bluuebunny/crossref_metadata_2025_split huggingface dataset:
A V740L mutation in glycoprotein IIb defines a novel epitope (War) associated with fetomaternal alloimmune thrombocytopenia
Authors: Poles Anthony , Woźniak Marcin J. , Walser Piers , Ridgwell Kay , Fitzgerald Joan , Green Ann , Gilmore Ruth , Lucas Geoff 
Published: January 2013

BackgroundMost recently described human platelet antigens (HPAs) have been detected in cases of fetomaternal alloimmune thrombocytopenia (FMAIT) where the mother has been immunized against a low‐frequency antigen that the fetus has inherited from the father. Low‐frequency antigens are not represented in normal panel platelets (PLTs) and antibody detection and identification in such cases requires incubation of maternal serum with paternal PLTs and definition of the causative mutation.Study Design and MethodsA suspected case of FMAIT was investigated for PLT‐specific antibodies using a panel of both HPA‐typed and paternal PLTs. HPA typing was performed by polymerase chain reaction with sequence‐specific primers and further DNA analysis was performed using direct sequencing of the coding regions of the ITGA2B and ITGB3 genes.ResultsMaternal antibodies reactive only with paternal PLTs were localized to glycoprotein (GP)IIb/IIIa using the monoclonal antibody immobilization of PLT antibody assay. A single‐nucleotide polymorphism was detected in Exon 23 of ITGA2B in the father and affected child, which predicted a V740L substitution in the mature protein. Recombinant V740L mutated GPIIb expressed in HEK293 cells was specifically recognized by maternal antibodies. The polymorphism was not detected either in the mother or in a cohort of 100 donors.ConclusionThe V740L polymorphism defines a new low‐frequency antigen implicated in two cases of FMAIT in a single family. Low‐frequency HPAs are clinically important and their elucidation requires both crossmatch studies and gene sequencing in cases where there is strong clinical evidence of FMAIT but initial laboratory investigations do not support the diagnosis.
Virally inactivated human platelet concentrate lysate induces regulatory T cells and immunosuppressive effect in a murine asthma model
Authors: Lee Yueh‐Lun , Lee Lin‐Wen , Su Chen‐Yao , Hsiao George , Yang Yi‐Yuan , Leu Sy‐Jye , Shieh Ying‐Hua , Burnouf Thierry 
Published: January 2013

BackgroundPlatelet concentrate lysates (PCLs) are increasingly used in regenerative medicine. We have developed a solvent/detergent (S/D)‐treated PCL. The functional properties of this preparation should be unveiled. We hypothesized that, due to transforming growth factor‐β1 (TGF‐β1) content, PCLs may exert immunosuppressive and anti‐inflammatory functions.Study Design and MethodsPCL was prepared by S/D treatment, oil extraction, and hydrophobic interaction chromatography. The content of TGF‐β in PCL was determined by enzyme‐linked immunosorbent assay. Cultured CD4+ T cells were used to investigate the effects of PCL on expression of transcription factor forkhead box P3 (Foxp3), the inhibition of T‐cell proliferation, and cytokine production. The regulatory function of PCL‐converted CD4+ T cells was analyzed by suppressive assay. The BALB/c mice were given PCL‐converted CD4+ T cells before ovalbumin (OVA) sensitization and challenge using an asthma model. Inflammatory parameters, such as the level of immunoglobulin E (IgE), airway hyperresponsiveness (AHR), bronchial lavage fluid eosinophils, and cytokines were assayed. Recombinant human (rHu) TGF‐β1 was used as control.ResultsPCL significantly enhanced the development of CD4+Foxp3+‐induced regulatory T cells (iTregs). Converted iTregs produced neither Th1 nor Th2 cytokines and inhibited normal T‐cell proliferation. PCL‐ and rHuTGF‐β‐converted CD4+ T cells prevented OVA‐induced asthma. PCL‐ and rHuTGF‐β‐modified T cells both significantly reduced expression levels of OVA‐specific IgE and significantly inhibited the development of AHR, airway eosinophilia, and Th2 responses in mice.ConclusionS/D‐treated PCL promotes Foxp3+ iTregs and exerts immunosuppressive and anti‐inflammatory properties. This finding may help to understand the clinical properties of platelet lysates.
Participation of Calcitonin Gene Related Peptide Released via Axon Reflex in the Local Increase in Muscle Blood Flow following Manual Acupuncture
Authors: Shinbara Hisashi , Okubo Masamichi , Kimura Keisaku , Mizunuma Kunio , Sumiya Eiji 
Published: January 2013

Objective The purpose of this study was to determine how calcitonin gene related peptide (CGRP) via axon reflex participates in increasing local muscle blood flow (MBF) following manual acupuncture (MA). Methods Male Sprague–Dawley rats (N=56, 270–350 g) were used. We examined (1) the effects of MA on MBF in the tibialis anterior (TA) muscle in normal rats; (2) the effects of MA on MBF in the TA injected with saline or hCGRP8-37 (low: 2×10−4 mol/litre; high: 2×10−3 mol/litre), a competitive CGRP receptor antagonist, in rats; and (3) the effects of MA on MBF in the TA in capsaicin-treated rats. The capsaicin-treated rats were injected with capsaicin dissolved in an ethanol solution within 24 h after birth (50 mg/kg subcutaneously). MA was applied to the right TA for 1 min. 51Cr-labelled microspheres (15 μm in diameter) were used to measure MBF. Results MA significantly increased MBF without changing arterial blood pressure in normal rats (p<0.05). MA also significantly increased MBF in saline-injected, low hCGRP8-37-injected and high hCGRP8-37-injected rats (p<0.001, 005 and 0.05, respectively). The increases in low and high hCGRP8-37-injected rats were lower than those in saline-injected rats, but the difference was not significant. However, MA did not significantly increase MBF in capsaicin-treated rats (p=0.38). Conclusions We obtained conflicting results, suggesting that the participation of CGRP released via axon reflex may be limited to a local increase in MBF following MA.
GPUs as an opportunity for offloading garbage collection
Authors: Maas Martin , Reames Philip , Morlan Jeffrey , Asanović Krste , Joseph Anthony D. , Kubiatowicz John 
Published: January 2013

GPUs have become part of most commodity systems. Nonetheless, they are often underutilized when not executing graphics-intensive or special-purpose numerical computations, which are rare in consumer workloads. Emerging architectures, such as integrated CPU/GPU combinations, may create an opportunity to utilize these otherwise unused cycles for offloading traditional systems tasks. Garbage collection appears to be a particularly promising candidate for offloading, due to the popularity of managed languages on consumer devices.
We investigate the challenges for offloading garbage collection to a GPU, by examining the performance trade-offs for the mark phase of a mark & sweep garbage collector. We present a theoretical analysis and an algorithm that demonstrates the feasibility of this approach. We also discuss a number of algorithmic design trade-offs required to leverage the strengths and capabilities of the GPU hardware. Our algorithm has been integrated into the Jikes RVM and we present promising performance results.
The Collie
Authors: Iyengar Balaji , Tene Gil , Wolf Michael , Gehringer Edward 
Published: January 2013

We describe the Collie collector, a fully concurrent compacting collector that uses transactional memory techniques to achieve wait-free compaction. The collector uses compaction as the primary means of reclaiming unused memory, and performs "individual object transplantations" as transactions. We introduce new terms and requirements useful for analyzing concurrent relocating collectors, including definitions of referrer sets, object transplantation and the notion of individually transplantable objects. The Collie collector builds on these terms and on a detailed analysis of an object's legal states during compaction.
Collie uses a combination of read barriers, write barriers and transactional memory operations. Its read-barrier supports fast, direct object referencing while using a bound, constant time, wait- free triggering path. Collie thereby avoids the constant indirection cost of Brooks [9] style barriers or handle-based heaps [25]. Collie is demonstrated using speculative multi-address atomicity [11], a form of hardware transactional memory supported by the Azul Vega architecture [2].
We evaluate the Collie collector on the Azul platform, on which previous concurrent collectors such as the Pauseless Collector [12] and its generational variant [30] have been commercially available for several years. We discuss Collie's performance while running sustained workloads, and compare it to the Pauseless collector on the same platform. The Collie collector provides significant MMU [5] improvements even in the 1-msec time windows compared to the Pauseless collector. At the same time, it matches Pauseless in throughput and in the ability to scale to large heap sizes.
We believe that the Collie collector is the first garbage collector to leverage hardware-assisted transactional memory. While Collie directly leverages Vega's speculative multi-address atomicity feature (SMA) [11], its design can be easily adapted to other hardware- assisted transactional memory systems. Specifically, the upcoming Intel TSX instruction set extensions [21] include capabilities similar to SMA. We expect Collie to be easily implementable on future commodity servers based on Intel Haswell processors and following processor generations.
Alcohol Consumption, Folate Intake, Hepatocellular Carcinoma, and Liver Disease Mortality
Authors: Persson E. Christina , Schwartz Lauren M. , Park Yikyung , Trabert Britton , Hollenbeck Albert R. , Graubard Barry I. , Freedman Neal D. , McGlynn Katherine A. 
Published: January 2013

Abstract
Background: Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH–American Association of Retired Persons Diet and Health Study.
Methods: The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazards ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index, and diabetes. HCC incidence (n = 435) was determined through 2006 via linkage with cancer registries, and liver disease mortality (n = 789) was determined through 2008 via linkage to the U.S. Social Security Administration Death Master File and the National Death Index Plus by the National Center for Health Statistics.
Results: Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42–2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81–7.10), whereas folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction = 0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction = 0.54).
Conclusions: These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC.
Impact: Folate intake may be beneficial in the prevention of alcohol-associated HCC. Cancer Epidemiol Biomarkers Prev; 22(3); 415–21. ©2013 AACR.
Hormonal and Reproductive Risk Factors for Epithelial Ovarian Cancer by Tumor Aggressiveness
Authors: Poole Elizabeth M. , Merritt Melissa A. , Jordan Susan J. , Yang Hannah P. , Hankinson Susan E. , Park Yikung , Rosner Bernard , Webb Penelope M. , Cramer Daniel W. , Wentzensen Nicolas , Terry Kathryn L. , Tworoger Shelley S. 
Published: January 2013

Abstract
Background: Approximately half of epithelial ovarian cancers are fatal within 3 years; however, roughly 35% of women survive for at least 10 years. In the Nurses' Health Study, New England Case-Control Study, Australian Ovarian Cancer Study, and NIH-AARP Diet and Health Study, we investigated potential differences in the associations with ovarian cancer risk factors by tumor aggressiveness, defined on the basis of time from diagnosis until death.
Methods: We calculated relative risks (RR) and 95% confidence intervals (CI) for associations of known or suspected ovarian cancer risk factors with rapidly fatal (death within 3 years of diagnosis) and less aggressive tumors (all others) using Cox proportional hazards competing risks analysis (NHS and AARP) or polytomous logistic regression (NECC, AOCS). Results were combined using random effects meta-analysis.
Results: Increasing age was associated with greater risk of rapidly fatal versus less aggressive disease (RR, 5-year increase: 1.39; 95% CI, 1.29–1.49 vs. RR, 1.09; 95% CI, 1.03–1.16, respectively; Pdiff &lt; 0.0001). Oral contraceptive use was associated with a greater decreased risk of rapidly fatal (RR, 5-year increase: 0.69; 95% CI, 0.58–0.82) versus less aggressive disease (RR, 0.81; 95% CI, 0.74–0.89; Pdiff, 0.002). Conversely, increasing parity was associated only with less aggressive disease (RR per child, 0.87; 95% CI, 0.81–0.93).
Conclusion: In this analysis of 4,342 cases, there were clear differences in risk factors for rapidly fatal versus less aggressive ovarian tumors.
Impact: Differences in risk factor associations by tumor aggressiveness suggests the developmental pathways through which the tumors develop and may be important for developing primary preventive strategies for the most aggressive cancers. Cancer Epidemiol Biomarkers Prev; 22(3); 429–36. ©2013 AACR.
Mapping of the IRF8 Gene Identifies a 3′UTR Variant Associated with Risk of Chronic Lymphocytic Leukemia but not Other Common Non-Hodgkin Lymphoma Subtypes
Authors: Slager Susan L. , Achenbach Sara J. , Asmann Yan W. , Camp Nicola J. , Rabe Kari G. , Goldin Lynn R. , Call Timothy G. , Shanafelt Tait D. , Kay Neil E. , Cunningham Julie M. , Wang Alice H. , Weinberg J. Brice , Norman Aaron D. , Link Brian K. , Leis Jose F. , Vachon Celine M. , Lanasa Mark C. , Caporaso Neil E. , Novak Anne J. , Cerhan James R. 
Published: January 2013

Abstract
Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3′ untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10−6). This SNP was not associated with the other NHL subtypes (all P &gt; 0.05).
Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
Impact: These data provide support that a functional variant within the 3′UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk. Cancer Epidemiol Biomarkers Prev; 22(3); 461–6. ©2013 AACR.
Gene Expression Profile Identifies Tyrosine Kinase c-Met as a Targetable Mediator of Antiangiogenic Therapy Resistance
Authors: Jahangiri Arman , De Lay Michael , Miller Liane M. , Carbonell W. Shawn , Hu Yu-Long , Lu Kan , Tom Maxwell W. , Paquette Jesse , Tokuyasu Taku A. , Tsao Sean , Marshall Roxanne , Perry Arie , Bjorgan Kirsten M. , Chaumeil Myriam M. , Ronen Sabrina M. , Bergers Gabriele , Aghi Manish K. 
Published: January 2013

Abstract
Purpose: To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts.
Experimental Design: We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s).
Results: BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met–activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts.
Conclusion: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance. Clin Cancer Res; 19(7); 1773–83. ©2012 AACR.
Acquired factor XIII deficiency: a therapeutic challenge
Authors: Boehlen Françoise , Casini Alessandro , Chizzolini Carlo , Mansouri Behrouz , Kohler Hans Peter , Schroeder Verena , Reber Guido , Moerloose Philippe de 
Published: January 2013

SummaryLess than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associated to a strong and isolated FXIII inhibitor. No underlying disorder has been detected till now after three years of follow-up. Despite aggressive treatment with prednisone, rituximab, cyclophosphamide, immunoglobulin, immunoadsorption and immune tolerance his inhibitor is still present, although at low titre and with a clinical benefit since the patient has no more bleed since more than one year. Moreover the patient had a venous thromboembolic complication. After a review of the management of acquired FXIII deficiency patients and based on the management of acquired haemophilia we discuss a possible strategy for such difficult cases.
Intraventricular Fibrinolysis Does Not Increase Perihemorrhagic Edema After Intracerebral Hemorrhage
Authors: Volbers Bastian , Wagner Ingrid , Willfarth Wolfgang , Doerfler Arnd , Schwab Stefan , Staykov Dimitre 
Published: January 2013

Background and Purpose—
Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator (rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume.

Methods—
Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF, matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days 4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio of PHE volume and initial ICH volume.

Results—

The matching algorithm resulted in similar mean ICH volumes in both groups (20.01±17.5 mL, IVF vs 20.08±17.1 mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8±19.2 mL vs 9.2±13.4 mL). The mean total rtPA dose used for IVF was 8±6 mg. PHE increased over time in both groups until day 12. At all investigated time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39;
P
=0.844).

Conclusions—
IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem to be safe regarding PHE.
Extreme Rainfall in the Mediterranean: What Can We Learn from Observations?
Authors: Rebora N. , Molini L. , Casella E. , Comellas A. , Fiori E. , Pignone F. , Siccardi F. , Silvestro F. , Tanelli S. , Parodi A. 
Published: January 2013

AbstractFlash floods induced by extreme rainfall events represent one of the most life-threatening phenomena in the Mediterranean. While their catastrophic ground effects are well documented by postevent surveys, the extreme rainfall events that generate them are still difficult to observe properly. Being able to collect observations of such events will help scientists to better understand and model these phenomena. The recent flash floods that hit the Liguria region (Italy) between the end of October and beginning of November 2011 give us the opportunity to use the measurements available from a large number of sensors, both ground based and spaceborne, to characterize these events. In this paper, the authors analyze the role of the key ingredients (e.g., unstable air masses, moist low-level jets, steep orography, and a slow-evolving synoptic pattern) for severe rainfall processes over complex orography. For the two Ligurian events, this role has been analyzed through the available observations (e.g., Meteosat Second Generation, Moderate Resolution Imaging Spectroradiometer, the Italian Radar Network mosaic, and the Italian rain gauge network observations). The authors then address the possible role of sea–atmosphere interactions and propose a characterization of these events in terms of their predictability.