Citations

Abstract Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood–brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM. Clin Cancer Res; 18(22); 6239–48. ©2012 AACR.

Bilateral determinations of the blood pressures were made nonsimultaneously and simultaneously by the indirect method under basal conditions on 447 patients. In this group 26.6 per cent of the paired measurements by the nonsimultaneous indirect method exhibited systolic differences of 10 mm. Hg or greater and 15 per cent exhibited diastolic differences of this magnitude, whereas only 5.3 per cent of the measurements by the simultaneous indirect method had systolic differences and only 4 per cent had diastolic differences of this degree. This indicates that bilateral determinations of blood pressure must be performed simultaneously on patients being examined for possible inequalities of blood pressure. Bilateral differences in blood pressure obtained by the simultaneous indirect and simultaneous direct methods in 14 normal subjects and 53 selected patients were compared. In the normal subjects, 3 of the 42 paired indirect measurements and none of the paired direct measurements in either the radial or brachial arteries had systolic differences of 10 mm. Hg or greater, and none of the diastolic differences were of this level. In the 53 selected patients, 10 per cent of the indirect and 6 per cent of the direct measurements of systolic blood pressure differed by 10 mm. Hg or more and 8 per cent of the paired indirect measurements of diastolic blood pressure and less than 1 per cent of the paired direct measurements differed by this amount. These differences in bilateral blood pressures were characterized by their inconstancy and lack of agreement with subsequent measurements when studied by both the indirect and direct methods, which apparently separates them from those due to altered hemodynamics from pathologic conditions of the aortic arch or its tributaries. Bilateral differences of blood pressure are of clinical importance when they are great and are reproducible by the direct as well as by the indirect methods, as illustrated by a patient encountered in this study. In addition, 1 case of extreme obesity and 1 of advanced arteriosclerosis were reported. Both patients were found to have pseudohypertension, which was detected in this study. A slight increase in the incidence of bilateral differences in indirect blood pressures was found in a group of patients whose blood pressures were measured while they were in the supine and then in the sitting position. A slight increase in the incidence of bilateral differences was found at higher levels of blood pressure by comparing the blood pressures of nonhypertensive and hypertensive patients and of hypertensive patients before and during treatment with antihypertensive drugs. Bilateral inequalities of blood pressure did not appear to be related to the age or sex of the subjects. Likewise, differences in circumferences of the arm or right or left-handedness did not appear to influence these inequalities, and there was no marked side dominance for differences found. Bilaterally simultaneous, indirect measurements of blood pressure should be carried out on patients with hypertension who will be treated with antihypertensive drugs. Bilateral direct measurements may be used to verify the existence of inequality of blood pressures detected by the indirect method and to determine the correct pressure to be followed. This is particularly important in patients being screened for pheochromocytomas, since such differences may produce false-positive results.

Two hundred seventy-one patients with unequivocal systemic scleroderma for whom the diagnosis was first established at the Mayo Clinic between January 1, 1945, and December 31, 1952, have been studied. Follow-up information was obtained 5 to 13 years after the diagnosis at the clinic concerning 236 of these patients, 115 of whom were dead. The cases were analyzed in an effort to determine what factors had a bearing on prognosis. The following seemed to bear little relation to the ultimate prognosis: sex, mode of onset, Raynaud's phenomenon, involvement of lungs and periodontal membrane, calcinosis cutis, and trophic changes. The following were considered poor prognostic omens: cardiac or renal involvement, significant elevation of the erythrocyte sedimentation rate, and anemia. The prognosis in systemic scleroderma was found to be worse than previous reports had indicated. This study yielded no basis for the subdivision of systemic scleroderma into acrosclerosis and generalized progressive scleroderma.

The clinical and follow-up data on 520 non-diabetic patients less than 60 years of age who had a clinical diagnosis of arteriosclerosis obliterans of the lower extremities made at the Mayo Clinic in the period 1939 through 1948 were reviewed from the standpoint of pathogenesis, prognosis, and clinical course of the disease. The ratio of males to females was 11 to 1, and the mean concentration of plasma cholesterol in the male patients with arteriosclerosis obliterans was approximately 50 mg. per 100 ml. greater than that of either of 2 control groups of men without clinical evidence of atherosclerosis. The incidence of smoking among the men with this disease was higher than in a comparable group of men without it. Obesity was not commonly associated with arteriosclerosis obliterans, while hypertension was associated with the disease about 3 times as often as in a control group without the disease. The survival rate for patients with arteriosclerosis obliterans was less favorable than that of a normal population of a similar age and sex distribution, and the survival rate for patients with atherosclerotic aorto-iliac occlusion was significantly less favorable than that of patients with atherosclerotic occlusion of the femoral artery. In approximately three fourths of the patients who died, the cause of death was thought to be disease of the coronary arteries. The presence of atherosclerosis elsewhere than in the arteries supplying the extremities, as manifested by clinical coronary artery or cerebrovascular disease at the time of diagnosis, had an adverse effect on survival. Four per cent of the patients required amputation of a leg shortly after the diagnosis of arteriosclerosis obliterans was made at the clinic, and an additional 4.9 per cent subsequently required amputation during the 5-year period following the initial examination. Only 3.0 per cent of patients with intermittent claudication as the only symptom of their disease required an amputation during this period. Eleven and three-tenths per cent of patients who continued to smoke, but none who abstained from smoking, had amputations within 5 years. Since all patients of the series were treated before the advent of direct arterial surgery for segmental arterial occlusion, it is believed that the subsequent course of the disease in these patients may be used as a basis for comparative evaluation of results in patients subjected to direct arterial surgical procedures.

The successful treatment of essential hypertension remains one of the most difficult problems in medicine. Approximately 18 years have elapsed since extensive sympathectomy was first performed for essential hypertension. Extensive sympathectomy occasionally produces striking decrease in blood pressure of patients with essential hypertension; in many instances it fails to decrease blood pressure or modify the course of the disease. That which is most desired are some standards for preoperative selection of patients so that only patients who will be benefited by sympathectomy will be operated on. Unfortunately this apparently cannot be accomplished. The indications for sympathectomy remain at least partially uncertain and there is no agreement among those most experienced in the field of hypertension relative to the results of operation. There also are differences of opinion about the extensiveness of sympathectomy which is advisable. This paper indicates clearly differences of opinion among those most experienced in this field and emphasizes some of the points of agreement. It seems clear that additional technics of sympathectomy cannot be devised for the treatment of essential hypertension. There seems little doubt that sympathectomy would not be performed were adequate medical treatment available. This presentation gives the opinion of internists and surgeons who are particularly interested in hypertension and its treatment.

The authors investigated the effect of repeated inunction with 2 per cent glyceryl trinitrate in lanolin on the blood flow and skin temperature of the extremities in 14 cases of Raynaud's disease and in 8 cases in which Raynaud's phenomenon was associated with such vascular diseases as acrosclerosis (3 cases), chronic occlusive disease of the arteries (3 cases), occupational disease of the arteries (1 case) and livedo reticularis (1 case). The inunction almost invariably caused an increase in the blood flow and in the skin temperature of the digits in the 14 cases of Raynaud's disease.