Squalene Epoxidase Induces Nonalcoholic Steatohepatitis Via Binding to Carbonic Anhydrase III and is a Therapeutic Target

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Artificial Intelligence System to Determine Risk of T1 Colorectal Cancer Metastasis to Lymph Node

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Emerging Tests for Noninvasive Colorectal Cancer Screening

Colorectal cancer (CRC) is among the most common cancers globally and a major cause of cancer-related deaths. The American Cancer Society estimates that CRC will kill 1 in 60 Americans, and CRC screening is recommended for all Americans ≥45 years of age. Current CRC screening methods are effective for preventing CRC and have been shown to reduce CRC-related mortality. However, none of the currently available tests is ideal, and many people are not compliant with screening recommendations. Novel screening tests based on advances in CRC molecular biology, genetics, and epigenetics, combined with developments in sequencing technologies and computational analytic methods, have been developed to address the shortcomings of current CRC screening tests. These emerging tests include blood-based assays that use plasma-derived circulating tumor DNA and serum proteins to detect early CRC and advanced adenomas, assays that use stool DNA or mRNA, and methods for profiling the gut microbiome. Here we review current screening modalities, and we discuss the principles behind the most promising emerging CRC screening tests and the data supporting their potential to be used in clinical practice.     

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC

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Population-based Screening for Hereditary Colorectal Cancer Variants in Japan

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Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

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N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy

Background & AimsAdvanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.MethodsSpontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.ResultsThe conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.ConclusionsTogether, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.