Antitumor activity of cell-permeable p18(INK4c) with enhanced membrane and tissue penetration.

Practical methods to deliver proteins systemically in animals have been hampered by poor tissue penetration and inefficient cytoplasmic localization of internalized proteins. We therefore pursued the development of improved macromolecule transduction domains (MTDs) and tested their ability to deliver therapeutically active p18(INK4c). MTD103 was identified from a screen of 1,500 signal peptides; tested for the ability to promote protein uptake by cells and tissues; and analyzed with regard to the mechanism of protein uptake and the delivery of biologically active p18(INK4c) into cancer cells. The therapeutic potential of cell-permeable MTD103p18(INK4c) (CP-p18(INK4c)) was tested in the HCT116 tumor xenograft model. MTD103p18(INK4c) appeared to traverse plasma membranes directly, was transferred from cell-to-cell and was therapeutically effective against cancer xenografts, inhibiting tumor growth by 86-98% after 5 weeks (P < 0.05). The therapeutic responses to CP-p18(INK4c) were accompanied by high levels of apoptosis in tumor cells. In addition to enhancing systemic delivery of CP-p18(INK4c) to normal tissues and cancer xenografts, the MTD103 sequence delayed protein clearance from the blood, liver and spleen. These results demonstrate that macromolecule intracellular transduction technology (MITT), enabled by MTDs, may provide novel protein therapies against cancer and other diseases.

Experiences of adolescent witnesses to peer victimization: The bystander effect.

Many anti-bullying programs now emphasize the role of bystanders - youth who witness peer victimization. Using a large sample of adolescents (aged 12-18) from the United Kingdom who completed an online survey, the present study examined the types of bystander interventions, their outcomes, and reasons for intervening and not intervening. No significant group differences by any demographic group were found in intervening or not. Results showed that those who had a negative affective reaction when they witnessed bullying were more likely to intervene. Two intervening behaviors (telling the bully to stop and telling an adult) were the strongest predictors of positive results. The most frequently selected reason for not intervening was not knowing what to do, and for intervening, having prosocial and altruistic motives was most common. These and other results are discussed for theoretical and practical implications.

Right ventricular outflow tract dimensions in arrhythmogenic right ventricular cardiomyopathy/dysplasia-a multicentre study comparing echocardiography and cardiovascular magnetic resonance.

Aims: Right ventricular outflow tract (RVOT) dilation is one of the echocardiographic criteria in the 2010 revised Task Force Criteria (TFC) of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). However, studies comparing cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) suggest a lower diagnostic accuracy of TTE due to its operator dependence and limited reproducibility. The goal of this study was to compare the 2010 TFC measures of RVOT dilation with three alternative measures for improving the echocardiographic assessment of RVOT in patients with ARVC/D. Methods and results: In this multicentre study, CMR and TTE were performed in 38 patients with a definite, borderline, or possible ARVC/D diagnosis and in 10 healthy controls. Besides the echocardiographic RVOT measurements listed by the 2010 TFC, we assessed three additional end-diastolic RVOT diameters. These included the RVOT diameter defined by the parasternal long axis M-mode of the aortic sinus portion (RVOT3), that defined by the parasternal long axis M-mode of the left ventricle (RVOT4), and that obtained by the parasternal short axis view of the distal RVOT proximal to the pulmonary valve (RVOT5). RVOT4 provided the best correlation between CMR and TTE (r = 0.92, [95% confidence interval (CI): 0.84-0.96; P < 0.0001]) and enhanced diagnostic accuracy for diagnosing ARVC/D (area under the curve 0.92 [95% CI, 0.78-0.98]). Conclusion: Among all RVOT diameters examined, that defined by the parasternal long axis M-mode of the left ventricle (RVOT4) provides the best agreement between CMR and TTE and exhibits the best diagnostic accuracy for ARVC/D. This novel RVOT4 measurement carries the potential for improving the echocardiographic diagnosis of ARVC/D.

The incidence of venous thromboembolism is not lowin Korean patients with advanced pancreatic cancer [corrected]

Background: Pancreatic cancer is among the most common malignancies associated with venous thromboembolism (VTE). Asian patients are known to have a lower incidence of VTE compared to Caucasian patients. However, few studies have investigated the incidence of VTE in Asian patients with pancreatic cancer. Methods: This retrospective review of medical records was performed on 505 patients with histopathologically proven advanced stage pancreatic cancer, from January 2006 to December 2012, at Soonchunhyang University Hospitals. Results: Ninety-four patients (18.6%) had at least one pulmonary embolism (PE), deep vein thrombosis (DVT), or splanchnic vein thrombosis (SVT); 38 patients had isolated SVT; and 56 patients (11.1%) had at least one classic VTE (PE and/or DVT of lower extremities). Patients with more advanced stages of pancreatic cancer (distant metastatic stage, recurrence) or who had received chemotherapy had a higher incidence of classic VTE. Patients who were simultaneously diagnosed with pancreatic cancer and classic VTE had a poorer prognosis than patients with subsequent VTEs. There was a significant difference in overall survival (OS) between the presence and absence of a concurrent classic VTE diagnosis (median: OS, 2.1 mo vs. 10.7 mo; P<0.001). Even when VTE included SVT, the result was similar (P<0.001). Conclusion: In Korean patients with advanced pancreatic cancer, the incidence of VTEs is comparable to that of Caucasian patients. We also found that pancreatic cancer patients with concurrent VTEs had a poor prognosis compared to patients who developed VTEs later.

Perceived support in school adjustment.

This study examined the relationship between support by parents and teachers and school attachment and involvement in the first year of middle school for 157 sixth graders in a predominantly African-American urban middle school. Results suggested the importance of parental support in school attachment and involvement during early adolescence. Teachers' support was a significant predictor of overall school attachment (R2= .03) beyond the variance explained by parental support (R2= .11).

Bone age in unilateral spastic cerebral palsy: is there a correlation with hand function and limb length?

BACKGROUND: The purpose of this study was to analyze the bone age and the upper extremity segmental lengths between the affected and the unaffected side and to reveal the correlation between the difference of bone age and the upper limb length discrepancy in the unilateral spastic cerebral palsy (CP). We also evaluated the relationship between difference of bone age and hand function. METHODS: Seventy-eight patients participated in this study. The bone ages of hand-wrists of the patients were determined by the Greulich and Pyle atlas. Upper extremity segmental lengths were measured by radiograph. The side-to side length discrepancy was calculated as a percentage. Hand function was classified according to the Manual Ability Classification System (MACS). RESULTS: There was significant difference in the bone age between the affected and unaffected side (p<0.001). Segmental lengths of the upper extremities showed significant differences between the affected and unaffected side (p<0.001). The hand function of 56 patients was evaluated by MACS and the MACS level showed correlation with difference of side-to-side bone age (r=0.29, p=0.03) and all segmental upper limb length discrepancies (p<0.05). The hand function in the bone-age-delayed group was significantly better than the hand function in the bone-age-symmetrical group (p<0.01). CONCLUSIONS: The bone age of the affected side compared to the unaffected side is delayed and the hand function of the affected side is correlated with the difference of side-to-side bone age and the upper limb length discrepancy. Hand function might be helpful for predicting potential limb shortness and delayed bone age.

Changes in serum biomarker profiles after percutaneous mitral valve repair with the MitraClip system.

BACKGROUND: Mitral regurgitation (MR) is one of the most common valvular diseases. Percu-taneous mitral valve repair with the MitraClipTM system is a novel percutaneous mitral valve repair (PMVR) technique for high-surgical-risk patients. However, the effect of PMVR on cir-culating cardiac or inflammatory biomarkers and their association with individual functional, echocardiographic and clinical outcomes is poorly investigated. METHODS: A group of 144 patients with functional or degenerative MR (age, 75 ± 11 years; 41% females) underwent PMVR with the MitraClip system at the University Heart Center Zu-rich. Serum biomarkers as N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and creatinine were obtained from venous sampling at baseline and follow-up of 3-6 months. RESULTS: Median NT-proBNP decreased insignificantly from 2,942 (IQR 1,596-5,722) to 2,739 (IQR 1,440-4,296) ng/L, p = 0.21. NT-proBNP changes did not correlate with baseline left ventricular (LV) ejection fraction or LV dimensions, with New York Heart Association class on follow-up, or with clinical events on follow-up. CRP levels reached a peak on the third postoperative day at 34.0 mg/L with a subsequent slow decrease over the ensuing days. CONCLUSIONS: Despite successful PMVR, NT-proBNP remain fairly unchanged on follow-up and changes in NT-proBNP levels are poor predictors of functional improvement or clinical outcome after MitraClip treatment.

Cytoprotective effect of green tea extract and quercetin against hydrogen peroxide-induced oxidative stress.

In this study, we evaluated the cytoprotective effects of antioxidative substances in hydrogen peroxide (H2O2) treated Mel-Ab melanocytes. Tested substances include selenium, quercetin, green tea (GT) extract, and several vitamins (ascorbic acid, Trolox, and folic acid). Of these, both quercetin and GT extract were found to have strong cytoprotective effects on H2O2-induced cell death. We also examined additive effects, but no combination of two of any of the above substances was found to act synergistically against oxidative damage in Mel-Ab cells. Nevertheless, a multi-combination of GT extract, quercetin, and folic acid appeared to prevent cellular damage in a synergistic manner, which suggests that combinations of antioxidants may be of importance, and that co-treatment with antioxidants offers a possible means of treating vitiligo, which is known to be related to melanocyte oxidative stress.

Violence exposure and teen dating violence among African American youth.

This study examines the relationships between exposure to violence in the community, school, and family with dating violence attitudes and behaviors among 175 urban African American youth. Age, gender, state support and experiences with neglect, school violence, and community violence were the most significant predictors of acceptance of dating violence. Experiences with community violence and age were important predictors of dating violence perpetration and victimization. Findings highlight the importance of planning prevention programs that address variables affecting attitudes and behaviors of high-risk youth who have already been exposed to multiple types of violence.

Involvement of ERK AND p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells.

Cyclooxygenase-2 (COX-2) appears to play an important role in inflammation and carcinogenesis, and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a hydrophilic azo compound known to generate free radicals. Because reactive oxygen species (ROS) are known to elevate COX-2 expression, we evaluated the effect of AAPH on the expression of COX-2 in a human keratinocyte cell line, HaCaT. When cells were exposed to AAPH, marked COX-2 induction was observed. To clarify the signaling mechanism involved, we next investigated the effects of AAPH upon three major subfamilies of the mitogen-activated protein kinases (MAPKs). AAPH caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase (JNK). Furthermore, we found that PD98059, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished AAPH-induced COX-2 expression and PGE(2) production, whereas JNK inhibitor did not suppress COX-2 expression or PGE(2) production by AAPH. These findings suggest that the ERK and p38 MAPK pathways, but not the JNK pathway, are involved in AAPH-induced inflammatory progression. In addition, we found that both the water-soluble Vitamin E derivative, Trolox, and the green tea constituent, (-)-epigallocatechin gallate (EGCG), diminished AAPH-induced COX-2 expression and p38 activation.

Aggressive content of high school students' TV viewing.

The purpose of this study was to examine high school students' exposure to television programming with aggressive content and to explore whether consumption of aggressive TV varied by sex and ethnicity. Participants were 472 boys and girls from two high schools, one urban and one suburban. Definitions of both direct and indirect aggression were used to rate TV programs, and the participants' exposure to both was assessed. Analysis yielded a statistically significant effect for sex but not ethnicity as girls watched more TV programs containing indirect aggression. Also, exposure to aggressive TV content peaked in Grade 10 and fell sharply thereafter. The importance of educating adolescents about the images they view is highlighted. Implications for research are discussed.

Interparental Conflict, Parenting Behavior, and Children's Friendship Quality as Correlates of Peer Aggression and Peer Victimization Among Aggressor/Victim Subgroups in South Korea.

The focus of this study was to examine whether interparental conflict, maternal parenting behaviors, and children's friendship quality varied as a function of peer aggression/victim subgroups among a sample of 227 elementary school children and their mothers in South Korea. Both self-report and peer-report data indicated that the majority of the students were uninvolved in peer aggression situations, and the number of participants in the subgroups (aggressors, victims, and aggressor-victims) varied depending on the source of report. According to the self-report data, victims and aggressor-victims reported a higher level of maternal rejection than uninvolved youth. Aggressors, victims, and aggressor-victims reported higher maternal neglect than uninvolved youth. The highest level of interparental conflict was reported by victims, followed by aggressors. Interestingly, no significant differences were found in positive functioning of friendship quality among the subgroups, although results indicated a significant difference among groups in negative friendship quality.

A conceptual framework for understanding the association between school bullying victimization and substance misuse.

This article reviews current research findings and presents a conceptual framework for better understanding the relationship between bullying victimization (hereafter referred to as victimization) and substance misuse (hereafter referred to as SM) among adolescents. Although victimization and SM may appear to be separate problems, research suggests an intriguing relationship between the 2. We present a brief, empirical overview of the direct association between victimization and adolescent SM, followed by a proposed conceptual framework that includes co-occurring risk factors for victimization and SM within family, peer, and school and community contexts. Next, we discuss potential mediators linking victimization and SM, such as internalizing problems, traumatic stress, low academic performance, and school truancy and absence. We then identify potential moderating influences of age, gender and sex, social supports, and school connectedness that could amplify or abate the association between victimization and SM. Finally, we discuss practice and policy implications.

Iraqi American refugee youths' exposure to violence: relationship to attitudes and peers' perpetration of dating violence.

This exploratory study examines the relationships between exposure to violence in the community, school, home and dating relationships among Iraqi American youth. As Iraqi American youth are traditionally not allowed to date, dating violence measures focused on attitudes about and perceptions of abuse occurring in the relationships of friends. The number of friends known who were secretly dating was the most significant predictor of acceptability of dating violence and perceived prevalence of abuse. Youth who experienced child abuse perceived higher rates of dating violence among their peers. Findings highlight the complexities of prevention and intervention of teen dating violence within secretive relationships.

Study on the obesity and nutrition status of housewives in Seoul and Kyunggi area.

This study was conducted to evaluate the rate of obesity of 212 women (age 45-60 years) in Seoul and the Kyunggi area through analysis of BMI and the dietary life factors related to obesity using a survey on dietary habits, dietary assessment, and nutrient intake. The height of the underweight group was taller than normal. The height of the obese group was equal to that of the normal group, but the weight was 8.5 kg greater than the normal group. Women in the underweight group consumed meals irregularly, and only 33.4% ate breakfast. Additionally, the rate of overeating was low in the underweight group, and milk, dairy products (yogurt, etc.), fruit, and fruit juice were consumed more than once a day. It was found that 62.1% of the women in the obese group never ate out, and the rate of eating one serving of fruit, drinking one cup of fruit juice, and eating various kinds of foods was high. The average point of women's dietary life was 21.9 ± 2.9, and 12.7% of all women responded that their dietary life was good. However, in the obese group, only 6.9% of the women reported that their dietary life was good. Evaluation of snacking habits revealed that the underweight group consumed a high level of carbonated drinks and ice cream, whereas for in the obese group, 24.1% of the women consumed milk and its products and 5.6% regularly consumed fast and fried foods. Evaluation of nutrient intake revealed that the consumption of energy, protein, vitamin A, vitamin B(1), B(2), B(6), niacin, vitamin C, and vitamin E was high in all of the groups, but the intake of folic acid in the underweight group was lower than the required level. Overall, 24.1% of the women in the obese group were found to have metabolic diseases, mostly hypertension (43%). In conclusion, a balanced diet to avoid excessive nutrient intake is needed to prevent obesity.

Low-dose combinations of LBH589 and TRAIL can overcome TRAIL-resistance in colon cancer cell lines.

BACKGROUND: Despite the considerable advances in the treatment of colorectal cancer, substantial changes in treatment strategies are required to overcome the problems of drug resistance and toxicity. MATERIALS AND METHODS: Combinations of Pan-deacetylase inhibitor LBH589 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were studied in three colon cancer cell lines, HCT116, colo205, and HT29 (HCT116 and colo205 are TRAIL sensitive, whereas HT29 is TRAIL resistant). RESULTS: It was found that TRAIL-induced cytotoxicity was enhanced by LBH589 cotreatment in the TRAIL-sensitive cell lines, and in the TRAIL-resistant HT29 cell line. The cytotoxicity of low-dose TRAIL plus LBH589 was found to be comparable to that of high-dose TRAIL plus LBH589. Additionally, TRAIL and LBH589 were significantly less toxic to normal UCB mononuclear cells than to the three colon cancer cell lines examined. CONCLUSION: LBH589 enhances TRAIL-induced apoptosis in human colon cancer cell lines, especially those resistant to TRAIL-induced apoptosis.