Biology subjects

Cihakova, D.

Publications and source records attributed to Cihakova, D..

4 recordsLinked to original sources

bioRxiv2026

TiSAM: fusing spatial and histopathology foundation models for whole-slide image segmentation

Semantic segmentation of whole-slide images (WSIs) quantifies tissue composition and architecture, but existing models require extensive annotation and lose accuracy as the number of tissue classes increases or on heterogeneous, cross-scanner datasets. Here, we present the Tissue Segment Anything Model (TiSAM), which fuses SAM3 spatial features with UNI2-h pathology features within a multi-scale decoder. Because public benchmarks contain few tissue classes, we release MegaMouse, comprising 36,833 annotations of 52 tissue classes from 12 mouse organs, and an 11-class human pancreas dataset. TiSAM achieved the highest overall performance across four public datasets compared to existing convolutional neural network and vision transformer models, maintained high accuracy on MegaMouse, and maintained high accuracy in the human pancreas dataset when trained on as few as 5 annotated WSIs where previous integrations of SAM with pathology foundation models did not. TiSAM segmentations were also more consistent across eight slide scanners compared to other models. These results establish TiSAM as a general and highly adaptable framework for tissue segmentation, enabling studies containing many tissue classes, limited annotations, or images from multiple scanners.

bioinformatics↗

bioRxiv2026

Senescence and DNA Damage-Induced Inflammation Drive Heart Failure with Preserved Ejection Fraction in Cardiovascular Kidney Metabolic Syndrome

IntroductionHeart failure with preserved ejection fraction (HFpEF) is strongly associated with cardiometabolic comorbidities, including obesity, diabetes, hypertension, chronic kidney disease and aging, yet the mechanistic contribution of cellular senescence to HFpEF pathogenesis remains poorly defined. Methods and ResultsTo model clinically relevant HFpEF, we subjected p16-3MR mice to a novel chronic "four-hit" cardiovascular-kidney-metabolic stress regimen (10 months of a high-fat diet, low-dose streptozotocin, L-NAME, and aging). These mice developed a robust HFpEF phenotype characterized by left ventricular hypertrophy, impaired diastolic function (reduced E'/A' and elevated E/E'), preserved ejection fraction, reduced -dP/dt, exercise intolerance, pulmonary congestion, and increased cardiac CD68 macrophage infiltration. Cardiac proteomics identified 821 proteins significantly altered by four-hit stress. Selective genetic ablation of p16 senescent cells using ganciclovir ameliorated HFpEF phenotypes, reduced cardiac p16 expression and inflammation, and normalized proteomic remodeling, without affecting body weight or glycemic status. Comparative network analysis of mouse and human HFpEF cardiac proteomes revealed highly concordant upstream regulatory networks, prominently involving cell-cycle control, DNA damage responses, and inflammatory signaling. Immunohistochemical analysis of human HFpEF cardiac biopsies confirmed increased p16, {gamma}H2AX, STING, IRF3, NF-{kappa}B p65, and CD68 macrophages, mirroring the murine findings. The 4-Hit mice also developed chronic diabetic kidney disease with increased kidney inflammation, both of which were attenuated by Senolytic therapy. Mechanistically, the cGAS-STING (cyclic GMP-AMP synthase - stimulator of interferon genes) is activated in response to damaged DNA, which in turn activates the downstream immune responses, including NF-{kappa}B and interferons. Cross-species validation further demonstrated that combined metabolic stress impaired cardiac function and nephrocyte function in Drosophila. Cardiac and nephrocyte dysfunctions were independently rescued by cardiomyocyte-specific and nephrocyte-specific inhibition of the cGAS-STING pathway, respectively. In human iPSC-derived cardiomyocytes, irradiation and palmitate induced senescence, DNA damage sensing via ZBP1, and activation of the cGAS-STING-IRF3 signaling axis; ZBP1 knockdown or senolytic treatment suppressed this inflammatory axis. ConclusionsAcross mouse, human, fly, and human iPSC models, our findings identify DNA damage-driven senescence and ZBP1-cGAS-STING signaling as conserved, causal mechanisms linking cardiovascular-kidney-metabolic comorbidities to HFpEF, highlighting senescence and innate immune pathways as promising therapeutic targets.

pathology↗

bioRxiv2022

Hypereosinophilia causes progressive cardiac pathologies in mice

Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Cardiac pathologies are the main reason for its high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit therapeutic development. Here, we describe the cardiac pathologies that developed in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function at a young age which worsened with age. Mechanistically, we demonstrated infiltration of activated eosinophils into the heart tissue that led to an inflammatory environment. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to WT controls. This impairment may result from the inflammatory stress experienced by the cardiomyocytes and suggest that dysregulation of contractility and Ca2+ reuptake in cardiomyocytes contributes to cardiac dysfunction at the whole organ level in hypereosinophilic mice. TeaserToo many eosinophils cause inflammation in the heart and change cardiomyocyte contraction leading to poor heart function.

pathology↗

bioRxiv2019

Interleukin 17 and senescence regulate the foreign body response

Synthetic biomaterials and medical devices suffer to varying levels from fibrosis via the foreign body response (FBR). To explore mechanistic connections between the immune response and fibrosis from the FBR, we first analyzed fibrotic capsule surrounding human breast implants and found increased numbers of interleukin (IL)17-producing {gamma}{delta}+ T cells and CD4+ TH17 cells as well as senescent cells. Further analysis in a murine model demonstrated an early innate IL17 response to synthetic implants, mediated by innate lymphoid cells and {gamma}{delta}+ T cells, was followed by a chronic adaptive antigen dependent CD4+ TH17 cell response. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to materials and the development of p16INK4a senescent cells. Treatment with a senolytic agent reduced IL17 expression and fibrosis. Discovery of a feed-forward loop between the TH17 and senescence response to synthetic materials introduces new targets for therapeutic intervention in the foreign body response.

immunology↗