bluuebunny/crossref_metadata_2025_split huggingface dataset:
H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load
Authors: Boon Adrianus C. M. , Finkelstein David , Zheng Ming , Liao Guochun , Allard John , Klumpp Klaus , Webster Robert , Peltz Gary , Webby Richard J. 
Published: September 2011

ABSTRACT
The genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.

IMPORTANCE
Highly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.
Conversion of Commensal Escherichia coli K-12 to an Invasive Form via Expression of a Mutant Histone-Like Protein
Authors: Koli Preeti , Sudan Sudhanshu , Fitzgerald David , Adhya Sankar , Kar Sudeshna 
Published: September 2011

ABSTRACT

The HUα
E38K, V42L
mutant of the bacterial histone-like protein HU causes a major change in the transcription profile of the commensal organism
Escherichia coli
K-12 (Kar S, Edgar R, Adhya S, Proc. Natl. Acad. Sci. U. S. A. 102:16397–16402, 2005). Among the upregulated genes are several related to pathogenic interactions with mammalian cells, as evidenced by the expression of curli fibers, Ivy, and hemolysin E. When
E. coli
K-12/ HUα
E38K, V42L
was added to Int-407 cells, there was host cell invasion, phagosomal disruption, and intracellular replication. The invasive trait was also retained in a murine ileal loop model and intestinal explant assays. In addition to invasion, the internalized bacteria caused a novel subversion of host cell apoptosis through modification and regulation of the BH3-only proteins Bim
EL
and Puma. Changes in the transcription profile were attributed to positive supercoiling of DNA leading to the altered availability of relevant promoters. Using the
E. coli
K-12/HUα
E38K, V42L
variant as a model, we propose that traditional commensal
E. coli
can adopt an invasive lifestyle through reprogramming its cellular transcription, without gross genetic changes.

IMPORTANCE
Escherichia coli
K-12 is well established as a benign laboratory strain and a human intestinal commensal. Recent evidences, however, indicate that the typical noninvasive nature of resident
E. coli
can be reversed under specific circumstances even in the absence of any major genomic flux. We previously engineered an
E. coli
strain with a mutant histone-like protein, HU, which exhibited significant changes in nucleoid organization and global transcription. Here we showed that the changes induced by the mutant HU have critical functional consequences: from a strict extracellular existence, the mutant
E. coli
adopts an almost obligate intracellular lifestyle. The internalized
E. coli
exhibits many of the prototypical characteristics of traditional intracellular bacteria, like phagosomal escape, intracellular replication, and subversion of host cell apoptosis. We suggest that
E. coli
K-12 can switch between widely divergent lifestyles in relation to mammalian host cells by reprogramming its cellular transcription program and without gross changes in its genomic content.
Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours
Authors: Yan Benedict , Choo Shoa Nian , Mulyadi Patricia , Srivastava Supriya , Ong Chee Wee , Yong Kol Jia , Putti Thomas , Salto-Tellez Manuel , Lim Gkeok Stzuan Diana 
Published: September 2011

BackgroundOvarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.Aims/methodsThe authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay.ResultsThe authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001).ConclusionThe results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm.
Mast Cell Targeting Hampers Prostate Adenocarcinoma Development but Promotes the Occurrence of Highly Malignant Neuroendocrine Cancers
Authors: Pittoni Paola , Tripodo Claudio , Piconese Silvia , Mauri Giorgio , Parenza Mariella , Rigoni Alice , Sangaletti Sabina , Colombo Mario P. 
Published: September 2011

Abstract
Mast cells (MC) are c-Kit–expressing cells, best known for their primary involvement in allergic reactions, but recently reappraised as important players in either cancer promotion or inhibition. Here, we assessed the role of MCs in prostate tumor development. In prostate tumors from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated (PD) foci that coexist in the same tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipients mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9−/− MCs was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistently with epithelial-to-mesenchymal transition. Such a dual source of MMP-9 was confirmed in human tumors, suggesting that MCs could be a good target for early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. Taken together, these data underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer. Cancer Res; 71(18); 5987–97. ©2011 AACR.
Mathematical Modeling Predicts the Effect of Folate Deficiency and Excess on Cancer-Related Biomarkers
Authors: Neuhouser Marian L. , Nijhout H. Frederik , Gregory Jesse F. , Reed Michael C. , James S. Jill , Liu Amy , Shane Barry , Ulrich Cornelia M. 
Published: September 2011

Abstract
Background: Folate is an essential B-vitamin that mediates one-carbon metabolism reactions, including nucleotide synthesis and others related to carcinogenesis. Both low- and high-folate status influences carcinogenesis.
Methods: We used a mathematical model of folate-mediated one-carbon metabolism to predict the effect of a range of intracellular epithelial folate concentrations (0.25–15.0 μmol/L) on methylation rate and purine and thymidylate synthesis. We also examined the interaction of these folate concentrations with polymorphisms in two enzymes [methylene tetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS)] in relation to the biochemical products.
Results: TS enzyme reaction rate increased markedly in response to the modeled higher intracellular folate concentrations. Changes in methylation rate were modest, whereas purine synthesis was only minimally related to increases in folate concentrations with an apparent threshold effect at 5.0 to 6.0 μmol/L. The relationship between folate concentrations and thymidylate synthesis was modified by genetic variation in TS but less so by variation in MTHFR. These gene–folate interactions modestly influenced purine synthesis in a nonlinear manner but only affected methylation rate under conditions of very high MTHFR activity.
Conclusion: Thymidylate synthesis is very sensitive to changes in epithelial intracellular folate and increased nearly fivefold under conditions of high intracellular folate. Individuals with genetic variations causing reduced TS activity may present even greater susceptibility to excessive folate.
Impact: Our observation that thymidylate synthesis increases dramatically under conditions of very elevated intracellular folate provides biological support to observations that excessive folic acid intake increases risk of both precursor lesions (i.e., colorectal adenomas) and cancer. Cancer Epidemiol Biomarkers Prev; 20(9); 1912–7. ©2011 AACR.
No Association of Type 2 Diabetes Risk Variants and Prostate Cancer Risk: the Multiethnic Cohort and PAGE
Authors: Waters Kevin M. , Wilkens Lynne R. , Monroe Kristine R. , Stram Daniel O. , Kolonel Laurence N. , Henderson Brian E. , Le Marchand Loïc , Haiman Christopher A. 
Published: September 2011

Abstract
Background: Epidemiologic studies have found evidence of an inverse association between diabetes status and prostate cancer risk. We explored the hypothesis that common genetic variation may explain, in part, the inverse association between diabetes and prostate cancer.
Methods: We tested 17 diabetes risk variants for association with prostate cancer risk in a prostate cancer case–control study of 2,746 cases and 3,317 controls from five racial/ethnic groups in the Multiethnic Cohort (MEC) study.
Results: After adjustment for multiple testing, none of the alleles were statistically significantly associated with prostate cancer risk. Aggregate scores that sum the risk alleles were also not significantly associated with risk.
Conclusions: We did not find evidence of association of this set of diabetes risk alleles with prostate cancer.
Impact: Resequencing and fine-mapping of the loci for diabetes and prostate cancer that were identified by genome-wide association studies are necessary to understand any genetic contribution for the inverse association between these common diseases. Cancer Epidemiol Biomarkers Prev; 20(9); 1979–81. ©2011 AACR.
Investigation of the Prevalence and Number of Aberrant Crypt Foci Associated with Human Colorectal Neoplasm
Authors: Sakai Eiji , Takahashi Hirokazu , Kato Shingo , Uchiyama Takashi , Hosono Kunihiro , Endo Hiroki , Maeda Shin , Yoneda Masato , Taguri Masataka , Nakajima Atsushi 
Published: September 2011

Abstract
Background: Aberrant crypt foci (ACF) are considered to be useful as surrogate biomarker for colorectal cancer (CRC), but the biological significance of ACF remains controversial. We attempted to investigate the relationship between the presence of ACF and human colorectal carcinogenesis using a relatively large sample size.
Methods: We carried out high-magnification chromoscopic colonoscopy to identify ACFs in 861 subjects undergoing a diagnostic endoscopy at the Yokohama City University Hospital. The present study compared the prevalence and number of ACFs in three subject groups (normal subjects, adenoma cases, and CRC cases). The correlations between the demographic and behavioral characteristics of the subjects and the prevalence of ACFs were also assessed.
Results: The prevalence of ACF was 64%, 88%, and 95%, and the mean number of ACF was 3.6, 6.2, and 10.1, in normal subjects, adenoma cases, and CRC cases, respectively. When differences in the prevalence and number of ACFs among age- and sex-stratified subject groups were examined, significant stepwise increments from normal subjects to adenoma cases to CRC cases were apparent (P &lt; 0.001). Moreover, an age- and sex-adjusted multiple logistic regression analysis revealed that smoking and alcohol habits had a synergistic effect, increasing the prevalence of ACFs as well as the risk of CRC (P &lt; 0.001).
Conclusions: These results suggested that ACF may serve as a reliable surrogate biomarker for human colorectal carcinogenesis.
Impact: The use of ACF as an endpoint may enable the size, duration, and cost of CRC chemoprevention studies to be reduced. Cancer Epidemiol Biomarkers Prev; 20(9); 1918–24. ©2011 AACR.
Polymorphisms in Nucleotide Excision Repair Genes and Endometrial Cancer Risk
Authors: Doherty Jennifer A. , Weiss Noel S. , Fish Sherianne , Fan Wenhong , Loomis Melissa M. , Sakoda Lori C. , Rossing Mary Anne , Zhao Lue Ping , Chen Chu 
Published: September 2011

Abstract
Background: Exposure to estrogens increases the risk of endometrial cancer. Certain estrogen metabolites can form bulky DNA adducts, which are removed via nucleotide excision repair (NER), and the ability to carry out this repair might be related to endometrial cancer risk.
Methods: We examined 64 tag and functional single-nucleotide polymorphisms (SNPs) in the NER genes ERCC1, ERCC2 (XPD), ERCC3 (XPB), ERCC4 (XPF), ERCC5 (XPG), LIG1, XPA, and XPC in a population-based case–control study in Washington state, with 783 endometrial cancer cases and 795 controls.
Results: The presence of ERCC5 rs4150386 C, LIG1 rs3730865 C, XPA rs2808667 T, or XPC rs3731127 T alleles was associated with risk of endometrial cancer, with respective age-, county-, and reference year–adjusted per-allele ORs and 95% CIs of 0.68 (0.53–0.87, P = 0.002), 1.46 (1.02–2.10, P = 0.04), 0.71 (0.52–0.97, P = 0.03), and 1.57 (1.13–2.17, P = 0.007), respectively.
Conclusions: Certain ERCC5, LIG1, XPA, and XPC genotypes might influence endometrial cancer risk.
Impact: Because of multiple redundancies in DNA repair pathways (and therefore a low prior probability) and the large number of associations examined, false-positive findings are likely. Further characterization of the relation between variation in NER genes and endometrial cancer risk is warranted. Cancer Epidemiol Biomarkers Prev; 20(9); 1873–82. ©2011 AACR.
Genetic Variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF Genes Are Prognostic Markers of Prostate Cancer-Specific Mortality
Authors: Lin Daniel W. , FitzGerald Liesel M. , Fu Rong , Kwon Erika M. , Zheng Siqun Lilly , Kolb Suzanne , Wiklund Fredrik , Stattin Pär , Isaacs William B. , Xu Jianfeng , Ostrander Elaine A. , Feng Ziding , Grönberg Henrik , Stanford Janet L. 
Published: September 2011

Abstract
Background: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.
Methods: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P ≤ 0.01, FDR ≤ 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients.
Results: Five SNPs were validated (P ≤ 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2–1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (Ptrend = 0.001), adjusting for clinicopathologic factors known to influence prognosis.
Conclusion: Five genetic markers were validated to be associated with lethal prostate cancer.
Impact: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated. Cancer Epidemiol Biomarkers Prev; 20(9); 1928–36. ©2011 AACR.
Physical, Mental, and Neurocognitive Status and Employment Outcomes in the Childhood Cancer Survivor Study Cohort
Authors: Kirchhoff Anne C. , Krull Kevin R. , Ness Kirsten K. , Armstrong Gregory T. , Park Elyse R. , Stovall Marilyn , Robison Leslie L. , Leisenring Wendy 
Published: September 2011

Abstract
Introduction: We examined the relationship of physical, mental, and neurocognitive function with employment and occupational status in the Childhood Cancer Survivor Study.
Methods: We included survivors 25 years or older with available short form-36 (physical and mental health component scores), brief symptom inventory (depression, anxiety, and somatization), and neurocognitive questionnaire (task efficiency, emotional regulation, organization, and memory). We generated relative risks (RR) from generalized linear models for these measures on unemployment (n = 5,386) and occupation (n = 3,763) outcomes adjusted for demographic and cancer-related factors and generated sex-stratified models.
Results: Poor physical health was associated with an almost eightfold higher risk of health-related unemployment (P &lt; 0.001) compared to survivors with normal physical health. Male survivors with somatization and memory problems were approximately 50% (P &lt; 0.05 for both) more likely to report this outcome, whereas task efficiency limitations were significant for both sexes (males: RR = 2.43, P &lt; 0.001; females: RR = 2.28, P &lt; 0.001). Employed female survivors with task efficiency, emotional regulation, and memory limitations were 13% to 20% (P &lt; 0.05 for all) less likely to work in professional or managerial occupations than unaffected females.
Conclusions: Physical problems may cause much of the health-related unemployment among childhood cancer survivors. Whereas both male and female survivors with neurocognitive deficits—primarily in task efficiencies—are at risk for unemployment, employed female survivors with neurocognitive deficits may face poor occupational outcomes more often than males.
Impact: Childhood cancer survivors are at risk for poor employment outcomes. Screening and intervention for physical, mental, and neurocognitive limitations could improve employment outcomes for this population. Cancer Epidemiol Biomarkers Prev; 20(9); 1838–49. ©2011 AACR.
Serum 25-Hydroxy Vitamin D and Prostate Cancer Risk in a Large Nested Case–Control Study
Authors: Albanes Demetrius , Mondul Alison M. , Yu Kai , Parisi Dominick , Horst Ronald L. , Virtamo Jarmo , Weinstein Stephanie J. 
Published: September 2011

AbstractBackground: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations.Methods: The 25-hydroxy vitamin D [25(OH)D]–prostate cancer relation was examined in a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (±1 year) and fasting blood collection date (±30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided.Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56 (1.15–2.12), with Ptrend = 0.01. Analyses based on prespecified clinical categories and season-adjusted values yielded similar results. These findings seemed stronger for aggressive disease [OR (95% CI) for fifth quintile of serum 25(OH)D [1.70 (1.05–2.76), Ptrend = 0.02], among men with greater physical activity [1.85 (1.26–2.72), Ptrend = 0.002], higher concentrations of serum total cholesterol [2.09 (1.36–3.21), Ptrend = 0.003] or α-tocopherol [2.00 (1.30–3.07), Ptrend = 0.01] and higher intakes of total calcium [1.82 (1.20–2.76), Ptrend = 0.01] or vitamin D [1.69 (1.04–2.75), Ptrend = 0.08], or among those who had received the trial α-tocopherol supplements [1.74 (1.15–2.64), Ptrend = 0.006].Conclusion: Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer.Impact: Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels. Cancer Epidemiol Biomarkers Prev; 20(9); 1850–60. ©2011 AACR.