO_LIPORCN expression is highly dynamic during early cochlear development C_LIO_LIPORCN becomes restricted to the medial domains along the longitudinal axis. C_LIO_LIWnt medial specification is regulated at the level of WNT ligand secretion. C_LI

developmental biology↗

bioRxiv2019

First description of the sexual stage of Venturia effusa, causal agent of pecan scab

Venturia effusa, cause of pecan scab, is the most prevalent disease of pecan in the southeastern USA; epidemics of the disease regularly result in economic losses to the pecan industry. Recent characterization of the mating type distribution revealed the frequency of the MAT idiomorphs are in equilibrium at various spatial scales, indicative of regular sexual recombination. However, the occurrence of the sexual stage of V. effusa has never been observed, and the pathogen was previously believed to rely entirely on asexual reproduction. To explore the existence of a sexual cycle, we paired opposite mating types on oatmeal culture media. In initial experiments, cultures were incubated at 24 C for 2 mo for hyphal interactions to occur between mating types and then maintained at 4 C for 4 mo. Immature pseudothecia were initially observed but following exposure to a 12 h photoperiod for 2 weeks at 24 C, asci and ascospores developed. Further experiments explored the effect of time on pseudothecial development with 4 mo at 4 C as the optimal requirement. The results of this study demonstrate the heterothallic nature of V. effusa. Following experiments investigated progeny from a sexual cross of an albino and a wild-type isolate. Evaluation of isolate pigmentation, mating type, and multilocus genotyping of single ascospore progeny provided evidence that recombination occurred within the sexual crosses. The impact of determining the source of the overwintering ascostroma will aid in management decisions to reduce the primary inoculum in the disease cycle.

pathology↗

bioRxiv2019

Chromosome-level genome reference of Venturia effusa, causative agent of pecan scab

Pecan scab, caused by Venturia effusa, is a devastating disease of pecan (Carya illinoinensis), which results in economic losses on susceptible cultivars throughout the southeastern U.S. To enhance our understanding of pathogenicity in V. effusa, we have generated a complete telomere-to-telomere genome reference of V. effusa isolate FRT5LL7-Albino. By combining Illumina MiSeq and Oxford Nanopore MinION data, we assembled a 45.2 Mb genome represented by 20 chromosomes and containing 10,820 genes, of which 7,619 have at least one functional annotation. The likely causative mutation of the albino phenotype was identified as a single base insertion and a resulting frameshift in the gene encoding the polyketide synthase ALM1. This genome represents the first full chromosome level assembly of any Venturia species.

genomics↗

bioRxiv2018

Digital imaging to evaluate root system architectural changes associated with soil biotic factors

Root system architecture (RSA) is critical for plant growth, which is influenced by several edaphic, environmental, genetic and biotic factors including beneficial and pathogenic microbes. Studying root architecture and the dynamic changes that occur during a plants lifespan, especially for perennial crops growing over multiple growing seasons, is still a challenge because of the nature of their growing environment in soil. We describe the utility of an imaging platform called RhizoVision Crown to study RSA of alfalfa, a perennial forage crop affected by Phymatotrichopsis Root Rot (PRR) disease. Phymatotrichopsis omnivora is the causal agent of PRR disease that reduces alfalfa stand longevity. During the lifetime of the stand, PRR disease rings enlarge and the field can be categorized into three zones based upon plant status: asymptomatic, disease front and survivor. To study root architectural changes associated with PRR, a four-year old 25.6-hectare alfalfa stand infested with PRR was selected at the Red River Farm, Burneyville, OK during October 2017. Line transect sampling was conducted from four actively growing PRR disease rings. At each disease ring, six line transects were positioned spanning 15 m on either side of the disease front with one alfalfa root sampled at every 3 m interval. Each alfalfa root was imaged with the RhizoVision Crown platform using a backlight and a high-resolution monochrome CMOS camera enabling preservation of the natural root architectural integrity. The platforms image analysis software, RhizoVision Analyzer, automatically segmented images, skeletonized, and extracted a suite of features. Data indicated that the survivor plants compensated for damage or loss to the taproot through the development of more lateral and crown roots, and that a suite of multivariate features could be used to automatically classify roots as from survivor or asymptomatic zones. Root growth is a dynamic process adapting to ever changing interactions among various phytobiome components, by utilizing a low-cost, efficient and high-throughput Rhizo-Vision Crown platform we showed quantification of these changes occurring in a mature perennial forage crop.

plant biology↗