21444564
FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB.
OBJECTIVE
We evaluated the full range effects of FOXO3a in endothelial cells (ECs) by microarray analysis and investigated the role of FOXO3a regulating TNF receptor signaling pathway.


METHODS AND RESULTS
Human umbilical vein endothelial cells (HUVECs) were transfected with adenoviral vectors expressing constitutively active FOXO3a (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection caused remarkable apoptosis, which were accompanied with upregulation of genes related with TNF receptor signaling, such as TNF-alpha, TANK (TRAF-associated NF-kappaB activator), and TTRAP (TRAF and TNF receptor-associated protein). Furthermore, kappaB-Ras1 (IkappaB-interacting Ras-like protein-1) which is known to block IkappaB degradation was found increased, and intranuclear translocation of NF-kappaB was inhibited. GADD45beta and XIAP, negative regulators of c-Jun N-terminal kinase (JNK), were suppressed and JNK activity was increased. Attenuation of TNF signaling pathway either by blocking antibody for TNF receptor or by blocking JNK with DMAP (6-dimethylaminopurine) or Ad-TAM67 (dominant negative c-Jun) cotransfection, significantly reduced FOXO3a-induced apoptosis. Finally, treatment of vasculature with heat shock, an activator of endogenous FOXO3a, resulted in EC apoptosis, which was completely rescued by Ad-TAM67.


CONCLUSIONS
FOXO3a promotes apoptosis of ECs, through activation of JNK and suppression of NF-kappaB. These data identify a novel role of FOXO3a to turn TNF receptor signaling to a proapoptotic JNK-dependent pathway.
35489538
Prevalence and risk factors of masked hypertension identified by multiple self-blood pressure measurement.
To the Editor:

With great interest we read the article by O'Brien,1 comprehensively reviewing implementation of out-of-office blood pressure (BP) measurement, ie, ambulatory BP measurement and self-BP measurement (SBPM), for more precise evaluation and management of hypertension. Clearly, ambulatory BP measurement provides a greater amount of BP information and, thus, can be more sensitive than SBPM. However, ambulatory BP measurement is more expensive and may cause discomfort, interfering with subjects’ normal activity, which limit its routine use.2 Here, we introduce our investigation of the diurnal BP pattern and its determining factors by implementing a multiple SBPM strategy.

A total of 5009 hypertension patients in 500 primary care clinics in Korea, whose recent BP during the last 2 visits was stable without change in medication, were enrolled. This study was performed by multicenter, prospective, observational design. To minimize possible confounding factors and to compare the differential effect of various classes of antihypertensive agents, 2 strategies were used. First, enrolled patients were …
24763110
Clinic blood pressure responses to two amlodipine salt formulations, adipate and besylate, in adult Korean patients with mild to moderate hypertension: a multicenter, randomized, double-blind, parallel-group, 8-week comparison.
BACKGROUND
The commercially available formulation of amlodipine is conjugated with besylate salt to increase water solubility. Recently, a new amlodipine salt formulation has been developed in which the free base of amlodipine is conjugated with a chemically different salt, adipate.


OBJECTIVE
The goal of this study was to compare the antihypertensive effect and tolerability of amlodipine adipate with those of amlodipine besylate in patients with mild to moderate hypertension.


METHODS
This was a multicenter, randomized, doubleblind, parallel-group study in which patients received 8 weeks of treatment with either amlodipine adipate or amlodipine besylate. The primary efficacy variable was noninferiority of the difference in mean changes from baseline in trough diastolic blood pressure (DBP) after 8 weeks of treatment. Secondary efficacy variables included mean changes in DBP, systolic blood pressure (SBP), and response rate (defined as the proportion of patients whose DBP was <90 mm Hg or whose DBP had decreased from baseline by > or =10 mm Hg). The incidence of adverse events (AEs) was also assessed.


RESULTS
Two hundred eleven patients were randomly assigned to receive amlodipine adipate (n = 106) or amlodipine besylate (n = 105). Study patients were primarily female (54.5%), with a mean (SD) age of 52.2 (9.6) years and a mean body weight of 67.1 (10.2) kg; there were no between-group differences in demographic profiles. After 4 weeks of randomized treatment, 58 (27.5%) patients (29 [27.4%] amlodipine adipate, 29 [27.6%] amlodipine besylate) had not achieved a mean DBP <90 mm Hg, and their dose was doubled. Mean DBP changes at 8 weeks were -15.2 (7.3) mm Hg in the amlodipine adipate group and -14.2 (7.4) mm Hg in the amlodipine besylate group (P = NS). Because the 95% CI for the difference in mean DBP changes between groups (-0.53 to 2.55) was within the prespecified lower limit (-4 mm Hg), amlodipine adipate was considered noninferior to amlodipine besylate. Mean SBP changes were -24.9 (12.1) mm Hg in the amlodipine adipate group and -22.0 (14.7) mm Hg in the amlodipine besylate group (P = NS). The response rates were 92.0% for amlodipine adipate and 95.4% for amlodipine besylate (P = NS). The overall incidence of clinical AEs was 20.8% in the amlodipine adipate group and 25.7% in the amlodipine besylate group (P = NS). Drug-related clinical AEs occurred in 5.7% and 12.4% of patients in the respective treatment groups (P = NS). Serum uric acid levels decreased significantly from base-line in both groups (P < 0.001).


CONCLUSIONS
Eight weeks of treatment with amlodipine adipate produced significant reductions from baseline in blood pressure in these patients with mild to moderate hypertension. The efficacy of amlodipine adipate was not inferior to that of amlodipine besylate. Tolerability was comparable between the 2 treatment groups.
15313024
Aging and arterial stiffness.
Arterial walls stiffen with age. The most consistent and well-reported changes are luminal enlargement with wall thickening and a reduction of elastic properties at the level of large elastic arteries. Longstanding arterial pulsation in the central artery causes elastin fiber fatigue and fracture. Increased vascular calcification and endothelial dysfunction are also characteristic of arterial aging. These changes lead to increased pulse wave velocity, especially along central elastic arteries, and increases in systolic blood pressure and pulse pressure. Vascular aging is accelerated by coexisting cardiovascular risk factors, such as hypertension, metabolic syndrome and diabetes. Vascular aging is an independent risk factor for cardiovascular disease, from atherosclerosis to target organ damage, including coronary artery disease, stroke and heart failure. Various strategies, especially controlling hypertension, show benefit in preventing, delaying or attenuating vascular aging.
11700956
Cardio–renal protection with aliskiren, a direct renin inhibitor, in the ASPIRE HIGHER program
Aliskiren is the first in a new class of orally effective direct renin inhibitors. Initial results of clinical efficacy studies have demonstrated at least equivalent or superior blood pressure-lowering efficacy when compared with existing drugs, and a favorable side-effect profile either as monotherapy or as a component of combination therapy. This report aims to introduce and provide a critical appraisal of the initial results of the ASPIRE HIGHER program, evaluating the potential cardio–renal protective effects of aliskiren.
30188809
Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study of high-dose candesartan cilexetil combined with hydrochlorothiazide in Korean adults with stage II hypertension.
OBJECTIVE
The objective of this study was to evaluate the efficacy and tolerability of high-dose (32 mg) candesartan in Asians.


METHODS
In Korean adult patients with stage II hypertension, we evaluated the efficacy and tolerability of candesartan 16 mg/hydrochlorothiazide (HCT) 12.5 mg and candesartan 32 mg/HCT 12.5 mg compared with candesartan 16-mg and 32-mg monotherapy, respectively. This Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study, named CAESAR (Candesartan Effect in Second Stage Arterial Hypertension), enrolled 253 patients with stage II hypertension. Treatment started with either candesartan 16 mg or candesartan 16 mg/HCT 12.5 mg. After 4 weeks, the candesartan dose was forced titrated to 32 mg in both groups. The primary and secondary objectives were to compare the blood pressure (BP) changes after 4 weeks and 8 weeks between candesartan-HCT combination therapy and candesartan monotherapy. The proportion of patients achieving target BP (systolic blood pressure [SBP] <140 mm Hg, but <130 mm Hg for patients with diabetes mellitus or chronic kidney disease; diastolic blood pressure (DBP) <90 mm Hg, but <80 mm Hg for those with diabetes mellitus or chronic kidney disease) after 4 and 8 weeks of therapy was also evaluated. Adverse events were investigated both by spontaneous report by the patient and by the investigators' evaluations in each visit. Laboratory tests were performed at the end of the study to evaluate drug tolerability.


RESULTS
Study patients were all Asians, mostly male (65.7%), with a mean (SD) age of 49.4 (10.6) years and a mean body weight of 68.9 (12.1) kg; there were no between-group variances in demographic profiles except that the mean age in the candesartan-HCT group (51.0 [10.2] years) was about 3.2 years higher than that in the candesartan monotherapy group (47.8 [10.7] years; P = 0.02) despite random allocation. A total of 80.4% of the study patients had not been treated before, whereas 19.6% were previously treated and enrolled after 2 weeks of washout period. Baseline sitting systolic/diastolic BPs (SBP/DBP) were 160.7 (13.0)/104.6 (9.5) mm Hg. After 4 weeks, patients treated with candesartan 16 mg/HCT 12.5 mg showed significant decreases in SBP/DBP of 28.7 (17.5)/17.8 (10.2) mm Hg, and those in the candesartan 16 mg monotherapy group showed decreases of 20.5 (14.5)/14.1 (10.1) mm Hg (P < 0.01 between treatments for both SBP and DBP). After forced titration of candesartan from 16 mg to 32 mg at week 8, there was an additional reduction in SBP/DBP of 4.1 (12.7)/3.8 (8.3) mm Hg in the candesartan-HCT combination therapy group and 4.0 (11.6)/2.0 (8.5) mm Hg in the candesartan monotherapy group (P < 0.001 for SBP and DBP in both groups compared with values at week 4). A greater proportion of patients (70.6%) attained the target BP in the candesartan-HCT combination therapy group than in the candesartan monotherapy group (53.2%, P = 0.014). A total of 32 mg of candesartan was well tolerated both in combination therapy with HCT and in monotherapy. Dizziness was the most common adverse event in both groups (5 and 2 patients, respectively).


CONCLUSIONS
The candesartan-HCT combination was associated with a statistically significant lowering of BP compared with candesartan monotherapy. Clinicaltrials.gov: NCT00621153.
6780501
Z-Shaped Microcatheter Tip Shaping for Embolization of Aneurysms at the Proximal A1 Segment of the Anterior Cerebral Artery: A Technical Note
Embolization of an aneurysm at the proximal A1 segment of the anterior cerebral artery (ACA) is technically challenging. We treated four consecutive patients with unruptured aneurysms at the proximal portion of the A1 segment of the ACA. We tested various microcatheter tip shapes before we successfully embolized a lesion with a zigzag-shaped microcatheter tip, which was made by steam shaping. The shape of this microcatheter tip resembled the letter "Z", had a relatively long distal straight segment and was helpful in prompt catheterization of the aneurysm sac and stable placement of the catheter and delivery of coils.
18332803
Diagnostic Efficacy of PET/CT Plus Brain MR Imaging for Detection of Extrathoracic Metastases in Patients with Lung Adenocarcinoma
We aimed to evaluate prospectively the efficacy of positron emission tomography (PET)/computed tomography (CT) plus brain magnetic resonance imaging (MRI) for detecting extrathoracic metastases in lung adenocarcinoma. Metastatic evaluations were feasible for 442 consecutive patients (M:F=238:204; mean age, 54 yr) with a lung adenocarcinoma who underwent PET/CT (CT, without IV contrast medium injection) plus contrast-enhanced brain MRI. The presence of metastases in the brain was evaluated by assessing brain MRI or PET/CT, and in other organs by PET/CT. Diagnostic efficacies for metastasis detection with PET/CT plus brain MRI and with PET/CT only were calculated on a per-patient basis and compared from each other. Of 442 patients, 88 (20%, including 50 [11.3%] with brain metastasis) had metastasis. Regarding sensitivity of overall extrathoracic metastasis detection, a significant difference was found between PET/CT and PET/CT plus brain MRI (68% vs. 84%; P=0.03). As for brain metastasis detection sensitivity, brain MRI was significantly higher than PET/CT (88% vs. 24%; P<0.001). By adding MRI to PET/CT, brain metastases were detected in additional 32 (7% of 442 patients) patients. In lung adenocarcinoma patients, significant increase in sensitivity can be achieved for detecting extrathoracic metastases by adding dedicated brain MRI to PET/CT and thus enhancing brain metastasis detection.
31653327
Rhabdoid Tumor of the Kidney Is a Component of the Rhabdoid Predisposition Syndrome 


The rhabdoid predisposition syndrome (RPS) is characterized by pedigrees in which two or more individuals carry germline mutations of the hSNF5/INI1 tumor suppressor gene. The tumors associated with the syndrome include atypical teratoid/rhabdoid tumor (AT/RT), choroid plexus carcinoma, medulloblastoma, and extrarenal rhabdoid tumor. Rhabdoid tumor of the kidney (RTK) has not been described as part of the RPS. We report a case of a 7-month-old boy with RTK whose sister had a malignant cerebellar tumor followed by a malignant lung and pleural tumor of childhood with typical rhabdoid histology. Molecular genetic analysis of the RTK and tissue from the pleural tumor revealed in both cases identical nonsense mutations of the hSNF5/INI1 gene on chromosome 22q11.2, where thymidine was substituted for cytosine in base 472. The proband had an identical germline mutation. This is the fifth genetically analyzed RPS pedigree and the first to include an RTK.

16609814
Deguelin-Induced Inhibition of Cyclooxygenase-2 Expression in Human Bronchial Epithelial Cells
The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.
25306146
Response of Non–Small Cell Lung Cancer Cells to the Inhibitors of Phosphatidylinositol 3-Kinase/Akt- and MAPK Kinase 4/c-Jun NH2-Terminal Kinase Pathways: An Effective Therapeutic Strategy for Lung Cancer
Purpose: We previously showed that phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways cooperate to promote non–small cell lung cancer (NSCLC) cell proliferation in vitro. This study was designed to explore whether inhibition of these pathways effectively inhibits NSCLC tumor growth in vivo. Experimental Design: The effects of PI3K/Akt inhibitors {LY294002, adenoviruses expressing dominant-negative mutant of the p85α adaptor subunit of PI3K (Ad-dnp85α), dominant-negative Akt [Ad-HA-Akt(KM)], or PTEN (Ad-PTEN)}, MKK4/c-jun NH2-terminal kinase (JNK) inhibitor [SP600215, adenovirus expressing dominant-negative MKK4, Ad-MKK4(KR)], and their combinations on proliferation and apoptosis in NSCLC cells were tested in vitro and in vivo using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a flow cytometry-based terminal deoxynucleotidyl transferase–mediated nick-end labeling assay, Western blot and immunohistochemical analyses, and an NSCLC xenograft tumor model. Results: Ad-dnp85α significantly inhibited proliferation of a subset of NSCLC cell lines used in our study. Intratumoral injection of Ad-dnp85α induced a significant decrease in the growth of H1299 NSCLC xenograft tumors. Concurrent inhibition of the PI3K/Akt and MKK4/JNK pathways showed enhanced antiproliferative effects on H1299 cells in vitro and in vivo by increasing apoptosis. Conclusions: PI3K/Akt and MKK4/JNK pathways cooperate to stimulate NSCLC cell proliferation by maintaining cell survival, suggesting that simultaneously targeting these two pathways might be an effective therapeutic strategy against NSCLC.