Biology subjects

Buckley, A.

Publications and source records attributed to Buckley, A..

16 recordsLinked to original sources

bioRxiv2026

Focal radiotherapy improves CAR T cell therapy targeting prostate cancer

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as prostate cancer due to the immunosuppressive tumor microenvironment (TME). Combining CAR T cells with existing therapies that remodel the TME and promote endogenous immune responses, such as radiation therapy and chemotherapies, may strengthen antitumor responses. Here, we assessed the potency of combining focal radiotherapy (RT), cyclophosphamide (Cy) preconditioning, and prostate stem cell antigen (PSCA)-CAR T cells against syngeneic prostate cancer models. Focal RT alone increased T cell and dendritic cell infiltration and activation in the irradiated tumor. Furthermore, the combination of all three therapies was critical for enhanced antitumor responses and survival across multiple subcutaneous, bone-metastatic, and multifocal disease models. This combination, in the irradiated TME and tumor-draining lymph nodes (tdLN), led to greater antigen presentation by myeloid cells and endogenous T cell activation and cytotoxicity. Our study demonstrates the potency of combining focal RT with PSCA-CAR T cells, significantly improving therapeutic responses in the irradiated tumor and contributing to a more robust systemic immune response against metastatic burden in prostate cancer.

Cancer Biology↗

bioRxiv2026

Temporal transcriptomic and microbial changes in American bison during experimental SARS-CoV-2 challenge

SARS-CoV-2 continues to pose a threat to humans as well as domestic and wild animals. The variability in severity of clinical signs, the zoonotic potential, and the host-specific response to infection contribute to the persistence of circulation of disease. In wildlife species white-tailed deer have been shown to be more permissive to infection than bovids. However, amongst bovids, American bison have shown a greater susceptibility than cattle. In this study we investigate the transcriptomic response to experimental SARS-CoV-2 infection in bison over time. Substantial numbers of differentially expressed genes were identified between pre- and 2, 5, 7, 14, and 21 days post-infection. KEGG and GO term analysis identified associations with immune response, inflammatory response, and viral infection including COVID-19. IPA analysis of the SARS coronavirus pathway highlighted differences in signaling at days 2 versus 21 post-infection. We additionally examined changes in the nasal microbiome of bison over the course of experimental infection, which suggested an increase in opportunity for secondary infection causing pathogens such as Mannheimia. Collectively this study presents a profile of bison transcriptomic response to SARS-CoV-2 infection and continues to expand our understanding of variation in host response. SummarySARS-CoV-2 remains a threat to humans, domestic animals, and wildlife. Among bovids, American bison show greater susceptibility than cattle. We characterized the bison transcriptomic response to experimental infection across six timepoints, identifying extensive differential gene expression associated with immune, inflammatory, and antiviral pathways. KEGG, GO, and IPA analyses revealed activation of coronavirus-related signaling and shifts between days 2 and 21. We additionally examined changes in the nasal microbiome of bison over the course of experimental infection, which suggested an increase in opportunity for secondary infection causing pathogens such as Mannheimia. The results refine understanding of host responses to SARS-CoV-2 in bison.

immunology↗

bioRxiv2026

Protein-guided RNA barcoding links transcriptomes to synaptic architecture

Mammalian brain function relies on the precise synaptic architecture of diverse cell types, yet scalable methods for linking a neurons transcriptomic profile to its neuroanatomy remain limited. We present Synapse-seq, an in vivo strategy in which cell-identifying barcoded mRNAs are routed to subcellular compartments via targeting proteins and detected by single-cell and spatial genomics. Using AAV delivery for minimal perturbation of gene expression, we directed barcodes to presynaptic terminals (via synaptophysin) in four distinct circuits, or to postsynaptic sites (via nanobodies to endogenous PSD95) of hippocampal excitatory neurons. In the mouse primary visual cortex, presynaptic Synapse-seq recovered known long-range projections and discovered cortical layer subtypes with distinct thalamic innervation. In the anterior cortex, we elucidated simple topographic rules of corticostriatal innervation: intratelencephalic neurons followed a continuous depth-to-target gradient, while extratelencephalic neurons exhibited striatal collaterals that spatially correlated with medullary innervation. Finally, postsynaptic barcoding of excitatory neurons revealed cell type-specific variation in dendritic architectures across and within hippocampal subfields. These data establish Synapse-seq as a versatile, genomics-based approach for the integrated definition of molecular identity and synaptic organization across mammalian brains.

neuroscience↗

bioRxiv2025

The Infraslow Fluctuation of Sigma Power During Sleep in Young Individuals with Schizophrenia

A reduction in sleep spindles, a major electrophysiological characteristic of Non-Rapid Eye Movement sleep, has been suggested as a potential biomarker of schizophrenia. While research has primarily focused on the spindle quantity, recent studies have begun to explore their temporal dynamics throughout the night. In healthy individuals, sleep spindles fluctuate on an infraslow [~]50-second timescale, alternating between phases of high and low spindle activity. This fluctuation is referred to as the infraslow fluctuation of sigma power (ISFS), which is modulated by noradrenergic activity from the locus coeruleus and linked to the organization of arousal and memory reactivation processes during sleep. Given the known deficit in sleep spindles, dysregulation of noradrenergic activity, and impairments in sleep maintenance and memory in schizophrenia, this study investigates the ISFS in sleep electroencephalography data from individuals with either Childhood-Onset Schizophrenia (COS; N = 17) or Early-Onset Schizophrenia (EOS; N = 11), aged 9 to 21 years, alongside age- and sex-matched healthy controls (N = 56). The presence and strength of the ISFS were reduced in both COS and EOS groups compared to controls, particularly in central-parietal electrodes. No significant differences in these features of the ISFS were found between the two clinical groups, despite group differences in sleep spindle density and clinical characteristics. These findings suggest that the ISFS is observable but reduced in young patients with schizophrenia and support the notion that the timing of sleep spindles may inform pathomechanistic models of the disorder, as well as future diagnostic approaches and interventions.

neuroscience↗

bioRxiv2024

Leveraging clinical sleep data across multiple pediatric cohorts for insights into neurodevelopment: the Retrospective Analysis of Sleep in Pediatric (RASP) cohorts study

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. A better understanding of sleep in NDDs compared to typically developing children could therefore define mechanisms underlying abnormal development in NDDs and provide avenues for the development of therapeutic interventions to improve sleep quality and developmental outcomes. Here, we introduce and characterize a collection of 1527 pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance compared to a stager trained on adults. Using consistent staging across cohorts, we derived a panel of EEG micro-architectural features. This unbiased approach replicated broad trajectories previously described in typically developing sleep architecture. Further, we found sleep architecture disruptions in children with Downs Syndrome (DS) that were consistent across independent cohorts. Finally, we built and evaluated a model to predict age from sleep EEG metrics, which recapitulated our previous findings of younger predicted brain age in children with DS. Altogether, by creating a resource pooled from existing clinical data we expanded the available datasets and computational resources to study sleep in pediatric populations, specifically towards a better understanding of sleep in NDDs. This Retrospective Analysis of Sleep in Pediatric (RASP) cohorts dataset, including staging annotation derived from our automated stager, will be deposited at https://sleepdata.org. Statement of significanceWe introduce the RASP cohorts, a collection of 1527 clinical pediatric overnight polysomnographies that includes typically developing and neurodevelopmental disorder cases. As a first step towards addressing the analytic bottleneck inherent in manual sleep staging, we developed and validated a pediatric-specific sleep stager. Leveraging the retrospective RASP cohorts dataset, we redemonstrated known developmental trajectories in sleep architecture. To summarize changes in brain function reflected in sleep, we developed a model to predict brain age from sleep measures. We recapitulate younger predicted age in RASP Downs Syndrome cases. This work not only enhances our understanding of sleep disturbances in NDDs, but also provides a valuable resource for future research and underscores the utility of existing clinical polysomnography studies.

neuroscience↗

bioRxiv2024

Experimental reproduction of viral replication and disease in dairy calves and lactating cows inoculated with highly pathogenic avian influenza H5N1 clade 2.3.4.4b

Highly pathogenic avian influenza (HPAI) H5N1 of the hemagglutinin clade 2.3.4.4b was detected in the United States in late 2021 and continues to circulate in all four North American flyways to date. In addition to impacting poultry, these HPAI viruses caused mortality events in wild bird species and wild mammals. Transmission in multiple host species raises the concern for mammalian adaptation. On March 25, 2024, HPAI H5N1 clade 2.3.4.4b was confirmed in a dairy cow in Texas in response to a multi-state investigation into milk production losses. Over one hundred positive herds were rapidly identified in Texas and eleven other U.S. states. The case description included reduced feed intake and rumen motility in lactating cows, decreased milk production, and thick yellow milk. The diagnostic investigation revealed detections of viral RNA in milk and mammary tissue with alveolar epithelial degeneration and necrosis, and positive immunoreactivity of glandular epithelium by immunohistochemistry. A single transmission event, likely from avian species to dairy cattle, followed by limited local transmission preceded the onward lateral transmission of H5N1 clade 2.3.4.4b genotype B3.13. We sought to experimentally reproduce infection with genotype B3.13 in Holstein yearling heifers and lactating cows. The heifers were inoculated by an aerosol respiratory route and the cows by an intramammary route. Clinical disease was mild in the heifers, but infection was confirmed by virus detection, lesions, and seroconversion. Clinical disease in lactating cows included decreased rumen motility, changes to milk appearance, and production losses consistent with field reports of viral mastitis. Infection was confirmed by high levels of viral RNA detected in milk, virus isolation, lesions in mammary tissue, and seroconversion. This study provides the foundation to investigate additional routes of infection, transmission, and intervention strategies.

microbiology↗

bioRxiv2024

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

cancer biology↗

bioRxiv2023

Antimicrobial efficacy of in-situ plasma-generated ozone against Pseudomonas aeruginosa biofilms in drains and water-submerged surfaces

AimsTo demonstrate a novel method of gaseous disinfection that can eradicate biofilms inhabiting elusive regions of plumbing systems. Methods & ResultsHighly biocidal ozone is generated in-situ using the ambient air inside a model sink and drain, via portable plasma discharge, with the plasma device sealing the treated area, ensuring no ozone escape to the external environment. Subsequent bacterial recovery illustrates an approximate bioburden reduction of 5log10 for biofilms suspended in the drain, and 6log10 for biofilms placed in the sink. ConclusionsPlasma-generated ozone is a safe and effective method for controlling bioburden in periodically wetted, otherwise inaccessible pipework and drains, both above and below the water line. Significance and Impact of StudyThe ozone generation system described has potential for controlling healthcare associated infections (HAIs) and infections linked to closed environments, such as cruise ships, from bacteria arising from waste water systems by aerosolization or splash-back. The method has additional benefits provided by an absence of toxic residues after application, reducing risks to users and the waste water system. Cost effectiveness is high, requiring minimal energy input from the electrical supply and only ambient air (no additional feedstock gas is necessary) to generate ozone.

microbiology↗

bioRxiv2023

Spindle Chirp and other Sleep Oscillatory Features in Young Children with Autism

ObjectivesTo determine whether spindle chirp and other sleep oscillatory features differ in young children with and without autism. MethodsAutomated processing software was used to re-assess an extant set of polysomnograms representing 121 children (91 with autism [ASD], 30 typically-developing [TD]), with an age range of 1.35-8.23 years. Spindle metrics, including chirp, and slow oscillation (SO) characteristics were compared between groups. SO and fast and slow spindle (FS, SS) interactions were also investigated. Secondary analyses were performed assessing behavioural data associations, as well as exploratory cohort comparisons to children with non-autism developmental delay (DD). ResultsPosterior FS and SS chirp was significantly more negative in ASD than TD. Both groups had comparable intra-spindle frequency range and variance. Frontal and central SO amplitude were decreased in ASD. In contrast to previous manual findings, no differences were detected in other spindle or SO metrics. The ASD group displayed a higher parietal coupling angle. No differences were observed in phase-frequency coupling. The DD group demonstrated lower FS chirp and higher coupling angle than TD. Parietal SS chirp was positively associated with full developmental quotient. ConclusionsFor the first time spindle chirp was investigated in autism and was found to be significantly more negative than in TD in this large cohort of young children. This finding strengthens previous reports of spindle and SO abnormalities in ASD. Further investigation of spindle chirp in healthy and clinical populations across development will help elucidate the significance of this difference and better understand this novel metric.

neuroscience↗

bioRxiv2022

MiGut: a scalable in vitro platform for simulating the human gut microbiome - development, validation, and simulation of antibiotic induced dysbiosis

In vitro models of the human colon have been used extensively in developing understanding of the human gut microbiome and how internal and external factors affect the residing bacterial populations. Such models can be highly predictive of in vivo effects of antibiotics, and indeed more so than animal models. The complexity required by current in vitro models to closely mimic the physiology of the colon poses practical limits on their scalability. MiGut allows considerable expansion of model runs, increasing the capacity to test reproducibility or parameters under investigation. The MiGut platform has been assessed against a well-studied triple-stage chemostat model in a demanding nine-week study, with exposure to multiple antibiotics inducing a state of dysbiosis in the microbiome. A good correlation is found, both between individual MiGut models and against the triple-stage chemostat. Together with high-throughput molecular techniques for sample analysis, it is now conceivable that tens of in vitro models could be run simultaneously, allowing complex microbiome-xenobiotic interactions to be explored in far greater detail. MiGut is a unique platform whereby multiple colonic models can be run simultaneously with minimal added resource and complexity to support our understanding of the cause-effect relationships that govern the gut microbiome. This model system expands the capacity to generate clinically relevant data that can optimize interventions which target the gut microbiome directly or indirectly.

microbiology↗

bioRxiv2022

Cohesin erases genomic-proximity biases to drive stochastic Protocadherin expression for proper neural wiring

Clustered Protocadherin (Pcdh) proteins act as cell-surface recognition barcodes for neural circuit formation. Neurites expressing the same barcode repel each other, but this mechanism is deployed in two different ways. For instance, convergence of olfactory sensory neuron (OSN) projections requires stochastic expression of distinct Pcdh isoforms in individual cells, while tiling of neural arbors of serotonergic neurons (5-HTs) requires expression of the same isoform, Pcdhc2. Despite their essential role, however, the molecular mechanisms of cell-type specific Pcdh barcoding remain a mystery. Here, we uncover a new role of cohesin: that of regulating distance-independent enhancer-promoter interactions to enable random Pcdh isoform choice via DNA loop extrusion in OSNs. Remarkably, this step mediates DNA demethylation of Pcdh promoters and their CTCF binding sites, thus directing CTCF to the chosen promoter. In contrast, the uniform pattern of Pcdh expression in 5-HTs is achieved through conventional cohesin-independent, distance-dependent enhancer/promoter interactions, that favor choice of the nearest isoform. Thus, cell-type specific cohesin deployment converts a distance-dependent and deterministic regulatory logic into a distance-independent and stochastic one. We propose that this mechanism provides an elegant strategy to achieve distinct patterns of Pcdh expression that generate wiring instructions to meet the connectivity requirements of different neural classes.

genomics↗

bioRxiv2021

From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in white-tailed deer

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus), the most widely distributed cervid species in the Americas, were shown to be highly susceptible to SARS-CoV-2 in challenge studies and reported natural infection rates approaching 40% in free-ranging WTD in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2, WTD fawns shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent a with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in adult WTD. Infectious virus was recovered from respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple sites of virus replication. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field. Author summaryThe high susceptibility of white-tailed deer (WTD) to SARS-CoV-2, their ability to transmit the virus to other deer, and the recent findings suggesting widespread SARS-CoV-2 infection in wild WTD populations in the U.S. underscore the need for a better understanding of the infection and transmission dynamics of SARS-CoV-2 in this potential reservoir species. Here we investigated the transmission dynamics of SARS-CoV-2 over time and defined the major sites of virus replication during the acute phase of infection. Additionally, we assessed the evolution of the virus as it replicated and transmitted between animals. The work provides important information on the infection dynamics of SARS-CoV-2 in WTD, an animal species that - if confirmed as a new reservoir of infection - may provide many opportunities for exposure and potential zoonotic transmission of the virus back to humans.

microbiology↗

bioRxiv2021

Pilot study: Trehalose-induced remodelling of the human microbiota affects Clostridioides difficile infection outcome in an in vitro colonic model

Within the human intestinal tract, dietary, microbial- and host-derived compounds are used as signals by many pathogenic organisms, including Clostridioides difficile. Trehalose has been reported to enhance virulence of certain C. difficile ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from C. difficile infection (CDI). Here, we make preliminary observations to how to trehalose supplementation affects the microbiota in an in vitro model and show that trehalose can reduce the outgrowth of C. difficile, preventing simulated CDI. Three clinically reflective human gut models simulated the effects of sugar (trehalose or glucose) or saline ingestion on the microbiota. Models were instilled with sugar or saline and further exposed to C. difficile spores. The recovery of the microbiota following antibiotic treatment and CDI induction was monitored in each model. The human microbiota remodeled to utilise the bioavailable trehalose. Clindamycin induction caused simulated CDI in models supplemented with either glucose or saline; however, trehalose supplementation did not result in CDI, although limited spore germination did occur. The absence of CDI in trehalose model was associated with enhanced abundances of Finegoldia, Faecalibacterium and Oscillospira, and reduced abundances of Klebsiella and Clostridium spp., compared with the other models. Functional analysis of the microbiota in the trehalose model revealed differences in the metabolic pathways, such as amino acid metabolism, which could be attributed to prevention of CDI. Our data show that trehalose supplementation remodelled the microbiota, which prevented simulated CDI, potentially due to enhanced recovery of nutritionally competitive microbiota against C. difficile.

microbiology↗

bioRxiv2020

The Guaymas Basin Subseafloor Sedimentary Archaeome Reflects Complex Environmental Histories

We explore archaeal distribution and environmental niche differentiation in sedimentary subseafloor habitats of Guaymas Basin and the adjacent Sonora Margin, located in the Gulf of California, Mexico. Specifically, we survey diverse subseafloor habitats on the Guaymas Basin flanking regions that are extending from the spreading center, termed here "off-axis" sites. Sampling locations include (i) control sediments without hydrothermal or seep influence, (ii) Sonora Margin sediments underlying oxygen minimum zone water, (iii) compacted, highly reduced sediments from a pressure ridge with numerous seeps at the base of the Sonora Margin, and (iv) sediments impacted by hydrothermal circulation at the off-axis Ringvent site. Generally, archaeal 16S rRNA gene datasets are largely comprised of Bathyarchaeal lineages, members of the Hadesarchaea, MBG-D, TMEG, and ANME-1 groups. The most frequently observed 25 OTUs belong to members of these lineages, and correspond to approx. 40 to 80% of the sequence dataset in each sediment sample. Differential distribution patterns of these archaeal groups in downcore sediments uniquely characterize each major sedimentary environment. Variations in archaeal community composition reflect locally specific environmental challenges throughout the greater Guaymas Basin area. Background sediments are divided into surface and subsurface niches, reflecting increased selection of the archaeal community downcore. In sum, the environmental setting and history of a particular site, not isolated biogeochemical properties out of context, control the subseafloor archaeal communities in Guaymas Basin and Sonora Margin sediments.

ecology↗

bioRxiv2019

Lower limb chronic edema management program: Perspectives of disengaged patients on challenges, enablers and barriers to program attendance and adherence

BackgroundChronic edema (CO) is a progressive, physically disfiguring and currently incurable condition. A multifaceted program has been recommended to manage the swelling. However, there is little evidence investigating patients perspectives following the program, particularly for those who have poor adherence or are disengaged.\n\nAimTo investigate the perceived challenges faced by disengaged participants with lower limb CO by identifying their enablers and barriers to participating in a Physiotherapy CO program.\n\nMethodAn exploratory qualitative approach was used. A purposive sampling strategy was adopted to recruit participants. Those with more than three months swelling and who had low adherence or attendance (disengaged) to the CO program were invited to participate. Semi-structured interviews with six participants from a CO clinic in a tertiary hospital were conducted. Data was thematically analyzed and findings in terms of enablers and barriers were subsequently reflected in the light of a theoretical framework.\n\nResultsAll six participants were morbidly obese (BMI 47 {+/-} 4 kg/m2) with multiple chronic comorbidities. Enablers and barriers detected included physical, psychological and social factors that interplay to present multidimensional challenges that influence the participants adjustment to managing their CO. For the disengaged participants in this study, their under-managed lower limb CO was a progression towards being housebound and having a gradually increasing level of disability.\n\nConclusionChronic edema, if left unmanaged, can have a profound debilitating impact on the individual permanently. Understanding the challenges faced by patients with lower limb CO has implications for developing a more patient-centered multidisciplinary approach to clinical practice and suggests the need for further research.

scientific communication and education↗

bioRxiv2018

1,4-dihydroxy Quininib Attenuates Growth of Colorectal Cancer Cells and Xenografts and Regulates the TIE-2 Signaling Pathway in Patient Tumours

Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2 in. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.

cancer biology↗