Differential methylation of DNA promoter sequences in peripheral blood mononuclear cells as promising diagnostic biomarkers for colorectal cancer.

OBJECTIVES: Previous reports have indicated that the methylation profile in peripheral blood mononuclear cells (PBMCs) in different genes and loci is altered in colorectal cancer (CRC). Regarding the high mortality rate and silent nature of CRC, screening and early detection can meaningfully reduce disease-related deaths. Therefore, for the first time, we aimed to evaluate the early non-invasive diagnosis of CRC via quantitative promoter methylation analysis of RUNX3 and RASSF1A genes in PBMCs. MATERIALS AND METHODS: In the present study, we analyzed the methylation status of two important tumor suppressor genes including RUNX3 and RASSF1A in 70 CRC patients and 70 non-malignant subjects using methylation-quantification of endonuclease-resistant DNA (MethyQESD), and a bisulfite conversion-independent method. RESULTS: RUNX3 was significantly hypermethylated in PBMCs of CRC patients compared to healthy controls (P < 0.001). By determining the efficient cutoff value, the sensitivity, and specificity of RUNX3 promoter methylation for CRC diagnosis reached 84.28% and 77.14%, respectively. The receiver operating characteristic (ROC) curve analyses demonstrated that RUNX3 promoter methylation has high accuracy (areas under the curve [AUC] = 0.840, P < 0.001) for discriminating CRC subjects from healthy individuals. Moreover, RUNX3 methylation levels in PBMCs progressively increased with the stage of the disease (P < 0.001). Although the amount of RASSF1A promoter methylation was not significantly different between CRC patients and controls as well as in different stages of the disease (P > 0.05). CONCLUSION: Our findings confirmed that PBMCs are reliable sources of methylation analysis for CRC screening, and RUNX3 promoter methylation can be used as a promising biomarker for early diagnosis of CRC.

Immune checkpoint inhibitors and chemotherapy in first-line NSCLC: a meta-analysis.

This study is a meta-analysis of randomized controlled trials involving first-line studies in which immune checkpoint inhibitors were added to chemotherapy and were compared with chemotherapy alone. The primary end point was overall survival (OS). The analyses used random-effects models and the Grading of Recommendations Assessment, Development, and Evaluation system to rate the quality of the evidence. Nine articles were included for qualitative and quantitative synthesis. A meta-analysis of the nine randomized trials showed a significant benefit in terms of OS (hazard ratio: 0.75 [95% CI: 0.66-0.85]; p < 0.01). Only programmed death ligand-1 positive-high cancers derive a significant OS benefit. In this meta-analysis, there is moderate evidence that the addition of immune checkpoint inhibitors to chemotherapy may improve both OS compared with chemotherapy alone.

Lay abstract We provide a meta-analysis of randomized controlled trials in first-line studies where immune checkpoint inhibitors were added to chemotherapy (CT) and were compared with CT alone. Nine articles were included for qualitative and quantitative synthesis. A meta-analysis of the nine randomized trials indicated a significant benefit in terms of overall survival (OS; hazard ratio: 0.75 [95% CI: 0.66­0.85]; p < 0.01). Only programmed death ligand-1 positive-high cancers were observed to receive a significant OS benefit. In this meta-analysis, there is moderate evidence that the addition of immune checkpoint inhibitors to CT may improve OS as compared with CT alone.

Effects of metabolic syndrome on bone health in older adults: the Bushehr Elderly Health (BEH) program.

Based on the clinical, BMD, and TBS data of 2380 participants aged ≥ 60 which was gathered during the BEH program, stage II, we showed that MetS was positively associated with BMD, while a negative or no association was observed between MetS and TBS depending on the sex and the adjustment model. INTRODUCTION: The results of previous reports in regard to the effect of metabolic syndrome (MetS) on bone health are not conclusive. This study aimed to evaluate the association between MetS with bone mineral density (BMD) and trabecular bone score (TBS) as an indicator of bone quantity and quality, respectively. METHODS: Using a cross-sectional design, this study was carried out based on the data collected during the BEH Program, stage II. MetS was defined according to NCEP-ATP III criteria. BMD (at the lumbar spine and the hip) and lumbar spine TBS were assessed by dual-energy X-ray absorptiometry device. RESULTS: The data of 2380 participants (women = 1228, men = 1152) aged ≥ 60 were analyzed. In the fully adjusted regression models (including BMI), significant associations between MetS and mean BMD were observed across all locations in men (P values ≤ 0.001) and in the lumbar spine in women (P value = 0.003). In addition, the prevalence of osteoporosis (based on BMD) was significantly lower in those with MetS than those without MetS in both sexes, even after full adjustments (women, OR = 0.707, P value = 0.013; men, OR = 0.563, P value = 0.001). In contrast, in age-adjusted regression analyses, the prevalence of degraded bone microarchitecture (TBS ≤ 1.2) was significantly increased in those with MetS than those without, irrespective of the participants' sex (P values < 0.05). The mean TBS was also negatively associated with MetS in women (ß = - 0.075, P value = 0.007) but not in men (ß = - 0.052, P value = 0.077), in age-adjusted regression models. However, after including BMI in the adjusted models, all significant associations between TBS values and MetS disappeared. CONCLUSION: It seems that a positive association exists between MetS and BMD, while MetS is either not associated or negatively correlated with bone quality as measured by TBS.

Salvia officinalis hydroalcoholic extract improved reproduction capacity and behavioral activity in rats exposed to immobilization stress.

This study was conducted to evaluate the Salvia officinalis hydroalcoholic extract on fertility capacity and behavioral features in rats exposed to immobilization stress. Male rats were randomly divided into five groups; Control; Stressed rats; and Stressed rats received 50, 100 and/or 200 mg/kg bw S. officinalis hydroalcoholic extract. To induce stress, rats were immobilized for 49 days and received S. officinalis extract orally. On day 56, we analyzed behavioral tests and evaluated reproduction capacity by measuring LH, FSH, and testosterone. Sperm parameters such as motility, viability, and total count were also determined. Bodyweight changes were also calculated on day 56. Male rats from different groups were mated with healthy female rats. Data showed that the use of 100 and 200 mg/kg bw S. officinalis extract in stressed rats increased bodyweight gain and improved behavioral disorders compared to control-matched groups (p < .05). Besides, administration of 100 and 200 mg/kg bw S. officinalis extract had the potential to improve sperm parameters and fertility capacity in stressed rats (p < .05). Decreased testosterone levels were blunted in the stressed rats that received plant extract coincided with the reduction of LH and FSH compared to control-matched stressed rats (p < .05). We found neutral effects in stressed rats that received 50 mg/kg bw plant extract. Collectively, the hydroalcoholic extract of S. officinalis could improve the fertility capacity and behavioral features under stressful conditions in a dose-dependent manner.

Inverse association between cigarette and water pipe smoking and hypertension in an elderly population in Iran: Bushehr elderly health programme.

The collected data in Bushehr Elderly Health (BEH) Program which had detailed the data on participants' smoking status and habits, was analysed to investigate the association between smoking of both water pipes and cigarettes and hypertension in an elderly population. Three thousand elderly men and women who participated in the baseline assessment of the BEH Program-a prospective population-based study being conducted in Bushehr, Iran-were selected randomly through a multistage, stratified cluster sampling method. Systolic and diastolic blood pressures were measured twice using a mercury sphygmomanometer, and researchers asked participants about medical history of hypertension as well as history of cigarette and water pipe smoking. Researchers used binary logistic regression models to assess the association of hypertension and smoking, and found an inverse, statistically significant association between current smoking and hypertension (odds ratio (OR)=0.50 (95% confidence interval (CI)=0.41, 0.60)). The association remained statistically significant after controlling for age, education and body mass index (OR=0.54 (95% CI=0.45, 0.66)). Findings were consistent for cigarette and water pipe smoking by sex (all ORs were inverse and statistically significant). Both cigarette and water pipe smoking were associated with reduced hypertension among older people, but the strength of association was different between men and women and also between cigarette and water pipe smoking. The reasons behind the association as well as the differences observed need to be investigated through more comprehensive, longitudinal studies.

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

Effects of vertically aligned carbon nanotubes on shear performance of laminated nanocomposite bonded joints.

The main objective is to improve the most commonly addressed weakness of the laminated composites (i.e. delamination due to poor interlaminar strength) using carbon nanotubes (CNTs) as reinforcement between the laminae and in the transverse direction. In this work, a chemical vapor deposition technique has been used to grow dense vertically aligned arrays of CNTs over the surface of chemically treated two-dimensionally woven cloth and fiber tows. The nanoforest-like fabrics can be used to fabricate three-dimensionally reinforced laminated nanocomposites. The presence of CNTs aligned normal to the layers and in-between the layers of laminated composites is expected to considerably enhance the properties of the laminates. To demonstrate the effectiveness of our approach, composite single lap-joint specimens were fabricated for interlaminar shear strength testing. It was observed that the single lap-joints with through-the-thickness CNT reinforcement can carry considerably higher shear stresses and strains. Close examination of the test specimens showed that the failure of samples with CNT nanoforests was completely cohesive, while the samples without CNT reinforcement failed adhesively. This concludes that the adhesion of adjacent carbon fabric layers can be considerably improved owing to the presence of vertically aligned arrays of CNT nanoforests.

Comparison of naproxen with placebo for the management of noncyclical breast pain: a randomized, double-blind, controlled trial.

BACKGROUND: Breast pain is a common symptom in patients attending breast clinics. Although most patients experience mastalgia of mild to moderate severity, approximately 15% of patients suffer from severe pain that causes significant distress and some disturbance in their daily life that lead them to seek treatment. Despite a considerable number of drugs suggested for decreasing the severity of mastalgia, there is no standard treatment for the complaint. In this study, we investigated the effect of naproxen on reducing the complaint of breast pain compared with placebo. METHODS: Eighty-one women suffering from noncyclic breast pain were recruited to a randomized, double-blind, clinical trial between January 2002 and September 2004. All patients were suffering from this complaint for at least 3 months before the study. Patients were randomly assigned to two groups. Patients in the case group received naproxen 250 mg BD. Patients in the placebo group took placebo in a similar manner. The intensity of mastalgia was assessed before and twice after intervention by using a Visual Analogue Scale. RESULTS: Forty-two of 81 patients were recruited randomly as cases and the remaining 39 were assigned placebo. Of these 24 and 22 patients fulfilled the study protocol respectively. The mean age of patients was 35 (SD = 7.5; range, 19-55) years. The mean pain severity at the beginning of the study was 5.8 and 6.1 in naproxen and placebo groups, respectively. The severity of pain was decreased significantly at the end of the study in both groups (3.9 in patients and 3.7 in controls (P = 0.005 and 0.0001)). Although the decrease in pain severity in each individual group was statistically significant, it was not significant compared with one another (P = 0.64). CONCLUSIONS: Breast pain is a complex symptom that can be relieved significantly with reassurance. According to the result of this study, naproxen has no superiority over placebo in reducing noncyclic breast pain.

Chirality dependence of carbon single-walled nanotube material properties: axial Young's modulus.

The potential use of individual carbon nanotubes as nano devices warrants detailed investigation of their mechanical behavior based on structural and geometrical configurations. The objective of this paper is to unravel the structural and chirality dependence of the axial Young's modulus of a carbon single-walled nanotube by analytical and numerical approaches. In this work, we employ the general homogenization composite shell model developed based on the asymptotic homogenization technique for analytical modeling of single-walled nanotubes. We derive the working formulae for the effective elastic properties of carbon single-walled nanotube of any chirality and predict the structural and chiral dependence of the effective axial Young's modulus of the nanotube. Also, a finite element analysis on the chirality dependence of the axial Young's modulus of the carbon nanotube is reported. The outcomes of our analyses are compared with available experimental and simulation results.

Chirality dependence of carbon single-walled nanotube material properties: axial coefficient of thermal expansion.

Carbon nanotubes are one of the best candidates for applications where structural, thermal, and chemical stabilities are of great importance. Despite the fact that significant efforts have been devoted to study properties and behavior of the carbon nanotubes in recent years, there have not been sufficient results available on their thermoelastic properties. This paper investigates the chirality dependence of coefficient of thermal expansion of carbon single-walled nanotubes both analytically and numerically. The analytical approach in characterizing the chirality dependence of the coefficient of thermal expansion uses an asymptotic homogenization method. A second analytical interpretation follows a free-expansion strain method based on basic principles of thermoelasticity. The derived formulae make it easy to understand the dependencies of the nanotube thermoelastic properties on its geometrical parameters. The results from these analytical studies were verified using a finite element method. All three independent studies consistently demonstrate that the coefficient of thermal expansion of carbon single-walled nanotubes is independent of their chirality.

Multifunctional composites using reinforced laminae with carbon-nanotube forests.

Traditional fibre-reinforced composite materials with excellent in-plane properties fare poorly when out-of-plane through-thickness properties are important. Composite architectures with fibres designed orthogonal to the two-dimensional (2D) layout in traditional composites could alleviate this weakness in the transverse direction, but all of the efforts so far have only produced limited success. Here, we unveil an approach to the 3D composite challenge, without altering the 2D stack design, on the basis of the concept of interlaminar carbon-nanotube forests that would provide enhanced multifunctional properties along the thickness direction. The carbon-nanotube forests allow the fastening of adjacent plies in the 3D composite. We grow multiwalled carbon nanotubes on the surface of micro-fibre fabric cloth layouts, normal to the fibre lengths, resulting in a 3D effect between plies under loading. These nanotube-coated fabric cloths serve as building blocks for the multilayered 3D composites, with the nanotube forests providing much-needed interlaminar strength and toughness under various loading conditions. For the fabricated 3D composites with nanotube forests, we demonstrate remarkable improvements in the interlaminar fracture toughness, hardness, delamination resistance, in-plane mechanical properties, damping, thermoelastic behaviour, and thermal and electrical conductivities making these structures truly multifunctional.

Super-compressible foamlike carbon nanotube films.

We report that freestanding films of vertically aligned carbon nanotubes exhibit super-compressible foamlike behavior. Under compression, the nanotubes collectively form zigzag buckles that can fully unfold to their original length upon load release. Compared with conventional low-density flexible foams, the nanotube films show much higher compressive strength, recovery rate, and sag factor, and the open-cell nature of the nanotube arrays gives excellent breathability. The nanotube films present a class of open-cell foam structures, consisting of well-arranged one-dimensional units (nanotube struts). The lightweight, highly resilient nanotube films may be useful as compliant and energy-absorbing coatings.

Multifunctional brushes made from carbon nanotubes.

Brushes are common tools for use in industry and our daily life, performing a variety of tasks such as cleaning, scraping, applying and electrical contacts. Typical materials for constructing brush bristles include animal hairs, synthetic polymer fibres and metal wires (see, for example, ref. 1). The performance of these bristles has been limited by the oxidation and degradation of metal wires, poor strength of natural hairs, and low thermal stability of synthetic fibres. Carbon nanotubes, having a typical one-dimensional nanostructure, have excellent mechanical properties, such as high modulus and strength, high elasticity and resilience, thermal conductivity and large surface area (50-200 m2 g(-1)). Here we construct multifunctional, conductive brushes with carbon nanotube bristles grafted on fibre handles, and demonstrate their several unique tasks such as cleaning of nanoparticles from narrow spaces, coating of the inside of holes, selective chemical adsorption, and as movable electromechanical brush contacts and switches. The nanotube bristles can also be chemically functionalized for selective removal of heavy metal ions.