miR-9 Acts as an OncomiR in Prostate Cancer through Multiple Pathways That Drive Tumour Progression and Metastasis.

Identification of dysregulated microRNAs (miRNAs) in prostate cancer is critical not only for diagnosis, but also differentiation between the aggressive and indolent forms of the disease. miR-9 was identified as an oncomiR through both miRNA panel RT-qPCR as well as high-throughput sequencing analysis of the human P69 prostate cell line as compared to its highly tumorigenic and metastatic subline M12, and found to be consistently upregulated in other prostate cell lines including DU-145 and PC3. While miR-9 has been characterized as dysregulated either as an oncomiR or tumour suppressor in a variety of other cancers including breast, ovarian, and nasopharyngeal carcinomas, it has not been previously evaluated and proven as an oncomiR in prostate cancer. miR-9 was confirmed an oncomiR when found to be overexpressed in tumour tissue as compared to adjacent benign glandular epithelium through laser-capture microdissection of radical prostatectomy biopsies. Inhibition of miR-9 resulted in reduced migratory and invasive potential of the M12 cell line, and reduced tumour growth and metastases in male athymic nude mice. Analysis showed that miR-9 targets e-cadherin and suppressor of cytokine signalling 5 (SOCS5), but not NF-ĸB mRNA. Expression of these proteins was shown to be affected by modulation in expression of miR-9.

Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. I. Local cerebral blood flow and glucose utilization.

Diffuse cerebral ischemia was created in pentobarbital-anesthetized cats by basilar and bilateral carotid artery occlusions and hypotension. Local cerebral blood flow (ICBF) was assessed autoradiographically with 14C-antipyrine, and local cerebral glucose utilization with 14C-2-deoxyglucose. In animals without glucose pretreatment, 15 min of ischemia led to a homogeneous reduction of post-ischemic cerebral perfusion to 31% of control; ischemia of 30 min produced post-ischemic perfusion heterogeneities in the cerebral cortex and deep gray structures. In animals pretreated with dextrose, 1.5 gm/kg intravenously, heterogeneous cerebral perfusion was observed following only 15 min of ischemia, and a severe global impairment of cerebral reperfusion occurred after the 30 min insult. Deoxyglucose autoradiograms in the latter animals were remarkable for a complete suppression of tracer uptake in the cerebral cortex and a paradoxically increased tracer concentration in the cerebral white matter. Mean plasma glucose in the treated animals exceeded 1000 mg/100 ml. Large glucose loads prior to ischemia dramatically impair post-ischemic cerebral perfusion.

Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. II. Regional metabolite levels.

Glucose was infused intravenously into cats prior to cerebral ischemia. Brain concentrations of glucose, measured in 7 regions, were elevated 2.5-fold compared to those of non-infused animals. Ischemia of 15 or 30 minutes duration caused a greater accumulation of lactic acid in the brain of glucose-infused animals. Post-ischemic restitution of cerebral ATP, phosphocreatine, and lactate during 90 minutes of recirculation was severely impaired in the brain of animals pretreated with glucose compared to untreated animals. Thus, excess lactic acidosis may be a major factor interfering with metabolic restitution following cerebral ischemia.

Diffuse cerebral ischemia in the cat: III. Neuropathological sequelae of severe ischemia.

The neuropathological consequences of sever diffuse cerebral ischemia were investigated in an animal model in which postischemic alterations of regional brain blood flow and energy metabolism had been previously characterized. Pentobarbital-anesthetized cats received either 15 or 30 minutes of ischemia produced by basilar artery and bilateral carotid artery occlusions plus mild hypotension; this was followed by 60 to 90 minutes of normotensive recirculation. The brains were perfusion-fixed for light microscopy. Both insult durations resulted in unequivocal ischemic cell change affecting neurons of the cerebral neocortex, striatum, thalamus, and hippocampus and portions of the rostral brainstem. Animals with 30 minutes of prior ischemia differed from those with 15 minutes of ischemia in showing a more apparent regional accentuation of ischemic change in the parasagittal cortical gyri--the sites of previously documented focal postischemic heterogeneities of blood flow and metabolism. In other respects, however, the overall distribution and spectrum of severity of the ischemic alterations were similar for the two insult durations. These data support the view that significant permanent neuronal injury may result from a period of cerebral ischemia as brief as 15 minutes.

Diffuse cerebral ischemia in the cat: II. Regional metabolites during severe ischemia and recirculation.

Metabolite levels were measured in seven brain regions in cats after 15 or 30 minutes of a severe ischemic insult and after a 90-minute period of recirculation following 15 or 30 minutes of ischemia. Brain levels of phosphocreatine were depleted after a 15- or 30-minute insult, and lactate levels were extremely high at both times. The adenosine triphosphate (ATP) content in many brain areas and the presence of microregions of low reduced nicotinamine-adenine dinucleotide in the brains of the animals that had 15 minutes of ischemia suggested that the ischemia, though severe, was not complete. Recirculation following a 15-minute insult restored brain levels of ATP and phosphocreatine to 70 to 100% of control values in all regions analyzed. In contrast, metabolic recovery from a 30-minute insult was regionally heterogeneous. Thus, there was persistent depression of ATP and phosphocreatine and elevation of lactate, which was localized in discrete cortical foci near the longitudinal midline. The factors governing the localization of metabolic failure must have become manifest during the recirculation period since the ischemic insult itself caused similar metabolic perturbations in all cortical regions.

Modeling periodically surging glaciers.

A numerical model has been developed which produces periodic surging as a characteristic of some glaciers for a certain accumulation and bedrock distribution in contrast to the normal steady state for nonsurging glaciers. Results are presented to illustrate how the magnitude of changes in the length, thickness, and velocity of surging glaciers can be simulated by the model.