RÉSUMÉ
PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. RESULTS: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Cytokines/antagonistes et inhibiteurs , Leucémie aigüe myéloïde/traitement médicamenteux , Nicotinamide phosphoribosyltransferase/antagonistes et inhibiteurs , Protéines de répression/antagonistes et inhibiteurs , Sirtuines/antagonistes et inhibiteurs , Acrylamides/pharmacologie , Acrylamides/usage thérapeutique , Aminopyridines/pharmacologie , Aminopyridines/usage thérapeutique , Animaux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Lignée cellulaire tumorale , Altération de l'ADN , Réparation de l'ADN par jonction d'extrémités/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Techniques de knock-out de gènes , Histone deacetylases/génétique , Histone deacetylases/métabolisme , Humains , Acides hydroxamiques/pharmacologie , Acides hydroxamiques/usage thérapeutique , Indoles/pharmacologie , Indoles/usage thérapeutique , Leucémie aigüe myéloïde/anatomopathologie , Mâle , Souris , Phénylbutyrates/pharmacologie , Phénylbutyrates/usage thérapeutique , Réparation de l'ADN par recombinaison/effets des médicaments et des substances chimiques , Protéines de répression/génétique , Protéines de répression/métabolisme , Sirtuines/génétique , Sirtuines/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
A 4-year-old female spayed Pomeranian presented for being unable to use its pelvic limbs after a fall. The dog was paraplegic with absent pelvic limb nociception and a Schiff-Sherrington posture. Radiographs and Computed tomography showed a T11-T12 luxation. Spinal stabilization was performed for pain control. Twenty-four hours following surgery the patient lost pelvic limb reflexes. Twelve hours later she lost cutaneous trunci and forelimb proprioception and had increased respiratory effort. A diagnosis of progressive myelomalacia was made and the patient was euthanized. Most cases of progressive myelomalacia in dogs are due to intervertebral disc herniation. To the authors' knowledge, myelomalacia secondary to spinal fracture has not been reported.
Sujet(s)
Chiens/traumatismes , Déplacement de disque intervertébral/médecine vétérinaire , Maladies de la moelle épinière/médecine vétérinaire , Fractures du rachis/médecine vétérinaire , Vertèbres thoraciques , Chutes accidentelles , Animaux , Diagnostic différentiel , Chiens/chirurgie , Femelle , Déplacement de disque intervertébral/chirurgie , Complications postopératoires/diagnostic , Complications postopératoires/médecine vétérinaire , Maladies de la moelle épinière/diagnostic , Fractures du rachis/chirurgieRÉSUMÉ
A 4-year-old male neutered domestic shorthair cat was presented to The Ohio State University College of Veterinary Medicine for a 2-month history of severe weight loss, lethargy, anemia, and bilaterally hyperechoic kidneys with loss of corticomedullary distinction as reported by the referring veterinarian. Relevant initial laboratory results included severe non-regenerative normocytic hypochromic anemia, increased blood urea nitrogen, minimally concentrated urine, proteinuria, and an increased urine protein:creatinine ratio. Cytologic evaluation of a bone marrow aspirate revealed a markedly hypocellular marrow with abundant mucinous material. Gelatinous marrow transformation (GMT) was confirmed histologically by the presence of mucinous material in the bone marrow that stained positive for Alcian blue but negative for periodic acid-Schiff. The cat died despite repeated blood transfusions and supportive care. Gelatinous marrow transformation, immune complex-mediated membranoproliferative glomerulonephritis, and gastrointestinal hemorrhage were observed on autopsy and histology. It is likely that the development of GMT was secondary to chronic kidney disease (CKD) and that CKD, GMT, and gastrointestinal hemorrhage contributed to the cat's non-regenerative anemia.
Sujet(s)
Anémie/médecine vétérinaire , Maladies des chats/anatomopathologie , Anémie/anatomopathologie , Anémie/thérapie , Animaux , Transfusion sanguine/médecine vétérinaire , Moelle osseuse/anatomopathologie , Maladies des chats/thérapie , Chats , Issue fatale , MâleRÉSUMÉ
We present the first documented case of Trypanosoma cruzi-induced orchitis in a rhesus macaque. Additionally, we describe an in situ hybridization-based assay to confirm T. cruzi infection in formalin-fixed tissues.
Sujet(s)
Cardiomyopathie associée à la maladie de Chagas/médecine vétérinaire , Hybridation in situ/médecine vétérinaire , Macaca mulatta , Maladies des singes/diagnostic , Orchite/médecine vétérinaire , Trypanosoma cruzi/isolement et purification , Animaux , Cardiomyopathie associée à la maladie de Chagas/diagnostic , Cardiomyopathie associée à la maladie de Chagas/parasitologie , Hybridation in situ/méthodes , Mâle , Maladies des singes/parasitologie , Orchite/parasitologieRÉSUMÉ
OBJECTIVES: This study investigated the effects of cigarette smoke exposure on the pig larynx using an inhalation chamber. Specifically, we compared the effects of cigarette smoke exposure from either 3 cigarettes per day (3cd) or 15 cigarettes per day (15cd) for 20 days. STUDY DESIGN: In vivo prospective design. METHODS: Female pigs were exposed via an inhalation chamber to cigarette smoke (3R4F research cigarettes) from 3cd (nâ¯=â¯6) or 15cd (nâ¯=â¯6) for 20 days. Outcomes included histopathology of vocal fold and airway tissues; gene expression of interleukins, TNF-α, and VEGF; protein levels of TNF-α and IL-6; and number of coughs recorded in the chamber. RESULTS: Pigs exposed to cigarette smoke from 15cd exhibited mild vocal fold edema as compared to the 3cd group on histopathological evaluation. There was also minimal inflammation of nasal and tracheal tissue characterized by presence of more granulocytes in the 15cd group compared to the 3cd group. Cough frequency was significantly greater for the 15cd group compared to the 3cd group. CONCLUSIONS: A custom-designed large animal inhalation chamber successfully challenged pigs repeatedly, to varying levels of cigarette smoke. Future studies will combine such low levels of smoke exposure with other common challenges such as acid reflux to understand the multifactorial causation of laryngeal pathologies.
Sujet(s)
Fumer des cigarettes/effets indésirables , Toux/étiologie , Exposition par inhalation/effets indésirables , Oedème laryngé/étiologie , Fumée/effets indésirables , Plis vocaux , Animaux , Toux/métabolisme , Toux/anatomopathologie , Toux/physiopathologie , Cytokines/génétique , Cytokines/métabolisme , Femelle , Médiateurs de l'inflammation/métabolisme , Oedème laryngé/métabolisme , Oedème laryngé/anatomopathologie , Oedème laryngé/physiopathologie , Suidae , Porc miniature , Facteurs temps , Facteur de croissance endothéliale vasculaire de type A/génétique , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Plis vocaux/métabolisme , Plis vocaux/anatomopathologie , Plis vocaux/physiopathologieRÉSUMÉ
In a large-scale ageing study, 30 inbred mouse strains were systematically screened for histologic evidence of lesions in all organ systems. Ten strains were diagnosed with similar nail abnormalities. The highest frequency was noted in NON/ShiLtJ mice. Lesions identified fell into two main categories: acute to chronic penetration of the third phalangeal bone through the hyponychium with associated inflammation and bone remodelling or metaplasia of the nail matrix and nail bed associated with severe orthokeratotic hyperkeratosis replacing the nail plate. Penetration of the distal phalanx through the hyponychium appeared to be the initiating feature resulting in nail abnormalities. The accompanying acute to subacute inflammatory response was associated with osteolysis of the distal phalanx. Evaluation of young NON/ShiLtJ mice revealed that these lesions were not often found, or affected only one digit. The only other nail unit abnormality identified was sporadic subungual epidermoid inclusion cysts which closely resembled similar lesions in human patients. These abnormalities, being age-related developments, may have contributed to weight loss due to impacts upon feeding and should be a consideration for future research due to the potential to interact with other experimental factors in ageing studies using the affected strains of mice.
Sujet(s)
Vieillissement/anatomopathologie , Ongles malformés/anatomopathologie , Phalanges des orteils/anatomopathologie , Animaux , Remodelage osseux , Études transversales , Kyste épidermique/complications , Femelle , Inflammation/étiologie , Kératine-1/métabolisme , Kératine-10/métabolisme , Kératose/étiologie , Études longitudinales , Mâle , Métaplasie/anatomopathologie , Souris , Lignées consanguines de souris , Ongles malformés/étiologie , Ongles malformés/métabolismeRÉSUMÉ
BACKGROUND: Uremic encephalopathy is uncommon yet is one of the most severe complications of renal failure. We present a case of acute renal failure and associated cerebral and vascular lesions consistent with uremic encephalopathy in a rhesus macaque (Macaca mulatta). METHODS: A 14-year-old, female, specific-pathogen-free rhesus macaque presented in lateral recumbency, obtunded, severely dehydrated, and hypothermic, with severe azotemia, mild hyponatremia, hypokalemia, hypochloremia, increased anion gap, and hypercholesterolemia. Due to poor prognosis, the animal was euthanized and a complete necropsy was conducted. RESULTS: The animal had diffuse proximal renal tubular epithelial necrosis and loss; regeneration of tubular epithelium was not observed. There was bilateral necrosis and loss of neurons and glial cells in the hippocampus and deep cerebral cortex with edema and multifocal areas of hemorrhage. CONCLUSION: We present the first reported case of uremic encephalopathy in a rhesus macaque and describe the associated cerebral and vascular lesions.