Biology subjects

Cunningham, D.

Publications and source records attributed to Cunningham, D..

9 recordsLinked to original sources

bioRxiv2025

The effects of morning priming exercise on afternoon physical and cognitive performance in male rugby union players

ObjectiveTo assess the effect of morning resistance exercise on afternoon physical and cognitive performance in male rugby union players. MethodsOn two occasions (randomised, crossover design), 25 male rugby union players completed morning physical (countermovement jump, 40 m linear sprint) and cognitive (rapid visual information processing; spatial working memory; paired associates of learning) assessments. Control (passive rest) or intervention (barbell back squat, 3 x 3 repetitions at 85% of one repetition maximum and barbell squat jump, 5 x 3 repetitions at 40% one repetition maximum) trials were implemented 5.5 h before afternoon assessments. ResultsDifferences between morning and afternoon assessments were found in sprinting performance following intervention for 30 m fly (-0.08 {+/-} 0.13 s, P = 0.001, ES: -0.75) and 40 m (-0.12 {+/-} 0.17 s, P = 0.004, ES: -0.62) relative to control (0.03 {+/-} 0.07 s, 0.01 {+/-} 0.09 s, 30 m fly and 40 m, respectively). Afternoon countermovement jump flight time improved following intervention compared to control (2% vs. 0%, p = 0.012). Delta analysis discovered significant differences from morning to afternoon in intervention (0.385 ms {+/-} 0.053) but not control (0.405 ms {+/-} 0.057). No changes were found for cognitive assessments (P > 0.05). ConclusionMorning lower body resistance exercise, incorporating a combination of high intensity and ballistic exercises, was an effective morning strategy to improve afternoon markers of physical but not cognitive performance in male rugby union players.

physiology↗

bioRxiv2024

Differential responses and recovery dynamics of HSPC populations following Plasmodium chabaudi infection.

Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug-resistance. It is therefore paramount that we better understand how the hosts organism responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affecting HSPCs, however this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remains understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess HSPCs acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.

developmental biology↗

bioRxiv2024

Distinct Motor Map Characteristics for Biceps and Triceps Muscles in Persons with Chronic Tetraplegia: Implications for Arm Function

Following spinal cord injury (SCI), intact neural resources undergo widespread reorganization within the brain. Animal models reveal motor cortical representations devoted to spared muscles above injury expand at the expense of territories occupied by weaker muscles. In this study, we investigated whether motor representations are similarly reorganized between a relatively spared biceps muscle and a weakened triceps muscle in persons with chronic tetraplegia following traumatic cervical SCI in association with upper limb motor function. Twenty-four adults with cervical SCI and 15 able-bodied participants underwent motor mapping using transcranial magnetic stimulation. We determined following map characteristics: area, amplitude (maximal motor evoked potential and volume), and center of gravity. Maximal voluntary contraction (MVC) and motor function (Capabilities of the Upper Extremity Test or CUE-T) were also assessed. Findings reveal that participants with SCI had hyper-excitable biceps maps than triceps, and hyper-excitable biceps maps also compared to biceps maps in able-bodied participants. Higher amplitude of biceps and triceps maps was associated with better motor function (higher CUE-T) and more distal injury (i.e., more spared segments) in persons with SCI. Amplitudes of biceps but not the triceps maps were associated with higher muscle MVCs. In conclusion, over-excitable biceps than triceps map in SCI may represent deafferentation plasticity. For the first time, we demonstrate how map reorganization of spared and weaker muscles in persons with chronic cervical SCI is associated with upper limb motor status. Use-dependent mechanisms may shift neural balance in favor of spared muscles, supporting potential use as response biomarkers in rehabilitation studies. New & NoteworthyOur study reports evidence in humans with cervical SCI that motor representation for the relatively spared muscle becomes hyper-excitable compared to that for the weaker muscle to the extent that hyper-excitability is even higher compared to biceps maps in uninjured individuals. Use-dependent mechanisms likely favor such heightened excitability of spared maps. For the first time, we demonstrate clinical relevance of map excitability in humans with SCI, supporting potential use as a biomarker of recovery.

neuroscience↗

bioRxiv2023

Context-specific GITR agonism potentiates anti-PD-L1 and CD40-based immuno- chemotherapy combination in heterogeneous pancreatic tumors

Immunotherapy has shown limited success in pancreatic adenocarcinoma (PDAC) patients. To improve clinical management of cancer, it is crucial to identify alternative immunostimulatory targets associated with mechanisms of tumor evolution to facilitate the development of novel combination immunotherapies. Here we categorized PDACs and other cancers (n>7,500) into subgroups based on immunostimulatory glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related ligand (GITRL) and receptor (GITR) expression: GITRLhigh+GITRhigh and GITRLhigh/low+GITRlow. We characterized immune evasion mechanisms using immunotherapy preclinical trials in four representative immunocompetent mouse models, finding that the GITR agonist, DTA-1 significantly improved responses in GITRLhigh(+GITRhigh) tumors (n=2). Further characterization revealed increased activation of CD8+ T-cells (but not T-regulatory; Tregs cells) and enhanced interferon-{gamma}, immunoproteosome, antigen presentation, and T-cell receptor (TCR) gene expression in DTA-1 responders. In vivo clonal tracking using DNA barcoding showed that GITR agonist therapy significantly reduced tumor burden by targeting expansion of heterogeneous PDAC clones and not clone-initiating cells (representing potential resistance). However, emerging GITRLhigh+GITRhigh epithelial-like oligoclones from the responder model escaped immune surveillance to GITR agonist treatment via increased PD-L1, offering a combined anti-PD-L1, CD40 agonist and DTA-1 immunotherapy regimens (with/without chemotherapy) that further improved responses by decreasing PD-L1+ myeloid cells. Conversely, mesenchymal-enriched GITRLlow models exhibited primary (intrinsic) resistance to GITR agonist treatment due to reduced T-cells and increased myeloid and/or PD-L1+ non-immune cells. These results provide pre-clinical context for GITR+PD-L1+CD40- based personalized immuno-chemotherapy combinations for PDAC.

cancer biology↗

bioRxiv2022

Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/{beta}Catenin, mitogen-activated protein kinase and TGF{beta} receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.

cancer biology↗

bioRxiv2020

Mutational processes impact the evolution of anti-EGFR antibody resistance in colorectal cancer

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRC) but acquired resistance invariably evolves. Which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis, a transient cetuximab-induced increase in mutagenesis, contributes in patients is unknown. We investigated this in exome sequencing data of 42 baseline and progression biopsies from cetuximab treated CRCs. Mutation loads did not increase from baseline to progression. Evidence for a contribution of cetuximab-induced mutagenesis was limited. However, the mutational Signature 17 was a key contributer of specific KRAS/NRAS and EGFR driver mutations that are common at acquired resistance. Signature 17 activity before treatment predicted shorter progression free survival. This demonstrates the utility of mutational signatures to predict cancer drug resistance evolution. SIGNIFICANCEDrug resistance evolution occurs ubiquitously in solid tumours during treatment with targeted drugs. Biomarkers that can be assessed prior to treatment to predict the time to resistance evolution and the genetic resistance mechanisms that will evolve have not been described. We identified the mutational Signature 17 as the first candidate biomarker that predicts shorter time to progression and several specific KRAS/NRAS and EGFR mutations that will likely evolve in CRCs during cetuximab treatment. Understanding the mutational mechanism underlying Signature 17 may open opportunities to delay resistance acquisition. The potential of mutational signatures to predict resistance to a broader range of drugs in other tumor types should be assessed.

cancer biology↗

bioRxiv2018

Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

cancer biology↗

bioRxiv2017

Ultra-sensitive mutation detection and genome-wide DNA copy number reconstruction by error corrected circulating tumour DNA sequencing

Minimally invasive circulating free DNA (cfDNA) analysis can portray cancer genome landscapes but highly sensitive and specific genetic approaches are necessary to accurately detect mutations with often low variant frequencies. We developed a targeted cfDNA sequencing technology using novel off-the-shelf molecular barcodes for error correction, in combination with custom solution hybrid capture enrichment. Modelling based on cfDNA yields from 58 patients shows that our assay, which requires 25ng of cfDNA input, should be applicable to >95% of patients with metastatic colorectal cancer. Sequencing of a 163.3 kb target region including 32 genes detected 100% of single nucleotide variants with 0.15% variant frequency in cfDNA spike-in experiments. Molecular barcode error correction reduced false positive mutation calls by 98.6%. In a series of 28 patients with metastatic colorectal cancers, 80 out of 91 (88%) mutations previously detected by tumour tissue sequencing were called in the cfDNA. Call rates were similar for single nucleotide variants and small insertions/deletions. Mutations only called in cfDNA but not detectable in matched tumour tissue included, among others, a subclonal resistance driver mutation to anti-EGFR antibodies in the KRAS gene, multiple activating PIK3CA mutations in each of two patients (indicative of parallel evolution), and TP53 mutations originating from clonal haematopoiesis. Furthermore, we demonstrate that cfDNA off-target read analysis allows the reconstruction of genome wide copy number aberration profiles from 71% of these 28 cases. This error-corrected ultra-deep cfDNA sequencing assay with a target region that can be readily customized enables broad insights into cancer genomes and evolution.

genomics↗

bioRxiv2017

A Low-Cost Multiplex Biomarker Assay Stratifies Colorectal Cancer Patient Samples into Clinically-Relevant Subtypes

Previously, we classified colorectal cancers (CRCs) into five CRCA subtypes with different prognoses and potential treatment responses, using a 786-gene signature. We merged our subtypes and those described by five other groups into four consensus molecular subtypes (CMS) that are similar to CRCA subtypes. Here we demonstrate the analytical development and application of a custom NanoString platform-based biomarker assay to stratify CRC into subtypes. To reduce costs, we switched from the standard protocol to a custom modified protocol (NanoCRCA) with a high Pearson correlation coefficient (>0.88) between protocols. Technical replicates were highly correlated (>0.96). The assay included a reduced robust 38-gene panel from the 786-gene signature that was selected using an in-laboratory developed computational pipeline of class prediction methods. We applied our NanoCRCA assay to untreated CRCs including fresh-frozen and formalin-fixed paraffin-embedded (FFPE) samples (n=81) with matched microarray or RNA-Seq profiles. We further compared the assay results with CMS classification, different platforms (microarrays/RNA-Seq) and gene-set classifiers (38 and 786 genes). NanoCRCA classified fresh-frozen samples (n=39; not including those showing a mixture of subtypes) into all five CRCA subtypes with overall high concordance across platforms (89.7%) and with CMS subtypes (84.6%), independent of tumour cellularity. This analytical validation of the assay shows the association of subtypes with their known molecular, mutational and clinical characteristics. Overall, our modified NanoCRCA assay with further clinical assessment may facilitate prospective validation of CRC subtypes in clinical trials and beyond.\n\nNovelty and ImpactWe previously identified five gene expression-based CRC subtypes with prognostic and potential predictive differences using a 786-gene signature and microarray platform. Subtype-driven clinical trials require a validated assay suitable for routine clinical use. This study demonstrates, for the first time, how molecular CRCA subtype can be detected using NanoString Technology-based biomarker assay (NanoCRCA) suitable for clinical validation. NanoCRCA is suitable for analysing FFPE samples, and this assay may facilitate patient stratification within clinical trials.

cancer biology↗