bluuebunny/crossref_metadata_2025_split huggingface dataset:
Those who can, teach. Assessing medical students’ perception of a finals revision programme delivered by foundation and core trainees: a cross-sectional study
Authors: Mole Guy , Gillespie Liam 
Published: December 2012

ObjectiveTo determine whether medical students perceive a foundation and core trainee finals revision programme as useful.DesignQuestionnaires were used to assess students’ perception of the teaching programme.SettingA medical school in the South of England.ParticipantsThere were 106 final year medical students in the cohort.ResultsThe teaching scored well in all facets analysed and scored best on enthusiasm, interactivity and communication.ConclusionsWe provide a framework for how foundation and core trainees could provide a very well received teaching programme benefiting medical students, the doctors and the medical school.
Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study
Authors: Goodin Douglas S , Ebers George C , Cutter Gary , Cook Stuart D , O'Donnell Timothy , Reder Anthony T , Kremenchutzky Marcelo , Oger Joel , Rametta Mark , Beckmann Karola , Knappertz Volker 
Published: December 2012

ObjectivesCompared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.DesignLong-term follow-up (LTF) of the pivotal RCT of interferon β-1b.SettingEleven North American MS-centres participated.ParticipantsIn the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.InterventionsUsing multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.Primary outcomeAn independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.ResultsAmong the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.ConclusionsIn this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.
A cross-sectional study of the appropriateness of colonoscopy requests in the Spanish region of Catalonia
Authors: Puente Diana , Cantero Francesc Xavier , Llagostera Maria , Piñeiro Pilar , Nieto Raquel , Saladich Rosa , Mascort Juanjo , Marzo Mercè , Almeda Jesús , Segarra Manel ,   the CANCER-REAP Research Group
Published: December 2012

IntroductionColonoscopies are being requested with increasing frequency in the last few years, as they are used both as a diagnostic and therapeutic procedure in several gastrointestinal diseases. Our purpose is to describe the appropriateness of colonoscopy requests issued both from primary care centres and from hospitals, according to the EPAGE II guidelines (European Panel on the Appropriateness of Gastrointestinal Endoscopy).Methods and analysisCross-sectional study. Colonoscopy requests issued since January 2011 and received at the endoscopy units of all six reference hospitals serving the primary care centres of the South Metropolitan and Central Catalonia districts will be collected (total=1500 requests). Variables to be collected include gender, date of birth, origin of the request and reference hospital, priority of the procedure, type of clinician requesting the procedure, date and indication of request, abdominal examination performed, anal inspection examination performed, date of last colonoscopy if applicable, diagnosis and date of diagnosis. Using the available information and the EPAGE II website, colonoscopy requests will be assigned as an appropriateness score. The association between the variables collected and the EPAGE II scores will be assessed using a Student's t test and a χ2test. A multilevel logistic model will be generated on the factors associated with the appropriateness of the requests.Ethics and disseminationColonoscopy is a costly procedure and not free from complications. In order to increase cost effectiveness, reduce waiting lists and optimise resources, it is necessary to use tools such as the EPAGE II guidelines, which establish criteria to assess the appropriateness of colonoscopies. The purpose of this study is to describe the current situation and to discuss whether current clinical practice is appropriate. The results of the study will be published in the next few years. In consideration of the ethical principles and methods of the research study, approval was granted for the project.
A qualitative analysis of the elements used by palliative care clinicians when formulating a survival estimate
Authors: Clarkson Rose , Selby Debbie , Myers Jeff 
Published: December 2012

ObjectiveFor patients with advanced and/or incurable disease, clinicians are often called upon to formulate and communicate an estimate of likely survival duration. The objective of this study was to gain a deeper appreciation of this process by identifying and exploring the specific elements that may inform and/or impact a clinician's estimate of survival (CES).MethodsSemistructured interviews were conducted among a group of palliative care clinicians in the setting of a tertiary academic health sciences centre. Qualitative data were subsequently analysed using a grounded theory approach.ResultsFive major themes were identified as being central to the process of CES formulation: use of objective patient-specific elements, strength of the patient-clinician relationship, purpose and context of an individual CES, perceived role of hope and the overall likelihood of CES inaccuracy.ConclusionsFor any given patient, several elements have the potential to inform and/or impact the process of CES formulation. Study participants were aware of objective clinical factors known to correlate with actual survival duration and likely integrate this information when formulating a CES. Formulation occurs within a larger context comprised of a number of elements that may influence individual estimates. These elements exist against a background of awareness of the overall likelihood of CES inaccuracy. Clinicians are encouraged to develop a personalised and standardised approach to CES formulation whereby an awareness of the menu of potentially impacting elements is consciously integrated into an individual process.
Moesin Is a Glioma Progression Marker That Induces Proliferation and Wnt/β-Catenin Pathway Activation via Interaction with CD44
Authors: Zhu Xiaoping , Morales Fabiana C. , Agarwal Nitin Kumar , Dogruluk Turgut , Gagea Mihai , Georgescu Maria-Magdalena 
Published: December 2012

Abstract
Moesin is an ERM family protein that connects the actin cytoskeleton to transmembrane receptors. With the identification of the ERM family protein NF2 as a tumor suppressor in glioblastoma, we investigated roles for other ERM proteins in this malignancy. Here, we report that overexpression of moesin occurs generally in high-grade glioblastoma in a pattern correlated with the stem cell marker CD44. Unlike NF2, moesin acts as an oncogene by increasing cell proliferation and stem cell neurosphere formation, with its ectopic overexpression sufficient to shorten survival in an orthotopic mouse model of glioblastoma. Moesin was the major ERM member activated by phosphorylation in glioblastoma cells, where it interacted and colocalized with CD44 in membrane protrusions. Increasing the levels of moesin competitively displaced NF2 from CD44, increasing CD44 expression in a positive feedback loop driven by the Wnt/β-catenin signaling pathway. Therapeutic targeting of the moesin–CD44 interaction with the small-molecule inhibitor 7-cyanoquinocarcinol (DX-52-1) or with a CD44-mimetic peptide specifically reduced the proliferation of glioblastoma cells overexpressing moesin, where the Wnt/β-catenin pathway was activated. Our findings establish moesin and CD44 as progression markers and drugable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/β-catenin pathway. Cancer Res; 73(3); 1142–55. ©2012 AACR.
DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in Ewing Sarcoma
Authors: Hauer Kristina , Calzada-Wack Julia , Steiger Katja , Grunewald Thomas G.P. , Baumhoer Daniel , Plehm Stephanie , Buch Thorsten , da Costa Olivia Prazeres , Esposito Irene , Burdach Stefan , Richter Günther H.S. 
Published: December 2012

AbstractEwing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFβ1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells. Cancer Res; 73(2); 967–77. ©2012 AACR.
Novel Oncogene–Induced Metastatic Prostate Cancer Cell Lines Define Human Prostate Cancer Progression Signatures
Authors: Ju Xiaoming , Ertel Adam , Casimiro Mathew C. , Yu Zuoren , Meng Hui , McCue Peter A. , Walters Rhonda , Fortina Paolo , Lisanti Michael P. , Pestell Richard G. 
Published: December 2012

AbstractHerein, murine prostate cancer cell lines, generated via selective transduction with a single oncogene (c-Myc, Ha-Ras, and v-Src), showed oncogene-specific prostate cancer molecular signatures that were recapitulated in human prostate cancer and developed lung metastasis in immune-competent mice. Interrogation of two independent retrospective cohorts of patient samples using the oncogene signature showed an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98% to 99%. In a blinded study, the signature algorithm showed independent substratification of reduced recurrence-free survival by Kaplan–Meier analysis. The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, which metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy, whereas the molecular signatures identified herein provides further value over current gene signature markers of prediction and outcome. Cancer Res; 73(2); 978–89. ©2012 AACR.
Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer
Authors: Chou Chun-Hung , Yang Neng-Kai , Liu Ting-Yun , Tai Shyh-Kuan , Hsu Dennis Shin-Shian , Chen Ya-Wei , Chen Yann-Jang , Chang Cheng-Chi , Tzeng Cheng-Hwai , Yang Muh-Hwa 
Published: December 2012

Abstract
Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial–mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1–AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1. Cancer Res; 73(2); 953–66. ©2012 AACR.
Novel Mechanism of Apoptosis Resistance in Cancer Mediated by Extracellular PAR-4
Authors: Burikhanov Ravshan , Shrestha-Bhattarai Tripti , Qiu Shirley , Shukla Nidhi , Hebbar Nikhil , Lele Subodh M. , Horbinski Craig , Rangnekar Vivek M. 
Published: December 2012

AbstractTumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-κB, revealing that it can block PAR-4–mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. Cancer Res; 73(2); 1011–9. ©2012 AACR.
Hyperpolarized 13C-Pyruvate Magnetic Resonance Reveals Rapid Lactate Export in Metastatic Renal Cell Carcinomas
Authors: Keshari Kayvan R. , Sriram Renuka , Koelsch Bertram L. , Van Criekinge Mark , Wilson David M. , Kurhanewicz John , Wang Zhen J. 
Published: December 2012

Abstract
Renal cell carcinomas (RCC) are a heterogeneous group of tumors with a wide range of aggressiveness. Noninvasive methods to confidently predict the tumor biologic behavior and select appropriate treatment are lacking. Here, we investigate the dynamic metabolic flux in living RCC cells using hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) combined with a bioreactor platform and interrogated the biochemical basis of the MRS data with respect to cancer aggressiveness. RCC cells have significantly higher pyruvate-to-lactate flux than the normal renal tubule cells. Furthermore, a key feature distinguishing the localized from the metastatic RCC cells is the lactate efflux rate, mediated by the monocarboxylate transporter 4 (MCT4). The metastatic RCC cells have significantly higher MCT4 expression and corresponding higher lactate efflux, which is essential for maintaining a high rate of glycolysis. We show that such differential cellular transporter expression and associated metabolic phenotype can be noninvasively assessed via real-time monitoring of hyperpolarized 13C-pyruvate-to-lactate flux. Cancer Res; 73(2); 529–38. ©2012 AACR.
Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
Authors: Walsh Kyle M. , Gorlov Ivan P. , Hansen Helen M. , Wu Xifeng , Spitz Margaret R. , Zhang Huifeng , Lu Emily Y. , Wenzlaff Angela S. , Sison Jennette D. , Wei Chongjuan , Lloyd Stacy M. , Chen Wei , Frazier Marsha L. , Seldin Michael F. , Bierut Laura J. , Bracci Paige M. , Wrensch Margaret R. , Schwartz Ann G. , Wiencke John K. , Amos Christopher I. 
Published: December 2012

Abstract
Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.
Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.
Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5).
Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.
Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.
Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK
Authors: Kim Sae Won , Kim Su Jin , Park Sang Hoon , Yang Hyun Gul , Kang Moon Cheol , Choi Young Woo , Kim Seong Muk , Jeun Sin-Soo , Sung Young Chul 
Published: December 2012

Abstract
Purpose: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed.
Experimental Design: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated.
Results: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections.
Conclusion: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK. Clin Cancer Res; 19(2); 415–27. ©2012 AACR.
Integration of Cell Line and Clinical Trial Genome-Wide Analyses Supports a Polygenic Architecture of Paclitaxel-Induced Sensory Peripheral Neuropathy
Authors: Wheeler Heather E. , Gamazon Eric R. , Wing Claudia , Njiaju Uchenna O. , Njoku Chidiamara , Baldwin Robert Michael , Owzar Kouros , Jiang Chen , Watson Dorothy , Shterev Ivo , Kubo Michiaki , Zembutsu Hitoshi , Winer Eric P. , Hudis Clifford A. , Shulman Lawrence N. , Nakamura Yusuke , Ratain Mark J. , Kroetz Deanna L. , Cox Nancy J. , Dolan Mary Eileen 
Published: December 2012

Abstract
Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.
Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.
Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P &lt; 0.05) and the preclinical cytotoxicity study (P &lt; 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel.
Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients. Clin Cancer Res; 19(2); 491–9. ©2012 AACR.