Analyzer · Sparsifire

Analyze how specific documents activate the features of the SAE. Select a dataset, a run and a document to begin.

Dataset

SAE Model

Document

Active Features

1479

MIN ACTIVATION

0.0

Details List

#698 Feature 698

#237 Feature 237

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#268 Feature 268

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#708 Drug Resistance Mechanisms in Cancer

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#2232 Medical Case Reports & Cancer Research

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#3011 Feature 3011

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#1039 Feature 1039

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#1171 Feature 1171

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#1623 Feature 1623

#642 Feature 642

#1336 Feature 1336

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#2785 Feature 2785

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#1121 Feature 1121

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#2619 Feature 2619

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#2171 Molecular and Cellular Biological Processes

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#276 Feature 276

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#2667 Feature 2667

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#2401 Feature 2401

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#2410 Feature 2410

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#2519 Feature 2519

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#768 Feature 768

#1805 Feature 1805

#1334 Feature 1334

#1753 Feature 1753

#2674 Feature 2674

#137 Feature 137

#1764 Feature 1764

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#1734 Feature 1734

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#2622 Feature 2622

#2374 Feature 2374

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#525 Feature 525

#1743 Feature 1743

#1929 Feature 1929

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#233 Feature 233

#857 Feature 857

#1422 Feature 1422

#2962 Feature 2962

#410 Feature 410

#2043 Feature 2043

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#2451 Feature #2451

#3006 Feature 3006

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#1275 Feature 1275

#2267 Feature 2267

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#306 Feature 306

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#1912 Feature 1912

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#574 Feature 574

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#1407 Feature 1407

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#2972 Sensory-Motor Integration

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#3017 Feature 3017

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#1624 Feature 1624

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#23 Neuronal Circuitry and Cellular Processes

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#1311 Molecular Mechanisms and Biological Processes

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#1506 Justification/Rationale for Actions

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#2147 Feature 2147

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#1633 Feature 1633

#2330 Feature 2330

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#223 Feature 223

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#2131 Feature 2131

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Document Content

Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: the dalcetrapib experience.
Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator in clinical assessment for cardiovascular outcome benefits. In compliance with regulatory requirements, dalcetrapib was evaluated in rodent 2-year carcinogenesis bioassays. In the mouse bioassay, male mice demonstrated increased liver weight and statistically increased incidences of hepatocellular adenoma/carcinoma. Hepatic cytochrome p450 (Cyp) 2b10 mRNA induction and increased Cyp2b10 enzyme activity signify activation of hepatic nuclear receptor constitutive androstane receptor (CAR), a widely established promoter of rodent-specific hepatic tumors. We therefore monitored hepatic Cyp2b10 mRNA and its enzyme activity in a subset of dalcetrapib-treated male mice from the bioassay. Liver samples were obtained from ~1/3 of male mice from each dose group including vehicle-controls (mean and earliest study day of death 678 and 459 respectively). Quantitative real time PCR (qRT-PCR) was performed to determine Cyp2b10 mRNA expression and Cyp1a-, Cyp2b10- and Cyp3a-selective activities were monitored. Cyp2b10 mRNA was strongly induced by dalcetrapib with an expected wide inter-individual variation (5-1421-fold). Group average fold-induction versus vehicle-controls showed a dose-related increase from 48-fold (250mg/kg/day) to 160-fold (750mg/kg/day), which declined slightly at 2000mg/kg/day (97-fold). Cyp enzyme activities showed approximate doubling of total Cyp P450 content per milligram protein and a 9-fold increase in Cyp2b10-selective pentoxyresorufin O-dealkylase activity (750mg/kg/day). These data from hepatic Cyp2b10 monitoring are strongly suggestive of CAR activation by dalcetrapib, a mechanism devoid of relevance towards hepatocarcinogenesis in humans; results show feasibility of Cyp2b10 as a surrogate marker for this mechanism at cessation of a carcinogenesis bioassay.

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