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1.
Toxicol Pathol ; 46(6): 671-682, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29945496

RESUMEN

An increased incidence of renal tubular adenomas and carcinomas was identified in the 2-year CD-1 mouse carcinogenicity study with empagliflozin (sodium-glucose transporter 2 inhibitor) in high dose (1,000 mg/kg/day) male mice. A 13-week mouse renal investigative pathogenesis study was conducted with empagliflozin to evaluate dose dependency and temporal onset of nonneoplastic degenerative/regenerative renal tubular and molecular (genes, pathways) changes which precede neoplasia. Male and female CD-1 mice were given daily oral doses of 0, 100, 300, or 1,000 mg/kg/day (corresponding carcinogenicity study dose levels) for 1, 2, 4, 8, or 13 weeks. The maximum expected pharmacology with secondary osmotic diuresis was observed by week 1 at ≥100 mg/kg/day in both genders. Histopathologic kidney changes were first detected after 4 weeks of dosing in the male 1,000 mg/kg/day dose group, with progressive increases in the incidence and/or number of findings in this dose group so that they were more readily detected during weeks 8 and 13. Changes detected starting on week 4 consisted of minimal single-cell necrosis and minimal increases in mitotic figures. These changes persisted at an increased incidence at weeks 8 and 13 and were accompanied by minimal to mild tubular epithelial karyomegaly, minimal proximal convoluted tubular epithelial cell hyperplasia, and a corresponding increase in Ki-67-positive nuclei in epithelial cells of the proximal convoluted tubules. There were no corresponding changes in serum chemistry or urinalysis parameters indicative of any physiologically meaningful effect on renal function and thus these findings were not considered to be adverse. Similar changes were not identified in lower-dose groups in males nor were they present in females of any dose group. RNA-sequencing analysis revealed male mouse-specific changes in kidney over 13 weeks of dosing at 1,000 mg/kg/day. Treatment-related changes included genes and pathways related to p53-regulated cell cycle and proliferation, transforming growth factor ß, oxidative stress, and renal injury and the number of genes with significant expression change dramatically increased at week 13. These treatment-related changes in genes and pathways were predominant in high-dose males and complemented the observed temporal renal tubular changes. Overall, these mouse investigative study results support the role of early empagliflozin-related degenerative/regenerative changes only observed in high-dose male CD-1 mice as a key contributing feature to a nongenotoxic mode of renal tumor pathogenesis.


Asunto(s)
Compuestos de Bencidrilo/toxicidad , Glucósidos/toxicidad , Enfermedades Renales/inducido químicamente , Túbulos Renales/efectos de los fármacos , Lesiones Precancerosas/inducido químicamente , Inhibidores del Cotransportador de Sodio-Glucosa 2/toxicidad , Administración Oral , Animales , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/sangre , Relación Dosis-Respuesta a Droga , Femenino , Glucósidos/administración & dosificación , Glucósidos/sangre , Enfermedades Renales/patología , Pruebas de Función Renal , Túbulos Renales/patología , Masculino , Ratones Endogámicos , Necrosis , Lesiones Precancerosas/patología , Factores Sexuales , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/sangre , Pruebas de Toxicidad Subcrónica , Toxicocinética , Transcriptoma/efectos de los fármacos
2.
Arch Pathol Lab Med ; 141(9): 1267-1275, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28557614

RESUMEN

CONTEXT: - Novel therapeutics often target complex cellular mechanisms. Increasingly, quantitative methods like digital tissue image analysis (tIA) are required to evaluate correspondingly complex biomarkers to elucidate subtle phenotypes that can inform treatment decisions with these targeted therapies. These tIA systems need a gold standard, or reference method, to establish analytical validity. Conventional, subjective histopathologic scores assigned by an experienced pathologist are the gold standard in anatomic pathology and are an attractive reference method. The pathologist's score can establish the ground truth to assess a tIA solution's analytical performance. The paradox of this validation strategy, however, is that tIA is often used to assist pathologists to score complex biomarkers because it is more objective and reproducible than manual evaluation alone by overcoming known biases in a human's visual evaluation of tissue, and because it can generate endpoints that cannot be generated by a human observer. OBJECTIVE: - To discuss common visual and cognitive traps known in traditional pathology-based scoring paradigms that may impact characterization of tIA-assisted scoring accuracy, sensitivity, and specificity. DATA SOURCES: - This manuscript reviews the current literature from the past decades available for traditional subjective pathology scoring paradigms and known cognitive and visual traps relevant to these scoring paradigms. CONCLUSIONS: - Awareness of the gold standard paradox is necessary when using traditional pathologist scores to analytically validate a tIA tool because image analysis is used specifically to overcome known sources of bias in visual assessment of tissue sections.


Asunto(s)
Biomarcadores/análisis , Interpretación de Imagen Asistida por Computador/métodos , Inmunohistoquímica/métodos , Patología Clínica/métodos , Humanos
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