bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease
Authors: Brewin Jennifer , Mancao Christoph , Straathof Karin , Karlsson Helen , Samarasinghe Sujith , Amrolia Persis J. , Pule Martin 
Published: September 2009

AbstractEpstein-Barr virus (EBV)–driven posttransplantation lymphoproliferative disease (PTLD) is a serious complication of immunosuppression after either stem cell transplantation (SCT) or solid organ transplantation (SOT). Adoptive transfer of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) is an effective prophylaxis and treatment for PTLD after SCT, but not for PTLD after SOT when pharmacologic immunosuppression cannot be discontinued. We report the generation of calcineurin (CN) mutants that render EBV-CTL resistant to the immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA): mutant CNa12 confers resistance to CsA but not FK506, and mutant CNa22 confers resistance to FK506 but not CsA, whereas mutant CNb30 renders CTLs resistant to both calcineurin inhibitors. Untransduced EBV-CTLs do not proliferate in the presence of FK506/CsA. However, EBV-CTLs transduced with a retroviral vector coding for these mutants retain the ability to both proliferate and secrete normal levels of interferon-γ in the presence therapeutic levels of FK506 (CNa12), CsA (CNa22), or both (CNb30). The cytotoxicity and phenotype of EBV-CTL lines were unaffected by expression of these mutant CNs. This approach should allow effective immunotherapy with EBV-CTLs in the SOT setting without risking the graft by reduction in immunosuppression, and represents a generic approach to improving immunotherapy in the face of immunosuppression.
Gravity, a regulation factor in the differentiation of rat bone marrow mesenchymal stem cells
Authors: Huang Yan , Dai Zhong-Quan , Ling Shu-Kuan , Zhang Hong-Yu , Wan Yu-Min , Li Ying-Hui 
Published: September 2009

AbstractBackgroundStem cell therapy has emerged as a potential therapeutic option for tissue engineering and regenerative medicine, but many issues remain to be resolved, such as the amount of seed cells, committed differentiation and the efficiency. Several previous studies have focused on the study of chemical inducement microenvironments. In the present study, we investigated the effects of gravity on the differentiation of bone marrow mesenchymal stem cells (BMSCs) into force-sensitive or force-insensitive cells.Methods and resultsRat BMSCs (rBMSCs) were cultured under hypergravity or simulated microgravity (SMG) conditions with or without inducement medium. The expression levels of the characteristic proteins were measured and analyzed using immunocytochemical, RT-PCR and Western-blot analyses. After treatment with 5-azacytidine and hypergravity, rBMSCs expressed more characteristic proteins of cardiomyocytes such as cTnT, GATA4 and β-MHC; however, fewer such proteins were seen with SMG. After treating rBMSCs with osteogenic inducer and hypergravity, there were marked increases in the expression levels of ColIA1, Cbfa1 and ALP. Reverse results were obtained with SMG. rBMSCs treated with adipogenic inducer and SMG expressed greater levels of PPARgamma. Greater levels of Cbfa1- or cTnT-positive cells were observed under hypergravity without inducer, as shown by FACS analysis. These results indicate that hypergravity induces differentiation of rBMSCs into force-sensitive cells (cardiomyocytes and osteoblasts), whereas SMG induces force-insensitive cells (adipocytes).ConclusionTaken together, we conclude that gravity is an important factor affecting the differentiation of rBMSCs; this provides a new avenue for mechanistic studies of stem cell differentiation and a new approach to obtain more committed differentiated or undifferentiated cells.
Inflammatory cytokines, goblet cell hyperplasia and altered lung mechanics in Lgl1 +/- mice
Authors: Lan Jie , Ribeiro Leslie , Mandeville Isabel , Nadeau Katia , Bao Tim , Cornejo Salomon , Sweezey Neil B , Kaplan Feige 
Published: September 2009

AbstractBackgroundNeonatal lung injury, a leading cause of morbidity in prematurely born infants, has been associated with arrested alveolar development and is often accompanied by goblet cell hyperplasia. Genes that regulate alveolarization and inflammation are likely to contribute to susceptibility to neonatal lung injury. We previously clonedLgl1, a developmentally regulated secreted glycoprotein in the lung. In rat, O2toxicity caused reduced levels ofLgl1, which normalized during recovery. We report here on the generation of anLgl1knockout mouse in order to determine whether deficiency ofLgl1is associated with arrested alveolarization and contributes to neonatal lung injury.MethodsAnLgl1knockout mouse was generated by introduction of a neomycin cassette in exon 2 of theLgl1gene. To evaluate the pulmonary phenotype ofLgl1+/-mice, we assessed lung morphology,Lgl1RNA and protein, elastin fibers and lung function. We also analyzed tracheal goblet cells, and expression of mucin, interleukin (IL)-4 and IL-13 as markers of inflammation.ResultsAbsence ofLgl1was lethal prior to lung formation. PostnatalLgl1+/-lungs displayed delayed histological maturation, goblet cell hyperplasia, fragmented elastin fibers, and elevated expression of TH2 cytokines (IL-4 and IL-13). At one month of age, reduced expression ofLgl1was associated with elevated tropoelastin expression and altered pulmonary mechanics.ConclusionOur findings confirm thatLgl1is essential for viability and is required for developmental processes that precede lung formation.Lgl1+/-mice display a complex phenotype characterized by delayed histological maturation, features of inflammation in the post-natal period and altered lung mechanics at maturity.Lgl1haploinsufficiency may contribute to lung disease in prematurity and to increased risk for late-onset respiratory disease.
Biofilm formation as a novel phenotypic feature of adherent-invasive Escherichia coli(AIEC)
Authors: Martinez-Medina Margarita , Naves Plínio , Blanco Jorge , Aldeguer Xavier , Blanco Jesus E , Blanco Miguel , Ponte Carmen , Soriano Francisco , Darfeuille-Michaud Arlette , Garcia-Gil L Jesus 
Published: September 2009

Abstract

Background
Crohn's disease (CD) is a high morbidity chronic inflammatory disorder of unknown aetiology. Adherent-invasive Escherichia coli (AIEC) has been recently implicated in the origin and perpetuation of CD. Because bacterial biofilms in the gut mucosa are suspected to play a role in CD and biofilm formation is a feature of certain pathogenic E. coli strains, we compared the biofilm formation capacity of 27 AIEC and 38 non-AIEC strains isolated from the intestinal mucosa. Biofilm formation capacity was then contrasted with the AIEC phenotype, the serotype, the phylotype, and the presence of virulence genes.

Results
Specific biofilm formation (SBF) indices were higher amongst AIEC than non-AIEC strains (P = 0.012). In addition, 65.4% of moderate to strong biofilms producers were AIEC, whereas 74.4% of weak biofilm producers were non-AIEC (P = 0.002). These data indicate that AIEC strains were more efficient biofilm producers than non-AIEC strains. Moreover, adhesion (P = 0.009) and invasion (P = 0.003) indices correlated positively with higher SBF indices. Additionally, motility (100%, P < 0.001), H1 type flagellin (53.8%, P < 0.001), serogroups O83 (19.2%, P = 0.008) and O22 (26.9%, P = 0.001), the presence of virulence genes such as sfa/focDE (38.5%, P = 0.003) and ibeA (26.9%, P = 0.017), and B2 phylotype (80.8%, P < 0.001) were frequent characteristics amongst biofilm producers.

Conclusion
The principal contribution of the present work is the finding that biofilm formation capacity is a novel, complementary pathogenic feature of the recently described AIEC pathovar. Characterization of AIEC specific genetic determinants, and the regulatory pathways, involved in biofilm formation will likely bring new insights into AIEC pathogenesis.
Identifying primary care patients at risk for future diabetes and cardiovascular disease using electronic health records
Authors: Hivert Marie-France , Grant Richard W , Shrader Peter , Meigs James B 
Published: September 2009

Abstract

Background
Prevention of diabetes and coronary heart disease (CHD) is possible but identification of at-risk patients for targeting interventions is a challenge in primary care.

Methods
We analyzed electronic health record (EHR) data for 122,715 patients from 12 primary care practices. We defined patients with risk factor clustering using metabolic syndrome (MetS) characteristics defined by NCEP-ATPIII criteria; if missing, we used surrogate characteristics, and validated this approach by directly measuring risk factors in a subset of 154 patients. For subjects with at least 3 of 5 MetS criteria measured at baseline (2003-2004), we defined 3 categories: No MetS (0 criteria); At-risk-for MetS (1-2 criteria); and MetS (≥ 3 criteria). We examined new diabetes and CHD incidence, and resource utilization over the subsequent 3-year period (2005-2007) using age-sex-adjusted regression models to compare outcomes by MetS category.

Results
After excluding patients with diabetes/CHD at baseline, 78,293 patients were eligible for analysis. EHR-defined MetS had 73% sensitivity and 91% specificity for directly measured MetS. Diabetes incidence was 1.4% in No MetS; 4.0% in At-risk-for MetS; and 11.0% in MetS (p < 0.0001 for trend; adjusted OR MetS vs No MetS = 6.86 [6.06-7.76]); CHD incidence was 3.2%, 5.3%, and 6.4% respectively (p < 0.0001 for trend; adjusted OR = 1.42 [1.25-1.62]). Costs and resource utilization increased across categories (p < 0.0001 for trends). Results were similar analyzing individuals with all five criteria not missing, or defining MetS as ≥ 2 criteria present.

Conclusion
Risk factor clustering in EHR data identifies primary care patients at increased risk for new diabetes, CHD and higher resource utilization.
Association between leukocyte telomere shortening and exposure to traffic pollution: a cross-sectional study on traffic officers and indoor office workers
Authors: Hoxha Mirjam , Dioni Laura , Bonzini Matteo , Pesatori Angela Cecilia , Fustinoni Silvia , Cavallo Domenico , Carugno Michele , Albetti Benedetta , Marinelli Barbara , Schwartz Joel , Bertazzi Pier Alberto , Baccarelli Andrea 
Published: September 2009

Abstract

Background
Telomere shortening in blood leukocytes has been associated with increased morbidity and death from cardiovascular disease and cancer, but determinants of shortened telomeres, a molecular feature of biological aging, are still largely unidentified. Traffic pollution has been linked with both cardiovascular and cancer risks, particularly in older subjects. Whether exposure to traffic pollution is associated with telomere shortening has never been evaluated.

Methods
We measured leukocyte telomere length (LTL) by real-time PCR in blood DNA from 77 traffic officers exposed to high levels of traffic pollutants and 57 office workers (referents). Airborne benzene and toluene, as tracers for traffic exposure, were measured using personal passive samplers and gas-chromatography/flame-ionization detector analysis. We used covariate-adjusted multivariable models to test the effects of the exposure on LTL and obtain adjusted LTL means and 95% Confidence Intervals (CIs).

Results
Adjusted mean LTL was 1.10 (95%CI 1.04-1.16) in traffic officers and 1.27 in referents (95%CI 1.20-1.35) [p < 0.001]. LTL decreased in association with age in both traffic officers (p = 0.01) and referents (p = 0.001), but traffic officers had shorter LTL within each age category. Among traffic officers, adjusted mean relative LTL was shorter in individuals working in high (n = 45, LTL = 1.02, 95%CI 0.96-1.09) compared to low traffic intensity (n = 32, LTL = 1.22, 95%CI 1.13-1.31) [p < 0.001]. In the entire study population, LTL decreased with increasing levels of personal exposure to benzene (p = 0.004) and toluene (p = 0.008).

Conclusion
Our results indicate that leukocyte telomere length is shortened in subjects exposed to traffic pollution, suggesting evidence of early biological aging and disease risk.
Exon expression in lymphoblastoid cell lines from subjects with schizophrenia before and after glucose deprivation
Authors: Martin Maureen V , Rollins Brandi , Sequeira P Adolfo , Mesén Andrea , Byerley William , Stein Richard , Moon Emily A , Akil Huda , Jones Edward G , Watson Stanley J , Barchas Jack , DeLisi Lynn E , Myers Richard M , Schatzberg Alan , Bunney William E , Vawter Marquis P 
Published: September 2009

Abstract

Background
The purpose of this study was to examine the effects of glucose reduction stress on lymphoblastic cell line (LCL) gene expression in subjects with schizophrenia compared to non-psychotic relatives.

Methods
LCLs were grown under two glucose conditions to measure the effects of glucose reduction stress on exon expression in subjects with schizophrenia compared to unaffected family member controls. A second aim of this project was to identify cis-regulated transcripts associated with diagnosis.

Results
There were a total of 122 transcripts with significant diagnosis by probeset interaction effects and 328 transcripts with glucose deprivation by probeset interaction probeset effects after corrections for multiple comparisons. There were 8 transcripts with expression significantly affected by the interaction between diagnosis and glucose deprivation and probeset after correction for multiple comparisons. The overall validation rate by qPCR of 13 diagnosis effect genes identified through microarray was 62%, and all genes tested by qPCR showed concordant up- or down-regulation by qPCR and microarray. We assessed brain gene expression of five genes found to be altered by diagnosis and glucose deprivation in LCLs and found a significant decrease in expression of one gene, glutaminase, in the dorsolateral prefrontal cortex (DLPFC). One SNP with previously identified regulation by a 3' UTR SNP was found to influence IRF5 expression in both brain and lymphocytes. The relationship between the 3' UTR rs10954213 genotype and IRF5 expression was significant in LCLs (p = 0.0001), DLPFC (p = 0.007), and anterior cingulate cortex (p = 0.002).

Conclusion
Experimental manipulation of cells lines from subjects with schizophrenia may be a useful approach to explore stress related gene expression alterations in schizophrenia and to identify SNP variants associated with gene expression.
Spatially Uniform ReliefF (SURF) for computationally-efficient filtering of gene-gene interactions
Authors: Greene Casey S , Penrod Nadia M , Kiralis Jeff , Moore Jason H 
Published: September 2009

Abstract

Background
Genome-wide association studies are becoming the de facto standard in the genetic analysis of common human diseases. Given the complexity and robustness of biological networks such diseases are unlikely to be the result of single points of failure but instead likely arise from the joint failure of two or more interacting components. The hope in genome-wide screens is that these points of failure can be linked to single nucleotide polymorphisms (SNPs) which confer disease susceptibility. Detecting interacting variants that lead to disease in the absence of single-gene effects is difficult however, and methods to exhaustively analyze sets of these variants for interactions are combinatorial in nature thus making them computationally infeasible. Efficient algorithms which can detect interacting SNPs are needed. ReliefF is one such promising algorithm, although it has low success rate for noisy datasets when the interaction effect is small. ReliefF has been paired with an iterative approach, Tuned ReliefF (TuRF), which improves the estimation of weights in noisy data but does not fundamentally change the underlying ReliefF algorithm. To improve the sensitivity of studies using these methods to detect small effects we introduce Spatially Uniform ReliefF (SURF).

Results
SURF's ability to detect interactions in this domain is significantly greater than that of ReliefF. Similarly SURF, in combination with the TuRF strategy significantly outperforms TuRF alone for SNP selection under an epistasis model. It is important to note that this success rate increase does not require an increase in algorithmic complexity and allows for increased success rate, even with the removal of a nuisance parameter from the algorithm.

Conclusion
Researchers performing genetic association studies and aiming to discover gene-gene interactions associated with increased disease susceptibility should use SURF in place of ReliefF. For instance, SURF should be used instead of ReliefF to filter a dataset before an exhaustive MDR analysis. This change increases the ability of a study to detect gene-gene interactions. The SURF algorithm is implemented in the open source Multifactor Dimensionality Reduction (MDR) software package available from http://www.epistasis.org.
Referral, Receipt, and Completion of Chemotherapy in Patients With Early-Stage Breast Cancer Older Than 65 Years and at High Risk of Breast Cancer Recurrence
Authors: Buist Diana S.M. , Chubak Jessica , Prout Marianne , Yood Marianne Ulcickas , Bosco Jaclyn L.F. , Thwin Soe Soe , Gold Heather Taffet , Owusu Cynthia , Field Terry S. , Quinn Virginia P. , Wei Feifei , Silliman Rebecca A. 
Published: September 2009

Purpose Some women with early-stage breast cancer are at higher risk of recurrence and can benefit from chemotherapy. We describe patterns of referral, receipt, and completion of chemotherapy among older women at high risk of recurrence. Patients and Methods A total of 2,124 women age 65 years or older who were diagnosed with early-stage breast cancer between 1990 and 1994 and 1996 to 1999 were included; 1,090 of these were at high risk of recurrence. We reviewed medical records to categorize chemotherapy outcomes as follows: did not discuss or were not referred to a medical oncologist (n = 133); discussed and/or referred to a medical oncologist but received no chemotherapy (n = 742); received an incomplete chemotherapy course (n = 29), or received a completed chemotherapy course (n = 186). Results Overall, 19.7% of high-risk women received any chemotherapy, and 86.5% of these women completed their chemotherapy courses. Just greater than 10% of high-risk women did not have a discussion about chemotherapy as part of breast cancer treatment documented in the medical record; these women also received fewer diagnostic assessments of their initial tumors. Conclusion Individuals who receive chemotherapy for early-stage breast cancer are a select subgroup of patients at high risk of recurrence. This study identifies characteristics of women who were referred for and who received chemotherapy, and this study plays an important role in understanding generalizability of studies that examine chemotherapy treatment effectiveness. Outcomes after breast cancer could continue to be improved with increased receipt of chemotherapy among older women at high risk of breast cancer recurrence.
Phase III Trial of Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract
Authors: Bellmunt Joaquim , Théodore Christine , Demkov Tomasz , Komyakov Boris , Sengelov Lisa , Daugaard Gedske , Caty Armelle , Carles Joan , Jagiello-Gruszfeld Agnieszka , Karyakin Oleg , Delgado François-Michel , Hurteloup Patrick , Winquist Eric , Morsli Nassim , Salhi Yacine , Culine Stéphane , von der Maase Hans 
Published: September 2009

PurposeVinflunine (VFL) is a new microtubule inhibitor that has activity against transitional cell carcinoma of urothelial tract (TCCU). We conducted a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone in the treatment of patients with advanced TCCU who had experienced progression after a first-line platinum-containing regimen.Patients and MethodsThe study was designed to compare overall survival (OS) between patients receiving VFL + BSC (performance status [PS] = 0: 320 mg/m2, every 3 weeks; PS = 0 with previous pelvic radiation and PS = 1: 280 mg/m2subsequently escalated to 320 mg/m2) or BSC.ResultsThree hundred seventy patients were randomly assigned (VFL + BSC, n =253; BSC, n = 117). Both arms were well balanced except there were more patients with PS more than 1 (10% difference) in the BSC arm. Main grade 3 or 4 toxicities for VFL + BSC were neutropenia (50%), febrile neutropenia (6%), anemia (19%), fatigue (19%), and constipation (16%). In the intent-to-treat population, the objective of a median 2-month survival advantage (6.9 months for VFL + BSC v 4.6 months for BSC) was achieved (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12) but was not statistically significant (P = .287). Multivariate Cox analysis adjusting for prognostic factors showed statistically significant effect of VFL on OS (P = .036), reducing the death risk by 23% (HR = 0.77; 95% CI, 0.61 to 0.98). In the eligible population (n = 357), the median OS was significantly longer for VFL + BSC than BSC (6.9 v 4.3 months, respectively), with the difference being statistically significant (P = .040). Overall response rate, disease control, and progression-free survival were all statistically significant favoring VFL + BSC (P = .006, P = .002, and P = .001, respectively).ConclusionVFL demonstrates a survival advantage in second-line treatment for advanced TCCU. Consistency of results exists with significant and meaningful benefit over all efficacy parameters. Safety profile is acceptable, and therefore, VFL seems to be a reasonable option for TCCU progressing after first-line platinum-based therapy.
Long-Term Results of a Randomized Trial of Surgery With or Without Preoperative Chemotherapy in Esophageal Cancer
Authors: Allum William H. , Stenning Sally P. , Bancewicz John , Clark Peter I. , Langley Ruth E. 
Published: September 2009

Purpose OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years. Patients and Methods OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented. Results There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%. Conclusion Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.