NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Exploring new physics frontiers through numerical relativity

The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology

Evidence-Based Mental Health Programs in Schools: Barriers and Facilitators of Successful Implementation

Although schools can improve children’s access to mental health services, not all school-based providers are able to successfully deliver evidence-based practices. Indeed, even when school clinicians are trained in evidence-based practices (EBP), the training does not necessarily result in the implementation of those practices. This study explores factors that influence implementation of a particular EBP, Cognitive Behavioral Intervention for Trauma in Schools (CBITS). Semi-structured telephone interviews with 35 site administrators and clinicians from across the United States were conducted 6–18 months after receiving CBITS training to discuss implementation experiences. The implementation experiences of participants differed, but all reported similar barriers to implementation. Sites that successfully overcame such barriers differed from their unsuccessful counterparts by having greater organizational structure for delivering school services, a social network of other clinicians implementing CBITS, and administrative support for implementation. This study suggests that EBP implementation can be facilitated by having the necessary support from school leadership and peers

The economic pressures for biosimilar drug use in cancer medicine

The main rationale for using biosimilar drugs is for cost saving. The market development for biosimilar drugs will therefore depend on the degree to which cost saving measures are required by nations, medical insurers and individuals and the absolute savings that could be gained by switching from original drugs. This paper is designed to discover the degree to which financial constraints will drive future health spending and to discover if legal or safety issues could impact on any trend. A structured literature search was performed for papers and documents to 27 August 2011. Where multiple sources of data were available on a topic, data from papers and reports by multinational or national bodies were used in preference to data from regions or individual hospitals. Almost all health systems face current significant cost pressures. The twin driver of increasing cancer prevalence as populations age and cancer medicine costs rising faster than inflation places oncology as the most significant single cost problem. For some countries, this is predicted to make medicine unaffordable within a decade. Most developed countries have planned to embrace biosimilar use as a cost-control measure. Biosimilar introduction into the EU has already forced prices down, both the price of biosimilar drugs and competitive price reductions in originator drugs. Compound annual growth rates of use have been predicted at 65.8% per year. Most developed countries have planned to embrace biosimilar use as a major cost-control measure. Only legal blocks and safety concerns are likely to act against this trend. For centralised healthcare systems, and those with a strong tradition of generic medicine use, biosimilar use will clearly rise with predictions of more than 80% of prescriptions of some biologic drugs within 1 year of market entry in the USA. Delaying the implementation of such programmes however risks a real crisis in healthcare delivery for many countries and hospitals that few can now afford

Modeling emergency department visit patterns for infectious disease complaints: results and application to disease surveillance

BACKGROUND: Concern over bio-terrorism has led to recognition that traditional public health surveillance for specific conditions is unlikely to provide timely indication of some disease outbreaks, either naturally occurring or induced by a bioweapon. In non-traditional surveillance, the use of health care resources are monitored in "near real" time for the first signs of an outbreak, such as increases in emergency department (ED) visits for respiratory, gastrointestinal or neurological chief complaints (CC). METHODS: We collected ED CCs from 2/1/94 – 5/31/02 as a training set. A first-order model was developed for each of seven CC categories by accounting for long-term, day-of-week, and seasonal effects. We assessed predictive performance on subsequent data from 6/1/02 – 5/31/03, compared CC counts to predictions and confidence limits, and identified anomalies (simulated and real). RESULTS: Each CC category exhibited significant day-of-week differences. For most categories, counts peaked on Monday. There were seasonal cycles in both respiratory and undifferentiated infection complaints and the season-to-season variability in peak date was summarized using a hierarchical model. For example, the average peak date for respiratory complaints was January 22, with a season-to-season standard deviation of 12 days. This season-to-season variation makes it challenging to predict respiratory CCs so we focused our effort and discussion on prediction performance for this difficult category. Total ED visits increased over the study period by 4%, but respiratory complaints decreased by roughly 20%, illustrating that long-term averages in the data set need not reflect future behavior in data subsets. CONCLUSION: We found that ED CCs provided timely indicators for outbreaks. Our approach led to successful identification of a respiratory outbreak one-to-two weeks in advance of reports from the state-wide sentinel flu surveillance and of a reported increase in positive laboratory test results

The role of DNA microarrays in Toxoplasma gondii research, the causative agent of ocular toxoplasmosis

Ocular toxoplasmosis, which is caused by the protozoan parasite Toxoplasma gondii, is the leading cause of retinochoroiditis. Toxoplasma is an obligate intracellular pathogen that replicates within a parasitophorous vacuole. Infections are initiated by digestion of parasites deposited in cat feces or in undercooked meat. Parasites then disseminate to target tissues that include the retina where they then develop into long-lived asymptomatic tissue cysts. Occasionally, cysts reactivate and growth of newly emerged parasites must be controlled by the host’s immune system or disease will occur. The mechanisms by which Toxoplasma grows within its host cell, encysts, and interacts with the host’s immune system are important questions. Here, we will discuss how the use of DNA microarrays in transcriptional profiling, genotyping, and epigenetic experiments has impacted our understanding of these processes. Finally, we will discuss how these advances relate to ocular toxoplasmosis and how future research on ocular toxoplasmosis can benefit from DNA microarrays

Cost-analysis of XELOX and FOLFOX4 for treatment of colorectal cancer to assist decision-making on reimbursement

<p>Abstract</p> <p>Background</p> <p>XELOX (capecitabine + oxaliplatin) and FOLFOX 4 (5-FU + folinic acid + oxaliplatin) have shown similar improvements in survival in patients with metastatic colorectal cancer (MCRC). A US cost-minimization study found that the two regimens had similar costs from a healthcare provider perspective but XELOX had lower costs than FOLFOX4 from a societal perspective, while a Japanese cost-effectiveness study found XELOX had superior cost-effectiveness. This study compared the costs of XELOX and FOLFOX4 in patients with MCRC recently treated in two oncology departments in Hong Kong.</p> <p>Methods</p> <p>Cost data were collected from the medical records of 60 consecutive patients (30 received XELOX and 30 FOLFOX4) from two hospitals. Drug costs, outpatient visits, hospital days and investigations were recorded and expressed as cost per patient from the healthcare provider perspective. Estimated travel and time costs were included in a societal perspective analysis. All costs were classed as either scheduled (associated with planned chemotherapy and follow-up) or unscheduled (unplanned visits or admissions and associated tests and medicines). Costs were based on government and hospital sources and expressed in US dollars (US$).</p> <p>Results</p> <p>XELOX patients received an average of 7.3 chemotherapy cycles (of the 8 planned cycles) and FOLFOX4 patients received 9.2 cycles (of the 12 planned cycles). The scheduled cost per patient per cycle was$2,046 for XELOX and $2,152 for FOLFOX4, while the unscheduled cost was$240 and $421, respectively. Total treatment cost per patient was$16,609 for XELOX and $23,672 for FOLFOX4; the total cost for FOLFOX4 was 37$17,836 for XELOX and $27,455 for FOLFOX4. Sensitivity analyses showed XELOX was still less costly than FOLFOX4 when using full drug regimen costs, incorporating data from a US model with costs and adverse event data from their clinical trial and with the removal of oxaliplatin from both treatment arms. Capecitabine would have to cost around four times its present price in Hong Kong for the total resource cost of treatment with XELOX to equal that of FOLFOX4.</p> <p>Conclusion</p> <p>XELOX costs less than FOLFOX4 for this patient group with MCRC from both the healthcare provider and societal perspectives.</p