bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes
Authors: Miller Jennifer C. , Maylor-Hagen Heather , Ma Ying , Weis John H. , Weis Janis J. 
Published: April 2010

ABSTRACTWe recently discovered a critical role for type I interferon (IFN) in the development of murine Lyme arthritis.Borrelia burgdorferi-mediated induction of IFN-responsive genes by bone marrow-derived macrophages (BMDMs) was dependent upon a functional type I IFN receptor but independent of Toll-like receptor 2 (TLR2), TLR4, TLR9, and the adapter molecule MyD88. We now demonstrate that induction of the IFN transcriptional profile inB. burgdorferi-stimulated BMDMs occurs independently of the adapter TRIF and of the cytoplasmic sensor NOD2. In contrast,B. burgdorferi-induced transcription of these genes was dependent upon a rapid STAT1 feedback amplification pathway. IFN profile gene transcription was IRF3 dependent but did not utilizeB. burgdorferi-derived DNA or DNase-sensitive ligands. Instead, IFN-responsive gene expression could be induced byB. burgdorferi-derived RNA. Interferon regulatory factor 3 (IRF3)-dependent IFN profile gene transcription was also induced by sonicated bacteria, by the lipoprotein OspA, and by factors released into the BSKII medium during culture ofB. burgdorferi. The IFN-stimulatory activity ofB. burgdorfericulture supernatants was not destroyed by nuclease treatment. Nuclease digestion also had no effect on IFN profile induction mediated by sonicatedB. burgdorferi. Thus,B. burgdorferi-derived RNA, OspA, and non-nucleic acid ligands present in both sonicated bacteria andB. burgdorfericulture medium contribute to type I IFN-responsive gene induction. These findings suggest thatB. burgdorferiinvasion of joint tissue and the resultant type I IFN induction associated with Lyme arthritis development may involve multiple triggering ligands.
Chronic Intestinal Helminth Infections Are Associated with Immune Hyporesponsiveness and Induction of a Regulatory Network
Authors: Figueiredo Camila Alexandrina , Barreto Mauricio L. , Rodrigues Laura C. , Cooper Philip J. , Silva Nívea Bispo , Amorim Leila D. , Alcantara-Neves Neuza Maria 
Published: April 2010

ABSTRACTHelminth infections have been associated with protection against allergy and autoimmune diseases. We investigated the effects of chronic infections withAscaris lumbricoidesandTrichuris trichiura(measured twice over a 5-year period) on cytokine and antibody responses. We collected blood from 1,060 children aged 4 to 11 years living in a poor urban area of Brazil and measured Th1 (gamma interferon [IFN-γ]) and Th2 (interleukin-5 [IL-5] and IL-13) cytokines and the regulatory cytokine IL-10 in unstimulated and stimulated (with mitogen orA.lumbricoidesantigens) cultures of peripheral blood leukocytes and levels of total IgE and anti-A.lumbricoidesIgG4 and IgE in serum. Intestinal helminth infections were associated with an increased proportion of children producing IL-5 in response toA.lumbricoidesand producing IL-10 spontaneously, especially among coinfected and chronically infected children. Helminth infections were associated with a generalized suppression of cytokine responses to mitogen. Levels of total IgE and anti-A.lumbricoidesIgG4 and IgE were especially elevated in chronically infected children. In conclusion, intestinal helminth infections were associated with a typical Th2 immune response profile and with the induction of immune hyporesponsiveness that was associated with greater frequencies of the production of spontaneous IL-10.
Human Brucellosis Is Characterized by an Intense Th1 Profile Associated with a Defective Monocyte Function
Authors: Rodríguez-Zapata Manuel , Matías Marlene J. , Prieto Alfredo , Jonde Marco A. , Monserrat Jorge , Sánchez Lorenzo , Reyes Eduardo , De la Hera Antonio , Alvarez-Mon Melchor 
Published: April 2010

ABSTRACTIn animal models, a defective Th1 response appears to be critical in the pathogenesis of brucellosis, but the Th1 response in human brucellosis patients remains partially undefined. Peripheral blood from 24 brucellosis patients was studied before and 45 days after antibiotherapy. Twenty-four sex- and age-matched healthy donors were analyzed in parallel. Significantly increased levels of interleukin 1β (IL-1β), IL-2, IL-4, IL-6, IL-12p40, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), but not of IL-10, in serum and/or significantly increased percentages of samples with detectable levels of these cytokines, measured by enzyme-linked immunosorbent assays (ELISA), were found for untreated brucellosis patients, but these levels were reduced and/or normalized after treatment. Flow cytometry studies showed that the intracytoplasmic expression of IFN-γ, IL-2, and TNF-α, but not that of IL-4, by phorbol myristate-activated CD4+CD3+and CD8+CD3+T lymphocytes was significantly increased in untreated brucellosis patients and was also partially normalized after antibiotherapy. The percentage of phagocytic cells, the mean phagocytic activity per cell, and the phagocytic indices for monocytes at baseline were defective and had only partially reverted at follow-up. T lymphocytes from untreated brucellosis patients are activatedin vivoand show Th1 cytokine production polarization, with strikingly high serum IFN-γ levels. In spite of this Th1 environment, we found deficient effector phagocytic activity in peripheral blood monocytes.
Can we detect non-functional overreaching in young elite soccer players and middle-long distance runners using field performance tests?
Authors: Schmikli S L , Brink M S , de Vries W R , Backx F J G 
Published: April 2010

ObjectiveTo study whether field performance tests can make a valid distinction between non-functionally overreaching (NFO) athletes and control athletes.DesignMonthly field performance tests were used to determine a performance decrement (PD) throughout a season. Athletes with a minimum of 1 month PD were compared with control athletes without a PD on mood characteristics and resting levels of stress hormones.SettingSporting field and sports medical laboratory.Participants129 young elite athletes, 77 soccer players and 52 middle-long distance runners were followed prospectively during the 2006–2007 season. Fifteen of them were invited to the laboratory. Eight athletes showed a performance decrease lasting longer than 1 month, and seven athletes without a performance decrease acted as their controls.Main outcome measuresPerformance changes over time were measured using field tests. Profile of Mood States and resting levels of adrenocorticotrophic hormone (ACTH) and cortisol in blood were measured in the laboratory.ResultsPD athletes showed several symptoms typical of the non-functional state of overreaching (OR). The PD group scored higher on depression and anger than controls. They also showed a specific pattern of correlations between negative mood subscales (tension, fatigue and depression), which was absent in controls. ACTH levels at rest were similar, but lower cortisol levels in PD athletes pointed at a blunted cortisol response. Cortisol levels were decoupled from ACTH levels only in PD athletes.ConclusionsImplementing performance-related criteria in field tests can help coaches and sports physicians to distinguish NFO athletes from athletes with balanced workload and recovery.
Fibroblast Growth Factor Receptor 3 Mutation Analysis on Voided Urine for Surveillance of Patients with Low-Grade Non-Muscle–Invasive Bladder Cancer
Authors: Zuiverloon Tahlita C.M. , van der Aa Madelon N.M. , van der Kwast Theo H. , Steyerberg Ewout W. , Lingsma Hester F. , Bangma Chris H. , Zwarthoff Ellen C. 
Published: April 2010

Abstract
Purpose: Mutations in the fibroblast growth factor receptor 3 (FGFR3) have been found in 70% of the low-grade non-muscle–invasive bladder cancer (NMI-BC) tumors. We aim to determine the potential of FGFR3 mutation analysis on voided urine to detect recurrences during surveillance of patients with low-grade NMI-BC.
Experimental Design: FGFR3 mutation status of the study inclusion tumor was determined from 200 low-grade NMI-BC patients. Patients with an FGFR3-mutant inclusion tumor were selected for analysis and monitored by cystoscopy, and voided urine samples were collected. FGFR3 mutation analysis was done on 463 prospectively collected urines. Sensitivity and predictive value of the assay were determined for detection of concomitant recurrences. Longitudinal and Cox time-to-event analyses were done to determine the predictive value for detection of future recurrences.
Results: Median follow-up was 3.5 years. The sensitivity of the assay for detection of concomitant recurrences was 26 of 45 (58%). Of the 105 positive urine samples, 85 (81%) were associated with a concomitant or a future recurrence. An FGFR3-positive urine was associated with a 3.8-fold (P &lt; 0.0001) higher risk of having a recurrence in the Cox analysis. In contrast, only 41 of 358 (11%) FGFR3-negative urine samples were associated with a recurrence. Positive predictive value increased from 25% to 90% in patients having consecutive FGFR3-positive urine tests.
Conclusions: FGFR3 mutation analysis on voided urine is a simple and noninvasive diagnostic method for detection of recurrences during surveillance of patients presenting with a low-grade FGFR3-mutant NMI-BC tumor. Clin Cancer Res; 16(11); 3011–8. ©2010 AACR.
Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis
Authors: Lantuejoul Sylvie , Raynaud Christophe , Salameire Dimitri , Gazzeri Sylvie , Moro-Sibilot Denis , Soria Jean-Charles , Brambilla Christian , Brambilla Elizabeth 
Published: April 2010

Abstract
Purpose: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, and leading to DNA damage responses (DDR). As their inactivation in cancer increases genetic instability, our objective was to identify the chronology of telomere machinery critical events for malignant progression.
Experimental Design: We have evaluated telomere length by fluorescence in situ hybridization and analyzed DDR proteins p-CHK2, p-ATM, and p-H2AX, and telomeric maintenance proteins TRF1 and TRF2 expression by immunohistochemistry in normal bronchial/bronchiolar epithelium, and in 109 bronchial preneoplastic lesions, in comparison with 32 squamous invasive carcinoma (SCC), and in 27 atypical alveolar hyperplasia (AAH) in comparison with 6 adenocarcinoma in situ (AIS; formerly bronchiolo-alveolar carcinoma) and 24 invasive adenocarcinoma (ADC).
Results: Telomere length critically shortened at bronchial metaplasia stage to increase gradually from dysplasia to invasive SCC; in bronchiolo-alveolar lesions, telomere length decreased from normal to AIS and increased from stage I to II to stage III to IV ADC. Expression of TRF1 and TRF2 increased progressively from dysplasia to SCC and from AAH to invasive ADC. The expression of concomitant DDR proteins increased significantly from low- to high-grade dysplasia and from AAH to AIS and stage I to II ADC. P-CHK2 and p-H2AX expressions were highly correlated and both decreased, along with p-ATM, in SCC and advanced ADC.
Conclusion: Telomere attrition occurs at the earliest stage of lung carcinogenesis as an initiating event, preceding TRF1 and TRF2 overexpression for telomere stabilization. In contrast, dismiss of DDR, through p-H2AX and p-CHK2 downregulation, represents a late progressing event associated with SCC and ADC progression. Clin Cancer Res; 16(11); 2979–88. ©2010 AACR.
Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer
Authors: Lipkin Steven M. , Chao Elizabeth C. , Moreno Victor , Rozek Laura S. , Rennert Hedy , Pinchev Mila , Dizon Diana , Rennert Gad , Kopelovich Levy , Gruber Stephen B. 
Published: April 2010

Abstract
Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide. Cancer Prev Res; 3(5); 597–603. ©2010 AACR.
Equity home bias in Australian superannuation funds
Authors: Warren Geoffrey J. 
Published: April 2010

Equity home bias for Australia superannuation funds is examined under a model that reflects observed decision processes. The mix of Australian and international equities is evaluated as a two-asset choice under the influence of legacy, an objective function that trades off expected returns against portfolio risk and peer risk, and under expectations that are formed adaptively and allow for taxation differences. The model closely replicates the observed equity mix, particularly relative to more traditional mean-variance formulations. The main implication is that home bias may be better explained under models that reflect industry practices and allow for various commingled influences. JEL classifications G11, G23
Cutaneous extranodal NK/T-cell lymphoma: a clinicopathologic study of 5 patients with array-based comparative genomic hybridization
Authors: Berti Emilio , Recalcati Sebastiano , Girgenti Valentina , Fanoni Daniele , Venegoni Luigia , Vezzoli Pamela 
Published: April 2010

Abstract
Extranodal natural killer/T-cell (ENK/T) lymphoma is a rare neoplasm, subcategorized into ENK/T-nasal (ENK/T-N) and ENK/T-nasal type (ENK/T-NT) lymphomas. ENK/T-NT lymphoma with initial presentation in the skin is known as primary cutaneous ENK/T-NT (PC-ENK/T-NT) lymphoma. The aim of this study was to investigate pathogenesis, genomic alterations, and prognosis of cutaneous ENK/T lymphomas to provide further insights into clinicopathologic features and genetic mechanism of lymphomagenesis. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was performed. Most of the cases presented with multiple nodules and ulcerations localized on the extremities. A considerable percentage had disease in advanced stage with a 12-month survival rate of 40%. Genomic alterations were detected by array-based comparative genomic hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In conclusion, ENK/T lymphoma is a very aggressive entity, and, in our cases, the exclusively cutaneous presentation was not associated with a better prognosis. The results of our array comparative genomic hybridization analysis could be useful to better define the different ENK/T lymphoma subgroups with cutaneous involvement.
Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction
Authors: Fantin Alessandro , Vieira Joaquim M. , Gestri Gaia , Denti Laura , Schwarz Quenten , Prykhozhij Sergey , Peri Francesca , Wilson Stephen W. , Ruhrberg Christiana 
Published: April 2010

AbstractBlood vessel networks expand in a 2-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet it is not known which factors promote the fusion of neighboring tip cells to add new circuits to the existing vessel network. By combining the analysis of mouse mutants defective in macrophage development or VEGF signaling with live imaging in zebrafish, we now show that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified and unexpected role as vascular fusion cells. Moreover, we show that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell-surface proteins TIE2 and NRP1. Our findings suggest that tissue macrophages are a target for antiangiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularization in ischemic disease.
Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia
Authors: Long Jianting , Parkin Brian , Ouillette Peter , Bixby Dale , Shedden Kerby , Erba Harry , Wang Shaomeng , Malek Sami N. 
Published: April 2010

Abstract
The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small (∼ 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.
The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome–negative acute lymphoblastic leukemia in first and second complete remission
Authors: Marks David I. , Wang Tao , Pérez Waleska S. , Antin Joseph H. , Copelan Edward , Gale Robert Peter , George Biju , Gupta Vikas , Halter Joerg , Khoury H. Jean , Klumpp Thomas R. , Lazarus Hillard M. , Lewis Victor A. , McCarthy Philip , Rizzieri David A. , Sabloff Mitchell , Szer Jeff , Tallman Martin S. , Weisdorf Daniel J. 
Published: April 2010

AbstractWe examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m2 or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.
Comparison of human cord blood engraftment between immunocompromised mouse strains
Authors: McDermott Sean P. , Eppert Kolja , Lechman Eric R. , Doedens Monica , Dick John E. 
Published: April 2010

AbstractThe nonobese diabetic/severe combined immune deficiency (NOD-scid) xenotransplantation model is the “gold standard” for assaying human hematopoietic stem cell activity. Systematic advancements, such as depletion of natural killer cell activity with anti-CD122 antibody, direct intrafemoral injection, and deletion or truncation of IL2Rγ, have improved human cell engraftment; however, questions remain whether these mouse models are equivalent or, if not, which model is superior for assaying hematopoietic stem cell activity. To address this, we compared overall engraftment and multilineage differentiation of near-limiting doses of lineage-depleted human umbilical cord blood cells by direct intrafemoral injection into NOD/Lt-scid, NOD/Shi-scid, NOD/Lt-scid/IL2Rγnull (NSG), and NOD/Shi-scid/IL2Rγnull mice. Transplantation into NSG mice generated moderately higher human engraftment levels in bone marrow compared with other strains. At limiting doses, NSG mice of both sexes were 3.6-fold more sensitive in detecting SCID-repopulating cells compared with NOD/Lt-scid mice. However, NSG females exhibited higher engraftment at limiting cell doses, resulting in an overall increase in SCID-repopulating cell detection of 9-fold. Both NSG and NOD/Shi-scid/IL2Rγnull support significantly improved engraftment in peripheral tissues compared with NOD/Lt-scid and NOD/Shi-scid mice, whereas NSG mice provide greater human engraftment in bone marrow than all other strains, especially at limiting doses.