Prediction of m6A and m5C at single-molecule resolution reveals a transcriptome-wide co-occurrence of RNA modifications.

The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI's capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.

Regional yttrium-90 microsphere treatment of surgically unresectable and chemotherapy-refractory metastatic liver carcinoma.

PURPOSE: The aim of this prospective study was to assess the safety and tumor response of intra-arterial Y-90 microspheres for the treatment of surgically unresectable and chemotherapy-refractory liver metastases. MATERIALS AND METHODS: Forty-six (46) patients with metastatic cancer to the liver from various solid tumors, with tumor progression despite polychemotherapy, were included. All patients had baseline computed tomography (CT), 18-Fluoro-2-deoxy-D-glucose-positron emission tomography (F-18 FDG-PET), hepatic angiography, and intra-arterial Tc-99m macroaggregated albumin (MAA) scan for the assessment of extrahepatic aberrant perfusion and lung shunting fraction. Twenty-seven (27) and 19 patients were treated with Y-90 glass- or resin-based microspheres (but not both), respectively, on a lobar basis and were monitored over 3 months after last treatment using dedicated attenuation corrected PET. For each patient, regions of interest (ROIs) were drawn along the liver edge to measure total liver standard uptake value (SUV) on axial images covering the entire liver for comparing pre- and post-treatment total liver SUV change. RESULTS: There was a significant decrement in total liver SUV after treatment by either glass- or resin-based microspheres (p = 0.0013 and 0.028, respectively). There was no significant difference in the amplitudes of the mean percentage reduction of tumor metabolism between these two agents (20% +/- 25% vs. 10% +/- 30% for glass- vs. resin-based microspheres; p = 0.38). None of the patients in the glass-based group developed complications, whereas 3 patients had complications related to hyperbilirubinemia (1 transient and 2 permanent) in the resin-based group. CONCLUSIONS: Results suggest that there is significant mean reduction of hepatic metastatic tumor load (metabolism), as evaluated objectively by PET after Y-90 microsphere, for the treatment of unresectable metastatic disease to the liver. The Y-90 therapy provides encouraging and safe results by arresting the progression of metastatic cancer to the liver with decreasing tumor metabolism.

Reduction of metastatic load to liver after intraarterial hepatic yttrium-90 radioembolization as evaluated by [18F]fluorodeoxyglucose positron emission tomographic imaging.

PURPOSE: To assess the response of hepatic metastases after treatment with intraarterial yttrium 90 radioembolization (ie, use of SIR-Spheres) with use of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). MATERIALS AND METHODS: Nineteen patients with metastatic cancer to the liver from various solid tumors with progression despite polychemotherapy were included. All patients underwent baseline computed tomography, FDG PET, hepatic angiography, and intraarterial technetium 99 m macroaggregated albumin scan for assessment of lung shunting fraction. Patients were treated with 90Y resin microspheres on a lobar basis and were monitored for 3 months with use of dedicated attenuation-corrected PET. For each patient, regions of interest were drawn along the liver edge to measure total liver standard uptake value (SUV) on axial images, covering the entire liver. Visual estimates were also performed and graded as +1, 0, -1, -2, or -3 for progression, no change, and mild, moderate, and dramatic improvement by posttreatment PET. RESULTS: The median absorbed dose for the tumor was 76 Gy. There was a significant overall decrease in total liver SUV after treatment (baseline, 71,134 +/- 38,055; after SIR-Sphere treatment, 59,941 +/- 26,509; P = .028) for the entire group. Visual estimates placed 15 patients (79%) in response categories (-3 to -1) and four patients (21%) in nonresponse categories (0 to +1) for the liver. The percentage change of total liver SUV after treatment in the response group (-19%) was significantly greater and different in direction than that in the nonresponse group (+27%; P = .03). This percentage change was also correlated significantly with the respective visual estimates (r = 0.72; P < .0005) for each individual patient. Three patients had major complications related to hyperbilirubinemia (transient, n = 1; permanent, n= 2). CONCLUSIONS: The results suggest that there is significant reduction of hepatic metastatic load as evaluated objectively by PET after 90Y radioembolization for the treatment of unresectable metastatic disease to the liver. 90Y radioembolization provides encouraging results by arresting progression of metastatic cancer to the liver.