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There is an urgent need for the identification of reliable prognostic biomarkers for patients with intrahepatic cholangiocarcinoma (iCCA) and alterations in N-glycosylation have demonstrated an immense potential to be used as diagnostic strategies for many cancers, including hepatocellular carcinoma (HCC). N-glycosylation is one of the most common post-translational modifications known to be altered based on the status of the cell. N-glycan structures on glycoproteins can be modified based on the addition or removal of specific N-glycan residues, some of which have been linked to liver diseases. However, little is known concerning the N-glycan alterations that are associated with iCCA. We characterized the N-glycan modifications quantitatively and qualitatively in three cohorts, consisting of two tissue cohorts: a discovery cohort (n = 104 cases) and a validation cohort (n = 75), and one independent serum cohort consisting of patients with iCCA, HCC, or benign chronic liver disease (n = 67). N-glycan analysis in situ was correlated to tumor regions annotated on histopathology and revealed that bisected fucosylated N-glycan structures were specific to iCCA tumor regions. These same N-glycan modifications were significantly upregulated in iCCA tissue and serum relative to HCC and bile duct disease, including primary sclerosing cholangitis (PSC) (P < 0.0001). N-glycan modifications identified in iCCA tissue and serum were used to generate an algorithm that could be used as a biomarker of iCCA. We demonstrate that this biomarker algorithm quadrupled the sensitivity (at 90% specificity) of iCCA detection as compared with carbohydrate antigen 19-9, the current “gold standard” biomarker of CCA.Significance:This work elucidates the N-glycan alterations that occur directly in iCCA tissue and utilizes this information to discover serum biomarkers that can be used for the noninvasive detection of iCCA.

A. Scatterplots and correlations between N-glycans of interest (1339, 1257, 2158) and clinical information available (ALT, AST, ALK, and AFP). B. Multivariate model-Multiple logistic regression in CCA and PSC serum samples (n=40). Model 1: three N-glycans of interest and clinical information available (left panel). Model 2: Only the three N-glycans of interest (right panel). C. ROC curve of the combination of glycans and clinical information (red-solid line) and only glycans (green-dashed line) (left), classification performance table of the two models in B. p=0.5731, Delong’s test between model 1 and 2. CA19-9, ALT, AST, ALK, and AFP values were log-transformed for plotting and modeling convenience. logALT was removed from the multiple logistic regression analysis due to a high value of Variance inflation factor (VIF).

There is an urgent need for the identification of reliable prognostic biomarkers for patients with intrahepatic cholangiocarcinoma (iCCA) and alterations in N-glycosylation have demonstrated an immense potential to be used as diagnostic strategies for many cancers, including hepatocellular carcinoma (HCC). N-glycosylation is one of the most common post-translational modifications known to be altered based on the status of the cell. N-glycan structures on glycoproteins can be modified based on the addition or removal of specific N-glycan residues, some of which have been linked to liver diseases. However, little is known concerning the N-glycan alterations that are associated with iCCA. We characterized the N-glycan modifications quantitatively and qualitatively in three cohorts, consisting of two tissue cohorts: a discovery cohort (n = 104 cases) and a validation cohort (n = 75), and one independent serum cohort consisting of patients with iCCA, HCC, or benign chronic liver disease (n = 67). N-glycan analysis in situ was correlated to tumor regions annotated on histopathology and revealed that bisected fucosylated N-glycan structures were specific to iCCA tumor regions. These same N-glycan modifications were significantly upregulated in iCCA tissue and serum relative to HCC and bile duct disease, including primary sclerosing cholangitis (PSC) (P < 0.0001). N-glycan modifications identified in iCCA tissue and serum were used to generate an algorithm that could be used as a biomarker of iCCA. We demonstrate that this biomarker algorithm quadrupled the sensitivity (at 90% specificity) of iCCA detection as compared with carbohydrate antigen 19-9, the current “gold standard” biomarker of CCA.Significance:This work elucidates the N-glycan alterations that occur directly in iCCA tissue and utilizes this information to discover serum biomarkers that can be used for the noninvasive detection of iCCA.

Lists individual N-glycans, ALT (Alanine transaminase), AST (aspartate aminotransferase), ALK (Alkaline phosphatase), and AFP (Alpha-fetoprotein) of analysis to differentiate patients with iCCA from PSC. 1Possible biomarkers 2n: number of total patients 3distribution of iCCA (n=30) and PSC (n=17) patients. 4AUC (Area Under the Curve) 5CI (confidence interval) 6p value. Some iCCA patients were excluded from the analysis due to missing clinical information.

An overview of how HCC samples are classified into one of three subtypes based upon a variety of histological, clinical, and genetic data. Genetic data is generated through RNA-seq of the HCC samples.

Full list of glycans analyzed on the FT-ICR mass spectrometer.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically.Implications:Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.

"One must assume we are all familiar with what is commonly called ‘education.’" This is how Schleiermacher begins his famous 1826 lecture on the Art of Education. But in proceeding further—and unlike Rousseau or Locke before him—Schleiermacher carefully avoids assuming that education is primarily about a return to nature or about "soundness" of mind and body. Education is instead an ethical and political undertaking and a pragmatic art whose ultimate object and morality has differed greatly over time. It is exercised as a form of practical influence of the older generation on the younger: "A significant part of the activity of the older generation extends toward the younger," Schleiermacher reasons, and it "is more complete and perfect the more it is governed by an idea of what should happen—the more it has an exemplar to guide its action—the more it is an art." This book offers these and other insights on education—long canonical in Central and Northern Europe—for the first time to an English audience. It also provides five chapters by scholars in education and its history that discuss various aspects of Schleiermacher’s lecture.

The indoctrination debates have been a key feature of the philosophy of education over the past 50 years. While it is generally acknowledged that the pejorative associations of indoctrination only emerged over the last 100 years, those normative associations are widely taken to be an essential part of the concept itself as are the positive connotations of education. I explore some of the problems of assuming that the term must refer to something negative and the essentialism that this implies. The attempt to ‘transvaluate’ indoctrination results in the claim that the concept is virtually indistinguishable from education. Drawing on Ivan Snook's Indoctrination and Education, I examine several candidates for indoctrination to show that the pejorative label is not a good fit. I argue that much of what is framed as indoctrination turns out to be either impossible–implausible or necessary–inevitable; the fact that there is scarcely a gap between these extremes should give us pause to wonder about this term and its relation to education: By providing a term for those influences of which we generally disapprove, does the concept of indoctrination act as a way for educationalists to uphold and protect the normative view of education (that education must aim for something intrinsically worthwhile)? Eds.: This paper forms part of a Special Issue entitled ‘Beyond Virtue and Vice: Education for a Darker Age’ in which the editors invited authors to engage in exercises of ‘transvaluation’. Certain apparently settled educational concepts (from agency and fulfilment to alienation and ignorance) can be reinterpreted and transvaluated (in a Nietzschean vein) such that virtues become vices, and vices, virtues. The editors encouraged authors to employ polemics and some occasional exaggeration to reimagine educational values that are all too readily accepted within contemporary educational discourses.