bioRxiv - Pathology最新文献

{"title":"Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase","authors":"Marie Malier, Marie-Helene Laverriere, Maxime Henry, Malika Yakoubi, Pascale Bellaud, Celine Arellano, Anthony Sebillot, Fabienne Thomas, Veronique Josserand, Edouard Girard, Gael Roth, Arnaud MILLET","doi":"10.1101/2024.08.19.608621","DOIUrl":"https://doi.org/10.1101/2024.08.19.608621","url":null,"abstract":"Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, in the current study, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. In addition, we demonstrate the human specificity of this mechanism, as mouse macrophages do not express significant levels of thymidine phosphorylase. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. We also showed in human colorectal cancer that macrophages represent a major source of thymidine phosphorylase expression leading to chemoresistance.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223799","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":"Pix2Path: Integrating Spatial Transcriptomics and Digital Pathology with Deep Learning to Score Pathological Risk and Link Gene Expression to Disease Mechanisms","authors":"Xiaonan Fu, Yan Chen","doi":"10.1101/2024.08.18.608468","DOIUrl":"https://doi.org/10.1101/2024.08.18.608468","url":null,"abstract":"Spatial transcriptomics (ST) provides high-resolution mapping of gene expression within tissues, and integrating ST with digital pathology can offer unprecedented insights into the molecular mechanisms underlying various diseases. However, existing methods primarily focus on aligning these two distinct datasets, often neglecting the causal connections between spatial gene activity and pathological phenotype. We introduce Pix2Path, a deep learning-based approach utilizing conditional generative adversarial networks (cGANs), to bridge the gap between spatial transcriptomics and digital pathology. Pix2Path can process data from various spatial transcriptomics (ST) technologies, assess pathological risk scores across different conditions, and supports a leave-one-out spatial in silico gene perturbation strategy. As demonstrated in AD Aβ plaques pathology, this approach allows to link gene expression changes to tissue morphology and pathology without relying on predefined conditions, providing a new perspective on understanding disease mechanisms.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183096","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":"Early atrial remodelling drives arrhythmia in Fabry Disease","authors":"Ashwin Roy, Christopher O'Shea, Albert Dasi, Leena Patel, MAX CUMBERLAND, DANIEL NIEVES, Hansel Sujan Canagarajah, SOPHIE THOMPSON, AMAR AZAD, Anna M. Price, CAITLIN HALL, Amor Mia B Alvior, PHALGUNI RATH, BEN DAVIES, Blanca Rodriguez, Andrew P Holmes, Davor Pavlovic, Jonathan N. Townend, Tarekegn Geberhiwot, KATJA GEHMLICH, Richard P. Steeds","doi":"10.1101/2024.08.13.607853","DOIUrl":"https://doi.org/10.1101/2024.08.13.607853","url":null,"abstract":"Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency, resulting in multi-organ accumulation of sphingolipid, namely globotriaosylceramide (Gb3). This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death, a common cause of FD mortality. Atrial fibrillation (AF) is common in FD, yet the cellular mechanisms accounting for this are unknown. To address this, we conducted electrocardiography (ECG) analysis from a large cohort of adults with FD at varying stages of cardiomyopathy. Cellular contractile and electrophysiological function were examined in an atrial FD model, developed using gene-edited atrial cardiomyocytes and imputed into in-silico atrial models to provide insight into arrhythmia mechanisms. Methods: In 115 adults with FD, ECG P-wave characteristics were compared with non-FD controls. Induced pluripotent stem cells (iPSCs) were genome-edited using CRISPR-Cas9 to introduce the GLA p. N215S variant and differentiated into atrial cardiomyocytes (iPSC-CMs). Contraction, calcium handling and electrophysiology experiments were conducted to explore proarrhythmic mechanisms. A bi-atrial in-silico model was developed with the cellular changes induced by GLA p. N215S iPSC-CMs. Results: ECG analysis demonstrated P-wave duration and PQ interval shortening in FD adults before onset of cardiomyopathy on imaging and biochemical criteria. FD patients exhibited a higher incidence of premature atrial contractions and increased risk of developing AF. In our cellular model, GLA p. N215S iPSC-CMs were deficient in α-Gal A and exhibited Gb3 accumulation. Atrial GLA p. N215S iPSC-CMs demonstrated a more positive diastolic membrane potential, faster action potential upstroke velocity, greater burden of delayed afterdepolarizations, greater contraction force, slower beat rate and dysfunction in calcium handling compared to wildtype iPSC-CMs. Inputting these changes into the in-silico model resulted in similar P-wave morphology changes to those seen in early FD cardiomyopathy and increased the action potential duration (APD) restitution slope, causing APD alternans and","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182916","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":"Varietal screening of newly developed blackgram genotypes against Cercospora Leaf Spot (Cercospora canescens) in the Terai region of Nepal.","authors":"Siddhanta Shrestha, Sinchan Bohara, Sarita Oli, Anjal Nainabasti, Khem Raj Bohara, Kriti Upadhyaya, Indira Banet","doi":"10.1101/2024.08.12.607552","DOIUrl":"https://doi.org/10.1101/2024.08.12.607552","url":null,"abstract":"Screening of 12 blackgram genotypes against Cercospora Leaf Spot (Cercospora canescens) was carried out in RCB design with 3 replications in research plot of Mid-West Academy and Research Institute, Tulsipur, Dang during Bhadra to Mangsir, 2078 B.S where the climate is similar to all other Terai region of Nepal. The blackgram genotypes were brought from Grain Legumes Research Program, Khajura, Banke. Disease severity was taken 3 times at 40, 47, and 54 days after sowing. Disease scoring was done as a percentage of leaf area infected on the individual plant at 7-day intervals and disease incidence, disease severity, mean AUDPC, and mean yield was calculated. Disease incidence was not significant among the tested genotypes. Disease severity at 40, 47, and 54 DAS was highly significant among the genotypes. Mean disease score and mean area under disease progressive curve (AUDPC) were also highly significant. Among the genotypes, 10 genotypes were categorized as moderately resistant and 2 genotypes (BLG 0066-1-1 and BLG 0035-1) were categorized as moderately susceptible. The highest Mean AUDPC value (324.1) was possessed by BLG 0035-1 followed by BLG 0066-1-1 (317.6). The lowest mean AUDPC value (175) was possessed by BLG 0069-1. A highly significant difference was found in yield among the black gram genotypes. The highest yield (799 kg/ha) by obtained by BLG 0068-2 followed by Rampur mas (769 kg/ha). The lowest yield (495 kg/ha) was obtained by BLG 0066-1.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223816","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 and associated risk factors assessment of bovine fasciolosis in and around Bahir Dar, Ethiopia","authors":"Abraham Belete Temesgen, Tesfaye Mesfin","doi":"10.1101/2024.08.07.606800","DOIUrl":"https://doi.org/10.1101/2024.08.07.606800","url":null,"abstract":"Bovine fasciolosis is a parasitic disease of cattle caused by ingesting metacercariae of liver flukes from the genus Fasciola. A cross-sectional study was conducted from November 2021 to April 2022, encompassing a total of 384 cattle randomly selected from diverse locations. The study included cattle of various ages and genders, aiming to to determine the prevalence of bovine fasciolosis and its associated risk factors in and around Bahir Dar, Ethiopia. Fecal examinations were performed to detect fluke eggs, and data were analyzed using descriptive statistics in STATA Version 20.0 to summarize bovine fasciolosis prevalence. Chi-square tests assessed relationships with infection rates and risk factors, with significance set at P < 0.05. Out of 384 fecal samples analyzed, 49.21% tested positive for Fasciola eggs. Origin areas included Tikurit (50%), Sebatamit (61.84%), Latammba (27.65%), and Kebele 11 (59.37%). Cattle in poor condition showed higher prevalence (64%) compared to those in medium (50%) and fat condition (26.96%). Age showed differences with young cattle at 50.38%, adults at 47.33%, and old cattle at 50.47%. Sex distribution indicated 49.73% prevalence in males and 48.73% in females. Regarding breed, local cattle had a prevalence of 51.62%, while crossbreeds showed 46.15%. Significant variations were observed based on locality and body condition, whereas age, sex, and breed showed no statistically significant differences (p < 0.05). Despite these differences, bovine fasciolosis remains prevalent in the area. Enhancing farmer awareness, regular deworming, and effective management are crucial to control the disease and reduce economic losses.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944799","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":"Hematobiochemical Alterations and Lesion Characterization Caused by Fasciolosis in Cattle Slaughtered at Gondar ELFORA Abattoir, Ethiopia","authors":"Abraham Belete Temesgen, Tadegegn Mitiku, Mastewal Birhan, Mersha Chanie Kebede, Mohammed Yesuf, Muluken Yayeh, Moges Maru Alemayehu, Birhan Anagaw, Abdo Megra Geda, Aregash Wendimu Tumebo, Kefale Ambachew Shiferaw, Zerihun Getie Wassie, Genetu Kassahun Berie, Bemrew Admassu Mengistu, Melaku Getahun Feleke, Fikadu Edenshaw, Mulusew Tesfaye Yitie, Gashaw Enbiyale Kasse, Elias Melkamu","doi":"10.1101/2024.08.10.607441","DOIUrl":"https://doi.org/10.1101/2024.08.10.607441","url":null,"abstract":"Fasciolosis is a neglected zoonotic parasitic disease caused by Fasciola hepatica and Fasciola gigantica, which presents significant threats to livestock and human health. An abattoir-based cross-sectional study was conducted from January to September 2023 at Gondar ELFORA abattoir, Ethiopia, to assess hematobiochemical alterations and lesion characterization caused by fasciolosis in slaughtered cattle. The study involved 100 apparently healthy male local breed cattle, evenly split into 50 infected and 50 non-infected individuals, using a purposive sampling technique. Findings showed reductions in HGB, PCV, TEC, lymphocytes, monocytes, total protein, albumin, and glucose levels in infected cattle. Elevated TLC, eosinophils, neutrophils, AST, ALT, and ALP levels were noted. Liver changes included hepatomegaly with juvenile flukes in acute cases and smaller, firmer livers with bile duct engorgement in chronic cases. Microscopic findings revealed eosinophil infiltration, hemosiderin pigmentation, and fibrous tissue proliferation with epithelial cell metaplasia. The results of hematobiochemical alterations were consistent with gross and microscopic findings, indicating a significant impact on liver physiology and histology, leading to substantial losses in meat and milk production. Keywords: Abattoir; Cattle; Fasciolosis; Hematobiochemical alterations; Lesion characterization","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944860","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":"A honey bee-associated virus remains infectious and quantifiable in postmortem hosts","authors":"Alexandria N Payne, Vincent Prayugo, Adam G Dolezal","doi":"10.1101/2024.08.08.607215","DOIUrl":"https://doi.org/10.1101/2024.08.08.607215","url":null,"abstract":"Corpse-mediated transmission is a potentially viable route through which naive hosts can become infected, but its likelihood for honey bee-associated viruses is largely unknown. While these viruses can be easily detected in deceased bees, it remains unclear if they stay infectious within postmortem hosts or if enough viral RNA degradation—and subsequently virus inactivation—occurs post-host death to render these viruses inviable. This knowledge gap has important implications for how researchers perform honey bee virus studies and for our general understanding of honey bee virus transmission. To better understand the resiliency of honey bee-associated viruses within deceased hosts, we first tested the hypothesis that postmortem specimens, stored in colony-normal temperature and humidity conditions, can be reliably used to quantify virus abundance. To determine this, we experimentally-infected adult honey bees with Israeli acute paralysis virus (IAPV) and then measured the virus levels of individuals sampled live or at different postmortem timepoints (4–, 12–, 24–, and 48–hours post-death) using RT-qPCR and a standard curve absolute quantification method. We found no significant differences based on when bees were sampled, indicating that postmortem honey bees are statistically comparable to using live-sampled bees and can be reliably used to quantify absolute IAPV abundance. We then performed a follow-up experiment that determined whether or not the IAPV detected in postmortem bees remained infectious over time. We found that IAPV extracted from postmortem bees remained highly infectious for at least 48–hours post-death, indicating that any viral RNA degradation that may have occurred during the postmortem interval did not adversely affect the overall infectivity of IAPV. The results from this study suggest that IAPV is more resilient to degradation than previously assumed, support the use of postmortem bees for downstream IAPV analyses, and indicate that postmortem hosts can act as sources of IAPV infection for susceptible individuals.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944801","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":"PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis","authors":"Thomas H. Sisson, John J. Osterholzer, Lisa Leung, Venkatesha Basrur, Alexey Nesvizhskii, Natalya Subbotina, Mark Warnock, Daniel Torrente, Ammara Q Virk, Jeffrey C. Horowitz, Mary Migliorini, Dudley K. Strickland, Kevin K. Kim, Steven K. Huang, Daniel A. Lawrence","doi":"10.1101/2024.08.06.606812","DOIUrl":"https://doi.org/10.1101/2024.08.06.606812","url":null,"abstract":"Plasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding site. In the present study, employing two distinct murine fibrosis models, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a previously unrecognized profibrotic PAI-1-protein interaction involving the VTN-binding site for PAI-1. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorlA) as the most highly enriched PAI-1 interactor in the fibrosing lung. We next investigated the role of SorlA in pulmonary fibrosis and found that SorlA deficiency protected against lung scarring in a murine model. We further show that, while VTN deficiency does not influence fibrogenesis in the presence or absence of PAI-1, SorlA is required for PAI-1 to promote scarring. These results, together with data showing increased SorlA levels in human IPF lung tissue, support a novel mechanism through which the potent profibrotic mediator PAI-1 drives lung fibrosis and implicate SorlA as a new therapeutic target in IPF treatment.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944802","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":"Pathophysiological response in experimental trauma-related acute kidney injury","authors":"Rebecca Halbgebauer, Lorena Schult, Onno Borgel, Arne Maes, Florian Weißhaupt, Christina Rastner, Alitsia Ast, Ludmila Lupu, Annette Palmer, Ulrich Wachter, Stefan A. Schmidt, Peter Boor, Reinhild Rösler, Sebastian Wiese, Greet Kerckhofs, Markus S. Huber-Lang","doi":"10.1101/2024.08.02.606294","DOIUrl":"https://doi.org/10.1101/2024.08.02.606294","url":null,"abstract":"<strong>Background</strong> Trauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944804","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":"Ethanol exposure model in zebrafish causes phenotypic, behavioral and gene expression changes that mimic Fetal Alcohol Spectrum Disorders in human birth cohorts","authors":"Elanur Yilmaz, Nastasia Nelson, Giuseppe Tosto, R. Colin Carter, Caghan Kizil","doi":"10.1101/2024.08.05.606708","DOIUrl":"https://doi.org/10.1101/2024.08.05.606708","url":null,"abstract":"Fetal Alcohol Spectrum Disorders (FASD) represent a significant global health challenge, characterized by physical and neurodevelopmental abnormalities in offspring resulting from prenatal alcohol exposure. This study aims to utilize the zebrafish to examine the phenotypic, behavioral, and molecular changes associated with embryonic ethanol exposure, providing a model for human FASD conditions. Our study exposed zebrafish embryos to 0.5% ethanol during a critical developmental window (2-24 hours post-fertilization) and documented significant craniofacial and cardiac deformities, which recapitulate what has been observed in human FASD in humans. Notably, exposed zebrafish exhibited reduced skull and eye sizes, thickened jaw size, and enlarged heart chambers. We found reduced burst swim distance following a touch stimulus, a novel behavioral assessment of potential deficits in sensory processing such as processing speed and/or stress/startle response, both of which are affected in human FASD. Whole-organism gene expression was found to be altered by ethanol for orthologs of four of five inflammation-related genes for which placental expression was previously found to be altered in response to alcohol in human placentas (<em>SERPINE1, CRHB, BCL2L1, PSMB4, PTGS2A</em>). We conclude that the zebrafish model effectively mimics several FASD phenotypes observed in humans, confirming gene expression changes we have previously documented in a human observational study and providing a valuable platform for exploring the underlying mechanisms of alcohol-induced embryonic alterations and for developing diagnostic markers and therapeutic targets for early intervention.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944803","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}