Inverse Dose-dependent Relationship Research Articles

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

The Association of Maternal Smoking and Drinking Changes During Pregnancy and Postpartum Breastfeeding Pattern and Duration.

Objectives: To conduct a secondary data analysis of how changes in smoking and drinking during pregnancy impact status of any breastfeeding and breastfeeding duration in a national cohort. Materials and Methods: A cross-sectional study was conducted using Pregnancy Risk Assessment Monitoring System (PRAMS) data between 2009 and 2017 (n = 334,203). Univariate and multivariate analyses were conducted on the status of any breastfeeding and breastfeeding duration. Results: A dose-dependent inverse relationship was found in which women who smoked the same or more or resumed smoking during pregnancy showed the lowest likelihood and shortest duration of breastfeeding, followed by reduced smokers, quitters, and nonsmokers. Women with a history of alcohol use were significantly more likely to breastfeed compared with women without a history of alcohol use. Conclusions: The profile of smoking change during pregnancy impacts the likelihood and duration of breastfeeding in a dose-dependent and inverse manner. No such relationship was found with drinking change during pregnancy. Public Health Implications: Significant public health efforts should focus on implementing and sustaining evidence-based interventions for prenatal smoking cessation and educating providers and maternal populations on the adverse effect of postpartum alcohol exposure.

Urine glyphosate exposure and serum sex hormone disruption within the 2013–2014 National Health and Nutrition Examination survey (NHANES)

Glyphosate-based herbicides (GBHs) are one of the most commonly used herbicides worldwide. Numerous in vitro and in vivo model system studies have demonstrated endocrine-disrupting chemical (EDC) properties associated with glyphosate/GBH exposure. The present hypothesis-testing study evaluated the potential inverse dose-dependent relationship between increasing urinary glyphosate and decreasing concentrations of blood sex hormones. Demographic and newly available lab test data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) were analyzed with survey regression modeling (adjusted for age, gender, race, and country of birth) in Statistical Analysis System (SAS) software. A total of 225, 615, 858 weighted-persons (sample n = 2130 persons) were examined for concentrations of urinary glyphosate and serum sex hormones (including: total testosterone, total estradiol, and sex hormone binding globulin (SHBG)) among males and females, 6 years-old or older. This study revealed about 82% of the population of the United States examined had detectable urinary concentrations of glyphosate. A significant inverse correlation between concentrations of glyphosate and total estradiol and a trend towards an inverse correlation between concentrations of glyphosate and total testosterone were observed. Concentrations of SHBG and glyphosate did not correlate. Ratios of total testosterone:SHBG and total estradiol:SHBG (estimating the fraction of active sex hormones in the blood) were significantly inversely correlated with urinary concentrations of glyphosate. This epidemiological study associates widespread and ongoing glyphosate/GBH exposures with human endocrine-disruptions. Future studies should examine these phenomena in other databases and other endocrine-related disorders.

Adequate Intake and Supplementation of B Vitamins, in Particular Folic Acid, can Play a Protective Role in Bone Health.

In vitro and animal model studies have shown that vitamin B (VB) deficiency has negative consequences on bone as a result of direct or mediated activity of hyperhomocysteinemia. However, there are still no precise indications regarding a possible VB role in order to maintain bone health. So, the aim of this narrative review was to consider state of the art correlation between VB dietary intake, blood levels and supplementation and bone health (bone mineral density (BMD), bone turnover markers and fractures risk) in humans. This review includes 29 eligible studies. Considering VB blood levels, the 14 studies considered have shown that low serum folate can be a risk factor for reduced BMD and fractures in the elderly, particularly women; no independent association was found for other VB. Studies that evaluate the relationship between VB dietary intake and BMD are only 2; one, conducted on 1869 women, demonstrated a positive effect of folate intake on BMD. Another demonstrated a dose-dependent inverse relationship between vitamin B6 dietary intake and risk of hip fracture, but only for 35298 female participants. Regarding the relationship between BV supplementation and bone health (9 studies with only VB and 4 with other nutrients), all studies that considered patients with hyperhomocysteinemia or with low folate blood levels, are in agreement in demonstrating that folate supplementation (500mcg- 5mg) is useful in improving BMD. In conclusion, a request for folate and homocysteine blood levels in elderly patients with osteopenia/osteoporosis is mandatory. For patients with hyperhomocysteinemia or with low folate blood levels, folate supplementation (500mcg-5mg) is crucial.

Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog

PurposeWe have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer’s disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs.MethodBeagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aβ levels were quantified using multiplexed selected reaction monitoring mass spectrometry.ResultsAfter systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement.ConclusionThis study demonstrates translational attributes of BBB-crossing Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Relationship of dietary magnesium intake and serum magnesium with hypertension: a review.

The relationship between magnesium and hypertension has been intensively investigated in the last few decades. Most of the so far reviews were focused on either dietary magnesium or serum magnesium or magnesium supplements. Our goal was to merge these findings with a more comprehensive approach. Internet search was performed in PubMed database without date limits, using the following search terms "dietary magnesium," "serum magnesium," "magnesium supplements," "hypertension," "drinking water," "food," "endothelial dysfunction," "arterial smooth muscle," and "arterial spasms." In general, there exists an inverse dose-dependent relationship between dietary magnesium intake and serum magnesium and the risk of hypertension. A negative correlation has been found between the serum magnesium concentration and Framingham risk score and intima-media carotid thickness and cardiovascular mortality. On the other hand, concentration of extracellular magnesium in the normal range acts as a natural calcium channel blocker, eliminates endothelial dysfunction, increases nitric oxide, and induces direct and indirect vasodilatation. In conclusion, an average magnesium dietary intake is below the recommended values and magnesium supplementation in the prevention and treatment of hypertension might be justified.

Abnormal and Euthyroid Ranges of Thyroid Hormones in Serum and Liver Cancer Mortality: A Cohort Study.

This study aimed to evaluate the relationship of serum thyrotropin (TSH) and thyroid hormone concentration with liver cancer mortality. A cohort of 517,996 Korean adults, who did not have liver cancer at baseline and attended a health screening including free thyroxine (FT4) and TSH, were followed for up to 16 years. High and low TSH and FT4 were defined as those above the upper bound of reference interval and those below the lower bound of reference interval of their corresponding reference intervals, respectively. Mortality information was ascertained through National Death Records. The adjusted HR (aHR) with 95% confidence interval (CI) were estimated using a Cox proportional hazard model. During a median follow-up of 8.1 years, 376 deaths from liver cancer were identified. Subjects with low FT4 levels were associated with an elevated risk of liver cancer mortality with a corresponding multivariable aHR 2.25 (95% CI: 1.62-3.12) compared with those with normal FT4 levels. Within the euthyroid range, there was also a dose-dependent inverse relationship between FT4 level and liver cancer mortality (P < 0.001). Levels of TSH and free T3 had no significant association with liver cancer mortality. The risk of liver cancer mortality increased as FT4 level decreased, both within the normal and abnormal ranges of thyroid function. Thyroid function within the abnormal and normal ranges might affect liver cancer mortality. Further study is warranted to elucidate the role of thyroid hormone in development of liver cancer including the underlying biological mechanism.

Serum Albumin as a Potential Predictor of Pneumonia after an Acute Ischemic Stroke.

Serum albumin level is associated with infection after stroke, but whether albumin predicts post-stroke pneumonia is unclear. The potential relationship between albumin level and pneumonia in patients with acute ischemic stroke (AIS) was evaluated in this study. A consecutive sample of 798 AIS patients who were admitted to West China Hospital within 24 h after onset, from the year 2017 to 2018, were retrospectively analyzed. Blood was collected on admission and assayed for serum albumin. Univariate analyses, multivariate logistic regression, and stratified logistic regression were performed to identify the risk factors of post-stroke pneumonia. Out of the 798 patients, 240 (30.2%) developed pneumonia at a median of 48 h after onset (interquartile range, 27-74 h). Patients with pneumonia had significantly lower serum albumin levels than those without pneumonia (40.6 vs. 42.9 g/l, p<0.001). After adjustment, the albumin level was still significantly associated with pneumonia in multivariate logistic regression (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.81-0.94). The association between serum albumin and pneumonia tended to depend on National Institutes of Health Stroke Scale score (p = 0.045), but this was significant only in patients with mild stroke (OR 0.84, 95% CI 0.77-0.93). A dosedependent inverse relationship was found between albumin levels and the risk of pneumonia after AIS. Albumin values predicted pneumonia with an area under the curve of 0.661 (95% CI 0.620- 0.701), and the optimal cutoff was 42.6 g/L. Low serum albumin levels may be independent predictors of pneumonia in patients with AIS, especially in mild stroke. In fact, the risk of pneumonia may vary inversely with albumin level.

Antibacterial efficacy of black seed honey in combination with penicillin and amoxiclav against gram-positive bacteria

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; The emergence of antimicrobial resistance possesses a great threat for the existence of mankind. Antibiotics like penicillin and amoxiclav are at the brink of losing their efficacy entirely in exposure to resistant bacteria. Thus, the present study was aimed to find out the antibacterial efficacy of black seed honey as an alternative natural source which can act independently and boost the efficacy of standard drugs alongside.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Penicillin, amoxiclav and black seed honey were first individually trailed against four gram-positive bacteria - &lt;em&gt;Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis &lt;/em&gt;and&lt;em&gt; Micrococcus luteus&lt;/em&gt;.&lt;strong&gt; &lt;/strong&gt;Afterwards, penicillin and amoxiclav were used in combination with honey and compared the synergistic effects with their individual efficacy. Zones of inhibition from well diffusion method, percentage inhibition, minimum inhibitory and bactericidal concentrations by microdilution method were determined in the present study. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Black seed honey alone demonstrated great inhibitory potential against &lt;em&gt;S. aureus &lt;/em&gt;(9.7 mm), &lt;em&gt;S. epidermidis &lt;/em&gt;(9.9 mm) and &lt;em&gt;M. luteus&lt;/em&gt; (9.3 mm) in well diffusion method. Moreover, its combination with amoxiclav showed synergistic effect against all bacteria except &lt;em&gt;S. epidermidis&lt;/em&gt;. However, its conjugation with penicillin was not able to produce any synergism as exhibited by zones of inhibition. The lowest concentration (1.56%) of honey applied individually or in combination in microdilution method found&lt;strong&gt; &lt;/strong&gt;highly effective which established an inverse dose dependent relationship with efficacy.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; From the data it can be concluded that the black seed honey is a highly potent natural agent which can be utilized in antimicrobial therapy. However, further investigation is recommended to identify the responsible compound for such activity.&lt;/p&gt;

Circulating osteocalcin: A potential predictor of ketosis in type 2 diabetes

Osteocalcin contributes to the regulation of endocrine system. However, the association between osteocalcin and ketosis has not been evaluated. We thus aimed to explore the relationship between total osteocalcin and risk of ketosis in type 2 diabetes (T2DM). We identified 6157 diabetes patients from Shanghai Tenth People's Hospital between 1 January 2011 and 1 March 2017. Six hundred eight subjects were enrolled in the retrospective cross-sectional study: 304 T2DM patients with ketosis whose age, gender, and body mass index were matched with 304 T2DM patients without ketosis. A further retrospective nested case-control study was conducted in 252 T2DM patients without ketosis for a mean duration of 21.58 ± 12.43 months to investigate the occurrence of ketosis. Osteocalcin levels were negatively correlated with blood ketones (adjusted r = -0.263) and urine ketones (adjusted r = -0.183). The inverse dose-dependent relationship of osteocalcin and risk of ketosis was present across osteocalcin level quintiles (top quintile as the reference, adjusted odds ratio [95% CI] = 2.56 [0.80-8.17], 3.71 [0.90-15.29], 10.77 [2.63-44.15], 23.81 [4.32-131.17] per osteocalcin quintile, respectively). Ketosis occurred in 17 of the 252 T2DM patients during follow-up. The Cox regression analysis indicated that osteocalcin was an independent protective factor against development of ketosis (adjusted hazard ratio [95% CI]: 0.668 [0.460-0.971]). Total osteocalcin can be used as a predictor of ketosis in T2DM.

Use of cyclooxygenase inhibitor and the risk of hepatocellular carcinoma in patients with chronic hepatitis B: A nested case-control study using a nationwide population-based data.

The study aimed to investigate the relationship between the use of COX inhibitors and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB) using a nationwide population-based data.A nested case-control study was conducted using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2002 to 2013 in Korea. We compared the use of COX inhibitors between HCC cases and matched controls by categorizing 5 groups according to the cumulative defined daily dose (cDDD, <28, 28-90, 91-180, 181-360, and >360) adjusting the use of antiviral agents. A total of 4980 patients with CHB were analysed as 996 HCC cases and 3984 matched controls. The number of COX inhibitor users (≥28cDDD) was 358 patients (36%) and 1814 patients (45%) in the HCC group and control group, respectively. The use of COX inhibitors was significantly associated with a decreased risk of HCC development compared with nonusers (adjusted odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.73, P<.001). There was a dose-dependent inverse relationship between the use of COX inhibitors and the risk of HCC. The adjusted ORs were 0.75 (95% CI: 0.63-0.90), 0.41 (95% CI: 0.31-0.56), 0.38 (95% CI: 0.25-0.57) and 0.49 (95% CI: 0.31-0.79) for the 28-90, 91-180, 181-360 and >360 cDDDs, respectively (P<.01). In conclusion, the use of COX inhibitors was associated with a reduced risk of HCC in CHB. COX inhibitor may have a chemopreventive role in HCC development in patients with chronic liver disease.

A novel electrochemical mast cell-based paper biosensor for the rapid detection of milk allergen casein

Developing low-cost, portable and simple analysis tools is of vital importance for food safety point-of-care testing. Therefore, herein, a new low-cost, simple to fabricate, disposable, electrochemical mast cell-based paper sensor is proposed and developed to sensitively determine the major milk allergen casein. Then, a graphene (GN)/carbon nanofiber (CN)/ Gelatin methacryloyl (GelMA) composite material with high conductivity and good biocompatibility was modified on the cell-based paper sensor to improve the electrical conductivity and provide a sensing recognition interface for the immobilization of rat basophilic leukemia (RBL-2H3) mast cells. The cyclic voltammetry and differential pulse voltammetry measurement of the mast cells in the paper sensor revealed an irreversible anodic peak, whose peak current is proportional to the number of cells in the range from 1 × 102 to 1 × 108 cells/mL. For the milk allergen detection tests, mast cells exposed to the casein caused a significant reduction in the current signal, displaying an inverse dose-dependent relationship. The developed cell sensor exhibited a range of linearity between 1 × 10−7 and 1 × 10−6 g/mL of casein with a detection limit of 3.2 × 10−8 g/mL and a great reproducibility and selectivity. The electrochemical responses obtained using the cell-based paper sensor were well consistent with the conventional detection assay, with good stability and reproducibility. Therefore, a simple and novel electrochemical method for food allergens detection was developed, demonstrating its potential application in the food safety determination and evaluation.

The Inverse Relationship between Digital Media Exposure and Childhood Flourishing

To describe the relationship between digital media exposure (DME) and parental perception of childhood flourishing, or overall positive well-being. It is hypothesized that there is an inverse association between parent-reported measures of childhood flourishing and increasing daily DME. Parental responses for children ages 6-17 years (N = 64 464) from the 2011-2012 National Survey of Children's Health were analyzed. Average weekday DME that was not school work related was categorized in 2-hour intervals: 0 to <2, 2 to < 4, 4 to < 6, and ≥6 hours. Bivariate analyses and logistic regression models were used to examine the relationship between DME and parent-reported frequency of 5 childhood flourishing markers: completing homework, caring about academics, finishing tasks, staying calm when challenged, and showing interest in learning. Only 31% reported <2 hours of weekday DME. For the remaining children, daily DME was 2 to <4 hours (36%), 4 to <6 hours (17%), or ≥6 hours (17%). In a model adjusted for age, sex, race, poverty level, primary language spoken at home, and highest maternal education level, there was a dose-dependent decrease in the odds of demonstrating all 5 markers of flourishing as weekday DME increased (test for trend for each outcome P < .001). In stratified analyses, this relationship held true regardless of the child's age group, sex, or poverty level. This study provides evidence that, among school-aged children, increasing weekday DME has an inverse dose-dependent relationship with multiple childhood flourishing markers.

Artificial Light at Night of Different Spectral Compositions Differentially Affects Tumor Growth in Mice: Interaction With Melatonin and Epigenetic Pathways.

Lighting technology is rapidly advancing toward shorter wavelength illuminations that offer energy-efficient properties. Along with this advantage, the increased use of such illuminations also poses some health challenges, particularly breast cancer progression. Here, we evaluated the effects of artificial light at night (ALAN) of 4 different spectral compositions (500-595 nm) at 350 Lux on melatonin suppression by measuring its urine metabolite 6-sulfatoxymelatonin, global DNA methylation, tumor growth, metastases formation, and urinary corticosterone levels in 4T1 breast cancer cell-inoculated female BALB/c mice. The results revealed an inverse dose-dependent relationship between wavelength and melatonin suppression. Short wavelength increased tumor growth, promoted lung metastases formation, and advanced DNA hypomethylation, while long wavelength lessened these effects. Melatonin treatment counteracted these effects and resulted in reduced cancer burden. The wavelength suppression threshold for melatonin-induced tumor growth was 500 nm. These results suggest that short wavelength increases cancer burden by inducing aberrant DNA methylation mediated by the suppression of melatonin. Additionally, melatonin suppression and global DNA methylation are suggested as promising biomarkers for early diagnosis and therapy of breast cancer. Finally, ALAN may manifest other physiological responses such as stress responses that may challenge the survival fitness of the animal under natural environments.

Local and Systemic Inflammation May Mediate Diesel Engine Exhaust-Induced Lung Function Impairment in a Chinese Occupational Cohort.

Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (eg, the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (eg, serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE-induced lung function impairment using a unique cohort of diesel engine testers (DETs, n = 137) and non-DETs (n = 127), made up of current and noncurrent smokers. Urinary metabolites, FeNO, serum markers, and spirometry were assessed. A 19% reduction in CC16 and a 94% increase in CRP were identified in DETs compared with non-DETs (all p values <10-4), which were further corroborated by showing a dose-response relationship with internal dose for DE exposure (all p values <.04) and a time-course relationship with DE exposure history (all p values <.005). Mediation analysis showed that 43% of the difference in FEV1 between DETs and non-DETs can be explained by circulating CC16 and CRP (permuted p < .001). An inverse dose-dependent relationship between FeNO and internal dose for cigarette smoke was identified (p = .0003). A range of 95% lower bounds of benchmark dose of 1.0261-1.4513 μg phenanthrols/g creatinine in urine as an internal dose was recommended for regulatory risk assessment. Local and systemic inflammation may be key processes that contribute to the subsequent development of obstructive lung disease in DE-exposed populations.

Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study

Selenium (Se) is a trace element which plays an important role in adipocyte hypertrophy and adipogenesis. Some studies suggest that variations in serum Se may be associated with obesity. However, there are few studies examining the relationship between dietary Se and obesity, and findings are inconsistent. We aimed to investigate the association between dietary Se intake and a panel of obesity measurements with systematic control of major confounding factors. A total of 3214 subjects participated in the study. Dietary Se intake was determined from the Willett food frequency questionnaire. Body composition was measured using dual-energy X-ray absorptiometry. Obese men and women had the lowest dietary Se intake, being 24% to 31% lower than corresponding normal weight men and women, classified by both BMI and body fat percentage. Moreover, subjects with the highest dietary Se intake had the lowest BMI, waist circumference, and trunk, android, gynoid and total body fat percentages, with a clear dose-dependent inverse relationship observed in both gender groups. Furthermore, significant negative associations discovered between dietary Se intake and obesity measurements were independent of age, total dietary calorie intake, physical activity, smoking, alcohol, medication, and menopausal status. Dietary Se intake alone may account for 9%–27% of the observed variations in body fat percentage. The findings from this study strongly suggest that high dietary Se intake is associated with a beneficial body composition profile.

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

X-linked primate-specific melanoma antigen-A11 (MAGE-A11) is a human androgen receptor (AR) coactivator and proto-oncogene expressed at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer where it is required for androgen-dependent cell growth. In this report, we show that MAGE-A11 is targeted for degradation by human p14-ARF, a tumor suppressor expressed from an alternative reading frame of the p16 cyclin-dependent kinase inhibitor INK4a/ARF gene. MAGE-A11 degradation by the proteasome was mediated by an interaction with p14-ARF and was independent of lysine ubiquitination. A dose-dependent inverse relationship between MAGE-A11 and p14-ARF correlated with p14-ARF inhibition of the MAGE-A11-induced increase in androgen-dependent AR transcriptional activity and constitutive activity of a splice variant-like AR. Reciprocal stabilization between MAGE-A11 and AR did not protect against degradation promoted by p14-ARF. p14-ARF prevented MAGE-A11 interaction with the E2F1 oncoprotein and inhibited the MAGE-A11-induced increase in E2F1 transcriptional activity. Post-translational down-regulation of MAGE-A11 promoted by p14-ARF was independent of HDM2, the human homologue of mouse double minute 2, an E3 ubiquitin ligase inhibited by p14-ARF. However, MAGE-A11 had a stabilizing effect on HDM2 in the absence or presence of p14-ARF and cooperated with HDM2 to increase E2F1 transcriptional activity in the absence of p14-ARF. We conclude that degradation of MAGE-A11 promoted by the human p14-ARF tumor suppressor contributes to low levels of MAGE-A11 in nontransformed cells and that higher levels of MAGE-A11 associated with low p14-ARF increase AR and E2F1 transcriptional activity and promote the development of castration-resistant prostate cancer.

Paper-based cell impedance sensor and its application for cytotoxic evaluation

Disposable analytical devices for developing sensitive and label-free monitoring of cancerous cells would be attractive for cancer research. Here, paper-based electroanalytical devices based on impedance spectrometry were applied for the study of K562 cells and the toxic effect of anticancer drugs. The proposed device integrating gold nanorods modified ITO electrodes could provide a biocompatible surface for immobilization of living cells maintaining their bioactivity. The impedance results exhibited good correlation to the logarithmic value of cell numbers ranging from 7.5 × 102 to 3.9 × 106 cells mL−1 with a detection limit of 500 cells mL−1. Furthermore, this strategy was used to evaluate the cytotoxic effects of arsenic trioxide and cyclophosphamide. Results obtained by the impedimetric method correlate well with the conventional cell viability assay. Cells exposed to drugs exhibited a prominent reduction of impedance data, showing an inverse dose-dependent relationship. This simple, cost-effective and portable paper-based electrochemical analytical device could provide a new impedance platform for applications in monitoring cell behavior, pharmacological studies and toxicological analyses.

In Vitro Study of the Adverse Effect of Nicotine and Physical Strain on Human Gingival Fibroblasts as a Model of the Healing of Wounds Commonly Found in the Military

Significant adverse effects on fibroblast growth and metabolism are observed with nicotine. We investigated the synergistic effects of nicotine and cyclical mechanical strain (CMS) on human gingival fibroblasts (HGFs) in a wound-healing model. HGFs were isolated and grown in Dulbecco's modified Eagle's medium. Three-millimeter wounds were created on a confluent cell monolayer grown in a media containing 0, 1, 2, or 4 mM nicotine, with or without CMS. The applied deformation regimen remains constant for 6 days. On days 1, 2, 4, and 6, the cells were stained with hematoxylin and eosin Y for the evaluation of wound repopulation. The application of CMS alone demonstrates a biphasic response, with an initial stimulatory effect on wound repopulation (days 1-2) and less repopulation during the later phase (days 4-6). The addition of nicotine clearly demonstrated a time and inverse dose-dependent relationship on wound repopulation, with no effect during the early phase and reduced wound repopulation during the later phase. Initial treatment of HGF wounds with CMS resulted in faster wound repopulation regardless of nicotine presence. By day 6, wound healing of HGF exposed to both nicotine and CMS is delayed. These findings suggest that CMS and nicotine may affect fibroblasts and delay wound healing at other sites in the body as well.

Association of nut consumption with total and cause-specific mortality

Background: Nuts are known to have numerous health benefits but most such data have come from small studies only. In addition, the effect of nut consumption on the hard end-point of all-cause or disease-specific mortality has also not been studied adequately. Material and methods: Data from two large prospective studies – the Nurses' Health Study (NHS, 76,464 women) and the Health Professionals Follow-up Study (HPFS, 42,498 men) were analyzed to determine the association between nut consumption and subsequent total and cause-specific mortality. Average duration of follow-up in NHS was 30 years and in HPFS 24 years. Nut consumption (1 serving = 1 oz) was assessed at baseline and updated every 2–4 years. Participants with a history of cancer, heart disease, or stroke were excluded. Extensive statistical analyses and sub-group analyses were performed to eliminate the effects of various known and unknown confounding factors. Results: A total of 27,429 deaths (16,200 women and 11,229 men) occurred over 3,038,853 person-years of follow-up. There was a significant, dose-dependent inverse relationship between nut consumption and total mortality in both the studies. The pooled multivariate hazard ratios for death among participants who ate nuts were 0.93, 0.89, 0.87, 0.85 and 0.80 for those who consumed nuts less than once per week, once per week, two to four times per week, five or six times per week, and seven or more times per week, respectively (p < 0.001 for trend). This relationship persisted across all subgroups based on age, physical activity, body-mass index, smoking status, aspirin use, consumption of fruits/vegetables, etc. A similar beneficial effect of nut consumption was seen on cause-specific mortality also, with significant inverse associations observed for deaths due to cancer, heart disease, and respiratory disease. Finally, comparison between peanuts and tree-nuts revealed similar associations with total and cause-specific mortality for both the types of nuts. Conclusions: The two large, independent cohort studies involving nurses and other health professionals demonstrated that nut consumption was inversely associated, in a dose-dependent manner, with total and cause-specific mortality. This relationship was independent of other predictors of death.