Increased aortic wave reflection and smaller pulse pressure amplification in smokers and passive smokers confirmed by urinary cotinine levels: The Nagahama Study.

[Background]Central blood pressure (cSBP) is suggested to be a better predictor of cardiovascular risk than brachial BP. Although brachial BP levels among smokers have been reported to be the same or somewhat lower than those in nonsmokers, it is suggested that smoking might have a substantial impact on cSBP. [Methods]We conducted a cross-sectional study to clarify the association of smoking habit with arterial tone and cSBP in a general population of 8557 participants using urinary cotinine levels as an objective marker of smoking intensity. Absolute pressure of the late systolic peak (SBP2) was obtained by calibrating the radial waveform with brachial systolic BP (bSBP) and considered to be the cSBP. [Results]Confounding factor-adjusted mean pulse pressure amplification (PPa = bSBP − cSBP) was significantly smaller in habitual smokers (current, 9.3 ± 0.15; past, 10.2 ± 0.13; never, 10.6 ± 0.10 mm Hg; p < 0.001). Further, among smokers, PPa was linearly decreased with increasing urinary cotinine quartile (Q1, 10.9 ± 0.38; Q2, 10.9 ± 0.39; Q3, 10.4 ± 0.39; Q4, 9.7 ± 0.41 mm Hg; p = 0.020). Multiple linear regression analysis identified both smoking habit (p = 0.003) and urinary cotinine levels (p = 0.008) as independent determinants of PPa. Urinary cotinine was also detected in a small fraction of never smokers (1.8%). These passive smokers showed a smaller PPa (passive smoker, 9.4 ± 0.4; never smoker, 10.4 ± 0.12 mm Hg, p = 0.020) but not bSBP (122.7 ± 0.6, 123.1 ± 0.2 mm Hg, p = 0.474). [Conclusions]Not only habitual smoking but also passive smoking had harmful effects on AIx and central BP. Our results strongly emphasize the importance of avoiding passive smoking to the prevention of cardiovascular risks of which the subject is likely unaware

CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment

Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study.

[Background]Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia. [Methods] A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. [Results] As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥ 12 h, P < 0.001) or near-fasting (5–11 h, P < 0.001) conditions, and not in those taken under non-fasting (< 5 h, P = 0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (β = 0.052, P < 0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA⁎glucose; β = 0.036, P < 0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s. [Conclusions] Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature

Association Between Tooth Loss and Longitudinal Changes in B-Type Natriuretic Peptide Over 5 Years in Postmenopausal Women: The Nagahama Study

BACKGROUND: There is disparity between the sexes in cardiovascular diseases including heart failure (HF). This study aimed to investigate the effect of periodontal disease (PD) on plasma B-type natriuretic peptide (BNP) concentration across sex, age, and menopausal status, as well as the interaction effect of MT and diabetes mellitus (DM) on BNP. METHODS: This large-scale prospective cohort study enrolled 7, 539 individuals with no myocardial infarctions or angina pectoris at baseline from the general Japanese population. The association between baseline number of missing teeth (MT) and the longitudinal changes in BNP over 5 years (ΔBNP) was evaluated according to sex and menopausal status. RESULTS: Among 7, 539 participants, 3, 190 were postmenopausal women with a mean age ± standard deviation of 61.1 ± 7.6 at baseline. Multivariate analysis revealed a positive association between MT and ΔBNP among postmenopausal women even after adjusting for covariates, including traditional HF risk factors (coefficient, 0.210; 95% confidence interval [CI], 0.107 to 0.312; P 50. Including an interaction term (MT × DM) in the multivariate model revealed a positive interaction between MT and DM in ΔBNP among postmenopausal women (coefficient for interaction, 1.365; 95% CI, 0.902 to 1.827; P for interaction <0.001). CONCLUSIONS: Our study showed a positive association between MT and ΔBNP, as well as a positive effect of the interactive association between MT and DM, among postmenopausal women. Our results suggest a sex difference of an adverse effect of PD on initial myocardial wall stress in the ventricles

Combined association of clinical and lifestyle factors with non-restorative sleep: The Nagahama Study.

Background:Non-restorative sleep (NRS) was suggested to be associated with cardiovascular outcomes. However, causative factors for NRS have not been fully elucidated. This study aimed to clarify factors and their relationships with NRS to better understand the clinical and epidemiological implications of NRS and to develop a score that can objectively evaluate NRS status.Methods:Study subjects consisted of 9,788 community residents (age 53.6 ± 13.4 y). Subjective NRS as well as possible clinical and lifestyle factors for NRS were investigated by questionnaires. Other clinical parameters were obtained from personal records of information obtained at the baseline examination.Results:A total of 3,261 participants complained of NRS. Factors independently associated with subjective NRS were younger age (odds ratio = 1.43), use of a hypnotic drug (2.04), irregular sleep schedule (2.02), short sleep duration (<5 h, 11.7; 5-6 h, 4.81; 6-7 h, 2.40), frequent sleepiness (2.33), routine stress (4.63), no habitual exercise (1.61), nocturia symptoms (1.43), symptoms of gastroesophageal reflux disease (1.44), and depression (1.46) (all P <0.001). The NRS score comprised of these 10 factors was linearly associated with the frequency of subjective NRS (Ptrend <0.001). Frequency of individuals with a high NRS score was greater in women (52.3%) than in men (42.1%, P<0.001), while no clear association was observed with common risk factors for cardiovascular diseases.Conclusions:NRS was a phenomenon representing various clinical and lifestyle features. Careful attention should be paid to individuals with a high NRS score who might be at risk for mental fatigue and have unfavorable lifestyle factors

Rapidly and Slowly Growing Lineages in Chromosomal Instability-Type Gland-Forming Gastric Carcinomas as Revealed by Multisampling Analysis of DNA Copy-Number Profile.

BACKGROUND:To examine whether gastric carcinoma (GC) with chromosomal instability (CIN-type GC), the largest category in the Cancer Genome Atlas classification, consists of a single genetic lineage, we conducted a multisampling analysis of genomic DNA copy-number profile.METHODS:We performed array-based comparative genomic hybridization using formalin-fixed paraffin-embedded tissues from 54 gland-forming GCs containing a total of 106 DNA samples from mucosal, extramucosal invasive, and lymph node lesions. Microarray data were analyzed by unsupervised hierarchical clustering and penetrance plots. Epstein-Barr virus infection status and mismatch repair(MMR) enzyme-silencing/p53/mucin expression were examined by in situ hybridization and immunohistochemistry, respectively.RESULTS:The samples examined were divided into gain-rich cluster A and loss-rich cluster B, which were different in tumor locus and patient age. The T1/T2-4 ratio, the frequency of small cancers (diameter 2-4 cm), and intestinal mucin expression were higher in cluster B than in cluster A, but there were no significant differences in the frequencies of MMR silencing, mutant p53 pattern, and lymph node metastasis between the 2 clusters.CONCLUSIONS:We demonstrated that CIN-type GC could be categorized into 2 genetic lineages which are different in terms of rapidity of local extension but similar in terms of nodal metastasis risk

Expressions of ezrin, ERK, STAT3, and AKT in tongue cancer and association with tumor characteristics and patient survival.

Ezrin, ERK, STAT3, and AKT are proteins that are overexpressed in various types of cancer, although their expressions in tongue cancer has received less focus. This study aimed to address associations between the expression levels of these proteins and with characteristics of the tumor and patient survival. We performed immunohistochemical staining of ezrin, ERK, STAT3, and AKT in tumors from patients with tongue carcinoma in situ (CIS, n = 17) and tongue squamous cell carcinoma (SCC, n = 46). Statistical differences between the SCC versus the CIS cohorts were estimated by calculations of bivariate odds ratios of low versus high expression of the proteins. Fisher\u27s exact tests were used to appraise interassociations between the proteins, as well as expression levels versus patient and tumor characteristics. Survival based on Kaplan-Meier statistics in combination log-rank tests were used to address potential effects of the patient and tumor characteristics versus 5-year survival rate. The relative high: low expression of all four proteins in the two cohorts differed, and particularly ERK was markedly overexpressed in the SCC versus the CIS cohort (odds ratio = 45.3, p < .01). The relative high: low expression each protein versus patient and tumor characteristics; showed associations between AKT expression and T stage (p = .002) plus node metastases (p = .12), and between ERK expression and drinking (p = .01) and smoking history (p = .01). There was no significant difference observed between ERK and the three other molecules, nor any significant difference between the degree of expression of each protein and the 5-year disease-specific survival rate. Ezrin, ERK, STAT3, and AKT appear to be involved in the progress from carcinoma in situ in the tongue into squamous cell carcinoma. ERK in particular is overexpressed, suggesting that ERK may be a novel therapeutic target for preventing tongue cancer

Lineage analysis of early and advanced tubular adenocarcinomas of the stomach: continuous or discontinuous?

<p>Abstract</p> <p>Background</p> <p>Eradication of early gastric carcinoma (GC) is thought to contribute to reduction in the mortality of GC, given that most of the early GCs progress to the advanced GCs. However, early GC is alternatively considered a dormant variant of GC, and it infrequently progresses to advanced GC. The aim of this study was to clarify the extent of overlap of genetic lineages between early and advanced tubular adenocarcinomas (TUBs) of the stomach.</p> <p>Methods</p> <p>Immunohistochemical staining for p53 was performed using 28 surgically resected stomachs with 13 intramucosal and 15 invasive TUBs. By chromosome- and array-based comparative genomic hybridization (CGH), genomic copy number constitution was compared between the mucosal and invasive parts of the invasive TUBs and between the mucosal parts of the invasive and intramucosal TUBs, using 25 and 22 TUBs, respectively. <it>TP53 </it>mutation in exons 5-8 was examined in 20 TUBs.</p> <p>Results</p> <p>Chromosomal CGH revealed that 4q+ and 11q+ were more common in advanced and early TUBs, respectively, whereas copy number changes in 8q and 17p showed no significant differences between early and advanced TUBs. However, array CGH revealed that, of the 13 intramucosal TUBs examined, loss of <it>MYC </it>(<it>MYC</it>-) and gain of <it>TP53 </it>(<it>TP53</it>+) was detected in 9 TUBs and <it>MYC</it>+ and/or <it>TP53</it>- was detected in 3 TUBs. Of the mucosal samples of 9 invasive TUBs, 7 showed <it>MYC</it>-/<it>TP53</it>+ and none showed <it>MYC</it>+ and/or <it>TP53</it>-. Of the 9 samples from the invasive parts, 1 (from submucosal cancers) showed <it>MYC</it>-/<it>TP53</it>+ and 6 (1 from submucosal and 5 from advanced cancers) showed <it>MYC</it>+ and/or <it>TP53</it>-. The latter 6 tumours commonly showed a mutant pattern (diffuse or null) in p53 immunohistochemistry, and 4 of the 6 tumours assessable for <it>TP53 </it>sequence analysis revealed mutations. The overall array CGH pattern indicated that, between the mucosal and invasive parts, genetic lineage was found discontinuous in 5 advanced cancers and continuous in 3 submucosal cancers.</p> <p>Conclusions</p> <p>Genetic lineages often differed between early and advanced TUBs. <it>MYC</it>-/<it>TP53</it>+ and <it>MYC </it>+ and/or <it>TP53</it>- may be the signatures of dormant and aggressive TUBs, respectively, in the stomach.</p