PDGFRß promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRß. Blocking PDGFRß kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRß-driven human ALCL in vivo, we identify PDGFRß as a driver of aggressive tumor growth. Mechanistically, PDGFRß induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRß as a novel biomarker and introduce PDGFRß-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRß or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

Cerebral and Peripheral Metabolism to Predict Successful Reperfusion After Cardiac Arrest in Rats: A Microdialysis Study.

BACKGROUND: In clinical practice, monitoring of the efficacy of resuscitation can be challenging. The prediction of cerebral and overall outcome in particular is an unmet medical need. Microdialysis is a minimally invasive technique for the continuous determination of metabolic parameters in vivo. Using this technique, we set out to establish a model allowing for concomitant determination of cerebral and peripheral metabolism in a cardiac arrest setting in rodents. METHODS: Microdialysis settings were optimized in vitro and then used in male Sprague-Dawley rats. Probes were implanted into the CA1 region of the right hippocampus and the right femoral vein. With a time interval of 8 min, glucose, lactate, pyruvate, and glutamate levels were determined during baseline conditions, untreated ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation (CPR), reperfusion, and death. RESULTS: In 16 rodents, restoration of spontaneous circulation was achieved in seven animals. Characteristic metabolic changes were evident during cardiac arrest and reperfusion with both probes. Ischemic patterns in peripheral compartments were delayed and more variable compared to the changes in cerebral metabolism highlighting the importance of cerebral metabolic monitoring. Microdialysis allowed distinguishing between survivors and non-survivors 8 min after termination of CPR. Cerebral glutamate showed a trend toward higher levels in non-survivors during CPR. CONCLUSIONS: We established a new rodent model for research in hypoxic ischemic encephalopathy. This setting allows to investigate the impact of resuscitation methods on cerebral and peripheral metabolism simultaneously. The present model may be used to evaluate different resuscitation strategies in order to optimize brain survival in future studies.

Spongy degeneration with cerebellar ataxia in Malinois puppies: a hereditary autosomal recessive disorder?

BACKGROUND: There is a high incidence of hereditary degenerative diseases of the central nervous system in purebred dogs. HYPOTHESIS: Cerebellar ataxia in Malinois puppies, caused by degenerative changes that predominate in cerebellar nuclei and the granular cell layer, is a hereditary disorder that is distinct from cerebellar cortical abiotrophies. ANIMALS: Thirteen Malinois puppies with cerebellar ataxia. METHODS: Retrospective study. Records of Malinois puppies with spongy degeneration of the cerebellar nuclei were analyzed including clinical signs, histopathological changes, and pedigree data. RESULTS: Signs of cerebellar dysfunction were observed in puppies of both sexes from 5 different litters (1995-2009) of phenotypically normal parents. Clinical signs started before the age of 2 months and resulted in euthanasia of all puppies by the age of 13 weeks. Histopathology disclosed marked bilateral spongy degeneration of the cerebellar nuclei and vacuoles in the granular cell layer and foliate white matter of the cerebellum. In some puppies, discrete vacuoles in gray and white matter were present in other parts of the brain. Furthermore, spheroids and dilated myelin sheaths were observed. Pedigree data and segregation frequency support an autosomal recessive hereditary disorder. CONCLUSIONS AND CLINICAL IMPORTANCE: Malinois suffer from a hereditary spongiform degeneration that predominates in the cerebellum and causes an early onset of clinical signs with unfavorable prognosis. Future efforts should increase awareness among veterinarians and breeders and aim to identify underlying metabolic mechanisms and the affected genes.

Benign intrapericardial lipoma in a dog.

SUMMARY: Canine lipomas generally develop in subcutaneous tissue. Intrapericardial lipomas are extremely rare benign tumours and can develop on the pericardial surface of the heart or inside the cardiac chambers. As the thoracic cavity is an unusual site for lipomas in dogs, we describe, clinically and pathologically, a case of intrapericardial lipoma in an 18-months old German Shepherd.