Biology subjects

Irshad, S.

Publications and source records attributed to Irshad, S..

5 recordsLinked to original sources

bioRxiv2025

SMART: A Spatio-Molecular Atlas of Response Trajectories in Triple-Negative Breast Cancer

A major challenge in treating Triple-Negative Breast Cancer (TNBC) lies in its molecular, morphological and clinical heterogeneity, which hampers accurate prediction of responses to neoadjuvant treatment. To address this, we introduce SMART: Spatio-Molecular Atlas of Response Trajectories, a comprehensive, multimodal resource compiled from 129 TNBC samples across 89 patients, obtained before, during, and after neoadjuvant chemotherapy (NACT). SMART comprises of 5,096 high quality manually selected spatial transcriptomic profiles enriched for epithelial, immune, or stromal compartments; paralleled with histological annotations, imagebased network analysis and protein expression. Seven novel spatial epithelial archetypes (EAs), seven tumour-immune microenvironments (TIMEs) and their co-localisation patterns were defined, revealing an opposing prevalence of functionally divergent EAs between response groups and the prognostic significance of B-cell enriched TIMEs, in particular those surrounding histologically normal epithelium adjacent to the tumour. The SMART dataset and analytical tools are publicly available via the PharosAI platform, providing the research community with the most comprehensive, manually annotated spatio-molecular transcriptomics atlas of NACT-treated TNBC to date.

cancer biology↗

bioRxiv2025

Bacteria-induced colitis in naked mole rats is alleviated by probiotic treatment: a new mammalian model for acute inflammatory disease

Enteropathogenic bacteria are a major cause of morbidity and mortality globally. Mouse models have been indispensable in advancing our understanding of infectious diseases caused by intestinal pathogens and in identifying physical, chemical and immunological barriers that limit these infections. However, there are significant differences between laboratory mice and human intestinal microbiota and immunobiology that underscore the need to develop other models that recapitulate the disease pathology and mucosal immune responses of human enteric diseases. Here we report how the pathogenic expansion of Citrobacter braakii in naked mole rats (NMRs) leads to colonic inflammation and epithelial injury that mimics pathological features of human hemorrhagic colitis. We observe mucosal erosions, ulcerations, depletion of goblet cells, extension of proliferative compartments to the surface of the glands, and active inflammation in the colonic lamina propria of infected NMRs. Without intervention, systemic inflammation associated with sepsis ensues in infected NMRs and results in high mortality. Interestingly, we demonstrate a strong therapeutic effect of probiotics comprising Lactobacillus, Bifidobacterium, Streptococcus salvarius subsp. thermophilus and Enterococcus faecium strains. Treatment with probiotics induces mucosal healing and restores intestinal homeostasis, including suppression of excessive proliferation of epithelial cells, replenishment of goblet cells and also has an anti-inflammatory effect. Taken together, we demonstrate that NMRs, beyond their use as an anti-ageing and disease-resistance model, can also be used to address disease mechanisms underlying infectious colitis, including disruptions in the mucosal barrier permeability, gut microbial ecology and in local and systemic immune regulation; and in testing functional probiotics strains as potential therapeutics.

pathology↗

bioRxiv2024

Development of a Deep Learning model Tailored for HER2 Detection in Breast Cancer to aid pathologists in interpreting HER2-Low cases

IntroductionOver 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study, we evaluated the performance of a deep learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells staining intensity and completeness of membrane staining. MethodsWe trained a DL model on a multi-centric cohort of breast cancer cases with HER2- immunohistochemistry scores (n=299). The model was validated on 2 independent multi- centric validation cohorts (n=369 and n=92), with all cases reviewed by 3 senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. ResultsThe models concordance with the ground truth (ICC = 0.77 [0.68 - 0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the 3 senior pathologists (ICC = 0.45 [0.17 - 0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93%- 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumors respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumor-infiltrating lymphocytes, and necrosis, whilst some artifacts such as non- specific background cytoplasmic stain in the cytoplasm of tumor cells also cause discrepancy. ConclusionDeep learning can support pathologists interpretation of difficult HER2-low cases. Morphological variables and some specific artifacts can cause discrepant HER2-scores between the pathologist and the DL Model.

pathology↗

bioRxiv2024

GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche via stromal remodelling

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we used a disease-positioned mouse, and human tissue, to explore the consequences of pathological Bone Morphogenetic Protein (BMP) signalling dysregulation on epithelial- mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist GREM1, resulted in ectopic crypt formation with lineage tracing demonstrating the presence of Lgr5(-) stem/progenitor cells. Isolated epithelial cell Grem1 expression had no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with a novel anti-Grem1 antibody abrogated the polyposis phenotype, and triangulation of specific pathway inhibitors defined a pathological sequence of events, with wnt-ligand dependent ectopic stem cell niches formed through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function. One Sentence SummaryPathological epithelial GREM1 expression induces therapeutically reversible ectopic stem cell niches through stromal remodelling

cancer biology↗

bioRxiv2023

A rapid method for generating transplantable and biologically responsive colonic tissue from human induced pluripotent stem cells.

BackgroundThe colonic mucosa consists of cell populations derived from multiple lineages. Induced pluripotent stem cells (iPSCs) are capable of generating large numbers of differentiated cells from any lineage. Thus, iPSCs are highly versatile for derivation of intestinal cells for generation of colonic mucosal tissue for clinical and biological applications. ObjectiveWe set out to create a human iPSC (hiPSC) multi-lineage co-differentiation platform capable of generating colonic mucosal tissue in vitro. DesignWe used hiPSCs and designed a differentiation protocol consisting of small molecules and recombinant growth factors to generate multiple cell lineages. Cells were seeded onto collagen hydrogels (forming colonic patches - CoPs) and modulated with multiple growth factors important in intestinal biology. CoPs were transplanted into immunosuppressed mice. Generated cells and tissues were profiled with transcriptomic analysis. ResultshiPSC co-differentiation led to multiple intestinal epithelial, mesenchymal and endothelial cell populations. Seeded onto collagen scaffolds these cells created CoPs, which were transplanted into mouse subcutis. Engrafted CoPs developed into normal-looking colonic mucosa containing epithelial crypts (with enterocytes, goblet cells and neuroendocrine cells), multiple lamina propria-resident stromal populations and muscularis mucosae smooth muscle. They anastomosed to murine vasculature and maintained in-vitro for several weeks. We demonstrated that CoPs respond to known signalling pathways important in colonic mucosal biology and fibrogenesis, showing potential to provide a complex model of colonic pathobiology. ConclusionThis platform could offer an accurate model of intestinal pathobiology, supply cells for regenerative cell therapies to treat intestinal disease, and provide therapeutic autologous grafts to repair damaged colon.

cell biology↗