Automated analysis of lymphocytic infiltration, tumor budding, and their spatial relationship improves prognostic accuracy in colorectal cancer

Funding: Medical Research Scotland, and Indica Labs, Inc. provided in-kind resource.Both immune profiling and tumor budding significantly correlate with colorectal cancer (CRC) patient outcome, but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II CRC. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3+CD8+ T cells, and tumor buds (TBs), across whole slide images of three independent cohorts (training cohort: n = 114, validation cohort 1: n = 56, validation cohort 2: n = 62). Machine learning algorithms were used for feature selection and prognostic risk model development. High numbers of TBs (HR = 5.899, 95% CI, 1.875 - 18.55), low CD3+ 11 T cell density (HR = 9.964, 95% CI 3.156 - 31.46), and low mean number of CD3+CD8+ T cells within 50 μm of TBs (HR = 8.907, 95% CI 2.834 - 28.0) were associated with reduced disease-specific survival. A prognostic signature, derived from integrating TBs, lymphocyte infiltration, and their spatial relationship, reported a more significant cohort stratification (HR = 18.75, 95% CI 6.46–54.43), than TBs, Immunoscore, or pT stage. This was confirmed in two independent validation cohorts (HR = 12.27, 95% CI 3.524–42.73, HR = 15.61, 95% CI 4.692-51.91). The investigation of the spatial relationship between lymphocytes and TBs within the tumor microenvironment improves accuracy of prognosis of patients with stage II CRC through an automated image analysis and machine learning workflow.PostprintPeer reviewe

Reception of the Herzog Stjepan Vukcic Kosaca in Herzegovina in the Second Half of the 20th Century

U radu se nastoji prikazati recepcija hercega Stjepana Vukčića Kosače u Hercegovini u drugoj polovici 20. stoljeća s posebnim naglaskom na razdoblje u kojemu je Bosna i Hercegovina bila jedna od republika bivše Jugoslavije. S obzirom na činjenicu da bi se barem početno znanje o hercegu Stjepanu trebalo steći tijekom osnovnoga i srednjoškolskoga obrazovanja, najprije je dat osvrt na nastavne planove i programe u kojima su, između ostaloga, naznačeni ciljevi (zadatci) nastave povijesti, a zatim se analiziraju tekstovi u udžbenicima povijesti koji su bili u uporabi u bh. školama (osnovnim i gimnazijama), u kojima se u određenim nastavnim jedinicama obrađuje djelovanje hercega Stjepana. Sudeći prema nastavnim planovima i programima, kao i sadržaju udžbenika iz druge polovice 20. stoljeća (barem nama dostupnima), mladež u Hercegovini u razmatranom razdoblju nije mogla mnogo saznati i naučiti o ovoj povijesnoj osobi, s čijom je titulom povezano ime prostora u kojemu žive. Na kraju istražuje se hercegova prisutnost u nazivima ulica, trgova i institucija u hercegovačkim gradovima i općinama. Istraživanje pokazuje da je tek u novije vrijeme evidentan interes nekih pojedinaca i institucija koje žele ovoj povijesnoj osobi dati značenje koje joj pripada. Naime, sve ulice u Hercegovini koje nose njegovo ime, kao i jedna institucija, imenovane su nakon 1990. godine.With the aim of presenting the reception of the Herzog Stjepan Vukcic Kosaca in Hercegovina in the second half of the 20th century, the paper analyzes the contents of history textbooks that write about the life and work of the Herzog Stjepan and his presence in the names of streets, squares and institutions in Herzegovinian towns and municipalities. Considering the second half of the 20th century, most attention is paid to the period in which Bosnia and Herzegovina was one of the republics of the former Yugoslavia. To illustrate the contents from medieval history, or the ones related to Stjepan, most important are school curricula, in which, apart from the teaching units and lessons, the teaching of history was particularly indicative, when during this period the constant task was "spreading fraternity and unity" or "developing patriotic awareness among students", the emphasis being on teaching history of the "newer period". Judging by the curricula and the content of textbooks from the second half of the 20th century (at least those available to us), the youth of Herzegovina in the mentioned period could not learn much about this historical person whose name is associated with the name of the area in which they live. Namely, by looking at the texts of the textbooks up to the 90s, it is evident that the texts in the textbooks differ, both in scope and emphasis on certain facts. What all the authors mention is taking of the \u27Herzog\u27 title in 1448 and the fall of Herzegovina under the Ottoman rule, whereas all the other facts about the Herzog Stjepan vary from one text to another. As there were no official textbooks in the region of Herzegovina in the 90s of the 20th century, the paper, as an example, presents the texts only from two textbooks (one for elementary school and the other for grammar school) used in some schools in Herzegovina which worked according to the Croatian curriculum, where we can find hardly any information about the Herzog Stjepan. Finally, the results of the research of the Herzog\u27s presence in the names of streets, squares and institutions of the Herzegovinian cities and municipalities show that the interest of some individuals and institutions, who want to give this historical person the significance he deserves, has only recently become evident. Namely, all the streets in Herzegovina named after the Herzog, as well as one institution, got this name after 1990

Assessment of immunological features in muscle-invasive bladder cancer prognosis using ensemble learning

Funding: This research received financial support from Definiens GmbH and the Industrial Centre for AI Research in digital Diagnostics (iCAIRD) which is funded by Innovate UK on behalf of UK Research and Innovation (UKRI) [project number: 104690].The clinical staging and prognosis of muscle-invasive bladder cancer (MIBC) routinely includes the assessment of patient tissue samples by a pathologist. Recent studies corroborate the importance of image analysis in identifying and quantifying immunological markers from tissue samples that can provide further insight into patient prognosis. In this paper, we apply multiplex immunofluorescence to MIBC tissue sections to capture whole-slide images and quantify potential prognostic markers related to lymphocytes, macrophages, tumour buds, and PD-L1. We propose a machine-learning-based approach for the prediction of 5 year prognosis with different combinations of image, clinical, and spatial features. An ensemble model comprising several functionally different models successfully stratifies MIBC patients into two risk groups with high statistical significance (p value < 1×10−5). Critical to improving MIBC survival rates, our method correctly classifies 71.4% of the patients who succumb to MIBC, which is significantly more than the 28.6% of the current clinical gold standard, the TNM staging system.Publisher PDFPeer reviewe

Spatial immune profiling of the colorectal tumor microenvironment predicts good outcome in stage II patients

This study was funded by Medical Research Scotland and Indica Labs, Inc., who also provided in-kind resource.Cellular subpopulations within the colorectal tumor microenvironment (TME) include CD3+ and CD8+ lymphocytes, CD68+ and CD163+ macrophages, and tumor buds (TBs), all of which have known prognostic significance in stage II colorectal cancer. However, the prognostic relevance of their spatial interactions remains unknown. Here, by applying automated image analysis and machine learning approaches, we evaluate the prognostic significance of these cellular subpopulations and their spatial interactions. Resultant data, from a training cohort retrospectively collated from Edinburgh, UK hospitals (n = 113), were used to create a combinatorial prognostic model, which identified a subpopulation of patients who exhibit 100% survival over a 5-year follow-up period. The combinatorial model integrated lymphocytic infiltration, the number of lymphocytes within 50-μm proximity to TBs, and the CD68+/CD163+ macrophage ratio. This finding was confirmed on an independent validation cohort, which included patients treated in Japan and Scotland (n = 117). This work shows that by analyzing multiple cellular subpopulations from the complex TME, it is possible to identify patients for whom surgical resection alone may be curative.Publisher PDFPeer reviewe

Automated tumour budding quantification by machine learning augments TNM staging in muscle-invasive bladder cancer prognosis

Tumour budding has been described as an independent prognostic feature in several tumour types. We report for the first time the relationship between tumour budding and survival evaluated in patients with muscle invasive bladder cancer. A machine learning-based methodology was applied to accurately quantify tumour buds across immunofluorescence labelled whole slide images from 100 muscle invasive bladder cancer patients. Furthermore, tumour budding was found to be correlated to TNM (p = 0.00089) and pT (p = 0.0078) staging. A novel classification and regression tree model was constructed to stratify all stage II, III, and IV patients into three new staging criteria based on disease specific survival. For the stratification of non-metastatic patients into high or low risk of disease specific death, our decision tree model reported that tumour budding was the most significant feature (HR = 2.59, p = 0.0091), and no clinical feature was utilised to categorise these patients. Our findings demonstrate that tumour budding, quantified using automated image analysis provides prognostic value for muscle invasive bladder cancer patients and a better model fit than TNM staging.Publisher PDFPeer reviewe

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease

© 2020, The Author(s). Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation

Simplicity in Visual Representation: A Semiotic Approach

Simplicity, as an ideal in the design of visual representations, has not received systematic attention. High-level guidelines are too general, and low-level guidelines too ad hoc, too numerous, and too often incompatible, to serve in a particular design situation. This paper reviews notions of visual simplicity in the literature within the analytical framework provided by Charles Morris' communication model, specifically, his trichotomy of communication levels—the syntactic, the semantic, and the pragmatic. Simplicity is ultimate ly shown to entail the adjudication of incompatibilities both within, and between, levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68281/2/10.1177_105065198700100103.pd

APOE ε2 resilience for Alzheimer’s disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Introduction The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer\u27s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer\u27s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer\u27s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer\u27s disease and as such represent a potential therapeutic target

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼ 456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P \u3c 1 × 10−3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases