Biology subjects

Han, N. S.

Publications and source records attributed to Han, N. S..

3 recordsLinked to original sources

bioRxiv2026

A COJEC-chemotherapy resistant model of Th-ALK(F1174L)/MYCN neuroblastoma offers insights into tumour immune evasion and development of the bone marrow metastatic niche

Multi-agent COJEC chemotherapy is the main-stay of induction treatment for patients diagnosed with high-risk neuroblastoma. However, at least 10% of patients will be primary refractory to chemotherapy and only 50% achieve 5-year overall survival. The bone marrow is the most frequent site of metastasis in these patients. Novel approaches are required to improve response rates but the inter- and intra- patient tumour heterogeneity and dynamics of the neuroblastoma immune microenvironment makes anticipation of resistance phenotypes incredibly challenging. We present here a novel immunocompetent C57 Bl/6 model of Th-ALK(F1174L)/MYCN neuroblastoma, in which spontaneous abdominal tumours are driven by expression of mutant Anaplastic Lymphoma Kinase and over-expression of Mycn in the neural crest. We have used this model to generate a personalised dosing schedule inducing COJEC-chemotherapy resistance, in which individual mice receive chemotherapy cycles dependent upon the progression of their neuroblastoma tumours. Using both single cell RNA sequencing and spatial immunophenotyping gave us extraordinary precision in our comprehensive analysis of the tumour intrinsic and microenvironmental factors associated with COJEC resistance. We found that the resistance phenotype was driven by Cdk8 upregulation in adrenergic and mesenchymal tumour cells. Infiltration of immunosuppressive myeloid-derived immune cells and remodeling of the tumour-associated stroma further contributed to COJEC resistance. In the bone marrow we observed expansion of neutrophils and evidence of NETosis associated with micro-metastatic disease. Our results further endorse the development of CDK8-targeting therapeutics for neuroblastoma patients which might boost the anti-tumour immune response. Additional studies will be required to define the roles of neutrophils and neutrophil NETosis in neuroblastoma progression and metastasis. Our C57 Bl/6 model will be pivotal in future preclinical studies of immune-modulating therapeutics.

cancer biology↗

bioRxiv2024

Naturally acquired IgG responses to Plasmodium falciparum do not target the conserved termini of the malaria vaccine candidate merozoite surface protein 2

Malaria remains a significant burden, and a fully protective vaccine against Plasmodium falciparum is critical for reducing morbidity and mortality. Antibody responses against the blood-stage antigen merozoite surface protein 2 (MSP2) are associated with protection from P. falciparum malaria, but its extensive polymorphism is a barrier to its development as a vaccine candidate. New tools, such as long-read sequencing and accurate protein structure modelling allow us to more easily study the genetic diversity and immune responses towards antigens from clinical isolates. This study sought to better understand naturally acquired MSP2-specific antibody responses. IgG responses against recombinantly expressed full- length, central polymorphic regions, and peptides derived from the conserved termini of MSP2 variants sequenced from patient isolates, were tested in plasma from travelers with recent, acute malaria and from individuals living in an endemic area of Tanzania. IgG responses towards full MSP2 and truncated MSP2 antigens were variant specific. IgG antibodies in the plasma of first-time infected or previously exposed travelers did not recognize the conserved termini of expressed MSP2 variants by ELISA, but they bound 13- amino acid long linear epitopes from the termini in a custom-made peptide array. Alphafold3 modelling suggests extensive structural heterogeneity in the conserved termini upon antigen oligomerization. IgG from individuals living in an endemic region, many who were asymptomatically infected, did not recognize the conserved termini by ELISA. Our results suggest that responses to the variable regions are important for the development of naturally acquired immunity towards MSP2.

immunology↗

bioRxiv2022

FiNuTyper: an automated deep learning-based platform for simultaneous fiber and nucleus type analysis in human skeletal muscle

SummaryWhile manual quantification is still considered the gold standard for skeletal muscle histological analysis, it is time-consuming and prone to investigator bias. We assembled an automated image analysis pipeline, FiNuTyper (Fiber and Nucleus Typer), from recently developed deep learning-based image segmentation methods, optimized for unbiased evaluation of fresh and postmortem human skeletal muscle. We validated and utilized SERCA1 and SERCA2 as type-specific myonucleus and myofiber markers. Parameters including myonuclei per fiber, myonuclear domain, central myonuclei per fiber, and grouped myofiber ratio were determined in a fiber type-specific manner, revealing a large degree of gender- and muscle-related heterogeneity. Our platform was also tested on pathological muscle tissue (ALS) and adapted for the detection of other resident cell types (leukocytes, satellite cells, capillary endothelium). In summary, we present an automated image analysis tool for the simultaneous quantification of myofiber and myonuclear types, to characterize the composition of healthy and diseased human skeletal muscle. HighlightsO_LIA deep learning-based automated platform for skeletal muscle microscopic analysis C_LIO_LIHigh-fidelity identification and characterization of myonuclei and myofibers C_LIO_LIValidation of SERCA1 and SERCA2 as markers for myofiber and myonuclear subtypes C_LIO_LICharacterization of healthy and pathological human skeletal muscle tissue features C_LIO_LIAdaptations provided for studies on other resident cell types like satellite cells C_LI eTOC BlurbAn automated platform for unbiased analysis of skeletal muscle immunohistochemical images, focusing on type-specific myofiber-myonucleus relationships, facilitating high-throughput studies of healthy and diseased tissues.

cell biology↗