Biology subjects

Jiang, W.

Publications and source records attributed to Jiang, W..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

Single Cell Transcriptomics-informed Induced Pluripotent Stem Cells Differentiation to Tenogenic Lineage

During vertebrate embryogenesis, axial tendons develop from the paraxial mesoderm and differentiate through specific developmental stages to reach the syndetome stage. While the main roles of signaling pathways in the earlier stages of the differentiation have been well established, pathway nuances in syndetome specification from the sclerotome stage have yet to be explored. Here, we show stepwise differentiation of human iPSCs to the syndetome stage using chemically defined media and small molecules that were modified based on single cell RNA-sequencing and pathway analysis. We identified a significant population of branching off-target cells differentiating towards a neural phenotype overexpressing Wnt. Further transcriptomics post-addition of a WNT inhibitor at the somite stage and onwards revealed not only total removal of the neural off-target cells, but also increased syndetome induction efficiency. Fine-tuning tendon differentiation in vitro is essential to address the current challenges in developing a successful cell-based tendon therapy.

developmental biology↗

bioRxiv2023

Mammalian Esophageal Stratified Tissue Homeostasis is Maintained Distinctively by the Epithelial Pluripotent p63+Sox2+ and p63-Sox2+ Cell Populations

Self-renewing, damage-repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snap-shot immunostaining and functional analyses of stratified "matured" rEOs define that the epithelial pluripotent stem-cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63+Sox2+ and p63-Sox2+, of which the p63+Sox2+ population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation whereas the p63-Sox2+ population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage-repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63-Sox2+ population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2 dependent cell lineage populations required for the tissue renewing, damage-repair and protection of carcinogenesis in mammalian esophagi.

cell biology↗

bioRxiv2023

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCs in vitro. The recreated pain phenotype activated functional sensory neurons response in vitro and induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVD in vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP. One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

molecular biology↗

bioRxiv2023

An ULK1/2-PXN mechanotransduction complex suppresses breast cancer cell migration

The remodeling and stiffening of the extracellular matrix (ECM) associated with breast cancers is a well-recognized modulator of disease progression. However, how changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remains poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We demonstrate that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs), and as a consequence impedes cell contraction and migration. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn impedes the mechanotransduction of breast cancer cells. ULK1/2 and the well characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Thus, our study reveals ULK1/2 as important regulators of PXN-dependent mechanotransduction. HighlightsO_LIULK1/2 interact with PXN and phosphorylate PXN at S32 and S119 in response to mechanical stimuli C_LIO_LIULK1/2-mediated phosphorylation of PXN regulates mechanotransduction and migration of breast cancer cells C_LIO_LIULK1/2 modulate the biomaterial properties of focal adhesions through PXN phosphorylation C_LIO_LIULK1/2 and FAK/Src act antagonistically in mechanotransduction through competitive phosphorylation of PXN C_LI

cell biology↗

bioRxiv2023

Host-microbe interactions mediate doramectin-promoted metabolic reprogramming of CD8+ T-cells and amplify antitumor immunity

The intestinal microbiota and its metabolites influence the host metabolic environment and CD8+ T-cell function. Metabolic changes in T-cells are thought to enhance the antitumor immune response. Here, we show that doramectin (DOR), a macrocyclic lactone (ML) of the avermectin (AVM) family, can modify CD8+ T-cell metabolism to increase and accelerate effector function. However, the functional capability of DOR depends mainly on the accessibility of gut microbiota. Using metagenomic and metabolomic techniques, we describe for the first time the interplay between gut microbiota and host metabolism involved in metabolic reprogramming of CD8+-T cells following DOR administration. Interestingly, we found that, after DOR administration, Firmicutes phylum not only impact DOR transport and absorption, but also boost amino acid levels in CD8+ T-cells, consistent with increased production of tumor necrosis factor alpha (TNF-) and, in particular, interferon gamma (IFN-{gamma}), which together play an important role in antitumor immunity. In contrast, the dysbiotic microbial community may abrogate the anticancer efficacy of DOR and lead to enhanced tumor growth and decreased survival. This finding likely supports the view that the presence of certain bacteria in the gut governs extra-intestinal immune responses and may be associated with metabolic adaptations necessary for efficient function of CD8+ T-cells upon DOR administration.

cancer biology↗

bioRxiv2023

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

BackgroundThe Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. MethodsWe isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. ResultsWe determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. ConclusionsOur findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.

neuroscience↗

bioRxiv2022

FCGRT, a cancer-derived immunoglobulin G binding protein, mediates the malignant phenotype of glioma

CIgG has received increasing attention, and was first discovered by our group to indicate poor prognosis in glioma. Furthermore, by protein mass spectrometry, we found that FCGRT can combine with CIgG. However, the study of FCGRT in glioma has not been reported. We used the CGGA325, TCGA dataset and immunohistochemistry to verify the importance of FCGRT on the prognosis of glioma patients. Single cell sequencing data analysis evaluated that the role of FCGRT in the microenvironment of glioma. Estimate, ssGSEA, EPIC and xCell were used for immune infiltration analysis. FCGRT was knocked down in U251 cells to detect the effect of FCGRT on the malignant development of glioma. These results showed that patients with higher FCGRT expression had a shorter overall survival. FCGRT was closely related to the tumor microenvironment, especially to macrophages in the tumor microenvironment (r=0.743, p<0.001). Interestingly we also found that FCGRT was positively correlated with IGHG1. Finally, we found that knock-down of FCGRT resulted in a decrease in proliferation, migration and invasion of U251 cells. Taken together, we believe that FCGRT is an independent prognostic factor for glioma patients, and its possible mechanism is to promote proliferation and invasion of tumor cells by interacting with CIgG.

bioinformatics↗

bioRxiv2022

PXN/Paxillin Phase Separation Promotes Focal Adhesion Assembly and Integrin Signaling

Focal adhesions (FAs) are transmembrane protein assemblies mediating cell-matrix connection. Tools to manipulate the compositionally intricate and dynamic FAs are currently limited, rendering many fundamental hypotheses untestable. Although protein liquid-liquid phase separation (LLPS) has been tied to the organization and dynamics of FAs, the underlying mechanisms remain unclear. Here, we experimentally tune the LLPS of PXN/Paxillin, an essential scaffold protein of FAs, by utilizing light-inducible Cry2 system. In addition to nucleating FA components, light-triggered PXN LLPS potently activates integrin signaling and subsequently accelerates cell spreading. PXN favors homotypic interaction-driven LLPS in vitro. In cells, PXN condensates are associated with plasma membrane, and modulated by actomyosin contraction and client proteins of FAs. Interestingly, non-specific weak inter-molecular interactions, together with specific molecular interactions, underlie the multicomponent condensation of PXN, and are efficient to promote FA assembly and integrin signaling. Thus, our data establish an active role of PXN phase transition into a condensed membrane-associated compartment in promoting assembly/maturation of FAs.

cell biology↗

bioRxiv2022

Discovery and remodeling of Vibrio natriegens as a microbial platform for efficient formic acid biorefinery

Formic acid (FA), an organic one-carbon source that is easily produced from CO2, has emerged as a promising CO2-equivalent feedstock for one-carbon biorefinery. However, developing efficient formatotrophs for an economically competitive FA utilization system remains a grand challenge. Here, we discovered that the gram-negative bacterium Vibrio natriegens has exceptional FA tolerance and metabolic capacity natively. This strain was then remodeled by rewiring the serine cycle and the TCA cycle which resulted in a non-native closed loop (S-TCA) for enhancing FA assimilation. The rational design generated a powerful metabolic sink that enabled rapid emergence of the evolved strains with further significantly improved performance in using FA as the major or sole carbon source. Furthermore, the introduction of a foreign indigoidine-forming pathway into the best-performing V. natriegens strain (S-TCA-2.0) led to production of 29.0 g{middle dot}L-1 indigoidine and consumption of 233.7 g{middle dot}L-1 formate within 72 h, achieving an order of magnitude higher formate consumption rate (3.2 g{middle dot}L-1{middle dot}h-1) than the reported highest level in microorganisms. This work represents a significant step towards the development of industrially viable microorganisms for FA biorefinery.

microbiology↗

bioRxiv2022

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

immunology↗

bioRxiv2022

Different tissues in the maternal-fetal interface harbor distinct microbiomes showing associations related to their anatomical position or function

The human placenta was thought to be sterile in healthy pregnancies which has been challenged by the development of DNA sequence-based techniques, although it is still open to controversy. Nonetheless, little is known whether different parts of fetal appurtenances contain district microbiome profiles. Here, DNA 16S rRNA sequencing was performed of the amniotic fluid cells (AC), amnion membrane (AM), the placenta of fetal surface (remove the amniotic membrane, PL), maternal blood (MB), and umbilical cord blood (UCB) at V3-V4 hypervariable region from participants with cesarean delivery. Then sequence raw data were followed by taxonomic classification at 97% similarity and diversity analysis at the genus level. The differences and associations among the five tissues were analyzed. At the phylum composition level, the most abundant microorganisms were Proteobacteria in all five tissues, and followed by Firmicutes in AC, AM, and MB groups, Actinobacteria in UCB and Bacteroidetes in PL, respectively. As the maternal-fetal barrier, PL and AM had the lower OUT number and weaker co-occurrence network compared with the other three tissues. At the beta diversity clustering level, the microbiota constituents in the MB and UCB were highly similar; the microbiota profiles of PL and AM were also remarkably alike; AC was immensely different from those two clusters. Therefore, the five tissues were distinctly separated into three clusters. Our study reveals that different pregnancy-related anatomical sites harbor unique microbial compositions and show different degrees of correlation with other tissues.

microbiology↗

bioRxiv2022

KDM5A/B promotes HIV-1 latency and KDM5 inhibitors promote HIV-1 lytic reactivation

Combinational antiretroviral therapy (cART) effectively suppresses HIV-1 infection, replication, and pathogenesis in HIV-1 patients. However, the patients HIV-1 reservoir still cannot be eliminated by current cART or other therapies. One putative HIV-1 eradication strategy is "shock and kill", which reactivates HIV-1 in latently-infected cells and induces their cytopathic effect or immune clearance to decrease the patients reservoir size. KDM5A and KDM5B act as the HIV-1 latency-promoting genes, decreasing the HIV-1 viral gene transcription and reactivation in infected cells. Depletion of KDM5 A/B by siRNA knockdown (KD) increases H3K4 trimethylation (H3K4me3) in HIV-1 Tat-mediated transactivation. We also found that the KDM5-specific inhibitor JQKD82 can increase H3K4me3 at the HIV-1 LTR region during HIV-1 reactivation and induce cytopathic effects. We applied the JQKD82 in combination with the non-canonical NF-{kappa}B activator AZD5582, which synergistically induced HIV-1 reactivation and cell apoptosis in HIV-1 infected cells. These results suggested that the KDM5 inhibition can be a putative HIV-1 latency-reversing strategy for the HIV-1 "shock and kill" eradication therapy.

microbiology↗

bioRxiv2022

POGZ suppresses 2C transcriptional program and retrotransposable elements

The POGZ gene has been found frequently mutated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). We have recently shown that POGZ maintains mouse embryonic stem cells (ESCs) as a chromatin regulator and a transcription factor. However, the exact mechanisms remain unclear. Here we show that POGZ plays important role in the maintenance of ESCs by silencing the Dux gene and certain endogenous retroviruses (ERVs). POGZ directly binds to the Dux gene and ERVs, and its depletion leads to up-regulation of 2C genes and the repetitive elements such as RLTR9E and IAP (the intracisternal A-type particles), resulting in transition to a 2C-like (2CLC) state and genome instability. POGZ regulates ESC heterochromatin state by association and recruiting TRIM28 and SETDB1, and its loss leads to increased H3K4me3 and H3K27ac, and decreased H3K9me3 at local chromatin. Activation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes. Chimeric transcripts that are initiated within ERVs and spliced to genic exons are highly expressed in Pogz-/- ESCs. Our findings establish that POGZ is required for the maintenance of ESCs by repressing Dux and silencing ERVs, which may provide important insights into the disease pathology caused by POGZ dysfunction. HighlightsO_LIPOGZ depletion leads to activation of 2C genes C_LIO_LIPOGZ depletion leads to deregulation of ERVs C_LIO_LIPOGZ directly binds and represses Dux C_LIO_LIPOGZ associates with TRIM28/SETDB1 to maintain heterochromatin state to silence ERVs C_LIO_LIActivation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes C_LI

molecular biology↗

bioRxiv2022

Engineering a Single Extracellular Vesicle Protein and RNA Assay (siEVPRA) via In Situ Fluorescence Microscopy in a UV Micropatterned Array

The physical and molecular heterogeneity of extracellular vesicles (EVs) confounds bulk biomarker characterization, thus encouraging the development of novel assays capable of profiling EVs at a single-vesicle resolution. Here, we present a single EV (siEV) protein and RNA assay (siEVPRA) to simultaneously detect proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs) in siEVs. The siEVPRA consists of an array of microdomains embedded on a polyethylene glycol (PEG)-coated glass surface produced via UV photopatterning, functionalized with antibodies to target siEV subpopulations. Fluorescently labeled antibodies and RNA-targeting molecular beacons (MBs) were used to generate signals for proteins, mRNAs, and miRNAs on siEVs detected by total internal reflection fluorescence microscopy (TIRFM), outperforming the sensitivities of ELISA and PCR by three orders of magnitude. Using the siEVPRA, we analyzed EVs harvested from glioblastoma (GBM) cell lines and demonstrated vesicular heterogeneity in protein, mRNA, and miRNA expression through colocalization analyses, and validated the results by bulk RNA sequencing. We further demonstrated the clinical utility of the siEVPRA by detecting different mRNAs and miRNAs associated with GBM in patient samples. Together, these results indicate that the siEVPRA provides an effective platform to investigate the heterogeneity of proteins and RNAs in subpopulations of EVs.

bioengineering↗

bioRxiv2022

Binding Free Energies of Piezo1 Channel Agonists at Protein-Membrane Interface

Mechanosensitive Piezo channels convert mechanical stimuli into biological signals in vertebrates. Piezo1 chemical modulators are anticipated to yield many clinical benefits. To date, Yoda1 is the most potent and widely used Piezo1-selective agonist, yet how Yoda1 interacts with Piezo1 at the protein-membrane interface and stabilizes Piezo1s open state remains elusive. Here, using a previously identified putative Yoda1 binding site and three molecular dynamics (MD)-based methods, we computed the binding free energies of Yoda1 and its analogs in a Piezo1 cryo-EM closed state and an in silico open state. Our computed absolute binding free energy of Yoda1 in the closed state agrees well with the experimental Kd in which Piezo1 is expected to be in a closed state. More importantly, Yoda1 binds the open state better than the closed state, in agreement with its agonist effects. All three methods predicted that Dooku1, a Yoda1 analog, binds the closed state stronger than Yoda1, but binds the open state weaker than Yoda1. These results are consistent with the fact that Dooku1 antagonizes the effects of Yoda1 but lacks the ability to activate Piezo1. The relative binding free energies of seven Yoda1 analogs recapitulate key experimental structure-activity-relationships (SAR). Based on the state-dependent binding free energies, we were able to predict whether a molecule is an agonist or inhibitor and whether a chemical modification will lead to a change in affinity or efficacy. These mechanistic insights and computational workflow designed for transmembrane binders open an avenue to structural-based screening and design of novel Piezo1 agonists and inhibitors.

biophysics↗

bioRxiv2022

Protective human anti-poxvirus monoclonal antibodies are generated from rare memory B cells isolated by multicolor antigen tetramers

Smallpox, an epidemic disease caused by Orthopoxvirus variola, was eradicated worldwide through immunization. The immunization against smallpox was discontinued in 1980. However, incidences of monkeypox virus infection in humans have occurred sporadically, and there is also great fear that engineered forms of poxvirus could be used as biological weapons. Therefore, monoclonal antibodies against poxvirus are in urgent need for the detection and treatment of poxvirus infection. The vaccinia virus extracellular envelope protein A33 is a potential candidate for subunit vaccine. We used multi-fluorescence-labeled tetrameric A33 antigen to identify rare poxvirus specific memory B cells from PBMC of volunteers with vaccinia virus immunization more than 40 years ago. Despite extremely low frequencies of the poxvirus specific memory B cells, we successfully sorted A33 tetramer-labeled single memory B cells and reconstructed antibodies with single-cell RT-PCR of the B-cell receptor. Among the monoclonal antibodies, one clone H2 exhibited high specificity and affinity with A33. H2 efficiently inhibited viral infection and spread in cells. Passive immunotherapy of H2 in mice protected mice from lethal infection when administered either prophylactically or therapeutically. These results suggest the potential of the anti-A33 human antibody-based detection and therapeutics for poxvirus infection.

immunology↗

bioRxiv2022

Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice

Overweight and obesity are rapidly becoming the "new normal" in developed countries, which promotes a widespread negative impact on human health. Amongst recently developed obesity medications are the serotonin 2C receptor (5-HT2CR) agonist lorcaserin and glucagon-like peptide-1 receptor (GLP-1R) agonists, but the brain circuits employed by these medications to produce their therapeutic effects remain to be fully defined. 5-HT2CRs and GLP-1Rs are widely distributed in the brain, including in the key homeostatic region the nucleus of the solitary tract (NTS) where GLP-1 is produced by preproglucagon (PPGNTS) neurons. PPGNTS cells were profiled using histochemistry and single nucleus RNA sequencing (Nuc-Seq) of mouse brainstem. Transcriptomic analyses revealed 5-HT2CR expression was widespread in PPGNTS clusters. Demonstrating the functional significance of this co-expression, lorcaserin required PPGNTS to reduce food intake. Analysis of second order neurons revealed that local GLP1-R neurons within the NTS are necessary for 5-HT2CRNTS food intake suppression. In contrast, GLP-1RNTS were not required for GLP-1R agonist liraglutide and exendin-4s short term feeding reduction, suggesting scope for lorcaserin and GLP1-R agonist combination therapy. In support of this, lorcaserin+liraglutide and lorcaserin+exendin-4 produced greater reductions in food intake when administered in combination as compared to monotherapies. These data provide insight into the therapeutic mechanisms of lorcaserin and identify a combination strategy to improve the therapeutic profile of lorcaserin and GLP1-R agonists.

neuroscience↗

bioRxiv2022

-Labeled PARP-1 PET Imaging of PSMA Targeted Alpha Particle Radiotherapy Response

MotivationThe growing interest and clinical translation of alpha particle () therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide -treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways - such as those induced by irradiation. Materials and MethodsHere, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and analyzed, along with and correlative autoradiography and histology acquired. Results[18F]-PARPZ was able to distinguish treated from control (saline) xenografts by uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response. ConclusionsTogether, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the -therapy space.

cancer biology↗