PaperPlayer biorxiv pathology

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.13.201582v1?rss=1

Authors: Yu, G., Xie, T., Xu, C., Shi, X.-H., Wu, C., Meng, R.-Q., Meng, X.-H., Wang, K.-S., Xiao, H.-M., Deng, H.-W.

Abstract:

PurposesThe machine-assisted recognition of colorectal cancer using pathological images has been mainly focused on supervised learning approaches that suffer from a significant bottleneck of requiring a large number of labeled training images. The process of generating high quality image labels is time-consuming, labor-intensive, and thus lags behind the quick accumulation of pathological images. We hypothesize that semi-supervised deep learning, a method that leverages a small number of labeled images together with a large quantity of unlabeled images, can provide a powerful alternative strategy for colorectal cancer recognition.

MethodWe proposed semi-supervised classifiers based on deep learning that provide pathological predictions at both patch-level and the level of whole slide image (WSI). First, we developed a semi-supervised deep learning framework based on the mean teacher method, to predict the cancer probability of an individual patch by utilizing patch-level data generated by dividing a WSI into many patches. Second, we developed a patient-level method utilizing a cluster-based and positive sensitivity strategy on WSIs to predict whether the WSI or the associated patient has cancer or not. We demonstrated the general utility of the semi-supervised learning method for colorectal cancer prediction utilizing a large data set (13,111 WSIs from 8,803 subjects) gathered from 13 centers across China, the United States and Germany. On this data set, we compared the performances of our proposed semi-supervised learning method with those from the prevailing supervised learning methods and six professional pathologists.

ResultsOur results confirmed that semi-supervised learning model overperformed supervised learning models when a small portion of massive data was labeled, and performed as well as a supervised learning model when using massive labeled data. Specifically, when a small amount of training patches (~3,150) was labeled, the proposed semi-supervised learning model plus ~40,950 unlabeled patches performed better than the supervised learning model (AUC: 0.90 {+/-} 0.06 vs. 0.84 {+/-} 0.07,P value = 0.02). When more labeled training patches (~6,300) were available, the semi-supervised learning model plus ~37,800 unlabeled patches still performed significantly better than a supervised learning model (AUC: 0.98 {+/-} 0.01vs. 0.92 {+/-} 0.04, P value = 0.0004), and its performance had no significant difference compared with a supervised learning model trained on massive labeled patches (~44,100) (AUC: 0.98 {+/-} 0.01 vs. 0.987 {+/-} 0.01, P value = 0.134). Through extensive patient-level testing of 12,183 WSIs in 12 centers, we found no significant difference on patient-level diagnoses between the semi-supervised learning model (~6,300 labeled, ~37,800 unlabeled training patches) and a supervised learning model (~44,100 labeled training patches) (average AUC: 97.40% vs. 97.96%, P value = 0.117). Moreover, the diagnosis accuracy of the semi-supervised learning model was close to that of human pathologists (average AUC: 97.17% vs. 96.91%).

ConclusionsWe reported that semi-supervised learning can achieve excellent performance at patch-level and patient-level diagnoses for colorectal cancer through a multi-center study. This finding is particularly useful since massive labeled data are usually not readily available. We demonstrated that our newly proposed semi-supervised learning method can accurately predict colorectal cancer that matched the average accuracy of pathologists. We thus suggested that semi-supervised learning has great potentials to build artificial intelligence (AI) platforms for medical sciences and clinical practices including pathological diagnosis. These new platforms will dramatically reduce the cost and the number of labeled data required for training, which in turn will allow for broader adoptions of AI-empowered systems for cancer image analyses.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.13.200337v1?rss=1

Authors: Hsiao, C.-Y., Chen, T.-H., Lee, Y.-C., Wang, M.-C.

Abstract:

BackgroundUrolithiasis is a common cause of urinary tract obstruction and urinary tract infection (UTI). This study aimed to identify whether urolithiasis with or without hydronephrosis has an impact on acute kidney injury (AKI) in patients with UTI.

Methods and findingsThis retrospective study enrolled hospitalized UTI patients who underwent imaging in an acute care setting from January 2006 to April 2019. Of the 1113 participants enrolled, 191 (17.2%) had urolithiasis and 76 (6.8%) had ureteral stone complicated with hydronephrosis. Multivariate logistic regression analysis showed that in UTI patients with urolithiasis, the presence of ureteral stone with concomitant hydronephrosis was an independent risk factor for AKI (odds ratio [OR] 2.345, 95% confidence interval [CI] 1.128-4.876, P = 0.023). In addition, urolithiasis was associated with an increased risk for AKI (OR 2.484, 95% CI 1.398-4.415, P = 0.002) in UTI patients without hydronephrosis.

ConclusionThe presence of ureteral stone with hydronephrosis increases the risk for AKI of UTI patients with urolithiasis, and urolithiasis remains a risk factor of AKI in UTI patients without hydronephrosis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.10.196733v1?rss=1

Authors: David Unnersjoe-Jess, Linus Butt, Martin Hoehne, Anna Witasp, Lucas Kuehne, Peter F Hoyer, Jaakko Patrakka, Paul T Brinkkoetter, Annika Wernerson, Bernhard Schermer, Thomas Benzing, Lena Scott, Hjalmar Brismar, Hans Blom

Abstract:

Many light-microscopy protocols have in recent years been published for visualization of ultrastructure in the kidney. These protocols present researchers with new tools to evaluate both foot process anatomy and effacement, as well as protein distributions in foot processes, the slit diaphragm and in the GBM. However, these protocols either involve the application of different complicated super-resolution microscopes or lengthy sample preparation protocols. We here present a fast and simple, 5-hour long procedure for the full three-dimensional visualization of podocyte foot processes using conventional confocal microscopy. The protocol combines and optimizes different optical clearing and tissue expansion concepts to produce a mild swelling, sufficient for resolving foot processes using a diffraction-limited confocal microscope. We further show that the protocol can be used for common visualization of large-scale renal histology, pathology, and kidney protein distributions. Thus, we believe that our fast and simple protocol can be beneficial for routine conventional microscopic evaluation of kidney tissue integrity both in research and in the clinic.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.10.197277v1?rss=1

Authors: Yasmine A Issah, Amruta Naik, Soon Yew Tang, Kaitlyn Forrest, Thomas G Brooke, Nicholas Lahens, Katherine N Theken, Amita Sehgal, Scott G Worthen, Garret A FitzGerald, Shaon Sengupta

Abstract:

Adverse early life exposures having a lasting negative impact on health. For examples, neonatal hyperoxia which is a risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) confers susceptibility to respiratory infections like Influenza A (IAV) later in life. Given our previous findings that the circadian clock exerts a protective effect on injury from IAV, we asked if the long-term impact of neonatal hyperoxia includes disruption of circadian rhythms. We show here that neonatal hyperoxia abolishes the circadian clock mediated time of day protection from IAV, not through the regulation of viral burden, but through host tolerance pathways. We further discovered that that this dysregulation is mediated through the intrinsic clock in the lung, rather than through central or immune system clocks. Loss of circadian protein, Bmal1, in AT2 cells of the lung recapitulates the increased mortality, loss of temporal gating and other key features of hyperoxia-exposed animals. Taken together, our data suggest a novel role for the circadian clock in AT2 clock in mediating long-term effects of early life exposures to the lungs.

Brief SummaryNeonatal hyperoxia abrogates the circadian protection from Influenza infection in recovered adults.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.09.196170v1?rss=1

Authors: Jessica M Snyder, Guo Zhong, Cathryn Hogarth, Weize Huang, Traci Topping, Jeffrey LaFrance, Laura Palau, Lindsay C Czuba, Michael Griswold, Gabriel Ghiaur, Nina Isoherranen

Abstract:

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.06.182972v1?rss=1

Authors: FitzGerald, E. S., Jamieson, A. M.

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. While there are many theories for the cause of this pathology, including hyper inflammation and excess tissue damage, the cellular and molecular underpinnings are not yet clear. By analyzing transcriptomic data sets from experimental and clinical research teams, we determined that changes in the gene expression of genes important in the extrinsic coagulation cascade in the lung epithelium may be important triggers for COVID-19 coagulopathy. This regulation of the extrinsic blood coagulation cascade is not seen with influenza A virus (IAV)-infected NHBEs suggesting that the lung epithelial derived coagulopathies are specific to SARS-Cov-2 infection. This study is the first to identify potential lung epithelial cell derived factors contributing to COVID-19 associated coagulopathy.

GRAPHICAL ABSTRACT

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/182972v1_ufig1.gif" ALT="Figure 1">

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[email protected]@11714c7org.highwire.dtl.DTLVardef@551fa2org.highwire.dtl.DTLVardef@8fd43c_HPS_FORMAT_FIGEXP M_FIG C_FIG AUTHOR SUMMARYO_ST_ABSWhy was this study done?C_ST_ABSO_LISevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic.

C_LIO_LIIn addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients.

C_LIO_LICurrently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. Understanding the molecular basis of dysregulated blood coagulation during SARS-CoV-2 infection may help promote new therapeutic strategies to mitigate these complications in COVID-19 patients.

C_LI

What did the researchers do and find?O_LIWe analyzed three publicly available RNA sequencing datasets to identify possible molecular etiologies of COVID-19 associated coagulopathies. These data sets include sequencing libraries from clinically isolated samples of bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMCs) from SARS-CoV-2 positive patients and healthy controls. We also analyzed a publicly available RNA sequencing dataset derived from in vitro SARS-CoV-2 infected primary normal human bronchial epithelial (NHBE) cells and mock infected samples.

C_LIO_LIPathway analysis of both NHBE and BALF differential gene expression gene sets. We found that SARS-CoV-2 infection induces the activation of the extrinsic blood coagulation cascade and suppression of the plasminogen activation system in both NHBEs and cells isolated from the BALF. PBMCs did not differentially express genes regulating blood coagulation.

C_LIO_LIComparison with influenza A virus (IAV)-infected NHBEs revealed that the regulation of the extrinsic blood coagulation cascade is unique to SARS-CoV-2, and not seen with IAV infection.

C_LI

What do these findings mean?O_LIThe hyper-activation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2 infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems.

C_LIO_LIThe gene transcription pattern in SARS-CoV-2 infected epithelial cells is distinct from IAV infected epithelial cells with regards to the regulation of blood coagulation.

C_LI

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.04.187864v1?rss=1

Authors: Kuo, T., Du, W., Miyachi, Y., Dadi, P. K., Jacobson, D. A., Accili, D.

Abstract:

Genetic and acquired abnormalities contribute to pancreatic {beta}-cell failure in diabetes. Transcription factors Hnf4 (MODY1) and FoxO1 are respective examples of these two components, and are known to act through {beta}-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature {beta}-cells leads to increased selection of FoxO1 enhancers by Hnf4. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4 in {beta}-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective {beta}-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of {beta}-cell dysfunction with an antagonistic network regulating glycolysis, including {beta}-cell "disallowed" genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of {beta}-cell dysfunction.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.03.187237v1?rss=1

Authors: Levy, J., Azizgolshani, N., Andersen, M., Suriawinata, A. A., Liu, X., Lisovsky, M., Ren, B., Christensen, B., Vaickus, L. J.

Abstract:

Non-alcoholic steatohepatitis (NASH) is a type of fatty liver disease characterized by accumulation of fat in hepatocytes and concurrent inflammation. It is associated with significant morbidity as it can progress to cirrhosis and liver failure and increases the risk of developing hepatocellular carcinoma. NASH has become increasingly prevalent in the US and is a leading cause of liver transplantation for end stage liver disease and a significant public health burden. Grading and staging NASH involves liver core biopsy, followed by microscopic examination of histologic preparations of the tissue. Tissue sections are stained with hematoxylin and eosin (H&E) to grade NASH activity, and stained with trichrome to help stage fibrosis. Methods to computationally transform one stain into another on digital whole slide images (WSI) can reduce the need for additional physical staining besides H&E, alleviating personnel, equipment, and time costs. Recent computational techniques have shown promise and success for virtual staining of tissue. We conducted a large-scale validation study of the viability of virtual staining technologies for H&E to trichrome conversion on WSI (n=574). Our results demonstrate that virtual trichrome technologies present an immediate software solution that can be readily employed in the clinical setting as a diagnostic decision aid.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.02.183616v1?rss=1

Authors: Ramirez Paredez, G., Verner-Jeffreys, D., Papadopoulou, A., Monaghan, S., Smith, L., Haydon, D., Wallis, T., Davie, A., Adams, A., Migaud, H.

Abstract:

Atypical Aeromonas salmonicida (aAs) and Vibrionaceae related species are bacteria routinely recovered from diseased ballan wrasse used as cleaner fish in Atlantic salmon farming. Autogenous multivalent vaccines formulated from these microorganisms are widely used by the industry to protect farmed wrasse despite limited experimental proof that they are primary pathogens. In this study, the components of a commercial multivalent injection wrasse vaccine were tested for infectivity, pathogenicity and virulence via intra peritoneal injection at pre-deployment size (25-50g) and the efficacy of the vaccine for protection against aAs assessed. Injection with 3.5x109, 8x109 1.8x109 and 5x109 cfu/fish of Vibrio splendidus, V. ichthyoenteri, Aliivibrio logeii and A. salmonicida, respectively, did not cause significant mortalities, lesions or clinical signs after a period of 14 days. IP injection with both aAs and Photobacterium indicum successfully reproduced the clinical signs and internal lesions observed during natural outbreaks of the disease. Differences in virulence (LD50 at day 8-post infection of 3.6x106 cfu/fish and 1.6x107 cfu/fish) were observed for two aAs vapA type V isolates. In addition, the LD50 for Photobacterium indicum was 2.2x107 cfu/fish. The autogenous vaccine was highly protective against the two aAs vapA type V isolates after 700-degree days of immunisation. The RPSFINAL values for the first isolate were 95 and 91% at 1x106 cfu/fish and 1x107 cfu/fish, respectively, and 79% at 1x107 cfu/fish for the second isolate tested. In addition, significantly higher anti aAs seral antibodies (IgM), were detected by ELISA in vaccinated fish in contrast with control (mock vaccinated) fish. These results suggest wrasse can be effectively immunised and protected against aAs infection by injection with oil adjuvanted vaccines prepared with inactivated homologous isolates. Further work should assess the efficacy of vaccination against other isolates that have proven to be pathogenic such as aAs type VI and Photobacterium indicum and explore the feasibility of immersion vaccination. In addition, a full characterisation of aAs isolates within the same vapA types should be performed as differences in virulence between vapA type V isolates were observed and partial genome analysis indicated small but potentially important genomic differences in these isolates.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.06.30.181297v1?rss=1

Authors: Xu, Q., Chen, L., Zhang, L., Li, X., Zheng, J.

Abstract:

Since the end of 2019, COVID-19 pandemic caused by the SARS-CoV-2 emerged globally. The angiotensin-converting enzyme 2 (ACE2) on the cell surface is crucial for SARS-COV-2 entering into the cells. The expression of ACE2 in skin suggested that skin might be a way of transmitting SARS-CoV-2. We found the elevated ACE2 level of patients with psoriasis but downregulated after IL-17 antibody treatment. Further results showed that ACE2 expression increased either in psoriasis or in atopic dermatitis, which were typical inflammatory skin disorders with barrier dysfunction. And elevated ACE2 level was also detected in mouse models of dermatitis induced by imiquimod, calcipotriol, repeated tape-stripping or 1-Fluoro-2,4-dinitrobenzene (DNFB) respectively. Moreover, alleviation of cutaneous inflammation with skin recovery moisture also lowered expression of ACE2 in mouse models with barrier deteriorated inflammatory skin disorders. Furthermore, inflammatory skin disorders with barrier dysfunction increased the penetration of topical FITC conjugated spike protein into the skin. Conversely, improvement in skin permeability barrier could prevent this penetration. Thus, indicating the special link between inflammatory skin disorders with skin barrier dysfunction and increasing risk of COVID-19.

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