Achievement rate of target blood pressure in patients with hypertension treated by hypertension specialists and non-specialists in a real-world setting.

Hypertension remains a major global healthcare issue. Considering that most Japanese patients with hypertension are managed by general practitioners, hypertension specialists should be involved in actual clinical practice. We investigated the blood pressure (BP), guidelines recommended for achievement rate of the target BP, and clinical variables of patients with hypertension treated by hypertension specialists and those treated by non-specialists in a real-world setting. Factors associated with the target BP achievement in this population were also investigated. Outpatients with hypertension from 12 medical facilities in Okinawa Prefecture were enrolled (n = 1469 [specialist group, 794; non-specialist group, 675]; mean age, 64.2 years; females, 45.8%). For all patients, BP and rate of the target BP achievement were 129.0 ± 15.5/74.6 ± 10.6 mmHg, and 51.8%, respectively. BP and the rate of target of BP achievement were 128.0 ± 15.1/73.4 ± 10.4 mmHg and 56.7% in the specialist group, and they were 130.1 ± 15.9/76.0 ± 10.8 mmHg and 46.1% in the non-specialist group. The urinary salt excretion and obesity rates were comparable between the specialist and non-specialist groups. Multivariable logistic analyses indicated that hypertension specialists and good medication adherence were positive factors, whereas obesity, chronic kidney disease, diabetes mellitus, and urinary salt excretion were inverse factors associated with target BP achievement in this population. Initiatives for salt reduction, medication adherence, and proper obesity management are crucial to improving BP management in patients with hypertension. Hypertension specialists are expected to play an essential role in them. For all patients, the target blood pressure (BP) achievement rate were 51.8%. Hypertension specialists and good medication adherence were positive factors in achieving target BP; conversely, obesity, diabetes mellitus, chronic kidney disease, and high urinary salt excretion were inverse factors in achieving target BP among patients with hypertension.

Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect.

Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration.

Salt and potassium intake evaluated with spot urine and brief questionnaires in combination with blood pressure control status in hypertensive outpatients in a real-world setting.

Reducing salt and increasing potassium intake are recommended lifestyle modifications for patients with hypertension. The estimated 24-h urinary salt excretion value from spot urine using Tanaka's formula and the salt check-sheet scores, questionnaire-based scores of salt intake, are practical indices of daily salt intake. However, few studies have evaluated salt intake with these methods in hypertensive outpatients. We examined salt and potassium intake with the spot urine method and the salt check-sheet scores of hypertensive outpatients in a multi-facility, real-world setting and examined whether the salt or potassium intake evaluated with these methods related to inadequate blood pressure control. Hypertensive outpatients from 12 medical facilities in the Okinawa prefecture were enrolled from November 2011 to April 2014 (n = 1559, mean age 63.9 years, 46% women). The mean blood pressure, urinary salt excretion value, urinary potassium excretion value, and total score on the salt check-sheet were 129/75 mmHg, 8.7 g/day, 1.6 g/day, and 10.4 points, respectively. The urinary salt excretion value and total score on the salt check-sheet but not urinary potassium excretion value were associated with inadequate blood pressure control (≥140/90 mmHg). Higher body mass index, estimated glomerular filtration rate, urinary potassium excretion value, total score on the salt check-sheet, and presence of inadequate blood pressure control were associated with high urinary salt excretion (≥10.2 g/day). In conclusion, hypertensive outpatients with high urinary salt excretion values estimated using Tanaka's formula or with high scores on the salt check sheet may be candidates for more intensive salt reduction guidance.

PDGF-BB is a novel prognostic factor in colorectal cancer.

PURPOSE: Human platelet-derived growth factor BB (PDGF-BB) is thought to be involved in human malignancies. Its overexpression has been reported in some human tumors. However, its expression in colorectal cancer has not been studied. We thus investigated the clinicopathological and biological significance of PDGF-BB gene expression in human colorectal cancer. EXPERIMENTAL DESIGN: Using real-time reverse transcription-PCR, we evaluated PDGF-BB expression status and correlated data with clinicopathological parameters in 60 patients with colorectal cancer. Additionally, we established a colorectal cancer cell line expressing PDGF-BB and investigated its effects on cell invasion and proliferation. RESULTS: The incidence of vascular invasion was significantly greater in patients expressing PDGF-BB at a high level than in those at a low level (P < .05). Patients with high PDGF-BB expression had a significantly poorer survival rate than those with low PDGF-BB expression (P < .05). A multivariate analysis demonstrated that PDGF-BB expression was an independent prognostic factor. We demonstrated in vitro that cells transduced with PDGF-BB showed greater invasiveness (P < .05) and migration (P < .001) than did mock transduced cells. In a xenograft study, cells transduced with PDGF-BB had higher proliferation rates than mock transfected cells. CONCLUSION: PDGF-BB expression may be a new prognostic indicator for patients with colorectal cancer.

Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family.

PURPOSE: The high mobility group A2 (HMGA2) nonhistone chromosomal protein can modulate transcription by altering chromatin architecture. HMGA2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that HMGA2 is negatively regulated by the let-7 microRNA (miRNA) family. However, no studies have examined the clinical significance of HMGA2 and its relationship to the let-7 miRNA family in gastric cancer. EXPERIMENTAL DESIGN: Using quantitative real-time reverse transcription-PCR, we analyzed HMGA2 expression with respect to various clinicopathologic factors in 110 patients with gastric cancer. We also did an association study comparing HMGA2 expression and let-7 miRNA family expression in gastric cancer. RESULTS: Expression of HMGA2 in cancerous tissues was significantly higher than in noncancerous tissues (P < 0.05). Elevated HMGA2 expression was significantly correlated with serosal invasion (P < 0.05) and poor clinical prognosis (P < 0.05). A multivariate analysis showed that HMGA2 expression status was an independent prognostic factor (P < 0.05). An inverse correlation between HMGA2 and let-7a was found in gastric cancer cell lines (P = 0.08). The expressions of let-7a, let-7b, and let-7c in gastric cancer patients with low HMGA2 expression were significantly higher than those with high HMGA2 expression (P < 0.05). CONCLUSIONS: High expression of HMGA2 in gastric cancer correlates with tumor invasiveness and is an independent prognostic factor. Furthermore, our findings suggest that HMGA2 is negatively regulated by the let-7 miRNA family in human gastric cancer.

Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression.

This study consisted of 2 aims: (i) to determine genes associated with hepatocellular carcinoma (HCC) by microarray analysis; and (ii) to evaluate the clinicopathological significance of human ubiquitin-conjugating enzyme E2C (Ube2c) found to be overexpressed in HCC from microarray analysis. Laser microdissection and cDNA-microarray were performed to identify genes associated with HCC. We then focused on the Ube2c gene. Using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), Ube2c expression status and clinicopathological significance were studied in 65 clinical HCC samples. A number of genes upregulated in HCC cells compared to noncancerous liver cells were identified, one of which was the Ube2c gene. Ube2c gene expression in the cancer tissue was higher than in the corresponding noncancerous tissue in 62 of the 65 cases (95.4%, p < 0.01). Tumors with high Ube2c expression showed higher frequencies of tumor invasion to capsular formation (fc-inf), invasion to portal vein (vp) and tumor de-differentiation (p < 0.05). Patients with high Ube2c expression also showed significantly worse disease-free survival rates than those with low Ube2c expression (p < 0.01). In addition, Ube2c expression was found to be an independent prognostic factor for disease-free survival rate in multivariate analysis. We identified differentially expressed genes between HCC and normal liver tissues. Of those, the Ube2c gene appeared to be associated with HCC progression, and may be useful as a prognostic indicator for HCC patients.

Accumulation of 8-oxo-deoxyguanosine in cardiovascular tissues with the development of hypertension.

Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in DNA is associated with mutagenesis and cell death. Little attention has been given to the biological significance of 8-oxo-dG accumulation in cardiovascular tissues during the different stage of hypertension and its prevention. We thus investigated the levels and localization of both 8-oxo-dG accumulation and expression of MTH1, which hydrolyzes 8-oxo-dGTP to prevent its incorporation into DNA, in the thoracic aorta prepared from stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wister-Kyoto rats (WKY), aged 5-32 weeks. HPLC-MS/MS analysis revealed that the levels of nuclear 8-oxo-dG in the aorta increased significantly in SHRSP, but not WKY, with aging. Immunohistochemical study revealed that both TUNEL reactivity and 8-oxo-dG immunoreactivity were increased in smooth muscle cells (SMC) and endothelial cells (EC) of the aorta with aging, and they exhibited similar distributions in serial sections. The number of 8-oxo-dG and TUNEL positive cells in EC, but not in SMC, was significantly higher in SHRSP than WKY at 32 weeks of age. In contrast, the expression levels of Mth1mRNA and MTH1 protein in the aorta were similarly decreased both in SHRSP and WKY with aging. However, the number of MTH1 expressing EC was remarkably increased in the older SHRSP compared to the younger ones or age-matched WKY. Hypertension significantly increased not only 8-oxo-dG accumulation but also the expression of MTH1 in EC of the aorta during aging. While accumulation of 8-oxo-dG in SMC of the aorta was slightly increased, the expression of MTH1 protein in SMC was rather decreased by hypertension. We thus suggest that MTH1 may protect EC in the aorta from the oxidative damage increased by hypertension.

Opa interacting protein 5 (OIP5) is a novel cancer-testis specific gene in gastric cancer.

BACKGROUND: Identification of novel cancer-specific antigens is important for the advancement of immunotherapy. Our aim was to identify cancer-specific genes in gastric cancer. METHODS: Using cDNA microarray analysis, we detected genes overexpressed specifically in gastric cancer cells. The expression levels of selected genes, including OIP5, was confirmed by real time RT-PCR analysis in tumor/normal paired bulk samples of 58 clinical cases. The expression levels of selected genes in normal tissues were also determined with a human total RNA master panel. We also compared the expression status of OIP5 with that of the other known cancer-testis specific genes. RESULTS: Twenty-two genes were determined to be upregulated in gastric cancer cells. Among these, three genes (CDC6, Exo1, and OIP5) were selected and confirmed to be upregulated in the tumor tissue compared to normal tissue. A human total RNA master panel demonstrated that OIP5, but not Exo1 or CDC6, showed high specificity in testis. Thus OIP5 may be considered a cancer-testis specific gene. In 58 clinical cases of gastric cancer examined, we found OIP5 gene expression in 27 cases (47%). Thirteen of these 27 cases showed no expression of the known cancer specific genes such as MAGE-1, MAGE-3 or NY-ESO-1. CONCLUSIONS: Using a combination of LMD and microarray, we identified OIP5 as a cancer-testis specific gene. Further expression analysis in a set of clinical cases revealed that OIP5 may be a novel immunotherapy target for patients with gastric cancer.

Loss of MAL expression in precancerous lesions of the esophagus.

BACKGROUND: We have identified a novel function of MAL (T-cell differentiation-related gene) as a candidate suppressor gene in esophageal cancer. As the role of MAL expression in esophageal carcinogenesis is as yet undetermined, MAL expression in a rat multi-step carcinogenic model and in precancerous lesions of the human esophagus was investigated. Microarray analysis between MAL-transfectant and control cells was also carried out to clarify how MAL confers its anti-tumor effects. MATERIALS AND METHODS: (1) In the rat model, MAL expression levels in laser microdissected normal esophageal epithelium, dysplastic tissues and carcinoma tissues were examined by reverse transcription (RT)-PCR. (2) Immunostaining with MAL antibody was performed in 10 dysplastic lesions adjacent to cancer in six cases of esophageal cancer. (3) We established a MAL transfectant using a Tet-off vector in esophageal cancer cells and performed microarray analysis under MAL-positive and MAL-negative conditions. RESULTS: (1) In the rat model, MAL mRNA expression was observed only in the normal samples. (2) MAL expression was observed distinctively in differentiated or keratinized normal tissues and was not observed in either dysplastic lesions or carcinoma tissue. (3) Up-regulated genes in MAL-positive cells included keratin 18 (transfectant/control = 2.94) and keratin 10 (t/c = 2.82). CONCLUSION: MAL expression was lost in dysplastic lesions of the rat carcinoma model as well as the human esophagus. The up-regulated keratins revealed by microarray analysis and the strong staining of the differentiated normal tissues in immunohistochemical study support the role of MAL as a regulator of differentiation in esophageal epithelium.

Intracellular angiotensin II stimulates voltage-operated Ca(2+) channels in arterial myocytes.

Although the presence of intracellular angiotensin II (Ang II) and of Ang II-binding sites has been reported, their roles in cell function have not been fully clarified. The purpose of the present study was to test the hypothesis that intracellular Ang II modifies voltage-operated Ca(2+) channels in vascular smooth muscle. Ca(2+) channel currents were recorded in guinea pig mesenteric arterial myocytes with the whole-cell patch-clamp method. Intracellular dialysis of Ang II increased the amplitudes of Ca(2+) channel current (133 +/- 9% of the control with 10 nmol/L Ang II, n=16). Concomitant dialysis of the Ang II type 1 receptor antagonist, CV-11974 (1 micromol/L, n=11), but not the bath application of this drug, suppressed this Ang II action. In contrast, the dialysis of the Ang II type 2 receptor antagonist, PD123319 (1 micromol/L, n=5), failed to affect the Ang II action. Dialysis of either a phospholipase C inhibitor (U-73122, 10 micromol/L, n=5) or protein kinase C inhibitors (calphostin C, 100 nmol/L, n=5; protein kinase C inhibitor peptide-[19-36], 1 micromol/L, n=5) suppressed the Ang II action. Dialysis of KT5720 (100 nmol/L, n=5), an inhibitor of cAMP-dependent protein kinase, did not affect the Ang II action. Intracellular dialysis of angiotensin I (10 nmol/L) enhanced Ca(2+) channel currents (13 3 +/- 8%, n=6), which were sensitive to intracellular enalaprilat (1 micromol/L, n=5) or CV-11974 (n=5). These results suggest that intracellular Ang II has a stimulating action on voltage-operated Ca(2+) channels in vascular smooth muscle, possibly through intracellular binding sites similar to the Ang II type 1 receptor, which are associated with phospholipase C and protein kinase C.

[A case of brain ischemia presenting spectacular shrinking deficit in adult-onset Still's disease associated with antiphospholipid antibody syndrome].

A 63-year-old man presenting remittent fever and multiple arthralgia was diagnosed as adult-onset Still's disease (AOSD), and started with prednisolone treatment. However, he suddenly developed loss of consciousness, paresis of the right upper extremity and aphasia shortly after the treatment. We detected an increased signal of brain tissue lactate at the branch territory of left middle cerebral artery by MR spectroscopy (MRS), but no lesions by diffusion-weighted nor T2-weighted MRI, suggesting acute brain ischemia of embolic mechanism. Most of the symptoms resolved in a couple of hours after the onset, showing spectacular shrinking deficit (SSD). The patient also revealed complication of antiphospholipid antibody syndrome (APS), which may be associated with ischemic event. This is the first case of acute brain ischemia with SSD, which occurred in AOSD with APS. MRS was superior to diffusion MRI in detection of acute brain ischemia.