To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.

Fifty-one cases of canine peripheral nerve sheath tumors were reviewed. Signalment, presenting clinical signs, duration of clinical signs, physical and neurological examination findings, results of diagnostic procedures, type of surgery performed, tumor location, relapse-free intervals and survival times, and causes of death were evaluated. Tumors were divided into three anatomical groups: tumors involving nerves distal to the brachial or lumbosacral plexus (Peripheral Group), tumors involving nerves of the brachial or lumbosacral plexus (Plexus Group), and tumors involving the vertebral canal (Root Group). The most common clinical findings were unilateral forelimb lameness and muscle atrophy. The most useful diagnostic tests were myelography and electromyography. Although there was no significant difference, dogs in the Root Group tended to have shorter relapse-free intervals and survival times than dogs in the Plexus Group. The overall prognosis for surgical management of peripheral nerve sheath tumors is guarded to poor.

Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells (hMECs) activates Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway, which induces EMT-like reprogramming to fibroblastic morphology, loss of cell polarity, contact inhibition and acquired migratory and invasive phenotype. Notably, mtDNA reduction generates breast cancer stem cells. In addition to retrograde signaling markers, there is an induction of mesenchymal genes but loss of epithelial markers in these cells. The changes are reversed by either restoring the mtDNA content or knockdown of CnAα mRNA, indicating the causal role of retrograde signaling in EMT. Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells, which evade conventional therapies. We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs.

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Vascular hamartomas are considered developmental lesions rather than true neoplasms. Reports of such anomalies in the canine brain are scarce, and their classification is confusing. This case series of vascular hamartomas from the brains of five dogs was characterized using histochemistry and immunohistochemistry, in addition to gross and microscopic findings. All five hamartomas were located in the telencephalon, three in the pyriform lobe, without any predilection for the left or right side. Each hamartoma consisted of a proliferation of thin-walled vessels which varied in caliber. These vessels were elastin-negative, with varying amounts of collagen and no muscular component. In four of the five hamartomas, lining cells were actin- and factor VIII-positive. All five hamartomas contained glial fibrillary acid protein (GFAP)-positive parenchyma at moderate to high frequency, and four contained neurofilament-positive axons between component vessels. This report shows that vascular hamartomas in the canine brain are structural malformations for which immunohistochemistry is useful for accurate classification.