Histone H2AX Is Phosphorylated at Sites of Retroviral DNA Integration but Is Dispensable for Postintegration Repair

The histone variant H2AX is rapidly phosphorylated (denoted {gamma}H2AX) in large chromatin domains (foci) flanking double strand DNA (dsDNA) breaks that are produced by ionizing radiation or genotoxic agents and during V(D)J recombination. H2AX-deficient cells and mice demonstrate increased sensitivity to dsDNA break damage, indicating an active role for {gamma}H2AX in DNA repair; however, {gamma}H2AX formation is not required for V(D)J recombination. The latter finding has suggested a greater dependence on {gamma}H2AX for anchoring free broken ends versus ends that are held together during programmed breakage-joining reactions. Retroviral DNA integration produces a unique intermediate in which a dsDNA break in host DNA is held together by the intervening viral DNA, and such a reaction provides a useful model to distinguish {gamma}H2AX functions. We found that integration promotes transient formation of {gamma}H2AX at retroviral integration sites as detected by both immunocytological and chromatin immunoprecipitation methods. These results provide the first direct evidence for the association of newly integrated viral DNA with a protein species that is an established marker for the onset of a DNA damage response. We also show that H2AX is not required for repair of the retroviral integration intermediate as determined by stable transduction. These observations provide independent support for an anchoring model for the function of {gamma}H2AX in chromatin repair

Nonsteroidal Anti-Inflammatory Drugs and Risk of Melanoma

Because nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growth in vitro, we investigated the association between NSAIDs and melanoma to determine if there was epidemiologic evidence of a chemopreventive effect from these medications. Three hundred twenty-seven subjects with incident melanoma and 119 melanoma-free controls completed a structured interview assessing melanoma risk factors. The unadjusted odds ratio (OR) for use of nonaspirin NSAIDs was 0.58 (95% CI 0.31–1.11), in a comparison of subjects with melanoma to controls. After adjustment for melanoma risk factors, the OR was 0.71 (95% CI 0.23–2.02). Aspirin users had an unadjusted OR of 0.85 (95% CI 0.45–1.69) and an adjusted OR of 1.45 (95% CI 0.44–4.74). In this pilot study, we found no evidence of a significant association between analgesic use and melanoma risk when potential confounders are assessed. Based on conflicting reports in the literature, meta-analysis may be appropriate

Pretreatment minimal staging for non-small cell lung cancer: an updated consensus report

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31247/1/0000153.pd

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Colorectal Polyps in Carriers of the APC I1307K Polymorphism

The probability of colorectal cancer is moderately increased among carriers of the APC I1307K polymorphism. However, it is not known if endoscopic surveillance of this high-risk group is warranted. The prevalence of polyps and adenomas in specimens of colorectal cancer who are carriers and noncarriers of the APC I1307K polymorphism is compared.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41394/1/10350_2005_Article_167.pd

Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer

Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC

Tumor immune infiltration estimated from gene expression profiles predicts colorectal cancer relapse

A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance

An Experimental Exploration of the QCD Phase Diagram: The Search for the Critical Point and the Onset of De-confinement

The QCD phase diagram lies at the heart of what the RHIC Physics Program is all about. While RHIC has been operating very successfully at or close to its maximum energy for almost a decade, it has become clear that this collider can also be operated at lower energies down to 5 GeV without extensive upgrades. An exploration of the full region of beam energies available at the RHIC facility is imperative. The STAR detector, due to its large uniform acceptance and excellent particle identification capabilities, is uniquely positioned to carry out this program in depth and detail. The first exploratory beam energy scan (BES) run at RHIC took place in 2010 (Run 10), since several STAR upgrades, most importantly a full barrel Time of Flight detector, are now completed which add new capabilities important for the interesting physics at BES energies. In this document we discuss current proposed measurements, with estimations of the accuracy of the measurements given an assumed event count at each beam energy.Comment: 59 pages, 78 figure

Cost-Effectiveness of Adding Cetuximab to Platinum-Based Chemotherapy for First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer

To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system.We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%.In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of$386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab.The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy

Observation of charge-dependent azimuthal correlations and possible local strong parity violation in heavy ion collisions

Parity-odd domains, corresponding to non-trivial topological solutions of the QCD vacuum, might be created during relativistic heavy-ion collisions. These domains are predicted to lead to charge separation of quarks along the orbital momentum of the system created in non-central collisions. To study this effect, we investigate a three particle mixed harmonics azimuthal correlator which is a \P-even observable, but directly sensitive to the charge separation effect. We report measurements of this observable using the STAR detector in Au+Au and Cu+Cu collisions at $\sqrt{s_{NN}}$=200 and 62~GeV. The results are presented as a function of collision centrality, particle separation in rapidity, and particle transverse momentum. A signal consistent with several of the theoretical expectations is detected in all four data sets. We compare our results to the predictions of existing event generators, and discuss in detail possible contributions from other effects that are not related to parity violation.Comment: 17 pages, 14 figures, as accepted for publication in Physical Review C