BackgroundThe estimated number of new HIV infections in the United States reflects the leading edge of the epidemic. Previously, CDC estimated HIV incidence in the United States in 2006 as 56,300 (95% CI: 48,200–64,500). We updated the 2006 estimate and calculated incidence for 2007–2009 using improved methodology.MethodologyWe estimated incidence using incidence surveillance data from 16 states and 2 cities and a modification of our previously described stratified extrapolation method based on a sample survey approach with multiple imputation, stratification, and extrapolation to account for missing data and heterogeneity of HIV testing behavior among population groups.Principal FindingsEstimated HIV incidence among persons aged 13 years and older was 48,600 (95% CI: 42,400–54,700) in 2006, 56,000 (95% CI: 49,100–62,900) in 2007, 47,800 (95% CI: 41,800–53,800) in 2008 and 48,100 (95% CI: 42,200–54,000) in 2009. From 2006 to 2009 incidence did not change significantly overall or among specific race/ethnicity or risk groups. However, there was a 21% (95% CI:1.9%–39.8%; p = 0.017) increase in incidence for people aged 13–29 years, driven by a 34% (95% CI: 8.4%–60.4%) increase in young men who have sex with men (MSM). There was a 48% increase among young black/African American MSM (12.3%–83.0%; p<0.001). Among people aged 13–29, only MSM experienced significant increases in incidence, and among 13–29 year-old MSM, incidence increased significantly among young, black/African American MSM. In 2009, MSM accounted for 61% of new infections, heterosexual contact 27%, injection drug use (IDU) 9%, and MSM/IDU 3%.Conclusions/SignificanceOverall, HIV incidence in the United States was relatively stable 2006–2009; however, among young MSM, particularly black/African American MSM, incidence increased. HIV continues to be a major public health burden, disproportionately affecting several populations in the United States, especially MSM and racial and ethnic minorities. Expanded, improved, and targeted prevention is necessary to reduce HIV incidence.

5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracil analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors. [Cancer Res 2007;67(3):940-5]

The most common genetic change in aerobic organisms is a C:G to T:A mutation. C --> T transitions can arise through spontaneous hydrolytic deamination of cytosine to give a miscoding uracil residue. This is also a frequent DNA lesion induced by oxidative damage, through exposure to agents such as ionizing radiation, or from endogenous sources that are implicated in the aetiology of degenerative diseases, ageing and cancer. The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung(-/-) mice exhibit a moderate increase in genome-wide spontaneous mutagenesis. Here, we report that stable siRNA-mediated silencing of Smug1 in mouse embryo fibroblasts also generates a mutator phenotype. However, an additive 10-fold increase in spontaneous C:G to T:A transitions in cells deficient in both Smug1 and Ung demonstrates that these enzymes have distinct and nonredundant roles in suppressing C --> T mutability at non-CpG sites. Such cells are also hypersensitive to ionizing radiation, and reveal a role of Smug1 in the repair of lesions generated by oxidation of cytosine.

BackgroundThe best indicator of the impact of human immunodeficiency virus (HIV) prevention programs is the incidence of infection; however, HIV is a chronic infection and HIV diagnoses may include infections that occurred years before diagnosis. Alternative methods to estimate incidence use diagnoses, stage of disease, and laboratory assays of infection recency. Using a consistent, accurate method would allow for timely interpretation of HIV trends.ObjectiveThe objective of our study was to assess the recent progress toward reducing HIV infections in the United States overall and among selected population segments with available incidence estimation methods.MethodsData on cases of HIV infection reported to national surveillance for 2008-2013 were used to compare trends in HIV diagnoses, unadjusted and adjusted for reporting delay, and model-based incidence for the US population aged ≥13 years. Incidence was estimated using a biomarker for recency of infection (stratified extrapolation approach) and 2 back-calculation models (CD4 and Bayesian hierarchical models). HIV testing trends were determined from behavioral surveys for persons aged ≥18 years. Analyses were stratified by sex, race or ethnicity (black, Hispanic or Latino, and white), and transmission category (men who have sex with men, MSM).ResultsOn average, HIV diagnoses decreased 4.0% per year from 48,309 in 2008 to 39,270 in 2013 (P<.001). Adjusting for reporting delays, diagnoses decreased 3.1% per year (P<.001). The CD4 model estimated an annual decrease in incidence of 4.6% (P<.001) and the Bayesian hierarchical model 2.6% (P<.001); the stratified extrapolation approach estimated a stable incidence. During these years, overall, the percentage of persons who ever had received an HIV test or had had a test within the past year remained stable; among MSM testing increased. For women, all 3 incidence models corroborated the decreasing trend in HIV diagnoses, and HIV diagnoses and 2 incidence models indicated decreases among blacks and whites. The CD4 and Bayesian hierarchical models, but not the stratified extrapolation approach, indicated decreases in incidence among MSM.ConclusionsHIV diagnoses and CD4 and Bayesian hierarchical model estimates indicated decreases in HIV incidence overall, among both sexes and all race or ethnicity groups. Further progress depends on effectively reducing HIV incidence among MSM, among whom the majority of new infections occur.

BackgroundHIV incidence was substantially lower among circumcised versus uncircumcised heterosexual African men in three clinical trials. Based on those findings, we modeled the potential effect of newborn male circumcision on a U.S. male's lifetime risk of HIV, including associated costs and quality-adjusted life-years saved.Methodology/Principal FindingsGiven published estimates of U.S. males' lifetime HIV risk, we calculated the fraction of lifetime risk attributable to heterosexual behavior from 2005–2006 HIV surveillance data. We assumed 60% efficacy of circumcision in reducing heterosexually-acquired HIV over a lifetime, and varied efficacy in sensitivity analyses. We calculated differences in lifetime HIV risk, expected HIV treatment costs and quality-adjusted life years (QALYs) among circumcised versus uncircumcised males. The main outcome measure was cost per HIV-related QALY saved. Circumcision reduced the lifetime HIV risk among all males by 15.7% in the base case analysis, ranging from 7.9% for white males to 20.9% for black males. Newborn circumcision was a cost-saving HIV prevention intervention for all, black and Hispanic males. The net cost of newborn circumcision per QALY saved was $87,792 for white males. Results were most sensitive to the discount rate, and circumcision efficacy and cost.Conclusions/SignificanceNewborn circumcision resulted in lower expected HIV-related treatment costs and a slight increase in QALYs. It reduced the 1.87% lifetime risk of HIV among all males by about 16%. The effect varied substantially by race and ethnicity. Racial and ethnic groups who could benefit the most from circumcision may have least access to it due to insurance coverage and state Medicaid policies, and these financial barriers should be addressed. More data on the long-term protective effect of circumcision on heterosexual males as well as on its efficacy in preventing HIV among MSM would be useful.

The global mean sea level (GMSL) was reported to have dropped 5 mm due to the 2010/2011 La Niña and have recovered in 1 year. With longer observations, it is shown that the GMSL went further up to a total amount of 11.6 mm by the end of 2012, excluding the 3.0 mm/yr background trend. A reconciled sea level budget, based on observations by Argo project, altimeter, and gravity satellites, reveals that the true GMSL rise has been masked by El Niño–Southern Oscillation‐related fluctuations and its rate has increased since 2010. After extracting the influence of land water storage, it is shown that the GMSL has been rising at a rate of 4.4 ± 0.5 mm/yr for more than 3 years, due to an increase in the rate of both land ice loss and steric change.

The search for target genes involved in unbalanced acquired chromosomal abnormalities has been largely unsuccessful, because the breakpoints of these rearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursor acute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted through a variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9p resulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineated the breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusion gene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21), and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 was present. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resulted in the same underexpression of PAX5, which extended to the differential expression of the PAX5 target genes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show that specific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, acting through a variety of mechanisms. This approach indicates an application for the identification of cancer genes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent and few genes have been identified. It can be extrapolated that this strategy will reveal that the same mechanisms operate in cancer pathogenesis in general.ALL ͉ breakpoint cloning ͉ molecular copy number counting C hromosomal rearrangements are recurrent findings in human cancer and result in aberrant restructuring of the genome (1). Reciprocal (balanced) translocations may lead to abnormal gene function by direct disruption of coding sequences, such as the formation of chimaeric fusion genes. To date, 358 fusion genes have been identified in human malignancy, the majority of which are the result of balanced chromosomal rearrangements (2). However, the majority of translocations described in human cancer are unbalanced (3), suggesting that other cancer genes remain to be identified. The analysis of unbalanced translocations has largely failed to identify target genes because of the heterogeneity of the chromosomal breakpoints and the multiplicity of partner chromosomes. Thus, it has been assumed that these rearrangements affect gene function through the loss or gain of chromosomal material. Identification of the key molecular events resulting from unbalanced rearrangements would be a significant step toward understanding their role in cancer pathogenesis.Examples among which both breakpoint heterogeneity and multiplicity of partners are found are dicentric chromosomes: one of the cytogenetic features found in patients with B cell precursor acute lymphoblastic leukaemias (B...

Background: Persons who inject drugs (PWID) are at increased risk for poor health outcomes and bloodborne infections, including human immunodeficiency virus (HIV), hepatitis C virus and hepatitis B virus infections. Although substantial progress has been made in reducing HIV infections among PWID, recent changes in drug use could challenge this success.