bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture
Authors: Weisblum Yiska , Panet Amos , Zakay-Rones Zichria , Haimov-Kochman Ronit , Goldman-Wohl Debra , Ariel Ilana , Falk Haya , Natanson-Yaron Shira , Goldberg Miri D. , Gilad Ronit , Lurain Nell S. , Greenfield Caryn , Yagel Simcha , Wolf Dana G. 
Published: October 2011

ABSTRACT

Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the
ex vivo
modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3- to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection—providing a mechanistic basis for their clinical use in prenatal prevention. The
ex vivo
-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.
Rift Valley Fever Virus Vaccine Lacking the NSs and NSm Genes Is Safe, Nonteratogenic, and Confers Protection from Viremia, Pyrexia, and Abortion following Challenge in Adult and Pregnant Sheep
Authors: Bird Brian H. , Maartens Louis H. , Campbell Shelley , Erasmus Baltus J. , Erickson Bobbie R. , Dodd Kimberly A. , Spiropoulou Christina F. , Cannon Deborah , Drew Clifton P. , Knust Barbara , McElroy Anita K. , Khristova Marina L. , Albariño César G. , Nichol Stuart T. 
Published: October 2011

ABSTRACT

Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on the safety, immunogenicity, and efficacy of the ΔNSs-ΔNSm recombinant RVFV (rRVFV) vaccine (which lacks the NSs and NSm virulence factors) in a total of 41 sheep, including 29 timed-pregnant ewes. This vaccine was proven safe and immunogenic for adult animals at doses ranging from 1.0 × 10
3
to 1.0 × 10
5
PFU administered subcutaneously (s.c.). Pregnant animals were vaccinated with 1.0 × 10
4
PFU s.c. at day 42 of gestation, when fetal sensitivity to RVFV vaccine-induced teratogenesis is highest. No febrile reactions, clinical illness, or pregnancy loss was observed following vaccination. Vaccination resulted in a rapid increase in anti-RVFV IgM (day 4) and IgG (day 7) titers. No seroconversion occurred in cohoused control animals. A subset of 20 ewes progressed to full-term delivery after vaccination. All lambs were born without musculoskeletal, neurological, or histological birth defects. Vaccine efficacy was assessed in 9 pregnant animals challenged at day 122 of gestation with virulent RVFV (1.0 × 10
6
PFU intravenously). Following challenge, 100% (9/9) of the animals were protected, progressed to full term, and delivered healthy lambs. As expected, all 3 sham-vaccinated controls experienced viremia, fetal death, and abortion postchallenge. These results demonstrate that the ΔNSs-ΔNSm rRVFV vaccine is safe and nonteratogenic and confers high-level protection in sheep.
Increased Skin Papilloma Formation in Mice Lacking Glutathione Transferase GSTP
Authors: Henderson Colin J. , Ritchie Kenneth J. , McLaren Aileen , Chakravarty Probir , Wolf C. Roland 
Published: October 2011

Abstract
The glutathione S-transferase GSTP is overexpressed in many human cancers and chemotherapy-resistant cancer cells, where there is evidence that GSTP may have additional functions beyond its known catalytic role. On the basis of evidence that Gstp-deficient mice have a comparatively higher susceptibility to skin carcinogenesis, we investigated whether this phenotype reflected an alteration in carcinogen detoxification or not. For this study, Gstp−/− mice were interbred with Tg.AC mice that harbor initiating H-ras mutations in the skin. Gstp−/−/Tg.AC mice exposed to the proinflammatory phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) exhibited higher tumor incidence and multiplicity with a significant thickening of skin after treatment, illustrating hyperproliferative growth. Unexpectedly, we observed no difference in cellular proliferation or apoptosis or in markers of oxidative stress, although higher levels of the inflammatory marker nitrotyrosine were found in Gstp−/−/Tg.AC mice. Instead, gene set enrichment analysis of microarray expression data obtained from skin revealed a more proapoptotic and proinflammatory environment shortly after TPA treatment. Within 4 weeks of TPA treatment, Gstp−/−/Tg.AC mice displayed altered lipid/sterol metabolism and Wnt signaling along with aberrant processes of cytoskeletal control and epidermal morphogenesis at both early and late times. In extending the evidence that GSTP has a vital role in normal homeostatic control and cancer prevention, they also strongly encourage the emerging concept that GSTP is a major determinant of the proinflammatory character of the tumor microenvironment. This study shows that the GSTP plays a major role in carcinogenesis distinct from its role in detoxification and provides evidence that the enzyme is a key determinant of the proinflammatory tumor environment. Cancer Res; 71(22); 7048–60. ©2011 AACR.
EGFR-AKT-Smad Signaling Promotes Formation of Glioma Stem-like Cells and Tumor Angiogenesis by ID3-Driven Cytokine Induction
Authors: Jin Xun , Yin Jinlong , Kim Sung-Hak , Sohn Young-Woo , Beck Samuel , Lim Young Chang , Nam Do-Hyun , Choi Yun-Jaie , Kim Hyunggee 
Published: October 2011

Abstract
Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR–ID3–IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5–driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis. Cancer Res; 71(22); 7125–34. ©2011 AACR.
β-Blockers and Survival among Danish Patients with Malignant Melanoma: A Population-Based Cohort Study
Authors: Lemeshow Stanley , Sørensen Henrik Toft , Phillips Gary , Yang Eric V. , Antonsen Sussie , Riis Anders H. , Lesinski Gregory B. , Jackson Rebecca , Glaser Ronald 
Published: October 2011

Abstract
Background: To study whether use of β-blockers increases survival in patients with malignant melanoma because experimental data suggest that catecholamine hormones may be involved in stimulating the aggressiveness of malignant melanoma.
Methods: A total of 4,179 patients diagnosed with malignant melanoma in Denmark with a median follow-up of 4.9 years and identified in the Danish Cancer Registry participated. Data on β-blocker use, comorbidity, and survival were obtained from medical and administrative databases. Cox proportional hazards models were used to estimate HRs for all-cause mortality with 95% CIs with adjustment for prognostic factors.
Results: A total of 372 (8.9%) patients with malignant melanoma were treated with β-blockers within 90 days of melanoma diagnosis. The median β-blocker duration for exposure within 90 days of melanoma diagnosis, more than 90 days, and no prior exposure was 7.6, 1.4, and 0 years, respectively. The patients receiving β-blockers were older, had more comorbidities, and more cardiovascular and psychotropic drug user than the patients receiving no β-blockers prior to melanoma diagnosis. After adjustment for age and comorbidity index, the HR for melanoma death was 0.87 (95% CI: 0.64–1.20) and for all-cause mortality was 0.81 (95% CI: 0.67–0.97).
Conclusion: Increased survival time of patients with melanoma receiving β-blockers suggests that this class of drugs may hold promise in treatment strategy for these patients.
Impact: The observations described here suggest that catecholamines may retard melanoma progression and that β-blockers may have unrecognized potential as a therapeutic intervention for melanoma. Cancer Epidemiol Biomarkers Prev; 20(10); 2273–9. ©2011 AACR.
Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer
Authors: Roylance Rebecca , Endesfelder David , Gorman Patricia , Burrell Rebecca A. , Sander Jil , Tomlinson Ian , Hanby Andrew M. , Speirs Valerie , Richardson Andrea L. , Birkbak Nicolai J. , Eklund Aron C. , Downward Julian , Kschischo Maik , Szallasi Zoltan , Swanton Charles 
Published: October 2011

Abstract
Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes.
Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome.
Results: There was increased CIN and clonal heterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.
Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup.
Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. ©2011 AACR.
Cancer Fatalism: Deterring Early Presentation and Increasing Social Inequalities?
Authors: Beeken Rebecca J. , Simon Alice E. , von Wagner Christian , Whitaker Katriina L. , Wardle Jane 
Published: October 2011

Abstract
Background: Fatalistic beliefs about cancer have been implicated in low uptake of screening and delay in presentation particularly in low socioeconomic status (SES) groups, but no studies have systematically evaluated interrelationships between SES, fatalism, and early detection behaviors. We explored whether (i) fatalism is associated with negative attitudes toward early detection, (ii) lower SES groups are more fatalistic, and (iii) SES differences in fatalism partly explain SES differences in attitudes toward early detection.
Methods: In a population-representative sample of adults in Britain using computer-based interviews in the home setting, respondents (N = 2,018) answered two questions to index fatalism (expectations of cancer survival and cure) and two items on early detection attitudes (the perceived value of early detection and fear of symptom reporting). SES was indexed with a social grade classification.
Results: Fatalism was associated with being less positive about early detection (β = −0.40, P &lt; 0.001) and more fearful about seeking help for a suspicious symptom (β = 0.24, P &lt; 0.001). Lower SES groups were more fatalistic (β = −0.21, P &lt; 0.001). Path analyses suggest that SES differences in fatalism might explain SES differences in attitudes about early detection.
Conclusions: In this population sample, SES differences in fatalism partly explained SES differences in the perceived value of early detection and fear of symptom presentation.
Impact: Fatalistic beliefs about cancer should be targeted to promote early presentation of cancer and this may be particularly important for lower SES groups. Cancer Epidemiol Biomarkers Prev; 20(10); 2127–31. ©2011 AACR.
No Evidence for Human Papillomavirus in the Etiology of Colorectal Polyps
Authors: Burnett-Hartman Andrea N. , Newcomb Polly A. , Mandelson Margaret T. , Galloway Denise A. , Madeleine Margaret M. , Wurscher Michelle A. , Carter Joseph J. , Makar Karen W. , Potter John D. , Schwartz Stephen M. 
Published: October 2011

Abstract
Background: While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not.
Methods: We examined the association between oncogenic HPV infection and colorectal polyps in a case–control study of individuals with colorectal adenomas (n = 167), hyperplastic polyps (n = 87), and polyp-free controls (n = 250). We carried out real-time PCR for HPV-16 and -18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay.
Results: HPV DNA was not found in any of the 609 successfully assayed colorectal tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a history of polyps, among men [adenomas (n = 31), hyperplastic polyps (n = 28), and controls (n = 68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (OR = 3.0; 95% CI: 1.1–7.9).
Conclusions: Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations.
Impact: After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women. Cancer Epidemiol Biomarkers Prev; 20(10); 2288–97. ©2011 AACR.
Prognostic Significance of Cytoplasmic p27 Expression in Human Melanoma
Authors: Chen Guangdi , Cheng Yabin , Zhang Zhizhong , Martinka Magdalena , Li Gang 
Published: October 2011

Abstract
Background: The cyclin-dependent kinase inhibitor p27 plays important roles in cell proliferation, cell motility, and apoptosis. Interestingly, the nuclear and cytoplasmic p27 exert opposite biological functions. In this study, we investigated the prognostic impact of subcellular p27 expression.
Methods: We constructed melanoma tissue microarrays in a large series of melanoma patients, including 29 normal nevi, 52 dysplastic nevi, 270 primary melanomas, and 148 metastatic melanomas. The expression level of subcellular p27 in different stages of melanocytic lesions and its prognostic significance were evaluated.
Results: Compared with dysplastic nevi, nuclear p27 expression was remarkably reduced in primary melanomas and further reduced in metastatic melanoma (P &lt; 0.001 for both), whereas cytoplasmic p27 expression is significantly increased from dysplastic nevi to primary melanomas (P = 0.032) and further increased in melanoma metastases (P = 0.037). Although loss of nuclear p27 expression is correlated with a worse 5-year survival of primary melanoma patients in Kaplan–Meier analysis (P = 0.046), it is not a prognostic factor by multivariate Cox regression analysis. On the contrary, Kaplan–Meier analysis showed that gain of cytoplasmic p27 was associated with a poor 5-year survival of metastatic melanoma patients (P &lt; 0.001). Multivariate Cox regression analysis revealed that positive cytoplasmic p27 expression is an independent prognostic factor to predict metastatic melanoma patient outcome.
Conclusion: Cytoplasmic p27 may serve as a promising prognostic marker for metastatic melanoma.
Impact: Because there is no reliable prognostic marker for metastatic melanoma, our finding may have important clinical implications using cytoplasmic p27 as a prognostic biomarker for advanced melanoma. Cancer Epidemiol Biomarkers Prev; 20(10); 2212–21. ©2011 AACR.
Dissemination and Translation: A Frontier for Cancer Survivorship Research
Authors: Pollack Lori A. , Hawkins Nikki A. , Peaker Brandy L. , Buchanan Natasha , Risendal Betsy C. 
Published: October 2011

Abstract
As the field of survivorship research grows, the need for translation is imperative to expand new knowledge into arenas that directly impact survivors. This commentary seeks to encourage research focused on dissemination and translation of survivorship interventions and programs, including practice-based research. We overview diffusion, dissemination and translation in the context of cancer survivorship and present the RE-AIM and Knowledge to Action frameworks as approaches that can be used to expand research into communities. Many academic, governmental, and community-based organizations focus on cancer survivor. Future survivorship research should contribute to harmonizing these assets to identify effective interventions, maximize their reach and adoption, and integrate promising practices into routine care. Cancer Epidemiol Biomarkers Prev; 20(10); 2093–8. ©2011 AACR.
A Phase I Dose-Escalation Study of Tivantinib (ARQ 197) in Adult Patients with Metastatic Solid Tumors
Authors: Rosen Lee S. , Senzer Neil , Mekhail Tarek , Ganapathi Ram , Chai Feng , Savage Ronald E. , Waghorne Carol , Abbadessa Giovanni , Schwartz Brian , Dreicer Robert 
Published: October 2011

Abstract
Background: Tivantinib, an oral, non-ATP competitive, selective c-MET inhibitor, exhibited antitumor activity in preclinical models. This open-label, phase I, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of tivantinib in patients with advanced or metastatic solid tumors refractory to standard therapy.
Methods: Thirteen dose levels of tivantinib ranging from 10 to 360 mg twice a day were administered to patient cohorts in 21-day cycles (14 days on/7 days off); three active pharmaceutical ingredient forms of tivantinib (amorphous, crystalline A, and crystalline B) were also investigated. Treatment was continued until the occurrence of unacceptable toxicity, tumor progression, patient withdrawal, or death.
Results: A total of 79 patients with advanced solid tumors were enrolled. A maximum tolerated dose was not determined. Tivantinib was well tolerated, with mild to moderate toxicities. Two patients discontinued the study drug due to treatment-emergent adverse events. Dose-limiting grade of 3 or more toxicities including leukopenia, neutropenia, thrombocytopenia, vomiting, and dehydration, were observed in 2 patients treated with tivantinib 360 mg twice a day. The rate of absorption of tivantinib peaked approximately 2 to 4 hours after initial dosing, followed by a linear decrease in plasma concentrations. Increases in tivantinib exposure were not dose proportional. There was significant interpatient pharmacokinetic variability; however the clinical safety of tivantinib seemed unaffected. Three patients (3.8%) achieved a partial response and 40 patients (50.6%) maintained stable disease for a median of 19.9 weeks.
Conclusions: Tivantinib 360 mg twice a day was well tolerated in patients with refractory advanced solid tumors. The results of this trial warrant further clinical investigation. Clin Cancer Res; 17(24); 7754–64. ©2011 AACR.
Quantitative Detection of EGFR Mutations in Circulating Tumor DNA Derived from Lung Adenocarcinomas
Authors: Taniguchi Kazuya , Uchida Junji , Nishino Kazumi , Kumagai Toru , Okuyama Takako , Okami Jiro , Higashiyama Masahiko , Kodama Ken , Imamura Fumio , Kato Kikuya 
Published: October 2011

Abstract
Purpose: Examination of somatic epidermal growth factor receptor (EGFR) mutations is now a diagnostic routine for treatment of cancer using EGFR tyrosine kinase inhibitors (EGFR-TKI). Circulating tumor DNA is a promising target for noninvasive diagnostics. We evaluated its utility by quantitatively detecting activating and resistant mutations, which were measured with BEAMing (beads, emulsion, amplification, and magnetics).
Experimental Design: Twenty-three patients with lung cancer with progressive disease after EGFR-TKI treatment and 21 patients who had never been treated with EGFR-TKIs were studied. Their primary tumors were confirmed to have activating mutations. In the plasma DNA of each patient, the activating mutation found in the corresponding primary tumor and the T790M resistance mutation were quantified by BEAMing.
Results: In 32 of 44 patients, activating mutations were detected in the plasma DNA [72.7%; 95% confidence interval (CI), 58.0%–83.6%]. The T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% CI, 25.6%–53.4%). The ratio of T790M to activating mutations ranged from 13.3% to 94.0%. The peak of the distribution of the mutation allele fraction in the plasma DNA was in the 0.1% to 1% range.
Conclusions: The major advantage of BEAMing is its ability to calculate the fraction of T790M-positive alleles from the alleles with activating mutations. This feature enables the detection of increases and decreases in the number of T790M mutations in cancer cells, regardless of normal cell DNA contamination, which may be useful for monitoring disease progression. Circulating tumor DNA could potentially be used as an alternative method for EGFR mutation detection. Clin Cancer Res; 17(24); 7808–15. ©2011 AACR.