bluuebunny/crossref_metadata_2025_split huggingface dataset:
A UK cost of care model for inflammatory bowel disease
Authors: Ghosh Nivedita , Premchand Purushothaman 
Published: February 2015

ObjectivesThere are an estimated 620 000 patients with inflammatory bowel disease (IBD) in the UK. The rising incidence of IBD combined with its incurability has significant cost implications. The aim of this cost of care model was to calculate the annual cost per adult patient of treating ulcerative colitis (UC) and Crohn's disease (CD) from a NHS perspective, and to enable areas of potential cost savings to be explored.DesignThe cost of IBD was calculated by summing the costs of treatment, treatment side effects and disease-related complications, accounting for the proportions of patients incurring these costs. Default input values for costs, the percentage of patients receiving each treatment, and the percentage of patients experiencing treatment-related side effects or disease-related complications were determined from national sources and published literature. However, the model permitted the user to input local or alternative data.SettingThe model was designed to be used by NHS trusts in the UK.ResultsUsing default input values, the annual cost of treating any patient with UC was estimated to be £3084. For a patient with UC in remission, in relapse with mild-to-moderate UC or in relapse with severe UC, annual cost per patient was estimated to be £1693, £2903 and £10 760, respectively. The annual cost for any patient with CD was estimated to be £6156 (£1800 for patients in remission; £10 513 for patients in relapse).ConclusionsWhile IBD remains a costly condition with modest potential cost savings, this model facilitates calculation of annual costs per patient with UC and CD, and its customisability will help hospitals identify areas where savings could be made.
Cytokeratin 7 negative invasive breast carcinoma: clinicopathological and immunohistochemical analysis of 14 cases with clinical follow-up
Authors: Moatamed Neda A , Wu Annie , Sarah Khaled , Apple Sophia K 
Published: February 2015

Cytokeratin 7 (CK 7) negative breast tumours are reported to occur rarely. We studied 14 CK 7 negative cases of primary invasive ductal carcinoma (IDC) detected during sentinel lymph node metastases work-up and immunohistochemistry panel in the work-up of metastatic carcinoma of unknown origin. Axillary lymph node metastases were present in seven patients (50%). Oestrogen receptor (ER) was strongly positive in all cases: progesterone receptor in 78%, Her-2/neu in 7% and high proliferation index with Ki-67 >20% was seen in 71% of the cases.Metastatic and/or recurrence were found in 8 of 14 patients (57%) with the mean clinical follow-up of 55 months. Metastatic sites include multiple bones, brain, spinal cord, liver, pancreas, ovary, lung, lymph node other than ipsilateral axillary and skin. 12 of 14 patients received adjuvant chemotherapy. All 14 patients received hormonal therapy and radiation therapy. Morphologically, IDC with neuroendocrine features was noted in 57%. Synaptophysin stain was positive in 57% and chromogranin was positive in 21% of the cases. In conclusion, these CK 7 negative breast carcinomas were ER positive, mostly Her-2/neu negative, had high Ki-67 and frequently showed neuroendocrine differentiation. More than half of these cases had a poor outcome.
Low-grade fibromatosis-like spindle cell carcinomas of the breast are molecularly exiguous
Authors: Takano Elena A , Hunter Sally M , Campbell Ian G , Fox Stephen B 
Published: February 2015

BackgroundLow-grade fibromatosis-like spindle cell carcinomas are very rare breast carcinomas comprising <0.5% of all breast cancers. They demonstrate immunohistochemical (IHC) features of basal-like/metaplastic breast carcinomas, but the underlying molecular characteristics are unknown. We hypothesised that, as with IHC similarities, there may be common genomic alterations between spindle cell and basal-like/metaplastic carcinomas.Methods and resultsGenomic mutational profile and genomic copy number aberration (CNA) analyses were performed on three cases of this unusual entity, and findings were compared with that reported for basal-like/metaplastic breast carcinomas. Copy number analyses by molecular inversion probe assays of the three spindle cell carcinoma samples revealed little overall genomic CNAs with only minor changes identified (fraction of the genome altered; 1.3%–6.4%), but with a common 9p21.3 loss in 2 out of 3 samples, withCDKN2A(p16) being a likely candidate. No areas of commonality were identified in an in silico analysis compared with publically available basal-like/metaplastic carcinoma copy number data.ConclusionsThese tumours are characterised by low genomic instability, and share no CNAs with other metaplastic carcinomas. These findings favour this entity being a unique group genotype and belie their apparent homogeneous morphology and phenotype.
An evaluation of the burden placed on the General Internal Medicine team at the Role 3 Hospital in Camp Bastion by UK Armed Forces personnel presenting with symptoms resulting from previously identified disease
Authors: Cox Andrew T , D Linton T , Bailey K , Stacey M , Sharma S , Thomas L , Wilson D 
Published: February 2015

IntroductionDuring previous deployments of the British Armed Forces, a significant proportion of aeromedical evacuations were accounted for with recurrent symptoms from a known disease that had often triggered occupational medical downgrading. Many servicemen and women had deployed inappropriately, and by doing so became a burden on the deployed medical facilities. Commanders performing systematic medical risk assessments prior to departure might have prevented these individuals from deploying. This study was designed to assess the avoidable burden from recurrent disease during the current Afghanistan operation.MethodsA cross-sectional study reviewing the hospital and computerised primary care medical records of consecutive patients admitted under the General Physicians to the Role 3 Hospital in Camp Bastion over 9 months from April 2011. The occupational medical grading, diagnosis, disposal and whether the disease was recurrent were recorded.ResultsOf 270 patients admitted, 14 (5.2%) were medically downgraded. The computerised records were unavailable for 31 (11.5%) patients. All those patients who were medically downgraded were graded ‘Medically Limited Deployable’. In the downgraded group, only one patient presented with recurrent symptoms from their pre-existing condition (Crohn's disease). In the non-downgraded group, two patients presented with symptoms relating to their previous diagnoses. One presented with a second heat illness and should have been medically downgraded and not have been deployed, while the other patient had previously been investigated for recurrent syncope and was upgraded 6 months prior to deploying. All three patients underwent aeromedical evacuation but only two of these were considered to have been avoidable.DiscussionThe number of general medical admissions to the Role 3 Hospital due to a pre-existing disease is very low.
Relation between dietary pattern analysis (principal component analysis) and body mass index: a 5-year follow-up study in a Belgian military population
Authors: Mullie Patrick , Clarys P 
Published: February 2015

IntroductionIncreasing body mass index (BMI) has been related to many chronic diseases. Knowledge of nutritional determinants of BMI increase may be important to detect persons at risk.MethodsA longitudinal prospective study design was used in 805 Belgian soldiers. Daily nutrition was recorded with a validated food-frequency questionnaire. Weight and height were recorded from medical military data and principal component analysis was used to detect dietary patterns.ResultsDuring the 5 years follow-up, mean BMI increased from 25.8 (±3.3) kg/m2to 27.1 (±3.6) kg/m2(p<0.05). Consequently, the prevalence of being overweight and obesity increased from 46.2% and 9.6% to 51.6% and 19.9% (p<0.05), respectively. Mean (SD) weight gain differed between the BMI categories at baseline with a respective weight gain of 3.8 (±3.1) kg for normal weight at baseline, 4.2 (±3.2) kg for overweight and 5.1 (±3.4) kg for obesity (p for trend <0.05). Three dietary patterns were detected by principal component analysis: Meat, Sweet and Healthy dietary pattern. In energy-unadjusted and adjusted linear regressions, no dietary pattern was associated with BMI increase.ConclusionsNo specific dietary pattern was related to BMI increase. Prevention of obesity should focus on total energy intake at all BMI categories.
Random graphs, weak coarse embeddings, and higher index theory
Authors: Willett Rufus 
Published: February 2015

This paper studies higher index theory for a random sequence of bounded degree, finite graphs with diameter tending to infinity. We show that in a natural model for such random sequences the following hold almost surely: the coarse Baum–Connes assembly map is injective; the coarse Baum–Connes assembly map is not surjective; the maximal coarse Baum–Connes assembly map is an isomorphism. These results are closely tied to issues of expansion in graphs: in particular, we also show that such random sequences almost surely do not have geometric property (T), a strong form of expansion.The key geometric ingredients in the proof are due to Mendel and Naor: in our context, their results imply that a random sequence of graphs almost surely admits a weak form of coarse embedding into Hilbert space.
FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells
Authors: Liu Runhua , Liu Cong , Chen Dongquan , Yang Wei-Hsiung , Liu Xiuping , Liu Chang-Gong , Dugas Courtney M. , Tang Fei , Zheng Pan , Liu Yang , Wang Lizhong 
Published: February 2015

Abstract
FOXP3 functions not only as the master regulator in regulatory T cells, but also as an X-linked tumor suppressor. The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but its role during tumor progression remains controversial. Moreover, the mechanism of FOXP3-mediated tumor-suppressive activity remains largely unknown. Using chromatin immunoprecipitation (ChIP) sequencing, we identified a series of potential FOXP3-targeted miRNAs in MCF7 cells. Notably, FOXP3 significantly induced the expression of miR-146a/b. In vitro, FOXP3-induced miR-146a/b prevented tumor cell proliferation and enhanced apoptosis. Functional analyses in vitro and in vivo revealed that FOXP3-induced miR-146a/b negatively regulates NF-κB activation by inhibiting the expression of IRAK1 and TRAF6. In ChIP assays, FOXP3 directly bound the promoter region of miR-146a but not of miR-146b, and FOXP3 interacted directly with NF-κB p65 to regulate an miR-146–NF-κB negative feedback regulation loop in normal breast epithelial and tumor cells, as demonstrated with luciferase reporter assays. Although FOXP3 significantly inhibited breast tumor growth and migration in vitro and metastasis in vivo, FOXP3-induced miR-146a/b contributed only to the inhibition of breast tumor growth. These data suggest that miR-146a/b contributes to FOXP3-mediated tumor suppression during tumor growth by triggering apoptosis. The identification of a FOXP3–miR-146–NF-κB axis provides an underlying mechanism for disruption of miR-146 family member expression and constitutive NF-κB activation in breast cancer cells. Linking the tumor suppressor function of FOXP3 to NF-κB activation reveals a potential therapeutic approach for cancers with FOXP3 defects. Cancer Res; 75(8); 1703–13. ©2015 AACR.
Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling
Authors: Man Jianghong , Shoemake Jocelyn D. , Ma Tuopu , Rizzo Anthony E. , Godley Andrew R. , Wu Qiulian , Mohammadi Alireza M. , Bao Shideng , Rich Jeremy N. , Yu Jennifer S. 
Published: February 2015

Abstract
Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. Cancer Res; 75(8); 1760–9. ©2015 AACR.
Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case–Control Study
Authors: Wibom Carl , Späth Florentin , Dahlin Anna M. , Langseth Hilde , Hovig Eivind , Rajaraman Preetha , Johannesen Tom Børge , Andersson Ulrika , Melin Beatrice 
Published: February 2015

Abstract
Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case–control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.
Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.
Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.
Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.
Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. Cancer Epidemiol Biomarkers Prev; 24(5); 810–6. ©2015 AACR.
Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β
Authors: Chen Xiangmei , Zhang Ling , Zheng Sujun , Zhang Ting , Li Meng , Zhang Xiaolei , Zeng Zhenzhen , McCrae Malcolm A. , Zhao Jingmin , Zhuang Hui , Lu Fengmin 
Published: February 2015

Abstract
The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40–60 minutes to 80–110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3β, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3β along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3β. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. Cancer Prev Res; 8(5); 455–63. ©2015 AACR.
A Novel Target for Oral Cancer Chemoprevention? Notch Quite, Yet…
Authors: William William N. , El-Naggar Adel K. 
Published: February 2015

Abstract
The two major goals of oral cancer chemoprevention efforts are the ability to segregate the high-risk patients and the identification of an effective pharmacologic agent that halts progression to invasive cancer. Considerable progress has recently been achieved in profiling invasive head and neck squamous cell carcinomas, particularly with the use of high-throughput technologies. A similar molecular characterization of potentially malignant oral epithelial lesions (OPML; leukoplakia and erythroplakia) is yet to be accomplished. It is postulated, though, that molecular profiling could lead to the discovery of novel markers of cancer risk that could also serve as potential targets for chemoprevention. In this perspective, we comment on the work by Izumchenko and colleagues that reports a high prevalence of NOTCH1 gain-of-function mutations in Chinese patients with OPMLs. Although additional studies are needed to validate the findings, the study is the first to link alterations in this gene in oral premalignancy. These findings could serve as a first prototype of a single gene mutation as a potential target in clinical chemoprevention setting. Cancer Prev Res; 8(4); 262–5. ©2015 AACR.
See related article by Izumchenko et al., p. 277
Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus–Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma
Authors: Zheng Yong , Parsonage Greg , Zhuang Xiaodong , Machado Lee R. , James Christine H. , Salman Asmaa , Searle Peter F. , Hui Edwin P. , Chan Anthony T.C. , Lee Steven P. 
Published: February 2015

AbstractInfusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)–associated posttransplant lymphomas, and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV-transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favor outgrowth of T cells targeting viral antigens expressed within EBV+ lymphomas, but not in NPC. Here, we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a human leukocyte antigen (HLA) A*1101-restricted TCR, which would be widely applicable because 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms, we have optimized expression of the TCR and demonstrated high-avidity antigen-specific function (proliferation, cytotoxicity, and cytokine release) in both CD8+ and CD4+ T cells. The engineered T cells also inhibited LMP2+ epithelial tumor growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens. Cancer Immunol Res; 3(10); 1138–47. ©2015 AACR.
Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population
Authors: Justesen Johanne M. , Allin Kristine H. , Sandholt Camilla H. , Borglykke Anders , Krarup Nikolaj T. , Grarup Niels , Linneberg Allan , Jørgensen Torben , Hansen Torben , Pedersen Oluf 
Published: February 2015

Background—
There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health.

Methods and Results—

The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from
P
=3.3×10
–69
to
P
=1.1×10
–123
). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (
P
interaction
=9.8×10
–5
and 2.0×10
–5
, respectively, in combined analysis).

Conclusions—
Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.