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1.
Toxicol Pathol ; 47(5): 612-633, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31409264

RESUMEN

To further our understanding of the nonhuman primate kidney anatomy, histology, and incidences of spontaneous pathology, we retrospectively examined kidneys from a total of 505 control Cynomolgus monkeys (Macaca fascicularis; 264 male and 241 females) aged 2 to 6 years, from toxicity studies. Kidney weights, urinalysis, and kidney-related clinical biochemistry parameters were also evaluated. Although the functional anatomy of the monkey kidney is relatively similar to that of other laboratory animals and humans, a few differences and species-specific peculiarities exist. Unlike humans, the macaque kidney is unipapillate, with a relatively underdeveloped papilla, scarce long loops of Henle, and a near-equivalent cortical to medullary ratio. The most common spontaneous microscopic findings were interstitial infiltrates or interstitial nephritis and other tubular lesions, but several forms of glomerulopathy that may be interpreted as drug-induced were occasionally observed. Common incidental findings of little pathological significance included: papillary mineralization, epithelial pigment, multinucleate cells, cuboidal metaplasia of the Bowman's capsule, and urothelial inclusions. Kidney weights, and some clinical chemistry parameters, showed age- and sex-related variations. Taken together, these data will aid the toxicologic pathologist to better evaluate the nonhuman primate kidney and assess the species' suitability as a model for identifying and characterizing drug-induced injury.


Asunto(s)
Enfermedades Renales/patología , Riñón/anatomía & histología , Riñón/patología , Animales , Biomarcadores/metabolismo , Femenino , Inmunohistoquímica , Riñón/metabolismo , Enfermedades Renales/metabolismo , Pruebas de Función Renal , Macaca fascicularis , Masculino , Tamaño de los Órganos/fisiología , Especificidad de la Especie , Urinálisis
2.
Toxicol Pathol ; 46(8): 1037-1048, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30352538

RESUMEN

The toxicologic pathologist plays a vital role in the scientific community, using their unique blend of diagnostic and investigative skills to advance biomedical research, public health, drug discovery, or regulatory practices. But what exactly do toxicologic pathologists contribute? Where do these specialized professionals work? How can toxicologic pathologists maximize their efficiency and potential? To enlighten students and trainees, as well as early- or mid-career toxicologic pathologists, or even those approaching retirement, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled "Practical Strategies for Navigating Toxicologic Pathology in One's Early Career…and Beyond!" in conjunction with the STP 37th annual symposium. The workshop featured toxicologic pathologists from contract research organizations and the pharmaceutical industry, who provided their perspectives on career preparation, evolving veterinary pathologist roles within various sectors of toxicologic pathology, the fundamentals of safety assessment, logistics of projects involving good laboratory practices, tools for effective interpretation and communication of anatomic and clinical pathology results, and a recap of scientific resources available to support the toxicologic pathologist in his or her journey. This article provides brief summaries of the talks presented during this career development workshop.


Asunto(s)
Selección de Profesión , Patología , Toxicología , Humanos
3.
Toxicol Pathol ; 46(8): 865-897, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30282530

RESUMEN

The 2018 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Indianapolis, Indiana, at the Society of Toxicologic Pathology's 37th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in a Sprague Dawley rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated swith antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque, and rete ovarii proliferative ovarian lesions in various aged rat strains. One particularly provocative lesion was a malignant neoplastic proliferation in the renal pelvic region of a cynomolgus macaque from a 21-day study. Additional challenging lesions included thyroid proliferative lesions in zebra fish and gross findings in fish larvae during routine chemical screening. The Rabbit and Minipig International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups also presented a series of challenging lesions.


Asunto(s)
Toxicología , Animales
4.
Toxicol Appl Pharmacol ; 327: 59-70, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28433707

RESUMEN

The risk of human exposure to fiber nanoparticles has risen in recent years due to increases in the manufacture and utilization of carbon nanotubes (CNTs). CNTs are present as airborne particulates in occupational settings and their hazard potential has been demonstrated in experimental lung exposure studies using inbred mouse strains. However, it is not known whether different inbred strains differ in lung responses to CNTs by virtue of their genetics. In this work, common inbred strains (BALB/c, C57Bl/6, DBA/2, and C3H/He) were exposed to CNTs via oropharyngeal aspiration and lung histology and bronchoalveolar lavage (BAL) samples were evaluated over 28days with the objective of evaluating sensitivity/resistance among strains. C57Bl/6 mice developed significantly more extensive type II pneumocyte (T2P) hyperplasia and alveolar infiltrate compared to DBA/2 mice, which were resistant. Surprisingly, DBA/2 but not C57Bl/6 mice were extremely sensitive to increases in leukocytes recovered in BAL fluid. Underlying global gene expression patterns in the two strains were compared using mRNA sequencing to investigate regulatory networks associated with the different effects. The impact of exposure on gene networks regulating various aspects of immune response and cell survival was limited in DBA/2 mice compared to C57Bl/6. Investigation of B6D2F1 (C57Bl/6×DBA/2 hybrid) mice demonstrated inheritance of sensitivity to CNT exposures in regard to toxicologic lung pathology and BAL leukocyte accumulations. These findings demonstrate a genetic basis of susceptibility to CNT particle exposures and both inform the use of inbred mouse models and suggest the likelihood of differences in genetic susceptibility among humans.


Asunto(s)
Redes Reguladoras de Genes/efectos de los fármacos , Predisposición Genética a la Enfermedad , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/genética , Nanotubos de Carbono/toxicidad , Animales , Líquido del Lavado Bronquioalveolar/citología , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Recuento de Leucocitos , Pulmón/patología , Enfermedades Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Alveolos Pulmonares/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Especificidad de la Especie
5.
Toxicol Pathol ; 45(8): 1055-1066, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29233079

RESUMEN

To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study #1. Using the diagnostic approach described in part 1, these pathologists examined the same WSI heart sections (exercise #2) to determine whether that approach increased consistency of diagnosis of rodent progressive cardiomyopathy (PCM) lesions. In exercise #2, there was improved consistency of categorization of small borderline morphologies and mild lesions, but a decrement in consistency of categorizing minimal lesions. Exercises 1 and 2 suggest the described diagnostic approach is representative of that in use by the majority of toxicologic pathologists across companies/agencies and that application by all may improve diagnostic consistency of PCM/like lesions. Additionally, a criterion of approximately 5% heart section involvement is suggested for separating mild from moderate or greater severity. While evidence is not absolute, until further investigation shows otherwise, microscopic changes resembling PCM, but located in the epicardial and subepicardial region of the right ventricle, may be considered as part of the spectrum of PCM.


Asunto(s)
Cardiomiopatías/patología , Diagnóstico por Imagen/métodos , Ventrículos Cardíacos/patología , Ratas Sprague-Dawley , Enfermedades de los Roedores/patología , Pruebas de Toxicidad/métodos , Animales , Cardiomiopatías/veterinaria , Cardiotoxicidad/patología , Cardiotoxicidad/veterinaria , Simulación por Computador , Diagnóstico por Imagen/normas , Diagnóstico por Imagen/veterinaria , Progresión de la Enfermedad , Masculino , Pruebas de Toxicidad/veterinaria
6.
Toxicol Pathol ; 45(8): 1043-1054, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29173114

RESUMEN

Spontaneous rodent progressive cardiomyopathy (PCM) in the Sprague Dawley rat may confound identification and/or interpretation of potential test article (TA)-related cardiotoxicity. Pathologists apply diagnostic term(s) and thresholds for diagnosing and assigning severity grades for PCM and/or PCM-like (PCM/like) lesions consistently within a study, which is necessary to identify and interpret TA-related findings. Due to differences in training and/or experiences, diagnostic terms and thresholds may vary between pathologists. Harmonized terminology and thresholds across studies will generate better historical control data, will likely enhance interpretation of study data, and may further enhance our understanding of the spontaneous change. An assessment of the diagnostic approaches of a group of 37 pathologists identified an approach that is relatively easily applied; and if adopted, it could enhance diagnostic consistency across studies. This approach uses the single "slash" term "necrosis/inflammatory cell infiltrate (NICI)" as the diagnosis for the spectrum of lesions seen in younger rats, uses no threshold for diagnosis (e.g., diagnose all lesions clearly identifiable as PCM/like), and uses aggregate lesion size of approximately ≥45% of the field of view (FOV) using a 10×/22 eyepiece and the 40× objective or approximately ≥100% of the FOV using the 60× objective as the criterion separating minimal from mild severities.


Asunto(s)
Cardiomiopatías/patología , Diagnóstico por Imagen/métodos , Ratas Sprague-Dawley , Enfermedades de los Roedores/patología , Pruebas de Toxicidad/veterinaria , Animales , Cardiomiopatías/veterinaria , Cardiotoxicidad/patología , Cardiotoxicidad/veterinaria , Simulación por Computador , Diagnóstico por Imagen/normas , Diagnóstico por Imagen/veterinaria , Progresión de la Enfermedad , Masculino , Necrosis , Índice de Severidad de la Enfermedad
7.
Toxicol Pathol ; 44(2): 211-25, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26839332

RESUMEN

Carbon nanotubes (CNTs) are emerging as important occupational and environmental toxicants owing to their increasing prevalence and potential to be inhaled as airborne particles. CNTs are a concern because of their similarities to asbestos, which include fibrous morphology, high aspect ratio, and biopersistence. Limitations in research models have made it difficult to experimentally ascertain the risk of CNT exposures to humans and whether these may lead to lung diseases classically associated with asbestos, such as mesothelioma and fibrosis. In this study, we sought to comprehensively compare profiles of lung pathology in mice following repeated exposures to multiwall CNTs or crocidolite asbestos (CA). We show that both exposures resulted in granulomatous inflammation and increased interstitial collagen; CA exposures caused predominantly bronchoalveolar hyperplasia, whereas CNT exposures caused alveolar hyperplasia of type II pneumocytes (T2Ps). T2Ps isolated from CNT-exposed lungs were found to have upregulated proinflammatory genes, including interleukin 1ß (IL-1ß), in contrast to those from CA exposed. Immunostaining in tissue showed that while both toxicants increased IL-1ß protein expression in lung cells, T2P-specific IL-1ß increases were greater following CNT exposure. These results suggest related but distinct mechanisms of action by CNTs versus asbestos which may lead to different outcomes in the 2 exposure types.


Asunto(s)
Asbesto Crocidolita/toxicidad , Exposición por Inhalación/análisis , Pulmón/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Neumonía , Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/patología , Animales , Apoptosis , Histocitoquímica , Pulmón/citología , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Ratones , Neumonía/diagnóstico por imagen , Neumonía/patología
8.
Dev Biol ; 374(1): 96-107, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23201579

RESUMEN

Embryonic eyelid closure involves forward movement and ultimate fusion of the upper and lower eyelids, an essential step of mammalian ocular surface development. Although its underlying mechanism of action is not fully understood, a functional mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is required for eyelid closure. Here we investigate the molecular signatures of MAP3K1 in eyelid morphogenesis. At mouse gestational day E15.5, the developmental stage immediately prior to eyelid closure, MAP3K1 expression is predominant in the eyelid leading edge (LE) and the inner eyelid (IE) epithelium. We used laser capture microdissection (LCM) to obtain highly enriched LE and IE cells from wild type and MAP3K1-deficient fetuses and analyzed genome-wide expression profiles. The gene expression data led to the identification of three distinct developmental features of MAP3K1. First, MAP3K1 modulated Wnt and Sonic hedgehog signals, actin reorganization, and proliferation only in LE but not in IE epithelium, illustrating the temporal-spatial specificity of MAP3K1 in embryogenesis. Second, MAP3K1 potentiated AP-2α expression and SRF and AP-1 activity, but its target genes were enriched for binding motifs of AP-2α and SRF, and not AP-1, suggesting the existence of novel MAP3K1-AP-2α/SRF modules in gene regulation. Third, MAP3K1 displayed variable effects on expression of lineage specific genes in the LE and IE epithelium, revealing potential roles of MAP3K1 in differentiation and lineage specification. Using LCM and expression array, our studies have uncovered novel molecular signatures of MAP3K1 in embryonic eyelid closure.


Asunto(s)
Párpados/embriología , Párpados/metabolismo , Regulación de la Expresión Génica , Quinasa 1 de Quinasa de Quinasa MAP/biosíntesis , Quinasa 1 de Quinasa de Quinasa MAP/genética , Animales , ADN Complementario/metabolismo , Perfilación de la Expresión Génica , Genotipo , Captura por Microdisección con Láser/métodos , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , ARN/metabolismo , Factor de Respuesta Sérica/metabolismo , Transducción de Señal , Factores de Tiempo , Distribución Tisular , Factor de Transcripción AP-2/metabolismo
9.
Am J Physiol Heart Circ Physiol ; 306(4): H574-84, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24322617

RESUMEN

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2(-/-) mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2(-/-) mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca(2+) transients and sarcoplasmic reticulum Ca(2+) loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.


Asunto(s)
Canales de Calcio/metabolismo , Corazón/fisiología , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Canales de Calcio/genética , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Ratones , Ratones Noqueados , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Probenecid/farmacología , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/metabolismo , Canales Catiónicos TRPV/genética , Uricosúricos/farmacología
10.
Dis Model Mech ; 17(3)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38501211

RESUMEN

Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.


Asunto(s)
Células Epiteliales , Quinasa 1 de Quinasa de Quinasa MAP , Vagina , Animales , Femenino , Ratones , Células Epiteliales/metabolismo , Epitelio/metabolismo , Vagina/metabolismo , Vía de Señalización Wnt , Quinasa 1 de Quinasa de Quinasa MAP/genética , Quinasa 1 de Quinasa de Quinasa MAP/metabolismo
11.
bioRxiv ; 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37131749

RESUMEN

Mitogen-Activated Protein 3 Kinase 1 (MAP3K1) is a dynamic signaling molecule with a plethora of cell-type specific functions, most of which are yet to be understood. Here we describe a role for MAP3K1 in the development of female reproductive tract (FRT). MAP3K1 kinase domain-deficient ( Map3k1 ΔKD ) females exhibit imperforate vagina, labor failure, and infertility. These defects correspond to a shunted Müllerian duct (MD), the principle precursor of the FRT, in embryos, while they manifest as a contorted caudal vagina with abrogated vaginal-urogenital sinus fusion in neonates. In epithelial cells, MAP3K1 acts through JNK and ERK to activate WNT, yet in vivo MAP3K1 is crucial for WNT activity in mesenchyme associated with the caudal MD. Expression of Wnt7b is high in wild type, but low in Map3k1 knockout MD epithelium and MAP3K1-deficient keratinocytes. Correspondingly, conditioned media derived from MAP3K1-competent epithelial cells activate TCF/Lef-luciferase reporter in fibroblasts, suggesting that MAP3K1-induced factors released from epithelial cells trans-activate WNT signaling in fibroblasts. Our results reveal a temporal-spatial and paracrine MAP3K1-WNT crosstalk contributing to MD caudal elongation and FRT development. Highlights: MAP3K1 deficient female mice exhibit imperforate vagina and infertilityLoss of MAP3K1 kinase activity impedes Müllerian duct (MD) caudal elongation and fusion with urogenital sinus (UGS) in embryogenesisThe MAP3K1-MAPK pathway up-regulates WNT signaling in epithelial cellsMAP3K1 deficiency down-regulates Wnt7b expression in the MD epithelium and prevents WNT activity in mesenchyme of the caudal MD.

12.
JCI Insight ; 8(3)2023 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-36752209

RESUMEN

Acute kidney failure and chronic kidney disease are global health issues steadily rising in incidence and prevalence. Animal models on a single genetic background have so far failed to recapitulate the clinical presentation of human nephropathies. Here, we used a simple model of folic acid-induced kidney injury in 7 highly diverse mouse strains. We measured plasma and urine parameters, as well as renal histopathology and mRNA expression data, at 1, 2, and 6 weeks after injury, covering the early recovery and long-term remission. We observed an extensive strain-specific response ranging from complete resistance of the CAST/EiJ to high sensitivity of the C57BL/6J, DBA/2J, and PWK/PhJ strains. In susceptible strains, the severe early kidney injury was accompanied by the induction of mitochondrial stress response (MSR) genes and the attenuation of NAD+ synthesis pathways. This is associated with delayed healing and a prolonged inflammatory and adaptive immune response 6 weeks after insult, heralding a transition to chronic kidney disease. Through a thorough comparison of the transcriptomic response in mouse and human disease, we show that critical metabolic gene alterations were shared across species, and we highlight the PWK/PhJ strain as an emergent model of transition from acute kidney injury to chronic disease.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Ratones Endogámicos C57BL , NAD , Ratones Endogámicos DBA
13.
J Exp Med ; 220(4)2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-36787127

RESUMEN

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene-environment interactions. We tested the susceptibility of seven mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop hepatic inflammation and the only strain to progress to NASH with extensive fibrosis, while CAST/EiJ mice were completely resistant. Levels of mitochondrial transcripts and proteins as well as mitochondrial function were robustly reduced specifically in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the NASH gene expression profile of PWK/PhJ mice had the highest overlap with the human NASH signature. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model with features of the human NASH.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratones , Humanos , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Ratones Endogámicos C57BL , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Ratones Endogámicos , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Animales de Enfermedad
14.
J Histochem Cytochem ; 70(4): 273-287, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35193424

RESUMEN

B-cell maturation antigen (BCMA) is a target for the treatment of multiple myeloma with cytolytic therapies, such as chimeric antigen receptor T-cells or T-cell redirecting antibodies. To better understand the potential for "on-target/off-tumor" toxicity caused by BCMA-targeting cytolytic therapies in the brain, we investigated normal brain BCMA expression. An immunohistochemistry (IHC) assay using the E6D7B commercial monoclonal antibody was applied to 107 formalin-fixed, paraffin-embedded brain samples (cerebrum, basal ganglia, cerebellum, brainstem; 63 unique donors). Although immunoreactivity was observed in a small number of neurons in brain regions including the striatum, thalamus, midbrain, and medulla, this immunoreactivity was considered nonspecific and not reflective of BCMA expression because it was distinct from the membranous and Golgi-like pattern seen in positive control samples, was not replicated when a different IHC antibody (D6 clone) was used, and was not corroborated by in situ hybridization data. Analysis of RNA-sequencing data from 478 donors in the GTEx and Allen BrainSpan databases demonstrated low levels of BCMA RNA expression in the striatum of young donors with levels becoming negligible beyond 30 years of age. We concluded that BCMA protein is not present in normal adult human brain, and therefore on-target toxicity in the brain is unlikely.


Asunto(s)
Antígeno de Maduración de Linfocitos B , Mieloma Múltiple , Adulto , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/metabolismo , Encéfalo/metabolismo , Humanos , Inmunohistoquímica , Inmunoterapia Adoptiva , Mieloma Múltiple/terapia
15.
J Zoo Wildl Med ; 42(2): 304-8, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22946410

RESUMEN

Two of three captive adult African ostriches exhibited inappetance and weakness. In spite of treatment, the two birds were euthanized because of lack of clinical improvement. Postmortem examination demonstrated exocrine pancreatic degeneration, necrosis, and atrophy. Grossly, one ostrich had a markedly diminished pancreatic mass. Histologically, there was massive pancreatic acinar (exocrine) atrophy, marked interstitial fibrosis, and tubular complex formation in one animal, and the second ostrich had active pancreatic acinar necrosis. Toxicologic testing revealed markedly elevated liver zinc levels in the first two birds, whereas the third ostrich had normal serum levels of zinc and continues without apparent disease. This form of zinc toxicosis, while previously reported in different avian species, has been only rarely described in ratites.


Asunto(s)
Atrofia/veterinaria , Enfermedades de las Aves/inducido químicamente , Enfermedades Pancreáticas/veterinaria , Zinc/toxicidad , Animales , Atrofia/inducido químicamente , Atrofia/patología , Enfermedades de las Aves/patología , Femenino , Masculino , Páncreas/patología , Enfermedades Pancreáticas/inducido químicamente , Enfermedades Pancreáticas/patología , Struthioniformes
16.
Toxicol Sci ; 180(1): 51-61, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33483736

RESUMEN

Two young cynomolgus macaques (Macaca fascicularis) given a small molecule kinase inhibitor ((S)-4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-N-(2-hydroxypropyl)nicotinamide [SCIO-120]) via nasogastric intubation gavage, once-daily for 21 days at 400 mg/kg/day, developed an unusual epithelial proliferative process in the renal parenchyma. Morphological and immunohistochemical characterization of the lesions confirmed an invasive malignant epithelial neoplasm (carcinoma). A similar renal neoplasm was seen in a third macaque after a 14-day exposure to a second kinase inhibitor in the same chemical series ((S) 4-((2-(5-chloro-2-fluorophenyl)-5-methoxypyrimidin-4-yl)amino)-N-cyclopropylnicotinamide [SCIO-974]). Despite remarkably short latency periods, exposure to these kinase inhibitors was likely causally associated with the induction of the renal tumors, as renal carcinomas are exceedingly rare spontaneously in macaques. Both SCIO-120 and SCIO-974 were designed as potent TGFßR1 inhibitors (IC50s 37 and 39 nM, respectively). SCIO-120 and SCIO-974 inhibited additional kinases, most notably closely related ALK4 (IC50 = 34 and 20 nM, respectively), c-Jun n-Terminal kinase 3 (JNK3, IC50 = 10 and 20 nM, respectively), and Fms-related tyrosine kinase 1 (29 and 76 nM, respectively). TGFßR1 has been specifically implicated in epithelial proliferative disorders, including neoplasia. Neither SCIO-120 nor SCIO-974 was genotoxic based on bacterial reverse mutation and/or clastogenicity screening assays. The rapid appearance of renal carcinomas in primates following short-term treatment with nongenotoxic kinase inhibitors is remarkable and suggests that the compounds had noteworthy tumor-enhancing effects, hypothetically linked to their TGFßR1 inhibition activity. These observations have implications for mechanisms of carcinogenesis and TGFßR1 biology.


Asunto(s)
Neoplasias Renales , Neoplasias Glandulares y Epiteliales , Animales , Humanos , Macaca fascicularis , Proteína Quinasa 10 Activada por Mitógenos , Inhibidores de Proteínas Quinasas/toxicidad , Receptor 1 de Factores de Crecimiento Endotelial Vascular
17.
Mol Cancer Ther ; 16(11): 2432-2441, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28864682

RESUMEN

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432-41. ©2017 AACR.


Asunto(s)
Cardiopatía Carcinoide/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/genética , Animales , Cardiopatía Carcinoide/complicaciones , Cardiopatía Carcinoide/genética , Cardiopatía Carcinoide/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Everolimus/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazinas/administración & dosificación , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Toxicology ; 355-356: 9-20, 2016 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-27163630

RESUMEN

Epidemiological studies in humans and experimental work in rodents suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental toxicant, is associated with incidence of heart disease. Although TCDD toxicity depends by and large on the aryl hydrocarbon receptor (AHR), the role of the cardiac AHR in TCDD induced cardiovascular disease is not well defined. To determine whether the Ahr gene mediates disruption of heart function by TCDD, we generated a cardiomyocyte-specific Ahr knockout mouse by crossing Ahr(fx/fx) mice with ßMhc:cre/+ mice, in which expression of Cre recombinase is driven by the promoter of the ßMhc (myosin heavy chain-beta) gene. Starting at three months of age, mice with cardiomyocyte-specific Ahr ablation were exposed to 1µg/kg/week of TCDD or control vehicle by oral gavage for an additional three months. Relative to unexposed controls, TCDD-exposure induced cardiomyocyte Ahr-independent changes in males but not females, including a significant increase in body weight, blood pressure, and cardiac hypertrophy and a decrease in cardiac ejection fraction. TCDD exposure also induced cardiomyocyte Ahr-dependent changes in fibrosis and calcium signaling gene expression in both males and females. TCDD exposure appears to cause sexually dimorphic effects on heart function and induce fibrosis and changes in calcium signaling in both males and females through activation of the cardiomyocyte-specific Ahr.


Asunto(s)
Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/genética , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Femenino , Masculino , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología , Factores Sexuales , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
19.
Toxicol Sci ; 149(2): 346-57, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26572662

RESUMEN

The AHR is a ligand-activated transcription factor that mediates gene-environment interactions. Genome-wide expression profiling during differentiation of mouse ES cells into cardiomyocytes showed that AHR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin; Dioxin (TCDD), its prototypical ligand, disrupted the expression of multiple homeobox transcription factors and inhibited cardiomyocyte contractility. Here we treated ES cells with TCDD at daily differentiation intervals to investigate whether TCDD-induced loss of contractility had a developmental window of sensitivity. Surprisingly, contractility was an AHR-dependent TCDD target solely between differentiation days 0 and 3 during the period of panmesoderm development, when TCDD also disrupted expression of genes in the TGFß/BMP2/4 and wingless-type MMTV integration site (WNT)signaling pathways, suppressed the secretion of bone morphogenetic protein (BMP4), WNT3a, and WNT5a and elevated the secretion of Activin A, as determined by ELISA of the secreted proteins in the culture medium. Supplementing the culture medium with BMP4, WNT3a, or WNT5a during the first 3 days of differentiation successfully countered TCDD-induced impairment of contractility, while anti-WNT3a, or anti-WNT5a antibodies or continuous Noggin (a BMP4 antagonist) or Activin A treatment inhibited the contractile phenotype. In Ahr(+/+), but not in Ahr(-) (/) (-) ES cells, TCDD treatment significantly increased mitochondrial copy number, suggestive of mitochondrial stress and remodeling. Sustained AHR activation during ES cell differentiation appears to disrupt the expression of signals critical to the ontogeny of cardiac mesoderm and cause the loss of contractility in the resulting cardiomyocyte lineage.


Asunto(s)
Activinas/fisiología , Proteínas Morfogenéticas Óseas/fisiología , Células Madre Embrionarias de Ratones/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Células Madre Embrionarias de Ratones/citología , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/fisiología , Receptores de Hidrocarburo de Aril/fisiología , Transducción de Señal/fisiología
20.
Toxicol Sci ; 146(1): 52-64, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25820237

RESUMEN

Complex mixtures of environmental agents often cause mixture-specific health effects that cannot be accounted for by a single mechanism. To study the biological effects of exposure to a mixture of chromium-VI and benzo[a]pyrene (B[a]P), often found together in the environment, we exposed mice for 60 days to 0, 55, 550, or 5500 ppb Cr(VI) in drinking water followed by 90 days of coexposure to B[a]P at 0, 1.25, 12.5, or 125 mg/kg/day and examined liver and gastrointestinal (GI) tract for exposure effects. In the liver, the mixture caused more significant histopathology than expected from the sum of effects of the individual components, while in the GI tract, Cr(VI) alone caused significant enterocyte hypertrophy and increases in cell proliferation and DNA damage that were also observed in mice coexposed to B[a]P. Expression of genes involved in drug metabolism, tumor suppression, oxidative stress, and inflammation was altered in mixed exposures relative to control and to singly exposed mice. Drug metabolism and oxidative stress genes were upregulated and tumor suppressor and inflammation genes downregulated in the proximal GI tract, whereas most markers were upregulated in the distal GI tract and downregulated in the liver. Oral exposure to Cr(VI) and B[a]P mixtures appears to have tissue-specific differential consequences in liver and GI tract that cannot be predicted from the effects of each individual toxicant. Tissue specificity may be particularly critical in cases of extended exposure to mixtures of these agents, as may happen in the occupational setting or in areas where drinking water contains elevated levels of Cr(VI).


Asunto(s)
Benzo(a)pireno/toxicidad , Cromo/toxicidad , Tracto Gastrointestinal/efectos de los fármacos , Hígado/efectos de los fármacos , Animales , Ratones , Ratones Endogámicos C57BL
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