Biology subjects

Leo, S.

Publications and source records attributed to Leo, S..

12 recordsLinked to original sources

bioRxiv2026

Novel retinoic acid receptor-related orphan receptor gamma inverse agonist enhances checkpoint blockade in hepatocellular carcinoma: a preclinical mouse study

Background and Aims: Neutrophil-associated inflammation is associated with poor outcomes in hepatocellular carcinoma (HCC), but tumour-intrinsic regulators of neutrophil recruitment and checkpoint response remain unclear. We evaluated whether inhibiting retinoic acid receptor-related orphan receptor gamma (RORgamma) alters neutrophil recruitment, programmed death-ligand 1 (PD-L1) expression, and response to PD-L1 blockade. Approach and Results: Survival associations were analysed in The Cancer Genome Atlas HCC cohort. Neutrophil migration toward HCC cells and PD-L1 expression were assessed after RORC silencing or TF-S10 treatment. Immunocompetent mice bearing orthotopic Hep-55.1c tumours received vehicle, TF-S10, anti-PD-L1, or combination treatment. Higher S100A9 and CXCL8 expression was associated with shorter survival (P = 0.000459 and P = 0.0004413, respectively), and tumour-bearing mice had higher neutrophil-to-lymphocyte ratios (P < 0.0001). RORgamma; targeting reduced neutrophil migration and intratumoural Ly6G; infiltration while increasing tumour-cell PD-L1 expression in vitro. Combination treatment reduced endpoint liver tumour volume versus anti-PD-L1 monotherapy (P < 0.01). Half of combination-treated mice had tumour volumes less than or equal to 0.10 cm^3 and none exceeded 1.00 cm^3, compared with 62% of controls exceeding 1.00 cm^3. Histologically, 85% of combination-treated mice had less than 10% liver tumour involvement, versus no controls. Combination treatment also reduced tumour-associated neutrophil populations and peripheral neutrophil-to-lymphocyte ratios. All active treatments reduced pulmonary metastatic burden versus controls, without significant differences among treatment groups; 53% of combination-treated mice had no detectable lung metastases. Conclusions: RORgamma inhibition reduces neutrophil recruitment and increases tumour-cell PD-L1 expression. Combined RORgamma inhibition and PD-L1 blockade improves hepatic tumour control in preclinical HCC and warrants further investigation.

cancer biology↗

bioRxiv2026

RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression

Systemic inflammation is associated with poor outcomes in gastroesophageal adenocarcinoma (GEA), but how it contributes to disease progression remains unclear. We investigated retinoic acid receptor-related orphan receptor gamma (ROR{gamma}) as a regulator of tumour-conditioned myeloid responses. In treatment-naive GEA patients, elevated circulating neutrophil-to-lymphocyte ratio (cNLR) tracked with circulating ROR{gamma} positive neutrophils and tumoural spatial organization of ROR{gamma} positive myeloid cells, rather than neutrophil abundance. In syngeneic tumour models, pharmacologic ROR{gamma} inverse agonism altered marrow progenitor composition before tumour-growth divergence and remodeled myeloid organization across bone marrow, tumour and lung despite no endpoint change in circulating neutrophil proportions, which did not capture the earlier marrow response or subsequent tumour trajectory. ROR{gamma} perturbation enhanced longitudinal tumour control with PD-L1 blockade, whereas effects on metastatic establishment depended on tumour conditioning and treatment timing. These findings identify ROR{gamma} associated myeloid programming as a therapeutically tractable, context-dependent regulator linking systemic inflammation, hematopoiesis, tissue immune organization, and cancer progression.

cancer biology↗

bioRxiv2026

A Measurable Systemic Immune Phenotype Links Circulating Myeloid Dysfunction to Tumour Spatial Organization in Gastroesophageal Adenocarcinoma

Background: Both static and longitudinal measures of circulating neutrophil-to-lymphocyte ratio (cNLR) are prognostic markers across solid malignancies, including gastroesophageal adenocarcinoma (GEA). Despite this consistency, cNLR remains poorly integrated into clinical decision-making and is generally regarded as a nonspecific inflammatory or disease-burden signal rather than a defined biological state. Analysis of a large, prospectively assembled GEA cohort showed that cNLR was only weakly associated with tumour burden or pathological response, yet both baseline and postoperative cNLR independently predicted outcome. Methods: These observations prompted a retrospective biological investigation of what host biology cNLR captures. Using available clinically linked biospecimens, we performed multiscale analyses across complementary patient subsets encompassing peripheral-blood immune function and soluble signalling, tumour single-cell transcriptional programmes, and spatial myeloid organization within tissue. Results: High baseline cNLR was associated with reduced circulating cytotoxic and immune-trafficking mediators, elevated angiogenesis-associated factors, neutrophil-mediated suppression of lymphocyte proliferation, impaired tumour-cell killing, and enhanced spontaneous neutrophil extracellular trap formation. Single-cell profiling identified coordinated transcriptional differences across tumour compartments, including innate, cytokine and myeloid programmes. Spatial profiling showed that myeloid abundance and organization varied across anatomical compartments; greater tumour-periphery PDL1 positive myeloid clustering was associated with inferior recurrence-free survival. Baseline cNLR showed little relationship with static myeloid abundance, whereas pretreatment cNLR dynamics were associated with altered cross-compartment spatial relationships between CD8 positive cells and myeloid cells. Notably, higher early postoperative cNLR was associated with greater PDL1 positive myeloid clustering at the tumour periphery, linking the spatial architecture of the resected tumour with a systemic myeloid phenotype persisting after surgery. Conclusions: The data identify a prognostic, multilevel myeloid-associated host phenotype in GEA that is incompletely explained by tumour burden. Integrating systemic immune function, tumour single cell transcriptomics and spatial myeloid organization demonstrates that these biological domains provide distinct, yet convergent views of the host immune phenotype captured by cNLR. These findings establish a biological framework for the clinical utility of cNLR and highlight myeloid-associated immune processes as promising targets for therapeutic intervention.

cancer biology↗

bioRxiv2026

Buffaloed in Brandenburg: Germany's first Brush with Foot-and-Mouth Disease after four Decades of Freedom

Foot-and-mouth disease (FMD) virus is one of the most feared and most consequential pathogens of livestock worldwide. It can be spread rapidly by the transboundary movement of animals, animal products and byproducts. In January 2025, Germany detected its first FMD outbreak since 1988 in extensively reared water buffalo on a small farm in the state of Brandenburg, directly outside Berlin, the federal capital. Immediate control measures including a standstill for movements of susceptible animals and pre-emptive culling were implemented by the veterinary authorities. Whole-genome sequencing identified the virus as serotype O, topotype ME-SA, lineage SA-2018 and revealed extensive recombination, but cross-neutralization assays suggested good heterologous protection by an O/PanAsia-2 vaccine strain. Epidemiological back-calculation placed the time of virus introduction in late December 2024. Although the entry route remains unresolved, human-associated introduction is most likely. Network analysis revealed minimal farm connectivity, and simulations predicted low potential for onward transmission, which is consistent with the outbreak being ultimately restricted to a single herd. This event underscores the constant and unpredictable risk of introduction of the virus. Early detection through increased awareness and comprehensive differential diagnostics as well as the international collaboration of veterinary services, laboratories and experts are essential in the face of the global presence of FMD.

microbiology↗

bioRxiv2025

Radiotherapy Enhancement by Gold Nanocluster-functionalized Nanoliposomes Using Polychromatic Orthovoltage X-ray Irradiation

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, as the most effective chemoradiation therapies achieve unsatisfactory outcomes while associated with high toxicity. Nanoliposomal drug delivery systems are widely used to improve chemotherapy safety, yet passive release of amphiphilic drugs may still associate with adverse toxicity. To address this, we previously developed nanoliposomes functionalized with hydrophobic gold nanoclusters, demonstrating radiocatalytic activity and enhanced chemoradiotherapy effects in 3D PDAC microtumors under synchrotron irradiation. In this study, gold nanocluster-functionalized nanoliposomes (AuLPs) were optimized and evaluated under 220 kVp orthovoltage X-ray irradiation, widely used in preclinical irradiation systems. AuLPs containing 0.2 mol% gold nanoclusters produced 1.5-fold more reactive oxygen species than unloaded liposomes. However, higher molar ratios were necessary to improve radiotherapy outcomes in 3D PDAC microtumor models following 4 and 8 Gy irradiation. Pharmacokinetics and biodistribution evaluations showed a modest increase in tumor gold content 24 hours post-injection in orthotopic PDAC models. Altogether, these results underscore the potential of gold-radiotherapy-responsive liposomes while highlighting critical formulation challenges, which must be resolved for full therapeutic potential.

bioengineering↗

bioRxiv2023

Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities. Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/532413v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c0c371org.highwire.dtl.DTLVardef@15f6a92org.highwire.dtl.DTLVardef@14dbeedorg.highwire.dtl.DTLVardef@131d3eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

ACE2 expression and localization are regulated by CFTR: implications beyond cystic fibrosis

As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis (CF) could be considered a comorbidity for coronavirus disease 2019 (COVID-19)1. Instead, CF seems to constitute an advantage in COVID-19 infection2-5. To clarify whether host factors expressed by the CF epithelia may influence COVID-19 progression, we investigated the expression of SARS-CoV-2 receptor and coreceptors in primary airway epithelial cells. We found that angiotensin converting enzyme 2 (ACE2) expression and localization are regulated by cystic fibrosis transmembrane conductance regulator (CFTR) channels. Consistently, our results indicate that dysfunctional CFTR channels alter susceptibility to SARS-CoV-2 infection, resulting in reduced viral infection in CF cells. Depending on the pattern of ACE2 expression, the SARS-CoV-2 spike (S) protein induced high levels of Interleukin (IL)-6 in healthy donor-derived primary airway epithelial cells but a very weak response in primary CF cells. Collectively, these data support the hypothesis that CF condition is unfavorable for SARS-CoV-2 infection.

cell biology↗

bioRxiv2020

A cis-regulatory element promoting increased transcription at low temperature in cultured ectothermic Drosophila cells

Cells of many ectothermic species, including Drosophila melanogaster, maintain homeostatic function within a considerable temperature range. The cellular mechanisms enabling temperature acclimation are still poorly understood. At the transcriptional level, the heat shock response has been extensively analyzed. The opposite has received less attention. Here, using cultured Drosophila cells, we have identified genes with increased transcript levels at the lower end of the readily tolerated temperature range, as well as chromatin regions with increased DNA accessibility. Candidate cis-regulatory elements (CREs) for transcriptional upregulation at low temperature were selected and evaluated with a novel reporter assay for accurate assessment of their temperature-dependency. Robust transcriptional upregulation at low temperature could be demonstrated for a fragment from the pastrel gene, which expresses more transcript and protein at reduced temperatures. The CRE is controlled by the JAK/STAT signaling pathway and antagonizing activities of the transcription factors Pointed and Ets97D.

cell biology↗

bioRxiv2019

Community Standards for Open Cell Migration Data

Cell migration research has become a high-content field. However, the quantitative information encapsulated in these complex and high-dimensional datasets is not fully exploited due to the diversity of experimental protocols and non-standardised output formats. In addition, typically the datasets are not open for reuse. Making the data open and Findable, Accessible, Interoperable, and Reusable (FAIR) will enable meta-analysis, data integration, and data mining. Standardised data formats and controlled vocabularies are essential for building a suitable infrastructure for that purpose but are not available in the cell migration domain. We here present standardisation efforts by the Cell Migration Standardisation Organization, CMSO, an open community-driven organisation to facilitate the development of standards for cell migration data. This work will foster the development of improved algorithms and tools, and enable secondary analysis of public datasets, ultimately unlocking new knowledge of the complex biological process of cell migration.

bioinformatics↗

bioRxiv2018

The intestinal microbiota predisposes to traveller’s diarrhoea and to the carriage of multidrug-resistant Enterobacteriaceae after travelling to tropical regions

The risk of acquisition of multidrug-resistant Enterobacteriaceae (MRE) and of occurrence of diarrhoea is high when travelling to tropical regions. The relationships between these phenomena and the composition of human gut microbiota have not yet been assessed. Here, we investigated the dynamics of changes of metabolically active microbiota by sequencing total RNA from faecal samples taken before and after travel to tropical regions. We found that the occurrence of diarrhoea during the travel was associated with a higher relative abundance of Prevotella copri before departure and after return. The composition of microbiota, before travel as well as at return, was not correlated with the acquisition of MRE. However, the clearance of MRE one month after return was linked to a specific pattern of bacterial species that was also found before and after return.

microbiology↗

bioRxiv2017

OpenEHR modeling for genomics in clinical practice

The increasing usage of high throughput sequencing in personalized medicine brings new challenges to the realm of healthcare informatics. Patient records need to accommodate data of unprecedented size and complexity as well as keep track of their production process. In this work we present a solution for integrating genomic data into electronic health records via openEHR archetypes. We introduce new genomics-specific archetypes based on the popular variant call format and show their applicability to a practical use case. Finally, we discuss their structure in comparison with the HL7(R) FHIR(R) standard.

bioinformatics↗

bioRxiv2016

The Image Data Resource: A Scalable Platform for Biological Image Data Access, Integration, and Dissemination

Access to primary research data is vital for the advancement of science. To extend the data types supported by community repositories, we built a prototype Image Data Resource (IDR) that collects and integrates imaging data acquired across many different imaging modalities. IDR links high-content screening, super-resolution microscopy, time-lapse and digital pathology imaging experiments to public genetic or chemical databases, and to cell and tissue phenotypes expressed using controlled ontologies. Using this integration, IDR facilitates the analysis of gene networks and reveals functional interactions that are inaccessible to individual studies. To enable re-analysis, we also established a computational resource based on IPython notebooks that allows remote access to the entire IDR. IDR is also an open source platform that others can use to publish their own image data. Thus IDR provides both a novel on-line resource and a software infrastructure that promotes and extends publication and re-analysis of scientific image data.

bioinformatics↗