bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is omission of free text records a possible source of data loss and bias in Clinical Practice Research Datalink studies? A case–control study
Authors: Price Sarah J , Stapley Sal A , Shephard Elizabeth , Barraclough Kevin , Hamilton William T 
Published: May 2016

ObjectivesTo estimate data loss and bias in studies of Clinical Practice Research Datalink (CPRD) data that restrict analyses to Read codes, omitting anything recorded as text.DesignMatched case–control study.SettingPatients contributing data to the CPRD.Participants4915 bladder and 3635 pancreatic, cancer cases diagnosed between 1 January 2000 and 31 December 2009, matched on age, sex and general practitioner practice to up to 5 controls (bladder: n=21 718; pancreas: n=16 459). The analysis period was the year before cancer diagnosis.Primary and secondary outcome measuresFrequency of haematuria, jaundice and abdominal pain, grouped by recording style: Read code or text-only (ie, hidden text). The association between recording style and case–control status (χ2test). For each feature, the odds ratio (OR; conditional logistic regression) and positive predictive value (PPV; Bayes’ theorem) for cancer, before and after addition of hidden text records.ResultsOf the 20 958 total records of the features, 7951 (38%) were recorded in hidden text. Hidden text recording was more strongly associated with controls than with cases for haematuria (140/336=42% vs 556/3147=18%) in bladder cancer (χ2test, p<0.001), and for jaundice (21/31=67% vs 463/1565=30%, p<0.0001) and abdominal pain (323/1126=29% vs 397/1789=22%, p<0.001) in pancreatic cancer. Adding hidden text records corrected PPVs of haematuria for bladder cancer from 4.0% (95% CI 3.5% to 4.6%) to 2.9% (2.6% to 3.2%), and of jaundice for pancreatic cancer from 12.8% (7.3% to 21.6%) to 6.3% (4.5% to 8.7%). Adding hidden text records did not alter the PPV of abdominal pain for bladder (codes: 0.14%, 0.13% to 0.16% vs codes plus hidden text: 0.14%, 0.13% to 0.15%) or pancreatic (0.23%, 0.21% to 0.25% vs 0.21%, 0.20% to 0.22%) cancer.ConclusionsOmission of text records from CPRD studies introduces bias that inflates outcome measures for recognised alarm symptoms. This potentially reinforces clinicians’ views of the known importance of these symptoms, marginalising the significance of ‘low-risk but not no-risk’ symptoms.
Gender differences in the duration of non-work-related sickness absence episodes due to musculoskeletal disorders
Authors: Arcas M Marta , Delclos George L , Torá-Rocamora Isabel , Martínez José Miguel , Benavides Fernando G 
Published: May 2016

BackgroundThere is wide evidence that women present longer duration of sickness absence (SA) than men. Musculoskeletal disorders are influenced by gender due to the sexual division of work.Methods354 432 episodes of non-work-related SA due to musculoskeletal disorders, which were registered in Catalonia between 2005 and 2008, were selected. The outcome variable was the duration of SA. Frailty survival models, stratified by sex and adjusted for explanatory variables (age, employment status, case management, economic activity and repeated episode), were fitted to study the association between each variable and the duration of SA, obtaining HRs.ResultsWomen presented longer SA episodes than men in all variable categories. A trend from shorter to longer duration of SA with increasing age was observed in men, whereas in women, it had a fluctuating pattern. Analysing most frequent diagnostic subgroups from the sample, only ‘non-specific lumbago’ and ‘sciatic lumbago’ showed these age patterns. Frailty survival models applied to these 2 subgroups confirmed the described age patterns in SA duration.ConclusionsWomen have longer non-work-related SA due to musculoskeletal disorders than men. However, while men have longer absences as their age increases, in women some older groups have shorter absences than younger ones. These findings could be explained by gender differences in the interaction between paid work and family demands. Our results highlight the need for continued research on SA from a gender perspective, in order to improve management of SA in terms of clinical practice and public policies.
Does cessation of community water fluoridation lead to an increase in tooth decay? A systematic review of published studies
Authors: McLaren Lindsay , Singhal Sonica 
Published: May 2016

BackgroundCessation of community water fluoridation (CWF) appears to be occurring with increasing frequency in some regions. Our objective was to comprehensively review published research on the impact of CWF cessation on dental caries.MethodsWe searched 13 multidisciplinary databases. Results were synthesised qualitatively and quantitatively.ResultsWe identified 15 instances of CWF cessation (‘intervention’) in 13 countries, which covered a broad time frame (1956–2003) and diverse geographical and political/economic contexts. Overall, results were mixed, but pointed more to an increase in caries postcessation than otherwise. For example, of the 9 studies with at least moderate methodological quality based on criteria we developed for this review, 5 showed an increase in caries postcessation. 3 studies did not show an increase in caries postcessation; however, important postcessation changes (eg, implementation of alternative fluoride delivery programmes) and/or large-scale social change may have contributed to those effects. Of the 3 study groupings that permitted quantitative synthesis, 2 showed statistically significant mean overall increase in caries postcessation; however, quantitative synthesis results must be interpreted cautiously.ConclusionsOverall, the published research points more to an increase in dental caries post-CWF cessation than otherwise. However, the literature is highly diverse and variable in methodological quality. To build this literature, it is important to exploit research opportunities presented by CWF cessation. Remaining knowledge gaps include the impact of CWF cessation on the distribution of dental caries (ie, equitable or not) and understanding the decision-making circumstances around CWF cessation.
Elevated Expression of Human Papillomavirus-16/18 E6 Oncoprotein Associates with Persistence of Viral Infection: A 3-Year Prospective Study in China
Authors: Yu Lu-Lu , Kang Le-Ni , Zhao Fang-Hui , Lei Xiao-Qin , Qin Yu , Wu Ze-Ni , Wang Hong , Chen Wen , Qiao You-Lin 
Published: May 2016

Abstract
Background: An association between high-risk human papillomavirus (HR-HPV) oncoprotein expression and viral persistence has been suggested by the outcome of etiology studies, but there are no epidemiologic studies evaluating that link.
Methods: We performed a 3-year prospective study in which 2,498 Chinese women ages 25 to 65 years were screened by six screening tests, including the OncoE6 Cervical Test (Arbor Vita Corporation) in 2011 (baseline). Six-hundred and ninety women who were positive for any of the tests and a random sample of 164 women with all negative results received colposcopy, and cervical specimens for the cobas 4800 HPV test (“cobas,” Roche Molecular Systems) were collected before colposcopy; of this group, 737 cervical specimens were collected to perform cobas and OncoE6 Cervical Test in 2014 (follow-up). Twenty-four cases of HPV16/18 E6 positives and 204 selected controls at baseline, 13 cases of HPV16/18 E6 positive and another 204 selected controls at follow-up were analyzed separately using unconditional logistical regression models to estimate ORs and 95% confidence intervals (CI).
Results: Compared with women who were HPV16 E6 oncoprotein negative at baseline, women in the E6-positive group had a much higher risk of HPV persistence (adjusted OR, 54.64; 95% CI, 7.19–415.09) at 3-year follow-up; a statistically strong association was also found between HPV16/18 HPV persistence and E6 oncoprotein expression detected at follow-up (adjusted OR, 360.57; 95% CI, 28.30–4,593.55).
Conclusions: A single detection of HPV16/18 E6 oncoprotein expression was strongly associated with viral persistence.
Impact: HPV16/18 E6 oncoprotein constitutes a marker for risk of HPV persistence. Cancer Epidemiol Biomarkers Prev; 25(7); 1167–74. ©2016 AACR.
A Tissue Systems Pathology Assay for High-Risk Barrett's Esophagus
Authors: Critchley-Thorne Rebecca J. , Duits Lucas C. , Prichard Jeffrey W. , Davison Jon M. , Jobe Blair A. , Campbell Bruce B. , Zhang Yi , Repa Kathleen A. , Reese Lia M. , Li Jinhong , Diehl David L. , Jhala Nirag C. , Ginsberg Gregory , DeMarshall Maureen , Foxwell Tyler , Zaidi Ali H. , Lansing Taylor D. , Rustgi Anil K. , Bergman Jacques J.G.H.M. , Falk Gary W. 
Published: May 2016

AbstractBackground: Better methods are needed to predict risk of progression for Barrett's esophagus. We aimed to determine whether a tissue systems pathology approach could predict progression in patients with nondysplastic Barrett's esophagus, indefinite for dysplasia, or low-grade dysplasia.Methods: We performed a nested case–control study to develop and validate a test that predicts progression of Barrett's esophagus to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), based upon quantification of epithelial and stromal variables in baseline biopsies. Data were collected from Barrett's esophagus patients at four institutions. Patients who progressed to HGD or EAC in ≥1 year (n = 79) were matched with patients who did not progress (n = 287). Biopsies were assigned randomly to training or validation sets. Immunofluorescence analyses were performed for 14 biomarkers and quantitative biomarker and morphometric features were analyzed. Prognostic features were selected in the training set and combined into classifiers. The top-performing classifier was assessed in the validation set.Results: A 3-tier, 15-feature classifier was selected in the training set and tested in the validation set. The classifier stratified patients into low-, intermediate-, and high-risk classes [HR, 9.42; 95% confidence interval, 4.6–19.24 (high-risk vs. low-risk); P &lt; 0.0001]. It also provided independent prognostic information that outperformed predictions based on pathology analysis, segment length, age, sex, or p53 overexpression.Conclusion: We developed a tissue systems pathology test that better predicts risk of progression in Barrett's esophagus than clinicopathologic variables.Impact: The test has the potential to improve upon histologic analysis as an objective method to risk stratify Barrett's esophagus patients. Cancer Epidemiol Biomarkers Prev; 25(6); 958–68. ©2016 AACR.
Clinicopathologic Features of Colorectal Carcinoma in HIV-Positive Patients
Authors: Sigel Carlie , Cavalcanti Marcela S. , Daniel Tanisha , Vakiani Efsevia , Shia Jinru , Sigel Keith 
Published: May 2016

AbstractBackground: Emerging evidence suggests differences in colorectal cancer in HIV-infected patients (HIV+) compared with HIV− patients. Microsatellite instability (MSI), occurring in a subset of colorectal cancer, is present at a higher rate in certain cancers in HIV+ patients. Colorectal cancer with MSI share some characteristics with those reported for HIV+ colorectal cancer. On this premise, we studied clinical and pathologic features of HIV+ colorectal cancer and evaluated for MSI using matched HIV− colorectal cancer controls.Methods: Two nested, matched cohorts were identified from a hospital-based cohort of colorectal cancer patients. HIV+ colorectal cancers were identified and random control patients were matched for selected characteristics. Mismatch repair protein (MMR) IHC was performed as the detection method for MSI. Variables were compared between cases and controls using fixed-effects logit modeling to account for matching.Results: We included 184 colorectal cancer samples (38 HIV+, 146 HIV− control). Median patient age at colorectal cancer onset was 55. When compared with HIV− colorectal cancer, HIV+ patients were more likely to have smoked (P = 0.001), have right-sided colorectal cancer (37% vs. 14%; P = 0.003), and tumor-infiltrating lymphocytes (TIL) above 50/10 high-power fields (21% vs. 7%). There was no difference in MMR protein expression (P = 0.6). HIV+ colorectal cancer patients had reduced overall survival (P = 0.02) but no difference in progression-free survival.Conclusions: HIV+ patients developed colorectal cancer at a lower median age than population estimates, had a higher frequency of right-sided disease, and increased TILs, suggesting potential biologic differences compared with uninfected patients.Impact: Clinicopathologic differences in colorectal cancer of HIV+ persons may have implications for tumor pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(7); 1098–104. ©2016 AACR.
Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia
Authors: Ojha Juhi , Codd Veryan , Nelson Christopher P. , Samani Nilesh J. , Smirnov Ivan V. , Madsen Nils R. , Hansen Helen M. , de Smith Adam J. , Bracci Paige M. , Wiencke John K. , Wrensch Margaret R. , Wiemels Joseph L. , Walsh Kyle M. 
Published: May 2016

Abstract
Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility.
Methods: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case–control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1.
Results: Three of the eight LTL-associated SNPs were associated with CLL risk at P &lt; 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15–1.86; P = 1.8 × 10−3], TERT (OR = 1.23; 95% CI, 1.02–1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08–1.71; P = 9.6 × 10−3). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case–control sets (P = 9.4 × 10−4 and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination.
Conclusions: Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis.
Impact: A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043–9. ©2016 AACR.
PIWI-Interacting RNAs in Gliomagenesis: Evidence from Post-GWAS and Functional Analyses
Authors: Jacobs Daniel I. , Qin Qin , Lerro Michael C. , Fu Alan , Dubrow Robert , Claus Elizabeth B. , DeWan Andrew T. , Wang Guilin , Lin Haifan , Zhu Yong 
Published: May 2016

AbstractBackground: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number of studies have linked the PIWI–piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored.Methods: Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele.Results: Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 [OR, 1.80; 95% confidence interval (CI), 1.33–2.46; P = 1.69 × 10−4], cell proliferation was sharply increased.Conclusions: The genetic association analysis identifies several piRNAs associated with glioma risk, and follow-up functional analyses suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties.Impact: This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses and supports expanded investigation into the link between the PIWI–piRNA pathway and cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1073–80. ©2016 AACR.
Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab
Authors: Sade-Feldman Moshe , Kanterman Julia , Klieger Yair , Ish-Shalom Eliran , Olga Mizrahi , Saragovi Amijai , Shtainberg Hani , Lotem Michal , Baniyash Michal 
Published: May 2016

Abstract
Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR− MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.
Experimental Design: Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR− MDSC percentage, NO−, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).
Results: Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR− MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan–Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR− cells, were associated with significant short OS (P &lt; 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.
Conclusions: Our study suggests the use of CD33+CD11b+HLA-DR− cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661–72. ©2016 AACR.
In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype
Authors: Bossi Daniela , Cicalese Angelo , Dellino Gaetano I. , Luzi Lucilla , Riva Laura , D'Alesio Carolina , Diaferia Giuseppe R. , Carugo Alessandro , Cavallaro Elena , Piccioni Rossana , Barberis Massimo , Mazzarol Giovanni , Testori Alessandro , Punzi Simona , Pallavicini Isabella , Tosti Giulio , Giacó Luciano , Melloni Giorgio , Heffernan Timothy P. , Natoli Gioacchino , Draetta Giulio F. , Minucci Saverio , Pelicci PierGiuseppe , Lanfrancone Luisa 
Published: May 2016

Abstract
The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (&lt;15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone–lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways.
Significance: Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650–63. ©2016 AACR.
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High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial
Authors: Pearson Alex , Smyth Elizabeth , Babina Irina S. , Herrera-Abreu Maria Teresa , Tarazona Noelia , Peckitt Clare , Kilgour Elaine , Smith Neil R. , Geh Catherine , Rooney Claire , Cutts Ros , Campbell James , Ning Jian , Fenwick Kerry , Swain Amanda , Brown Gina , Chua Sue , Thomas Anne , Johnston Stephen R.D. , Ajaz Mazhar , Sumpter Katherine , Gillbanks Angela , Watkins David , Chau Ian , Popat Sanjay , Cunningham David , Turner Nicholas C. 
Published: May 2016

Abstract
FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.
Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838–51. ©2016 AACR.
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