bioRxiv - Pathology最新文献

{"title":"The penetration ring is a novel infection structure formed by the penetration peg for invading plant cell membrane in rice blast fungus","authors":"Wenqin Fang, Xiaoyu Zai, Jia Chen, Yakubu Saddeeq Abubakar, Qiu Wu, Zhenyu Fang, Xiuwei Huang, Xiang Gan, Daniel J. Ebbole, Zonghua Wang, Wenhui Zheng","doi":"10.1101/2024.07.11.603048","DOIUrl":"https://doi.org/10.1101/2024.07.11.603048","url":null,"abstract":"Many fungal pathogens develop specialized infection structures such as appressoria to penetrate plant cells. However, it is not clear whether special structures are formed after cell wall penetration before invading host cytoplasm membrane in hemibiotrophic pathogens. Here, we showed that a penetration ring consisting of Ppe1 secreted proteins is formed after appressorium-mediated cell wall penetration and remained at the base of penetration site after invading plant cytoplasm membrane in the rice blast fungus Magnaporthe oryzae. The same persistent Ppe1 ring is formed after the penetration of neighboring cells by transpressoria. PPE1 is specifically expressed during plant infection and the Delta ppe1 mutant is defective in penetration and invasive growth. Blockage of penetration peg formation impedes the development of the Ppe1 ring. Close examinations showed that the penetration ring is formed at the collar of penetration pegs between plant cell wall and cytoplasm membrane and it is persistent as a fixed ring even after invasive hyphae invaded neighboring cells. Furthermore, Ppe1 is a member of an expanded family of secreted proteins that are unique to fungal pathogens using extreme appressorium turgor for plant penetration. Other members of the Ppe1 family also localize to the penetration ring for anchoring on cytoplasm membrane during plant infection. Taken together, a penetration ring consisting of a family of secreted proteins is formed between plant cell wall and cytoplasm membrane, which may function as a novel physical structure at the interface between the tip of penetration pegs and plant cytoplasm membrane before the differentiation of invasive hyphae.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycystin-1 loss of function increases susceptibility to atrial fibrillation through impaired DNA damage response","authors":"Troy Hendrickson, Abigail Abigail Giese, Matthew Fiedler, William Perez, Ernesto Reyes-Sanchez, Monserrat Reyes-Lozano, Sufen Wang, Leslye Venegas-Zamora, Vincent Provasek, Aschraf El-Essawi, Ingo Breitenbach, Funsho E. Fakuade, Ingo Kutschka, Gabriele G Schiattarella, Niels Voigt, Miguel Valderrabano, Francisco Altamirano","doi":"10.1101/2024.07.08.602618","DOIUrl":"https://doi.org/10.1101/2024.07.08.602618","url":null,"abstract":"Background: The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF.\u0000Methods: We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches.\u0000Results: Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF.\u0000Conclusions: Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Immunoglobulin light chain amyloidosis in Caenorhabditis elegans","authors":"Margherita Romeo, Maria Monica Barzago, Alessandro Corbelli, Silvia Maglioni, Natascia Ventura, Carmina Natale, Andrea Conz, Mario Salmona, Giovanni Palladini, Mario Nuvolone, Fabio Fiordaliso, Giampaolo Merlini, Luisa Diomede","doi":"10.1101/2024.07.05.602215","DOIUrl":"https://doi.org/10.1101/2024.07.05.602215","url":null,"abstract":"Cardiac involvement determines the survival of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlining their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is instrumental. Taking advantage of the similarities between the vertebrate heart and C. elegans' pharynx, we developed a new transgenic nematode expressing a human amyloidogenic lamda LC whose sequence was deduced from an AL-affected patient with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling the bradycardia occurring in AL-affected patients, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model can allow the elucidation of the mechanisms underlying the cardiac-specific tropism occurring in AL amyloidosis, providing innovative insights into the pathophysiology.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise and disease state influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model","authors":"Gareth Hazell, Nina Ahlskog, Emma R Sutton, Magnus Okoh, Joseph M Hoolachan, Taylor Scaife, Sara Iqbal, Eve McCallion, Amarjit Bhomra, Anna J Kordala, Frederique Scamps, Cedric Raoul, Matthew JA Wood, Melissa Bowerman","doi":"10.1101/2024.07.05.602199","DOIUrl":"https://doi.org/10.1101/2024.07.05.602199","url":null,"abstract":"Background: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits. Methods: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14-/- mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14-/-, SOD1G93A and SOD1G93A;Fn14-/-).\u0000Results: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display an increased lifespan and decreased muscle pathology, without an impact on motor function, and that this is dependent on exposure to exercise. Indeed, we observe that endurance (rotarod) and resistance (grid test) exercises influence the positive effects of Fn14 deletion on survival and muscle phenotypes in SOD1G93A mice, which may be further influenced by genotype and disease state. Conclusions: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease and metabolic state. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism and exercise will be of importance in future studies.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural field diagnosis and molecular confirmation of fungal and bacterial watermelon pathogens in Bangladesh: A case study from Natore and Sylhet district","authors":"Raihan Ferdous","doi":"10.1101/2024.07.03.601980","DOIUrl":"https://doi.org/10.1101/2024.07.03.601980","url":null,"abstract":"The study investigated watermelon diseases in Sylhet and Natore Districts of Bangladesh, characterized by contrasting climatic conditions. Sylhet experiences lower temperatures and high rainfall, while Natore has higher temperatures and low rainfall. In these survey regions, 40 watermelon fields were selected, and 10 diseases were observed, including 4 fungal, 3 bacterial, 2 water mold, and 1 viral disease. The observed diseases were Anthracnose, Cercospora leaf spot, Fusarium wilt, Gummy stem blight, Downy mildew, Phytophthora fruit rot, Bacterial fruit blotch, Angular leaf spot, Yellow vine, and Watermelon mosaic disease. Molecular analysis was done in the Plant Pathology Lab at Sher-e-Bangla Agricultural University using the specific primers for fungal (ITS1/ITS4) and bacterial (27F/1492R) DNA regions and identified nine pathogen species, excluding the causal organism of the viral disease. The identified pathogens included Colletrotrichum orbiculare, Cercospora citrullina, Fusarium oxysporum, Stagonosporopsis cucurbitacearum, Pseudoperonospora cubensis, Phytophthora capsici, Acidovorax citrulli, Pseudomonas syringae, and Serratia marcescens. The sequencing of the identified pathogens revealed high homology (98.91-99.71%) with known sequences in the GenBank database. Phylogenetic analysis showed six clusters for fungal and water mold pathogen isolates and three for bacterial isolates where the percentages of replicate trees were 100% in all the cases. Among the identified diseases, the highest disease occurrence showed by Fusarium wilt (47.5%) following Gummy stem blight (41.5%) in the Sylhet region while Angular leaf spot (37.5%) followed Yellow vine (33%) in the Natore area. Fusarium wilt also showed high disease intensity showcasing its devastating impact on yield. The study highlights the influence of environmental conditions on disease prevalence and underscores the need for tailored management strategies. These findings provide a foundation for developing targeted disease management practices for sustainable watermelon cultivation in Bangladesh.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics unveils the in situ cellular and molecular hallmarks of the lung in fatal COVID-19","authors":"Carlos Garcia-Prieto, Eva Musulen, Veronica Davalos, Gerardo Ferrer, Daniela Grases, Eduard Porta-Pardo, Belen Perez Mies, Tamara Caniego Casas, Jose Palacios, Xavier Saenz Sarda, Elisabet Englund, Manel Esteller","doi":"10.1101/2024.07.03.601404","DOIUrl":"https://doi.org/10.1101/2024.07.03.601404","url":null,"abstract":"Severe Coronavirus disease 2019 (COVID-19) induces heterogeneous and progressive diffuse alveolar damage (DAD) highly disrupting lung tissue architecture and homeostasis, hampering disease management and leading to fatal outcomes. Characterizing DAD pathophysiology across disease progression is of ultimate importance to better understand the molecular and cellular features driving different DAD patterns and to optimize treatment strategies. To contextualize the interplay between cell types and assess their distribution, spatial transcriptomics (ST) techniques have emerged allowing unprecedented resolution to investigate spatial architecture of tissues. To this end, post-mortem lung tissue provides valuable insights into cellular composition and their spatial relationships at the time of death. Here, we have leveraged VisumST technology in post-mortem COVID-19 induced acute and proliferative DAD lungs including control samples with normal morphological appearance to unravel the immunopathological mechanisms underlying DAD providing novel insights into cellular and molecular communication events driving DAD progression in fatal COVID-19. We report a progressive loss of endothelial cell types, pneumocytes type I and natural killer cells coupled with a continuous increase of myeloid and stromal cells, mostly peribronchial fibroblasts, over disease progression. Spatial organization analysis identified variable cellular compartments, ranging from major compartments defined by cell type lineages in control lungs to increased and more specific compartmentalization including immune-specific clusters across DAD spectrum. Importantly, spatially informed ligand-receptor interaction (LRI) analysis revealed an intercellular communication signature defining COVID-19 induced DAD lungs. Transcription factor (TF) activity enrichment analysis identified TGF-B pathway as DAD driver, highlighting SMAD3 and SMAD7 TFs activity role during lung fibrosis. Integration of deregulated LRIs and TFs activity, allowed us to propose a downstream intracellular signaling pathway in peribronchial fibroblasts, suggesting potential novel therapeutic targets. Finally, spatio-temporal trajectories analysis provided insights into the alveolar epithelium regeneration program, characterizing markers of pneumocytes type II differentiation towards pneumocytes type I. In conclusion, we provide a spatial characterization of lung tissue architecture upon COVID-19 induced DAD progression, identifying molecular and cellular hallmarks that may help optimize treatment and patient management.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of GIT nematodes and associated risk factors of exotic chickens in selected farm of poultry in and around Ambo, Ethiopia","authors":"Abraham Belete Temesgen, Zerihun Getie Wassie, Saleamlak Abebe","doi":"10.1101/2024.07.02.601802","DOIUrl":"https://doi.org/10.1101/2024.07.02.601802","url":null,"abstract":"Poultry are raised worldwide in backyards and commercial systems with fewer social and religious taboos than other livestock. However, the chicken industry faces significant challenges from nematode parasites. A cross-sectional study with a random sampling technique was conducted from April to June 2019 to estimate gastrointestinal (GI) nematode parasites in chickens in selected farms in and around Ambo, Ethiopia. The fecal analysis results revealed that out of 70 samples collected, 60% were positive for gastrointestinal (GI) nematode eggs. Prevalence varied significantly by body condition, with the highest rates in chickens in poor condition (78.57%), followed by medium (54.54%) and good condition (40%). Location also played a significant role, with Ambo University Poultry Farm having the highest prevalence (83.87%), followed by Abebe Private Farm (55%) and Guder Campus Poultry Farm (26.31%). The main nematode species identified were Ascaridia galli (57.1%) and Heterakis gallinarum (2.9%). Infestation rates differed significantly by sex, age, location, and body condition, with males having higher rates of Ascaridia galli (61.53%) than females (56.14%), and Heterakis gallinarum exclusively affecting females (3.51%). Adults showed significantly higher rates of Ascaridia galli (85.71%) than young chickens (38.09%), with some infestation of Heterakis gallinarum (7.14%) observed in adults but absent in young chickens. This prevalence rate suggests limited awareness among chicken producers and insufficient control strategies in the study area. Hence, implementing targeted control strategies is advisable.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UNRAVELING THE LUNG VASCULAR REMODELING IN PULMONARY HYPERTENSION USING A QUANTITATIVE DIGITAL PATHOLOGY SOFTWARE","authors":"Cindy Serdjebi, Florine Chandes, Marzena Biernat, Bastien Lepoivre, Dany Salvail, Charles Edouard Laurent","doi":"10.1101/2024.07.01.601469","DOIUrl":"https://doi.org/10.1101/2024.07.01.601469","url":null,"abstract":"Pulmonary arterial hypertension (PAH) is a rare chronic life-threatening disorder, characterized by the elevation of the mean pulmonary arterial pressure above 20 mmHg at rest. Histologically, PAH induces lung vascular remodeling, with the thickening of vessel wall. The conventional histological analysis commonly used in non-clinical models to assess lung vascular remodeling relies on manual measurements of representative lung vessels and is time-consuming. We have developed a fully automated reader-independent software (MorphoQuant-Lung) to both specifically detect vessels and measure vascular wall components from a-SMA rat lung sections. Analysis was performed on monocrotaline- and Sugen/hypoxia-induced PH rat models, treated or not with Sildenafil. The software requires 3-5 minutes to detect up to 1500 vessels per section, classify them per size, quantify intima, media and wall thicknesses, and calculate their level of occlusion. A comparison of our digital analysis results with those of the pathologist's conventional visual analysis was performed for wall thickness and lumen radius showing a strong correlation between the two techniques (r: 0.80 and r: 0.88) regardless of the rat model. In addition, the occlusion estimated by automated analysis also strongly correlated with the mean pulmonary arterial pressure and the pulmonary vascular resistance (r ranging from 0.71 to 0.83) in both rat models. The added value of the present digital analysis paves the way for a more in-depth understanding of PAH physiopathology in preclinical research and provides a robust and reliable tool for efficient therapeutic drug development.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Deep Learning model Tailored for HER2 Detection in Breast Cancer to aid pathologists in interpreting HER2-Low cases","authors":"Pierre-Antoine Bannier, Glenn Broeckx, Loic Herpin, Remy Dubois, Lydwine Van Praet, Charles Maussion, Frederik Deman, Ellen Amonoo, Anca Mera, Jasmine Timbres, Cheryl Gillett, Elinor Sawyer, Patrycja Gazinska, Piotr Ziolkowski, Magali Lacroix-Triki, Roberto Salgado, Sheeba Irshad","doi":"10.1101/2024.07.01.601397","DOIUrl":"https://doi.org/10.1101/2024.07.01.601397","url":null,"abstract":"Introduction. Over 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. Methods. We 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.\u0000Results. The model 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.\u0000Conclusion: Deep 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.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"136 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Imaging of Lung Micro Structure: Amplifying Classical Histology by Paraffin Block μCT and same-slide Scanning Electron Microscopy","authors":"Johanna Reiser, Jonas Albers, Angelika Svetlove, Mara Mertiny, Felix KF Kommoss, Constantin Schwab, Anna Schneemann, Giuliana Tromba, Irene Wacker, Ronald E Curticean, Rasmus R Schroeder, Hans-Ulrich Kauczor, Mark O. Wielpuetz, Christian Dullin, Willi L. Wagner","doi":"10.1101/2024.06.29.601332","DOIUrl":"https://doi.org/10.1101/2024.06.29.601332","url":null,"abstract":"Classical histopathology of formalin fixed and paraffin embedded (FFPE) tissue using light microscopy (LM) remains the undisputed gold standard in biomedical microstructural lung tissue analysis. To extend this method, we developed an integrative imaging and processing pipeline which adds 3D context and screening capabilities by micro-CT (μCT) imaging of the entire paraffin block and adds ultrastructural information by correlative same-slide scanning electron microscopy (SEM). The different modalities are integrated by elastic registration to provide hybrid image datasets. Without compromising standard light microscopic readout, we overcome the limitations of conventional histology by combining and integrating several imaging modalities. The biochemical information contained in histological and immunohistological tissue staining is embedded into the 3D tissue configuration and is amplified by adding ultrastructural visualization of features of interest. By combining μCT and conventional histological processing, specimens can be screened, and specifically preselected areas of interest can be targeted in the subsequent sectioning process.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}