A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.

Intracranial aneurysm (IA), which is characterized by the ballooning of an intracerebral artery, is a common vascular abnormality, with a prevalence of 2% to 5% in the general population, and frequently leads to vascular rupture with high mortality.1,2 IA is considered to be influenced by various acquired and inherited factors. [3][4][5] Although IA incidence is associated with several acquired risk factors, including smoking and hypertension, 6-9 its genetic factors are poorly understood, and the generation of reliable disease models to recapitulate its pathogenesis has therefore been difficult. Current treatment of IA depends largely on surgical clipping or endovascular coiling without any therapeutic drug administration. 10 Clinical Perspective on p 1005In recent attempts to reveal genetic factors related to IA, a series of genome-wide association studies based on a large population of patients with IA suggested a few susceptible candidate loci, including Sox17. [11][12][13] The transcription factor Sox17 is an essential player in vascular development through the regulation of angiogenesis 14 and arterial differentiation. 15Although Sox17 plays a crucial role in tumor angiogenesis, 16 the relationship between Sox17 and other vascular abnormalities, including IA, during adulthood has not yet been studied. Because IA pathology has focused on vascular walls rather than on endothelial layers, how Sox17, which is specifically expressed in endothelial cells, is involved in IA formation remains to be explored. To address a potential link between IA formation and Sox17, we investigated the vascular changes in intracerebral arteries of a Sox17 loss-of-function mouse model. MethodsAn expanded Methods section can be found in the online-only Data Supplement.Background-Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. Methods and Results-The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Conclusions-Our findings demonstrate that Vascular Corrosion Casting and Scanning Electron MicroscopyMi...

Subanesthetic doses of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, in vivo (1) H-MRS and ex vivo (1) H high-resolution magic angle spinning (HR-MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX=512) was used to acquire the spectra in a 30-µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: n=12; saline group: n=12) anesthetized with isoflurane. After the in vivo (1) H-MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: n=7; saline group: n=7) for ex vivo (1) H HR-MAS spectroscopy (CPMG sequence, 2.0-s presaturation delay, 2.0-s acquisition time, 128 transients and 4-ms inter-pulse delay) using a 500-MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the in vivo spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (p<0.05). For the ex vivo HR-MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission.

ABSTRACT:The purpose of this work was to evaluate hydrocephalic ventricular changes using three quantitative analysis methods. The height, area and volume of the ventricles and brain were measured in 20 Yorkshire terriers (10 normal and 10 hydrocephalic dogs) using low-field MR imaging (at 0.2 Tesla). All measurements were averaged and the relative ventricle size was defined as a percentage (percent size of the ventricle/size of the brain). The difference between normal and hydrocephalic dogs was statistically significant for the average of each ventricle as well as for the percentage value. Five hydrocephalic symptoms were identified: circling, head tilting, seizures, ataxia, and strabismus. With respect to height, area and volume of the brain/ventricle, the difference between normal and hydrocephalic dogs was not significant. The ventricle/brain with height (1D) was related to the area (2D) and volume (3D). The correlations with area and volume were as good as the ventricle/brain height ratio in the case of hydrocephalic dogs. Therefore, one-, two-and three-dimensional quantitative methods may be complementary. We expect that the stage of hydrocephalic symptoms can be classified if statistical significance for ventricular size among symptoms is determined with the analysis of a large number of hydrocephalic cases.