Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma

Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F_3aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F_3aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ-F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F_3aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDV-hIFNβ-F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F_3aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.     

Defective recovery of QT dispersion following transcatheter aortic valve implantation: frequency, predictors and prognosis

Background Corrected QT dispersion (cQTD) has been correlated with non-uniform ventricular repolarisation and increased mortality. In patients with aortic stenosis, cQTD has been shown improved after surgical valve replacement, but the effects of transcatheter aortic valve implantation (TAVI) are unknown. Therefore, we sought to explore the frequency, predictors and prognostic effects of defective cQTD recovery at 6 months after TAVI. Methods A total of 222 patients underwent TAVI with the Medtronic-CoreValve System between November 2005 and January 2012. Patients who were on classⅠor Ⅲ antiarrhythmics or on chronic haemodialysis or who developed atrial fibrillation, a new bundle branch block or became pacemaker dependent after TAVI were excluded. As a result, pre-, post- and follow-up ECG (median: 6 months) analysis was available in 45 eligible patients. Defective cQTD recovery was defined as any progression beyond the baseline cQTD at 6 months. Results In the 45 patients, the mean cQTD was 47 ± 23 ms at baseline, 45 ± 17 ms immediately after TAVI and 40 ± 16 ms at 6 months (15% reduction, P = 0.049). Compared to baseline, cQTD at 6 months was improved in 60% of the patients whereas defective cQTD recovery was present in 40%. cQTD increase immediately after TAVI was an independent predictor of defective cQTD recovery at 6 months (per 10 ms increase; OR: 1.89, 95% CI: 1.15–3.12). By univariable analysis, defective cQTD recovery was associated with late mortality (HR: 1.52, 95% CI: 1.05–2.17). Conclusions Despite a gradual reduction of cQTD after TAVI, 40% of the patients had defective recovery at 6 months which was associated with late mortality. More detailed ECG analysis after TAVI may help to avoid late death.     

Genomic array as compared to karyotyping in myelodysplastic syndromes in a prospective clinical trial

Karyotyping is considered as the gold standard in the genetic subclassification of myelodysplastic syndrome (MDS). Oligo/SNP‐based genomic array profiling is a high‐resolution tool that also enables genome wide analysis. We compared karyotyping with oligo/SNP‐based array profiling in 104 MDS patients from the HOVON‐89 study. Oligo/SNP‐array identified all cytogenetically defined genomic lesions, except for subclones in two cases and balanced translocations in three cases. Conversely, oligo/SNP‐based genomic array profiling had a higher success rate, showing 55 abnormal cases, while an abnormal karyotype was found in only 35 patients. In nine patients whose karyotyping was unsuccessful because of insufficient metaphases or failure, oligo/SNP‐based array analysis was successful. Based on cytogenetic visible abnormalities as identified by oligo/SNP‐based genomic array prognostic scores based on IPSS/‐R were assigned. These prognostic scores were identical to the IPSS/‐R scores as obtained with karyotyping in 95%‐96% of the patients. In addition to the detection of cytogenetically defined lesions, oligo/SNP‐based genomic profiling identified focal copy number abnormalities or regions of copy neutral loss of heterozygosity that were out of the scope of karyotyping and fluorescence in situ hybridization. Of interest, in 26 patients we demonstrated such cytogenetic invisible abnormalities. These abnormalities often involved regions that are recurrently affected in hematological malignancies, and may therefore be of clinical relevance. Our findings indicate that oligo/SNP‐based genomic array can be used to identify the vast majority of recurrent cytogenetic abnormalities in MDS. Furthermore, oligo/SNP‐based array profiling yields additional genetic abnormalities that may be of clinical importance.     

Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement

This study seeks to generate analytic insights into risk management and probability of an identifiable primary immunodeficiency defect. The Jeffrey Modell Centers Network database, Jeffrey Modell Foundation’s 10 Warning Signs, the 4 Stages of Testing Algorithm, physician-reported clinical outcomes, programs of physician education and public awareness, the SPIRIT® Analyzer, and newborn screening, taken together, generates P values of less than 0.05%. This indicates that the data results do not occur by chance, and that there is a better than 95% probability that the data are valid. The objectives are to improve patients’ quality of life, while generating significant reduction of costs. The advances of the world’s experts aligned with these JMF programs can generate analytic insights as to risk management and probability of an identifiable primary immunodeficiency defect. This strategy reduces the uncertainties related to primary immunodeficiency risks, as we can screen, test, identify, and treat undiagnosed patients. We can also address regional differences and prevalence, age, gender, treatment modalities, and sites of care, as well as economic benefits. These tools support high net benefits, substantial financial savings, and significant reduction of costs. All stakeholders, including patients, clinicians, pharmaceutical companies, third party payers, and government healthcare agencies, must address the earliest possible precise diagnosis, appropriate intervention and treatment, as well as stringent control of healthcare costs through risk assessment and outcome measurement. An affected patient is entitled to nothing less, and stakeholders are responsible to utilize tools currently available. Implementation offers a significant challenge to the entire primary immunodeficiency community.     

Patterns of internet use and mental health of high school students in Istria County,Croatia: cross-sectional study

Aim

To examine associations between different forms of internet use and a number of psychological variables related to mental health in adolescents.

Methods

A cross-sectional survey was carried out on a representative sample of students (N = 1539) from all high schools in the region of Istria in Croatia (14-19 years). The associations between four factors of internet use and nine mental health indicators were analyzed using canonical correlation analysis.

Results

The four canonical functions suggested a significant association between different types of internet use and specific indicators of mental health (P < 0.001). Problematic internet use, more typical among boys, was associated with general aggressive behavior and substance abuse (P < 0.001). Experiences of harassment, more typical among girls, were associated with health complaints, symptoms of depression, loneliness, and fear of negative evaluation (P < 0.001). Using the internet for communication and entertainment was associated with better relationships with peers (P < 0.001), while use of the internet for academic purposes was associated with conscientiousness (P < 0.001).

Conclusion

The results suggest that different patterns of internet use are significantly associated with specific sets of positive and negative mental health indicators. The data support the assumption that internet use can have both positive and adverse effects on the mental health of youth.New technologies, and especially the use of computers and the internet, are part of the everyday lives of young people and have a significant impact on their psychological development. Indeed, this mass use of new media technologies presents parents and society with a challenge to protect and support the positive development of children and youth. To date, a number of studies have examined the positive and negative aspects of using internet technologies.Literature points to several positive aspects of internet use (1,2): for information acquiring, communication, and social networking, entertainment, and online shopping. More specifically, adolescents use the internet as a useful source of information about school assignments, daily events, interests and hobbies, or health and sexuality concerns. In these instances, online activities aimed at connecting with peers have a significant place. Visiting social networking sites and using communication tools such as email, chat, forums, and discussion groups enables the creation of friendships and social groups and contributes to the development of personal identity (3). The use of computers and the internet (cyberspace) has also been argued to provide opportunities for new and faster learning, exercising one''s self-control, considering different opinions, expressing one''s attitudes and tolerance, and developing skills in critical thinking and decision-making (4). Best et al (5) found that use of online communication technologies contributed to increased self-confidence, better perception of social support, greater social capital, positive experimenting with one’s own identity, and greater opportunities for open self-disclosure. Conversely, adolescents who do not use the internet might trail behind in the development of such positive attitudes and traits and risk being rejected by their peers (6). Finally, Livingstone et al (7) found that a certain amount of risk exposure was useful in building resilience.In contrast to these positive influences of internet use, harmful effects of internet abuse range from exposure to inappropriate sexual content, pornography, and violence (2,7) to humiliation and cyber-bullying (6,8-10) and internet addiction (11,12). Research has confirmed the link between internet abuse and social isolation, depression and, anxiety (1,5,13,14), alcohol and drug abuse and gambling (15), and problems with physical health (16). Ybarra and Mitchell (17) found a connection between experiences of threats or humiliation in the virtual world and absences from school, lower school achievement, substance use disorders, delinquency and depression. Fekkes et al (18) point to the association between victimizing experiences and a number of physical, emotional, and behavioral problems, such as headaches, tension, fatigue, loss of appetite, enuresis, and sleeping problems. Slonje and Smith (19) define such experiences as a product of cyber-bullying and argue that this can be viewed as another form of aggressive behavior. Gender has emerged as a significant predictor of the manner in which the internet is used. Specifically, girls tend to experience victimizing experiences, while boys more frequently demonstrate antisocial behavior (20,21).Although many studies have identified both positive and negative correlates of internet use, there have been only a few studies using complex multivariate analyses to identify broader patterns of internet use and adolescent mental health (22,23). Less is known about how adolescents exhibiting different personalities and different emotional and behavioral patterns engage in internet use and what might be the consequences of this engagement. The aim of this study was to determine the specific patterns of internet use and mental health among adolescents. The following hypotheses were tested:H1: Problematic internet use is associated with externalized symptoms and other negative indicators of mental health. Exposure to victimizing and disturbing content on the internet is associated with internalized symptoms and negative indicators of mental health.H2: Prosocial internet use (aimed at connecting with peers and entertainment) and internet use for school purposes are associated with positive aspects of mental health.H3: Problematic internet use is present more often in young men, while exposure to disturbing content on the internet is more frequently experienced by young women.     

Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers

A double-blind, randomized study involving 264 toddlers attending day care centers was conducted to document the effect of a 9-valent pneumococcal conjugate vaccine on the carriage rate of pneumococci. Of 3750 cultures done on nasopharyngeal samples obtained from subjects during a 2-year follow-up period after vaccination, 65% were positive for Streptococcus pneumoniae. In all age windows, the rate of carriage of vaccine-type pneumococci was lower among subjects who received the pneumococcal vaccine than among control subjects, because the acquisition rate was lower in the former group. The effect was most pronounced among subjects aged < or =36 months. The sample size enabled us to study protection against carriage of S. pneumoniae serotypes 6B, 9V, 14, 19F, and 23F; significant protection against all serotypes except 19F was seen in the pneumococcal-vaccine group. The rate of carriage of serotype 6A (not included in the vaccine) was also reduced significantly, but the rate of carriage of serotype 19A (not included in the vaccine) was not. The rate of carriage of non-vaccine-type pneumococci (excluding serotype 6A) was higher in the pneumococcal-vaccine group than in the control group.     

Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM‐003 trial for pomalidomide plus low‐dose dexamethasone

In the phase III MM‐003 trial, pomalidomide plus low‐dose dexamethasone (POM+LoDEX) improved overall survival (OS) versus high‐dose dexamethasone (HiDEX) in 455 patients with relapsed and refractory multiple myeloma (RRMM) after treatment with bortezomib and lenalidomide. Here, a two‐stage Weibull method was used to adjust for the crossover of patients in the HiDEX arm to pomalidomide‐based therapy. The adjusted difference in median OS between patients in the POM+LoDEX and HiDEX arms was 7·0 months (12·7 vs. 5·7 months, respectively). These findings provide important evidence for understanding the clinical efficacy of pomalidomide on OS benefits seen in RRMM patients.