Demethylation Therapy As A Novel Treatment For Human Papilloma Virus-Associated Head And Neck Cancer

5-azacytidine (5-aza) and its structural analog 5-aza-2’-deoxycytidine (decitabine) are demethylating agents currently used to treat myelodysplastic syndrome and acute myeloid leukemia. In addition to demethylating DNA, they are known to cause DNA damage and activate DNA damage response pathways, but our mechanistic understanding of these processes is incomplete. Given the unique epigenetic profile of human papilloma virus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC), we sought to develop demethylation therapy as a novel, targeted treatment for this subset of cancer that has less morbidity than current treatments. We wanted to characterize the DNA damage and describe the mechanism of damage induced by 5-aza in these cells, as well as the cellular response and effect on metastatic potential in cells, xenograft models, and tumors from patients treated in a clinical trial at the Yale Cancer Center. By using pulsed-field gel electrophoresis, we found that demethylation treatment induces DNA double strand break formation exclusively in HPV+ head and neck cancer cells, and that these breaks depend on active transcription, replication, and expression of a known antiviral enzyme, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3B). Furthermore, we found that demethylation therapy also reactivates p53, downregulates HPV genes, reduces the expression of matrix metalloproteinases, and reduces the metastatic potential in cells, xenograft models, and in patient tumors

A cross-linguistic comparison of address pronoun use in four European languages: Intralingual and interlingual dimensions

As part of a major ongoing project, we consider and compare contemporary patterns of address pronoun use in four major European languages- French, German, Italian and Swedish. We are specifically interested in two major aspects: intralingual behaviour, that is, within the same language community, and interlingual dimensions of address pronoun use. With respect to the former, we summarize our key findings to date. We then give consideration in a more preliminary fashion to issues and evidence relevant to the latter

Spread-Spectrum Random-Access Communications for HF Channels

Coordinated Science Laboratory was formerly known as Control Systems LaboratoryOffice of Naval Research / N00014-80-C-080

Schriftenschau

In der Schriftenschau zum Kochia-Band 1 werden 14 für die Flora von Deutschland relevante Neuerscheinungen aus den Jahren 2005 bis 2006 besprochen

Changes in body weight and food choice in those attempting smoking cessation: a cluster randomised controlled trial

<p><b>Background:</b> Fear of weight gain is a barrier to smoking cessation and significant cause of relapse for many people. The provision of nutritional advice as part of a smoking cessation programme may assist some in smoking cessation and perhaps limit weight gain. The aim of this study was to determine the effect of a structured programme of dietary advice on weight change and food choice, in adults attempting smoking cessation.</p> <p><b>Methods:</b> Cluster randomised controlled design. Classes randomised to intervention commenced a 24-week intervention, focussed on improving food choice and minimising weight gain. Classes randomised to control received "usual care".</p> <p><b>Results:</b> Twenty-seven classes in Greater Glasgow were randomised between January and August 2008. Analysis, including those who continued to smoke, showed that actual weight gain and percentage weight gain was similar in both groups. Examination of data for those successful at giving up smoking showed greater mean weight gain in intervention subjects (3.9 (SD 3.1) vs. 2.7 (SD 3.7) kg). Between group differences were not significant (p=0.23, 95% CI -0.9 to 3.5). In comparison to baseline improved consumption of fruit and vegetables and breakfast cereal were reported in the intervention group. A higher percentage of control participants continued smoking (74% vs. 66%).</p> <p><b>Conclusions:</b> The intervention was not successful at minimising weight gain in comparison to control but was successful in facilitating some sustained improvements in the dietary habits of intervention participants. Improved quit rates in the intervention group suggest that continued contact with advisors may have reduced anxieties regarding weight gain and encouraged cessation despite weight gain. Research should continue in this area as evidence suggests that the negative effects of obesity could outweigh the health benefits achieved through reductions in smoking prevalence.</p&gt

Efficacy of exercise counselling as an aid for smoking cessation: a randomized controlled trial.

To examine whether exercise counselling increases smoking abstinence and reduces tobacco withdrawal and gains in weight and body fat

Optimal scaling of average queue sizes in an input-queued switch: an open problem

We review some known results and state a few versions of an open problem related to the scaling of the total queue size (in steady state) in an n×n input-queued switch, as a function of the port number n and the load factor ρ. Loosely speaking, the question is whether the total number of packets in queue, under either the maximum weight policy or under an optimal policy, scales (ignoring any logarithmic factors) as O(n/(1 − ρ)).National Science Foundation (U.S.) (Grant CCF-0728554

Clinical use of lithium salts: guide for users and prescribers

Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers

The Role of Social Isolation and the Development of Depression: A Comparison of the Widowed and Married Oldest Old in Germany

Widowhood is common in old age, can be accompanied by serious health consequences and is often linked to substantial changes in social network. Little is known about the impact of social isolation on the development of depressive symptoms over time taking widowhood into account. We provide results from the follow-up 5 to follow-up 9 from the longitudinal study AgeCoDe and its follow-up study AgeQualiDe. Depression was measured with GDS-15 and social isolation was assessed using the Lubben Social Network Scale (LSNS-6). The group was aligned of married and widowed people in old age and education through entropy balancing. Linear mixed models were used to examine the frequency of occurrence of depressive symptoms for widowed and married elderly people depending on the risk of social isolation. Our study shows that widowhood alone does not lead to an increased occurrence of depressive symptoms. However, "widowed oldest old", who are also at risk of social isolation, have significantly more depressive symptoms than those without risk. In the group of "married oldest old", women have significantly more depressive symptoms than men, but isolated and non-isolated do not differ. Especially for people who have lost a spouse, the social network changes significantly and increases the risk for social isolation. This represents a risk factor for the occurrence of depressive symptoms

Global Genome Demethylation Causes Transcription-Associated DNA Double Strand Breaks in HPV-Associated Head and Neck Cancer Cells

High levels of DNA methylation at CpG loci are associated with transcriptional repression of tumor suppressor genes and dysregulation of DNA repair genes. Human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) have high levels of DNA methylation and methylation has been associated with dampening of an innate immune response in virally infected cells. We have been exploring demethylation as a potential treatment in HPV+ HNSCC and recently reported results of a window clinical trial showing that HNSCCs are particularly sensitive to demethylating agent 5-azacytidine (5-aza). Mechanistically, sensitivity is partially due to downregulation of HPV genes expression and restoration of tumor suppressors p53 and Rb. Here, for the first time, we show that 5-azaC treatment of HPV+ HNSCC induces replication and transcription-associated DNA double strand breaks (DSBs) that occur preferentially at demethylated genomic DNA. Blocking replication or transcription prevented formation of DNA DSBs and reduced sensitivity of HPV-positive head and neck cancer cells to 5-azaC, demonstrating that both replication and active transcription are required for formation of DSBs associated with 5-azaC