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Abstract Objective Selenium seems to be a risk factor for diabetes mellitus (DM) in recent studies, opposite to the previous expectation that it may contribute to prevent DM. The authors aimed to ascertain the relationship between selenium and DM. Methods Data were collected from the National Health and Nutrition Examination Survey conducted from 2011 to 2014. A multivariate logistic regression analysis with adjustment for age, sex, race/ethnicity, hypertension, dyslipidemia and body mass index was conducted to evaluate the odds ratio for DM. Results The total number of subjects was 19,931. Large proportion of subjects were excluded due to young age (< 20 years) and missing data. The data of 3406 participants were analyzed, and a total of 604 had DM. In a multivariate logistic regression model, the increase of 10 μg/L in selenium increased the prevalence of DM by 12% (OR: 1.12; 95% CI: 1.06–1.18). Further analysis with 1:1 propensity score matching data with age and sex showed a similar results (OR: 1.08; 95% CI: 1.01–1.15). In addition, the restricted cubic spline regression showed a dose-dependent relationship between selenium level and DM. Subgroup analysis showed a dose-dependent relationship between selenium level and DM regardless of sex or race/ethnicity Conclusions This large population study clearly demonstrates a positive association between selenium level and DM. This finding could have implications for nutritional supplementation in clinical settings. [ABSTRACT FROM AUTHOR]

In order to prove that porous piles are effective in remediating muddy tidal flat sediments and increasing the biomass, field experiments were carried out at the tidal flat of a brackish river located in Hiroshima City, Japan. Porous piles with a diameter of 16 cm and height of 50 cm were installed in the muddy sediment that covers the sand layer of the tidal flat. After installation, concentrations of dissolved oxygen in interstitial water in and around the porous piles increased to a maximum concentration of 6 mg/l due to enhancement of the groundwater flow. The increase of dissolved oxygen in the interstitial water produced a decrease in the concentration of ammonia and an increase in the individual number of benthos at the porous pile site. From these results, we concluded that the porous pile is an effective technology for remediation of muddy tidal flats. [ABSTRACT FROM AUTHOR]

In order to monitor health usually, the wearable type smart band module to measure the physiological signals from human body was designed, fabricated and characterized. Smart band module largely consisted of two parts, one was flexible sensors module and the other one was signal processing and communication module. And then two modules were interconnected with Cu wires. Finally, flexible temperature sensor of the fabricated smart band module was tested at the surfaces of ice pack, desk, and hot plate with temperature in the range of 4.5 ∼ 74.1̊C including skin temperature around 30 ∼ 33 ̊C. And GSR data were measured at the skin with high sensitivity and normal atmosphere to compare. Measured data from sensors were signally processed and transmitted using via Bluetooth 4.0 wireless network, so we could display successfully those data using software on the lab-top computer. In the near future, conductive yarns will be used for the interconnections instead of general Cu wires and we are going to measure the emotion change from physiological signals from human body during usual life. [ABSTRACT FROM AUTHOR]

Abstract: Artificial reefs (ARs) are important entities aimed to restore and enhance resources throughout the world. In order to develop Thailand’s AR program, the current distribution of ARs and natural reefs was investigated. Also the materials used for AR construction were studied. A high distribution of ARs was found in coastal areas (depth ≤30 m) that lacked natural reefs. Of the total sea areas, shallow water areas (depth ≤10 m) showed to have a higher distribution of ARs with a density ratio of 0.06. AR program’s trends from various coastal countries showed that the data presented a wide field of studies on AR in numerous countries, ranging from structure research to physical, biological, and economical monitoring. In comparison, however, a relatively narrow range of studies have been done for Thailand, most of which were concerned with productivity and ecological success. The data also reflected the use of various materials and types of structures in AR construction in other countries, but this variety was not visible in that of Thailand. In addition, while the use of a variety of structures has enabled many countries to deploy ARs in deeper waters to enhance and restore resources, Thailand’s AR deployment was shown to only have a high distribution and density ratio of ARs in shallow areas because of the use of relatively primitive structures and deployment methods. Upon comparison of AR programs in various countries, it seems that Thailand lacks the necessary technology, future plans and information about recent trends. Shallow waters (depth ≤10 m) will undoubtedly be important AR deployment sites for the restoration and enhancement resources, but in order to counteract the present environmental damages and decline of marine resources, it will be necessary to conduct a much wider field of studies. In addition, more effective deployment plans should be implemented to focus on deeper waters (depth >10 m), which may be beneficial for the future AR program development. According to previous studies, AR development in Thailand should be improved with more effective methods of structure construction, planning, and techniques in order to restore the environment and the coastal resources. [Copyright &y& Elsevier]

Abstract: Lung cancer is the leading cause of cancer deaths worldwide and is usually associated with late diagnosis and poor prognosis. Tumor-acquired methylation of the promoter CpG islands (CGIs) is an important mechanism for silencing tumor suppressor genes. The checkpoint kinase 2 (CHK2) is a tumor suppressor that plays a crucial role in regulating cell-cycle checkpoints and apoptosis following DNA damage. The methylation statuses of two CGIs, distal and proximal, of human CHK2 gene were determined in non-small cell lung cancers (NSCLCs) using a nested methylation-specific PCR and bisulfite sequencing. The methylation of distal CHK2 CGI was found in 39 (28.1%) of the 139 NSCLCs. Its frequency was significantly more frequent in squamous cell carcinomas than in adenocarcinomas (40.0% vs 19.0%, p =0.006) and was also higher in ever-smokers than in never-smokers with a borderline significance (31.7% vs 17.1%, p =0.071). RT-PCR analysis showed that the distal CGI methylation correlated with CHK2 mRNA expression. However, the methylation of the proximal CHK2 CGI is not specific to tumors and not related to gene expression. These results suggest that the down-regulation of CHK2 gene via distal CGI methylation may play a role in the pathogenesis of NSCLC, particularly squamous cell carcinoma. However, further studies with large numbers of patients are needed to confirm our findings. [Copyright &y& Elsevier]

Abstract: In diabetic nephropathy, transforming growth factor β1 (TGFβ1) is related to p38 mitogen-activated protein kinase (MAPK) that induces production of fibronectin in mesangial cells. We investigated the effects of α-lipoic acid (ALA), a potent antioxidant, on proteinuria and TGFβ1–p38 MAPK–fibronectin pathway in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. After ALA treatment for 5 weeks in OLETF rats at 30 weeks of age, plasma malondialdehyde, urinary protein excretion, renal cortical TGFβ1, and fibronectin protein levels were decreased; and urinary protein excretion was positively correlated with renal cortical TGFβ1 and fibronectin protein levels. Phospho-form but not total-form levels as well as fold activations of each protein consisting of p38 MAPK pathway were also attenuated. These results suggest that ALA ameliorates proteinuria by attenuating expressions of TGFβ1 and fibronectin proteins, and these favorable effects are related to inhibition of phosphorylating activation of p38 MAPK pathway in renal cortex of OLETF rats. [Copyright &y& Elsevier]

Abstract: ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) is an extracellular matrix metalloproteinase with protease activity and antiangiogenic activity. It has been suggested that ADAMTS1 plays an important role in tumor growth and metastasis. In this study, we examined ADAMTS1 expression in non-small cell lung cancer (NSCLC), and we also evaluated whether the loss of ADAMTS1 expression is due to aberrant methylation of the gene. In addition, we examined the relationship between ADAMTS1 methylation and clinicopathologic features in NSCLC patients. ADAMTS1 expression was examined using reverse-transcription polymerase chain reaction (PCR), and the methylation status of the gene was evaluated by methylation-specific PCR in NSCLC cell lines (n=10) and primary NSCLC tumors (n=98). Down-regulation of ADAMTS1 was observed in 30% (3/10) of the NSCLC cell lines, and this down-regulation was found to be concordant with aberrant methylation of the gene. Furthermore, ADAMTS1 expression was restored after treatment with the demethylating agent, 5-Aza-2’-deoxycytidine, in cell lines that lacked ADAMTS1 expression. Aberrant methylation of the gene was observed in 31.6% (31 of 98) of the NSCLC tumors, while it was found in only 7.1% (7/98) of the corresponding nonmalignant tissues. Methylation in NSCLC tumors was not correlated with the clinicopathologic features of the patients, such as age, gender, and histology and pathologic staging of the tumor. Taken together, these results suggest that aberrant methylation of ADAMTS1 frequently occurs in NSCLCs and that it may play a role in the pathogenesis of NSCLC. [Copyright &y& Elsevier]

Summary: We performed this study to investigate the aberrant methylation profile of the cancer-related genes in Korean non-small cell lung cancer (NSCLC) that previously exhibited high frequencies of methylation in Western populations. The aberrant promoter methylation of eight genes (GSTP1, p16, FHIT, APC, RASSF1A, hMLH1, hMSH2, AGT) was determined by MSP in 99 surgically resected NSCLCs and their corresponding nonmalignant lung tissues. Methylation in the tumor samples was detected at 15% for GSTP1, 22% for p16, 34% for FHIT1, 48% for APC, 40% for RASSF1A, 18% for hMLH1, 8% for hMSH2 and 21% for AGT, whereas it occurred at lower frequencies in the corresponding nonmalignant lung tissues, particularly in the p16 (1%) and RASSF1A (1%) genes. These results suggest that the methylation profiles of NSCLCs in a Korean population are similar to those in Western populations. [Copyright &y& Elsevier]

Abstract: In this work, we present an extended gate field effect transistor (EGFET)-based biosensor integrated with a silicon micro-fluidic channel for the electronic detection of streptavidin–biotin protein complexes. The connection between the EGFET and microfluidic system could be achieved with the proposed device, as it offers isolation between the device and solution, compatibility with the integrated circuit (IC) technology and, is applicable to the micro total analysis system (μ-TAS). The device was fabricated on the basis of semiconductor IC fabrication and micro-electro mechanical system (MEMS) technology. Au was used as the extended gate metal to form a self-assembled monolayer (SAM) with thiol. The bindings of the SAM, streptavidin and biotin were detected by measuring the electrical characteristics of the FET device. We also verified the interactions among the SAM, streptavidin, and biotin by using surface plasmon resonance (SPR) measurements. Furthermore, atomic force microscopy (AFM) images of the bio-layers formed on the Au electrode were taken in a solution in order to determine the presence of protein biomolecules with the proposed configuration. [Copyright &y& Elsevier]

Abstract: Several single-nucleotide polymorphisms of genes related to oxidative stress have been evaluated because intracellular reactive oxygen species are associated with development of diabetes and its microvascular complications. We performed a case-control study to investigate whether V16A polymorphism of manganese superoxide dismutase (Mn-SOD) gene is related to pathogenesis of diabetes and whether the polymorphism is associated with stages of albuminuria in Korean type 2 diabetic patients. Genotype distributions were studied in 178 nondiabetic subjects and 371 type 2 diabetic patients of 3 groups with a normoalbuminuria group (Normo group, n = 244), a microalbuminuria group (Micro group, n = 86), and an overt albuminuria group (Macro group, n = 41). The albumin/creatinine ratio (ACR) was defined as a urinary albumin/creatinine ratio. V16A genotypes were determined with polymerase chain reaction–restriction fragment length polymorphism method. Between nondiabetic subjects and type 2 diabetic patients, Mn-SOD genotype distribution (VV/VA + AA, 146/32 vs 314/57) and A allele frequency (0.121 vs 0.104) were not different. Patients with nephropathy, Micro and Macro groups, had significantly lower A allele frequency, longer diabetic duration, higher prevalence of hypertension, and greater ACR than those of patients without nephropathy (P < .05). A allele was significantly less frequent with progression of nephropathy (Normo group, 0.119; Micro group, 0.073; Macro group, 0.03; P < .05). In type 2 diabetic patients, A allele carriers had significantly lower prevalence of hypertension and lesser ACR than those of A allele noncarriers (P < .01). In multivariate analysis, hypertension, duration of diabetes, serum total cholesterol level, and A allele of Mn-SOD gene were independently associated with stages of albuminuria. These results suggest that V16A polymorphism of Mn-SOD gene is not related to pathogenesis of diabetes but is associated with stages of albuminuria in Korean type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Chromium picolinate (CrP) supplementation has been studied as a potential therapy of insulin resistance and lipid abnormalities. There have been some reports involving chromium supplementation in patients with diabetes, but the results are varied. The present study was conducted to assess the effects of CrP on insulin sensitivity and body weight in Goto-Kakizaki (GK) diabetic rats. We supplemented normal Sprague-Dawley (SD) rats and GK diabetic rats with supplemental CrP, 100 mg/kg/day once a day for 4 weeks. In the normal SD rats, the mean body weight of the control group increased by 50.5%, whereas that of the CrP-treated group increased by 65.9% (P < 0.05 vs control). Similarly, in the diabetic GK rats, CrP supplementation showed increased weight gain compared to the control group (133.4% vs 119.6% of the baseline weight, P < 0.01). Glucose tolerance tests (GTT) [ip injection of glucose; 2 g/kg] and insulin sensitivity tests [SQ injection of insulin (5 U/kg) plus ip injection of glucose (30 min after insulin injection)] were conducted. During insulin sensitivity tests at the end of treatment, the glucose levels were significantly lower in CrP-treated rats compared with the control rats (AUC0→120; 113.1 ± 32.0 vs 170.5 ± 49.0 mg-min/mL, P < 0.05). During GTTs, the glucose levels and insulin concentrations in the CrP-treated rats were not different from those in the control rats. The results of these studies suggest that CrP supplementation in GK diabetic rats leads to increase of weight gain and improvement of insulin sensitivity. This raises the possibility that CrP supplementation can be considered to improve carbohydrate metabolism in patients with type 2 diabetes mellitus. [Copyright &y& Elsevier]

The hyperexcitability and ectopic spontaneous discharge (ESD) of primary sensory neurons may be important for the generation or maintenance of neuropathic pain. To investigate the relationship between the electrical abnormalities of injured neurons and voltage-gated potassium (Kv) channel gene expression, the expression of the Kv channel α genes in the dorsal root ganglion (DRG) was monitored by reverse transcription-polymerase chain reaction (RT-PCR) in a chronic constriction injury (CCI) model of neuropathic pain. Electrophoresis of the RT-PCR products showed the presence of several Kv α transcript types with various levels of basal expression in lumbar 4, 5, and 6 DRGs. The Kv 1.2, 1.4, 2.2, 4.2, and 4.3 mRNA levels in the ipsilateral DRG were 63–73% of the contralateral sides of the same animal at 3 days and 34–63% at 7 days following CCI. In addition, Kv 1.1 mRNA levels declined to about 72% of the contralateral level at 7 days. No significant changes in Kv 1.5, 1.6, 2.1, 3.1, 3.2, 3.5, and 4.1 mRNA levels were detectable in the ipsilateral DRG at both days. These results suggest that the downregulation of Kv channel α gene expression in the DRG following CCI may result in the reduction of K+ current and contribute to neuronal excitability and ESD generation. [Copyright &y& Elsevier]

2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect. Macrophages produce cytokines that recruit other inflammatory cells and are responsible for the diverse effects of inflammation. In the present study, we comparatively evaluated the cytotoxicity of AS2006A to Raw264.7, H4IIE and L-929 cells as part of the studies on its anti-inflammatory effect. Among the cells examined, AS2006A was selectively cytotoxic to Raw264.7 cells, a macrophage cell line. AS2006A increased the number of cells positively stained with TdT-mediated dUTP nick end labeling (TUNEL), and upregulated the expression of the genes implicated with apoptosis, which included caspase-8, c-myc, iNOS, mdm2, NF-κB1, I-κBα and NF-κB p105 genes, as assessed by the membrane DNA array technique. The expression of the genes related with cell cycle control was not changed. Thus, the primary targets of AS2006A in macrophages might include the genes implicated with apoptosis. Immunoblot analysis revealed that AS2006A caused the release of cytochrome c from the mitochondria to the cytoplasm in macrophages. Caspase-3 activity and poly(ADP-ribose) polymerase cleavage were both increased by AS2006A in macrophages, indicating that AS2006A induced apoptosis. Viability of macrophages activated by lipopolysaccharide and their NO production were also decreased by AS2006A in a concentration-dependent manner. These results demonstrated that AS2006A selectively induces apoptosis of macrophages with cytochrome c release, caspase 3 activation and poly(ADP-ribose) polymerase cleavage, and that cytotoxicity of AS2006A to macrophages may contribute to anti-inflammatory and wound-healing effects. [Copyright &y& Elsevier]

Objectives Lung cancer is the leading cause of cancer-related deaths and is currently a major health problem owing to difficulties in diagnosis at the early stage of the disease. Changes in DNA methylation status have now been identified as a critical component in the initiation of lung cancer, and the detection of DNA methylation is expected to be an important method for the early diagnosis of lung cancer. Nicotine, the principal tobacco alkaloid, directly contributes to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAchRs). Materials and Methods To investigate the role of the CHRNB4 gene, which encodes the nAchR β4 subunit that is ubiquitously expressed on lung epithelial cells, we analyzed its methylation status in 266 patients with non-small cell lung cancer (NSCLC) by using methylation-specific polymerase chain reaction and compared it with clinicopathological parameters. Results and Conclusion The frequency of CHRNB4 unmethylation was 13.5% and 8.3% in malignant and nonmalignant tissues, respectively. CHRNB4 demethylation was associated with upregulation of its mRNA expression and was more frequent in squamous cell carcinoma and pathological stages II–IIIA disease than in adenocarcinoma and pathological stage I disease, respectively ( P = 0.003 and P = 0.01, respectively). Univariate and multivariate analyses showed that CHRNB4 unmethylation was significantly associated with unfavorable overall survival in the entire patient group as well as in men and ever-smokers. These results suggest that epigenetic regulation of CHRNB4 may affect tumor progression and survival in patients with NSCLC. Further investigation into the molecular basis of the role of CHRNB4 in the progression of NSCLC is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Liver kinase 1 (LKB1) plays a critical barrier role in lung tumorigenesis by controlling initiation, differentiation and metastasis. We searched for genetic and epigenetic alterations of the LKB1 gene in Korean non-small cell lung cancers (NSCLCs) and correlated the results with clinicopathological features. We also investigated the relationship between genetic and epigenetic alterations of LKB1 and mutations in the TP53 gene and epidermal growth factor receptor (EGFR) pathway genes. Methods: A total of 159 NSCLCs were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, and D19S878. Mutations and methylation status of LKB1 were examined by direct sequencing and a methylation-specific polymerase chain reaction, respectively. Results: A somatic mutation was found in one of the 159 tumors. LOH and promoter methylation was detected in 19.5% (31/159) and 13.2% (21/159) of the tumors, respectively. Four of the 159 tumors had concomitant LOH and methylation of LKB1. In total, 30.2% of the 159 NSCLCs harbored LKB1 LOH or promoter methylation, which were correlated with down-regulation of gene expression. LKB1 LOH was more frequent in males, smokers, and tumors with a TP53 mutation than in females, never-smokers, and tumors without a TP53 mutation, respectively. However, no significant correlation between LKB1 alterations and mutations in EGFR pathway genes was found. Conclusion: These results suggest that the prevalence of LKB1 genetic and epigenetic alterations in NSCLCs vary depending on patient ethnicity. Our results show that LKB1 alterations often occur simultaneously with mutations in EGFR pathway genes. [Copyright &y& Elsevier]

Abstract: Somatic mutations of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in non-small cell lung cancers (NSCLCs) have been investigated in but a small number of cases. In addition, the relationship between PTEN mutations and epidermal growth factor receptor (EGFR), KRAS, and TP53 mutations has not been investigated. Therefore, we investigated the frequency of PTEN mutations in 176 surgically resected NSCLCs and analyzed the relationship between PTEN mutations and EGFR, ERBB2, KRAS, and TP53 mutations. Mutations of PTEN (exons 1–9), EGFR (exons 18–21), ERBB2 (exons 19 and 20), KRAS (exon 1), and TP53 (exons 2–11) were determined by polymerase chain reaction and direct sequencing. PTEN mutations were present in 8 (4.5%) of the 176 tumors. PTEN mutations were only found in ever-smokers and were significantly more frequent in squamous cell carcinoma than in adenocarcinoma (10.2% vs 1.7%, P =0.02). Mutations of EGFR, ERBB2, KRAS, and TP53 genes were found in 36 (20.5%), 2 (1.1%), 11 (6.3%), and 66 (37.5%) cases, respectively. Of the 8 tumors with PTEN mutations, 1 case concurrently had an EGFR mutation and 4 cases had TP53 mutations. However, PTEN mutations were not found in the tumors with KRAS mutation. Our findings indicate that PTEN mutations are relatively common in NSCLC, and thus analysis of PTEN mutations may facilitate a comprehensive understanding of the genetic alterations related to the EGFR signaling pathway. [Copyright &y& Elsevier]

Abstract: Retinoid X receptors (RXRs) are nuclear receptors for retinoids that play a critical role in the regulation of growth and differentiation in normal and tumor cells. Deregulation of RXR expression has been reported in non-small cell lung cancer (NSCLC); however, the mechanism underlying the impaired expression of RXRs in lung cancer is not known. Aberrant methylation of promoter CpG islands is known to be a major mechanism for inactivation of tumor suppressor genes. We investigated the methylation status of the RXR genes in 139 surgically resected NSCLCs and correlated the results with the clinicopathologic characteristics of the patients. Methylation in the tumors was detected in all three genes: RXRA, 5.7%; RXRB, 4.3%; RXRG, 23.7%. Reverse transcriptase–polymerase chain reaction analysis showed that RXRG methylation correlates with mRNA expression. Methylation of the RXRG gene was not significantly associated with the prognosis of patients. When the patients were categorized by smoking status, however, the effect of RXRG methylation on prognosis was significantly different between never- and ever-smokers (P =0.003, test for homogeneity). Specifically, RXRG methylation was associated with a significantly worse survival in never-smokers; a trend to better survival outcome was observed for ever-smokers, although not statistically significant. This finding suggests that methylation-associated downregulation of the RXRG gene may play a differential role in the carcinogenesis of NSCLCs according to smoking status, but further studies are needed to confirm this. [Copyright &y& Elsevier]

Abstract: Background: Caspase7 (CASP7) is an executioner CASP that conducted a coordinated program of proteolysis that results in the destruction of critical cell structures, and it plays an important role in the development and progression of cancer. The purpose of this study is to comprehensively evaluate potential functional polymorphisms in the CASP7 gene in relation to the risk of lung cancer. Methods: We first captured seven single nucleotide polymorphisms (SNPs) in the regulating region, exons and exon–intron boundaries of the CASP7 gene using public database and then determined their frequencies in 27 healthy Korean individuals. Next, we examined four SNPs (rs12415607g.C>A; rs11593766g.T>G; rs2227310g.C>G; and rs10787498g.T>C) in a case–control study that consisted of 720 lung cancer patients and 720 healthy controls. Results: Of the four SNPs studied in the case–control study, only the distribution of the rs2227310g.C>G genotypes differed significantly between the cases and controls (P =0.03). The rs2227310 GG genotype was associated with a significantly increased risk of lung cancer when compared with the rs2227310 CC genotype [adjusted odds ratio (OR)=1.42, 95% confidence interval (CI)=1.05–1.93, P =0.02] and with the combined rs2227310 CC and CG genotype (adjusted OR=1.38, 95% CI=1.05–1.81, P =0.02). Consistent with the results of genotyping analysis, the ATGT haplotype (rs12415607A/rs11593766T/rs2227310G/rs10787498T) was associated with a significantly increased risk of lung cancer when compared to other haplotypes (adjusted OR=1.21, 95% CI=1.04–1.42, P =0.02). Conclusion: These results suggest that the CASP7 polymorphisms contribute to the genetic susceptibility to lung cancer. [Copyright &y& Elsevier]

Abstract: Background: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence. Objectives: The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population. Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC0−t, AUC0−∞, Cmax, Tmax, t1/2, and the elimination constant (ke), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for Cmax and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA). Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19–28 years]; height, 175.9 [5.4] cm [range, 162.0–185.0 cm]; and weight, 71.2 [9.5] kg [range, 61–96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC0−t, AUC0−∞ and Cmax were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of Tmax was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t1/2 and ke were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study. Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC0−t, AUC0−∞, and Cmax were found in this healthy Korean adult male population. [Copyright &y& Elsevier]

Abstract: Previously we reported that down-regulation of CKII activity is tightly associated with cellular senescence and that the mRNA and protein levels of CKIIα decrease during senescence. The present study demonstrates that the mRNA and protein levels of CKIIα'' also decrease during senescence. Knockdown of CKIIα'' in IMR-90 cells by RNA interference induced the senescent phenotype. Treatment of senescent IMR-90 cells with a demethylating agent 5-aza-2′-deoxycytidine induced CKIIα and CKIIα'' expression, suggesting that DNA hypermethylation might be involved in the silencing of CKIIα and CKIIα'' genes in senescent cells. However, bisulfite sequencing analysis revealed that the methylation status of the CpG islands within the reported CKIIα and CKIIα'' promoters was not associated with senescence. Instead, senescence-dependent hypermethylation was observed in the region ranging from position +1112 to +1128 of the CKIIα gene and at positions −527 and +829 of the CKIIα'' gene. In addition, this study indicates that DNA methylation-dependent down-regulation of transcription factors Sp1, Ets1 and NF-κB might be involved in silencing of the CKIIα and CKIIα'' genes during cellular senescence. [Copyright &y& Elsevier]

Abstract: The X-linked inhibitor of apoptosis protein (XIAP) is a potent mammalian IAP, and has been shown to play an important role in development and progression of cancer. Polymorphisms in the XIAP gene may influence XIAP production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the XIAP gene by direct sequencing of genomic DNA samples from 27 healthy Korean women and then performed a case–control study to evaluate the association between the polymorphisms and the risk of lung cancer. The XIAP genotypes were determined by polymerase chain reaction amplification and melting curve analysis in 582 lung cancer patients and in 582 healthy control subjects who were frequency-matched for age and sex. We identified 12 single nucleotide polymorphisms (SNPs), one novel SNP [30051C>G (A321G) in exon 3] and the following 11 known SNPs: 192G>C (rs5956578), 262C>T (rs28382699), 318C>T (rs5958318), and 374C>T (rs12687176) in the putative promoter; 26615A>G (rs2355676) in intron 1; 41725A>G (rs5958338) in intron 5; 42009A>C (Q423P, rs5956583) in exon 6; 48162T>C (rs17334739) and 48228C>T (rs28382739) in intron 6; and 48542A>G (rs28382740) and 49333G>T (rs28382742) in 3′-UTR. Four of these 12 SNPs were selected for large-scale genotyping based on their frequencies and haplotype tagging status: 262C>T, 318C>T, 374C>T, and 42009A>C. The four XIAP polymorphisms and their haplotypes exhibited no apparent relationship with the risk of lung cancer. In addition, we observed no evidence of effect modification by age, sex, smoking history, or tumor histology. These results suggest that XIAP polymorphisms do not significantly affect susceptibility to lung cancer in Koreans. [Copyright &y& Elsevier]

Summary: Background: The FAS and FASL system play an important role in regulating extrinsic apoptotic pathway and inappropriate regulation of this signaling pathway contributes to lung tumorigenesis. Polymorphisms in the promoter region of the FAS (−1377G>A and −670A>G) and FASL (−844C>T) have been shown to alter the transcriptional activities of these genes. In order to evaluate the contribution of these polymorphisms to the risk of lung cancer, we carried out a case–control study in a Korean population. Methods: The FAS and FASL genotypes were determined in 582 lung cancer patients and 582 healthy control subjects who were frequency-matched for age and gender. Results: The FAS and FASL genotypes and the FAS haplotypes exhibited no apparent relationship with the risk of lung cancer. In addition, there was no significant interaction between the FAS and FASL polymorphisms in the development of lung cancer. Conclusion: These results suggest that the FAS−1377G>A and −670A>G and FASL−844C>T polymorphisms do not significantly affect the susceptibility to lung cancer in Koreans. [Copyright &y& Elsevier]

Abstract: Caspase-8 (CASP-8) is an initiator CASP in the cell death receptor–mediated apoptotic pathway, and plays an important role in the development of cancer. Polymorphisms and their haplotypes in the CASP-8 gene can result in alterations in CASP-8 expression and/or activity, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we examined the association of -678_-673delAGTAAG (−678del) and IVS12-19G→A polymorphisms and their haplotypes with the risk of lung cancer in a Korean population. The CASP-8 genotypes were determined in 432 lung cancer patients and 432 healthy age- and gender-matched control subjects. The distributions of the CASP-8 −678del and IVS12-19G→A genotypes were not significantly different between the overall lung cancer cases and the controls. When the cases were categorized by tumor histology, however, the IVS12-19 AA genotype and the combined IVS12-19 GA + AA genotype were associated with a significantly decreased risk of small cell carcinoma (SmCC) compared with the IVS12-19 GG genotype [adjusted odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.03–0.64, P = 0.01; and adjusted OR = 0.56, 95% CI = 0.33–0.96, P = 0.03, respectively]. Consistent with the genotyping analyses, the −678del−/IVS12-19A haplotype containing 94% of the IVS12-19A allele in the study population was associated with a significantly decreased risk of SmCC compared with the −678del−/IVS12-19G (adjusted OR = 0.58, 95% CI = 0.36–0.93, P = 0.023, and Pc = 0.046). These findings suggest that the CASP-8 gene may contribute to an inherited predisposition to SmCC of the lung. [Copyright &y& Elsevier]

Go, a heterotrimeric G-protein, is enriched in brain and neuronal growth cones. Although several reports suggest that Go may be involved in modulation of neuronal differentiation, the precise role of Go is not clear. To investigate the function of Go in neuronal differentiation, we determined the effect of Goα, the α subunit of Go, on the expression of Cav2.2, the pore-forming unit of N-type calcium channels, at the transcription level. Treatment with cyclic AMP (cAMP), which triggers neurite outgrowth in neuroblastoma F11 cells, increased the mRNA level and the promoter activity of the Cav2.2 gene. Overexpression of Goα inhibited neurite extension in F11 cells and simultaneously repressed the stimulatory effect of cAMP on the Cav2.2 gene expression to the basal level. Targeted mutation of the Goα gene also increased the level of Cav2.2 in the brain. These results suggest that Go may regulate neuronal differentiation through modulation of gene expression of target genes such as N-type calcium channels. [Copyright &y& Elsevier]

As the most widely consumed endocrine-disrupting chemical, bisphenol A (BPA) has been linked to reproductive dysfunction, diabetes mellitus, and obesity. However, the evidence for an association between BPA and cardiovascular disease (CVD) remains insufficient. In the present study, we aimed to identify the association between BPA and CVD, using data from the 2003–2016 National Health and Nutrition Examination Surveys (NHANES). We estimated urine BPA concentration after adjustments for creatinine (ng/mg) and normalized the asymmetrical distribution using natural logarithmic transformation (ln-BPA/Cr). A multivariate logistic regression was performed to evaluate the odds ratio (OR) and 95% confidence interval (CI) for CVD, with ln-BPA/Cr concentration as predictor. We then performed a Mantel–Haenszel meta-analysis with five eligible studies and NHANES 2003–2016 data. Our subjects were 11,857 adults from the NHANES data. After adjusting for age, sex, race/ethnicity, body mass index (BMI), cigarette smoking, diabetes status, hypertension, and dyslipidemia, OR between ln-BPA/Cr and CVD was 1.13 (95% CI: 1.02–1.24). After propensity-score-matching with age, sex, race/ethnicity, BMI, cigarette smoking, diabetes, hypertension, and dyslipidemia, OR continued to be significant for the association between ln-BPA/Cr and CVD (OR: 1.18, 95% CI: 1.04–1.33). A restricted cubic spline plot of this relationship revealed a dose-dependent increase in OR. However, untransformed BPA had a linear relationship with CVD only at low concentrations, whereas the OR of BPA plateaued at high concentrations. In a meta-analysis with 22,878 subjects, after adjusting for age, sex, and various cardiometabolic risk factors, OR was 1.13 (95% CI, 1.03–1.23). In conclusion, our study provides additional epidemiological evidence supporting an association between BPA and CVD. Unlabelled Image • Association of bisphenol A and cardiovascular disease (CVD) has limited evidence. • Thus, we performed logistic regression using 2003–2016 NHANES and a meta-analysis. • In the 2003–2016 NHANES, bisphenol A was associated with CVD. • The meta-analysis also confirmed a significant association of bisphenol A with CVD. [ABSTRACT FROM AUTHOR]