bluuebunny/crossref_metadata_2025_split huggingface dataset:
Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
Authors: Ravel Jacques , Gajer Pawel , Fu Li , Mauck Christine K. , Koenig Sara S. K. , Sakamoto Joyce , Motsinger-Reif Alison A. , Doncel Gustavo F. , Zeichner Steven L. 
Published: December 2012

ABSTRACT

Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based “universal” placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of
Lactobacillus
spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by
Lactobacillus
spp., particularly
L. crispatus
, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates.

IMPORTANCE
Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low
in vivo
efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.
An unusual accumulation of crinoids from the Silurian of the Howgill Fells, Cumbria, UK
Authors: Donovan S. K. 
Published: December 2012

Summary
A slab of Wenlock sandstone from the valley of the River Rawthey in the Howgill Fells, Cumbria, northern England, preserves a monospecific association of long, parallel to sub-parallel crinoid pluricolumnals. No crowns or attachment structures are associated; this is either an artefact of cut effect or an indication that the columns had been autotomized in response to adverse environmental conditions. The accumulation is allochthonous, but may represent a life assemblage. Current direction corresponded to the long axes of the pluricolumnals, as indicated by an example of a ‘train crash’ crinoid pluricolumnal.
The anatomy of a Fenland roddon: sedimentation and environmental change in a lowland Holocene tidal creek environment
Authors: Smith Dinah M. , Zalasiewicz Jan A. , Williams Mark , Wilkinson Ian P. , Scarborough James J. , Knight Mark , Sayer Carl , Redding Martin , Moreton Steven G. 
Published: December 2012

Summary

A Holocene sand/silt-filled tidal creek, locally called a roddon, excavated at Must Farm near Whittlesey, Cambridgeshire, within the English Fenland, preserves an unprecedented record of Fenland tidal creek evolution. The tidal creek was formed sometime between
c
. 4735 BP and
c
. 3645 BP. Its infill comprised centimetre-scale, laminated, tidal sand-mud couplets, numbering some 600 in total, with microfossils that show marine and coastal derivation of the sediment. The nature of the infill suggests rapid sedimentation that choked the creek system, perhaps in as little as a few years. At least three successive generations of roddons are present in the Fenland, suggesting at least three distinct episodes of tidal creek formation. The Must Farm roddon belongs to the first generation. A later, mud-filled channel was subsequently incised into the roddon, perhaps initiated by a marine surge. It quickly transformed into a slowly flowing river, as suggested by molluscs, ostracods and diatoms. Infill of this late-stage channel was slow, perhaps over about 1200 years between
c
. 3250 and 2050 BP (
c
. 1300–100 cal BC), as shown by archaeological finds. The mud-filled channel superficially resembles late-stage, organic-rich channel infills visible on aerial photographs, but is wider and deeper and might have been part of a more substantial long-lived ‘river’, perhaps a tributary of the proto-Nene.

Supplementary

material is available at:
http://www.geolsoc.org.uk/SUP18584
.
Combination Aspirin and/or Calcium Chemoprevention with Colonoscopy in Colorectal Cancer Prevention: Cost-effectiveness Analyses
Authors: Pence Barbara C. , Belasco Eric J. , Lyford Conrad P. 
Published: December 2012

Abstract
Background: Clinical and cohort studies have shown that low-dose aspirin and calcium are effective low-risk strategies for primary prevention of colorectal cancer (CRC). We compared the cost-effectiveness of aspirin and calcium chemoprevention used with colonoscopy for primary prevention of CRCs.
Methods: Markov chain Monte Carlo simulations for a population of 100,000 persons, with a colonoscopy compliance rate of 50%, were used for the analysis. If adenomas were detected, colonoscopy was repeated every 4 years until no adenomas were evident. Data sources included adenoma transition rates, initial adenoma and CRC incidences, and treatment complication rates from existing literature. Age-adjusted U.S. standard population mortality rates were used and costs were from Medicare reimbursement data. The target population was U.S. adults, undergoing CRC screening from ages 50 to 75 years.
Results: Outcomes included incremental cost-effectiveness ratios (ICER), life-years saved (LYS), and cancer-free years saved (CFYS). The ICER per LYS for colonoscopy alone dominated compared with no screening. Compared with colonoscopy alone, colonoscopies with aspirin (ICER = $12,950/LYS) or calcium (ICER = $13,041/LYS) were the next most cost-effective strategies. ICERs per CFYS were $3,061 and $2,317 for aspirin and calcium, respectively, when added to colonoscopy. Sensitivity analyses indicated that initial prevalence of adenomas was a main determinant of prevention cost-effectiveness.
Conclusion: Low-dose aspirin or calcium supplementation may be beneficial when added to colonoscopy, for optimum CRC prevention, at small incremental costs.
Impact: Cost-effectiveness analyses suggest that aspirin and calcium in combination with colonoscopies are cost-effective for CRC prevention in average-risk populations. Cancer Epidemiol Biomarkers Prev; 22(3); 399–405. ©2012 AACR.
Menthol Cigarettes, Race/Ethnicity, and Biomarkers of Tobacco Use in U.S. Adults: The 1999–2010 National Health and Nutrition Examination Survey (NHANES)
Authors: Jones Miranda R. , Apelberg Benjamin J. , Tellez-Plaza Maria , Samet Jonathan M. , Navas-Acien Ana 
Published: December 2012

AbstractBackground: In the United States, cigarette flavorings are banned, with the exception of menthol. The cooling effects of menthol could facilitate the absorption of tobacco toxicants. We examined levels of biomarkers of tobacco exposure among U.S. smokers of menthol and nonmenthol cigarettes.Methods: We studied 4,603 White, African-American, and Mexican-American current smokers 20 years of age or older who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2010 and had data on cigarette type and serum cotinine, blood cadmium, and blood lead concentrations. Urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL) was studied in 1,607 participants with available measures.Results: A total of 3,210 (74.3%) participants smoked nonmenthol cigarettes compared with 1,393 (25.7%) participants who smoked menthol cigarettes. The geometric mean concentrations comparing smokers of nonmenthol with menthol cigarettes were 163.1 versus 175.9 ng/mL for serum cotinine; 0.95 versus 1.02 μg/L for blood cadmium; 1.87 versus 1.75 μg/dL for blood lead; and 0.27 versus 0.23 ng/mL for urine NNAL. After multivariable adjustment, the ratios [95% confidence interval (CI)] comparing smokers of menthol with nonmenthol cigarettes were 1.03 (0.95–1.11) for cotinine, 1.10 (1.04–1.16) for cadmium, 0.95 (0.90–1.01) for lead, and 0.81 (0.65–1.01) for NNAL.Conclusions: In a representative sample of U.S. adult smokers, current menthol cigarette use was associated with increased concentration of blood cadmium, an established carcinogen and highly toxic metal, but not with other biomarkers.Impact: These findings provide information regarding possible differences in exposure to toxic constituents among menthol cigarette smokers compared with nonmenthol cigarette smokers. Cancer Epidemiol Biomarkers Prev; 22(2); 224–32. ©2012 AACR.
Serum Levels of the Chemokine CXCL13, Genetic Variation inCXCL13and Its Receptor CXCR5, and HIV-Associated Non-Hodgkin B-Cell Lymphoma Risk
Authors: Hussain Shehnaz K. , Zhu Weiming , Chang Shen-Chih , Breen Elizabeth Crabb , Vendrame Elena , Magpantay Larry , Widney Dan , Conn Daniel , Sehl Mary , Jacobson Lisa P. , Bream Jay H. , Wolinsky Steven , Rinaldo Charles R. , Ambinder Richard F. , Detels Roger , Zhang Zuo-Feng , Martínez-Maza Otoniel 
Published: December 2012

AbstractBackground: CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B-cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated before HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.Methods: CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points. TagSNPs in CXCL13 (n = 16) and CXCR5 (n = 11) were genotyped in 183 AIDS-NHL cases and 533 controls. OR and 95% confidence intervals (CI) for the associations between one unit increase in log CXCL13 levels and AIDS-NHL, as well as tagSNP genotypes and AIDS-NHL, were computed using logistic regression. Mixed linear regression was used to estimate mean ratios (MR) for the association between tagSNPs and CXCL13 levels.Results: CXCL13 levels were elevated for more than 3 years (OR = 3.24; 95% CI = 1.90–5.54), 1 to 3 years (OR = 3.39; 95% CI = 1.94–5.94), and 0 to 1 year (OR = 3.94; 95% CI = 1.98–7.81) before an AIDS-NHL diagnosis. The minor allele of CXCL13 rs355689 was associated with reduced AIDS-NHL risk (ORTCvsTT = 0.65; 95% CI = 0.45–0.96) and reduced CXCL13 levels (MRCCvsTT = 0.82; 95% CI = 0.68–0.99). The minor allele of CXCR5 rs630923 was associated with increased CXCL13 levels (MRAAvsTT = 2.40; 95% CI = 1.43–4.50).Conclusions: CXCL13 levels were elevated preceding an AIDS-NHL diagnosis, genetic variation in CXCL13 may contribute to AIDS-NHL risk, and CXCL13 levels may be associated with genetic variation in CXCL13 and CXCR5.Impact: CXCL13 may serve as a biomarker for early AIDS-NHL detection. Cancer Epidemiol Biomarkers Prev; 22(2); 295–307. ©2012 AACR.
Lack of Replication of Seven Pancreatic Cancer Susceptibility Loci Identified in Two Asian Populations
Authors: Campa Daniele , Rizzato Cosmeri , Bauer Andrea S. , Werner Jens , Capurso Gabriele , Costello Eithne , Talar-Wojnarowska Renata , Jamroziak Krzysztof , Pezzilli Raffaele , Gazouli Maria , Khaw Kay-Tee , Key Timothy J. , Bambi Franco , Mohelnikova-Duchonova Beatrice , Heller Anette , Landi Stefano , Vodickova Ludmila , Theodoropoulos George , Bugert Peter , Vodicka Pavel , Hoheisel Jörg D. , Delle Fave Gianfranco , Neoptolemos John P. , Soucek Pavel , Büchler Markus W. , Giese Nathalia , Canzian Federico 
Published: December 2012

Abstract
Background: Two recent genome-wide association studies (GWAS) of pancreatic ductal adenocarcinoma (PDAC), conducted, respectively, in a Japanese and in a Chinese population, identified eight novel loci affecting PDAC risk.
Methods: We attempted to replicate the novel loci in a series of PDACs and healthy controls of European ancestry in the context of the newly formed PANcreatic Disease ReseArch (PANDoRA) consortium. We genotyped seven single-nucleotide polymorphisms (SNP): rs12413624, rs1547374, rs372883, rs5768709, rs6464375, rs708224, rs9502893 (one SNP identified in the Chinese GWAS is not polymorphic in Caucasians) in 1,299 PDAC cases and 2,884 controls. We also attempted stratified analysis considering the different stages of the disease and addressed the possible involvement of the selected SNPs on the survival of patients.
Results: None of the SNPs were significantly associated with PDAC risk if considering the overall population of the consortium. When stratifying for country of origin, we found that in the Polish subgroup, the G allele of rs372883 was statistically significantly associated with increased risk [OR, 6.40; 95% confidence interval (CI), 2.28–17.91]. However, the sample size of the subgroups was rather small; therefore, this result can be due to chance. None of the SNPs was associated with disease progression or survival.
Conclusions: None of the SNPs associated with PDAC risk in two Asian populations were convincingly associated with PDAC risk in individuals of European descent.
Impact: This study illustrates the importance of evaluation of PDAC risk markers across ethnic groups. Cancer Epidemiol Biomarkers Prev; 22(2); 320–3. ©2012 AACR.
Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents
Authors: Mao Muling , Tian Feng , Mariadason John M. , Tsao Chun C. , Lemos Robert , Dayyani Farshid , Gopal Y.N. Vashisht , Jiang Zhi-Qin , Wistuba Ignacio I. , Tang Xi M. , Bornman William G. , Bollag Gideon , Mills Gordon B. , Powis Garth , Desai Jayesh , Gallick Gary E. , Davies Michael A. , Kopetz Scott 
Published: December 2012

Abstract
Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies.
Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.
Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification.
Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.
Systemic Administration of a Novel Immune-Stimulatory Pseudovirion Suppresses Lung Metastatic Melanoma by Regionally Enhancing IFN-γ Production
Authors: Saga Kotaro , Tamai Katsuto , Yamazaki Takehiko , Kaneda Yasufumi 
Published: December 2012

AbstractPurpose: Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity against multiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment.Experimental Design: First, we found that culturing murine splenocytes with HVJ-E in combination with interleukin (IL)-12 resulted in a remarkable increase in IFN-γ production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-γ production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12–conjugated HVJ-E particle without hemagglutinating activity.Results: IL-12–conjugated HVJ-E dramatically enhanced the amount of IFN-γ produced by immune cells. Intratumoral injection of IL-12–conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12–conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12–conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs.Conclusion: IL-12–conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis. Clin Cancer Res; 19(3); 668–79. ©2012 AACR.
γ-H2AX Foci Formation as a Pharmacodynamic Marker of DNA Damage Produced by DNA Cross-Linking Agents: Results from 2 Phase I Clinical Trials of SJG-136 (SG2000)
Authors: Wu Jenny , Clingen Peter H. , Spanswick Victoria J. , Mellinas-Gomez Maria , Meyer Tim , Puzanov Igor , Jodrell Duncan , Hochhauser Daniel , Hartley John A. 
Published: December 2012

Abstract
Purpose: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs.
Experimental Design: γ-H2AX foci formation was validated preclinically in comparison with the Comet assay, and evaluated pharmacodynamically in two phase I studies of different dosing schedules of the novel cross-linking agent SJG-136 (SG2000).
Results: The measurement of γ-H2AX foci in human fibroblasts and lymphocytes in vitro was more than 10-fold more sensitive than Comet assay measurement of cross-linking, with peak γ-H2AX response 24 hours after the peak of cross-linking. In lymphocytes from a phase I study (every three week schedule), γ-H2AX foci were detectable 1 hour following the end of administration, and in all patients, maximum response was observed at 24 hours. Significant levels of foci were still evident at days 8 and 15 consistent with the known persistence of the DNA damage produced by this agent. In two tumor biopsy samples, foci were detected 4 hours postinfusion with levels higher than in lymphocytes. Extensive foci formation was also observed before the third dose in cycle 1 in lymphocytes from a second phase I study (daily × 3 schedule). These foci also persisted with a significant level evident before the second cycle (day 21). An increased γ-H2AX response was observed during the second cycle consistent with a cumulative pharmacodynamic effect. No clear relationship between foci formation and administered drug dose was observed.
Conclusion: This is the first use of γ-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting. Clin Cancer Res; 19(3); 721–30. ©2012 AACR.
Breast Cancer Stem Cells: We've Got Them Surrounded
Authors: Korkaya Hasan , Wicha Max S. 
Published: December 2012

Abstract
Breast cancer stem cells are regulated by cell intrinsic pathways as well as by elements in the tumor microenvironment. New evidence suggests that an important interaction between the interleukin (IL)-8 receptor CXCR1/2 and HER2 is involved in this regulation. Simultaneous targeting of these pathways provides a novel therapeutic approach. Clin Cancer Res; 19(3); 511–3. ©2012 AACR.
Roles of Keap1–Nrf2 System in Upper Aerodigestive Tract Carcinogenesis
Authors: Ohkoshi Akira , Suzuki Takafumi , Ono Masao , Kobayashi Toshimitsu , Yamamoto Masayuki 
Published: December 2012

Abstract
Cancers in the upper aerodigestive tract, including cancers of the tongue and the esophagus, are the third leading cause of cancer-related deaths in the world, and oxidative stress is well recognized as one of the major risk factors for carcinogenesis. The Keap1–Nrf2 system plays a critical role in cellular defense against oxidative stress, but little is known about its association with upper aerodigestive tract carcinogenesis. In this study, we examined whether loss of Nrf2-function exacerbates carcinogenesis by using an experimental carcinogenesis model that is induced by 4-nitroquinoline-1-oxide (4NQO). We found that Nrf2-knockout (Nrf2-KO) mice were more susceptible to 4NQO-induced tongue and esophageal carcinogenesis than wild-type mice, which suggests that Nrf2 is important for cancer prevention. We also examined how the suppression of Keap1 function or the induction of Nrf2 activity affected 4NQO carcinogenesis. Keap1-knockdown (Keap1-KD) mice were resistant to 4NQO-induced tongue and esophageal carcinogenesis. Importantly, no growth advantage was observed in tongue tumors in the Keap1-KD mice. These results show that the Keap1–Nrf2 system regulates an important defense mechanism against upper aerodigestive tract carcinogenesis. In addition to several important functions of Nrf2 that lead to cancer chemoprevention, we hypothesize that a mechanical defense of thickened keratin layers may also be a chemopreventive factor because thickened, stratified, squamous epithelium was found on the tongue of Keap1-KD mice. Cancer Prev Res; 6(2); 149–59. ©2012 AACR.