bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Genome-Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex
Authors: Davies Robert W. , Wells George A. , Stewart Alexandre F.R. , Erdmann Jeanette , Shah Svati H. , Ferguson Jane F. , Hall Alistair S. , Anand Sonia S. , Burnett Mary S. , Epstein Stephen E. , Dandona Sonny , Chen Li , Nahrstaedt Janja , Loley Christina , König Inke R. , Kraus William E. , Granger Christopher B. , Engert James C. , Hengstenberg Christian , Wichmann H.-Erich , Schreiber Stefan , Tang W.H. Wilson , Ellis Stephen G. , Rader Daniel J. , Hazen Stanley L. , Reilly Muredach P. , Samani Nilesh J. , Schunkert Heribert , Roberts Robert , McPherson Ruth 
Published: February 2012

Background—
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.

Methods and Results—

We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes–based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between
HCG27
and
HLA-C
was identified and achieved genome-wide significance in the combined analysis (rs3869109;
p
discovery
=3.3×10
−7
,
p
replication
=5.3×10
−4
p
combined
=1.12×10
−9
). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (
P
=4.1×10
−10
versus 3.2×10
−7
), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self–cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common
HLA
alleles into the discovery subjects; however, no single common
HLA
type contributed significantly or fully explained the observed association.

Conclusions—
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
Clinical Outcomes and Treatment After Drug-Eluting Stent Failure
Authors: Maluenda Gabriel , Ben-Dor Itsik , Gaglia Michael A. , Wakabayashi Kohei , Mahmoudi Michael , Sardi Gabriel , Laynez-Carnicero Ana , Torguson Rebecca , Xue Zhenyi , Margulies Adrian D. , Suddath William O. , Kent Kenneth M. , Bernardo Nelson L. , Satler Lowell F. , Pichard Augusto D. , Waksman Ron 
Published: February 2012

Background—
The optimal percutaneous treatment of drug-eluting stent (DES) in-stent restenosis (ISR) and the correlates for recurrent DES ISR remain unclear.

Methods and Results—

From 2003 to 2008, 563 patients presenting with recurrent symptoms of ischemia and angiographic ISR after DES implantation were included. Of these, 327 were treated with re-DES (58.1%), 132 underwent vascular brachytherapy (23.4%), and 104 were treated with conventional balloon angioplasty (18.5%). Variables associated with target lesion revascularization at 1 year were explored by individual proportional hazard models. This population presents a high prevalence of comorbidities, including diabetes (43.7%), previous myocardial infarction (MI) (45.8%), coronary bypass graft surgery (39.2%), chronic renal failure (18.8%), and heart failure (17.3%). Baseline clinical characteristics were balanced among the 3 groups; however, patients undergoing vascular brachytherapy presented with more complex lesions and a higher prevalence of prior stent/vascular brachytherapy failure than did the rest of the population. The overall incidence of recurrent DES failure at 1-year follow-up was 12.2%, which was similar among the 3 groups (
P
=0.41). The rate of the composite end point (death, Q-wave-MI and target lesion revascularization) at 1-year follow-up was 14.1% for re-DES, 17.5% for vascular brachytherapy, and 18.0% for conventional balloon angioplasty (
P
=0.57). After univariable analysis tested the traditional known covariates related to ISR, none of them were associated with repeat target lesion revascularization.

Conclusions—
Recurrence of ISR after DES treatment failure is neither infrequent nor benign, and optimal therapy remains unclear and challenging. Given the absence of traditional risk factors for ISR in this population, further research is required to elucidate both the correlates involved in DES ISR and the optimal treatment for this condition.
Multilag Correlation Estimators for Polarimetric Radar Measurements in the Presence of Noise
Authors: Lei Lei , Zhang Guifu , Doviak Richard J. , Palmer Robert , Cheong Boon Leng , Xue Ming , Cao Qing , Li Yinguang 
Published: February 2012

Abstract
The quality of polarimetric radar data degrades as the signal-to-noise ratio (SNR) decreases. This substantially limits the usage of collected polarimetric radar data to high SNR regions. To improve data quality at low SNRs, multilag correlation estimators are introduced. The performance of the multilag estimators for spectral moments and polarimetric parameters is examined through a theoretical analysis and by the use of simulated data. The biases and standard deviations of the estimates are calculated and compared with those estimates obtained using the conventional method.
Survivin SNP-carcinogen Interactions in Oral Cancer
Authors: Weng C.J. , Hsieh Y.H. , Chen M.K. , Tsai C.M. , Lin C.W. , Yang S.F. 
Published: February 2012

In Taiwan, oral cancer is causally associated with environmental carcinogens. Survivin is an anti-apoptotic protein and is generally considered a marker of malignancy. The current study explored the combined effect of survivin gene polymorphisms and environmental carcinogens on the risk and clinico-pathological development of oral cancer. Five single-nucleotide polymorphisms (SNPs) of survivin genes from 439 male patients with oral cancer and 424 male control participants (who did not have cancer) were analyzed. The survivin −31GG, +9194 GG, and +9809 TT homozygotes exhibited higher risk for oral cancer compared with the corresponding ancestral genotype, after adjustment for related confounders. The survivin −31, +9194, and +9809 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. The distribution frequency of the −31 G: +9194 A: +9809 T haplotype was significantly higher in oral cancer patients than in control participants. These results suggest that survivin gene polymorphisms and their interactions with environmental carcinogens may increase susceptibility to oral cancer in Taiwanese men. Abbreviations: AOR, adjusted odds ratio; CI, confidence intervals; PCR, polymerase chain-reaction; SNP, single-nucleotide polymorphisms.
An experimentally validated numerical model of indentation and abrasion by debris particles in machine-element contacts considering micro-hardness effects
Authors: Nikas George K 
Published: February 2012

Indentation and abrasion of machine-element contacts by solid contamination particles is a major problem in many industries and manufacturing processes involving the automotive, aerospace, medical and electronics industries among others. Published theoretical studies on indentation and soft abrasion of surfaces by ductile debris particles other than those of the author are based on several major simplifications concerning material properties, hardness, plasticity modelling, interfacial friction, kinematic conditions, etc. None of the studies published in the literature to date (2011) have those simplifications concurrently relaxed. In view of the shortcomings of existing numerical models on debris particle indentation and abrasion, and given the importance of dent geometry and size on fatigue life of machine elements, a greatly improved numerical model has been developed based on the previous studies of the author. The new model deals with elastoplastic indentation and abrasion of rolling–sliding, dry and lubricated contacts by spherical particles of any hardness, from very soft (e.g. 40 HV) to very hard (e.g. over 1000 HV), including harder than the contact counterfaces. The model incorporates strain-hardening and strain-gradient or indentation-size micro-hardness effects with an expanding-cavity plasticity model, a localised treatment of friction, generalised boundary and kinematic conditions involving localised stick and slip of the particle, linear and nonlinear work-hardening models of the particle, a basic approach on pile-up/sink-in plasticity effects and several other improvements. The model has passed extensive validation tests and found to give realistic predictions that are quantitatively quite close to the experimental results published by independent researchers in the literature concerning dent dimensions and slope. Moreover, it has verified and explained theoretically for the first time the formation of dimples inside and outside dents experimentally observed in rolling and rolling–sliding contacts. This article presents the mathematics of the model, the validation procedure with several real cases from the experimental literature, and a parametric study to show the model’s predictions on precise dent geometry in several realistic cases.
F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation
Authors: Chen Bill B. , Glasser Jennifer R. , Coon Tiffany A. , Zou Chunbin , Miller Hannah L. , Fenton Moon , McDyer John F. , Boyiadzis Michael , Mallampalli Rama K. 
Published: February 2012

AbstractHematologic maligancies exhibit a growth advantage by up-regulation of components within the molecular apparatus involved in cell-cycle progression. The SCF (Skip-Cullin1-F-box protein) E3 ligase family provides homeostatic feedback control of cell division by mediating ubiquitination and degradation of cell-cycle proteins. By screening several previously undescribed E3 ligase components, we describe the behavior of a relatively new SCF subunit, termed FBXL2, that ubiquitinates and destabilizes cyclin D2 protein leading to G0 phase arrest and apoptosis in leukemic and B-lymphoblastoid cell lines. FBXL2 expression was strongly suppressed, and yet cyclin D2 protein levels were robustly expressed in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patient samples. Depletion of endogenous FBXL2 stabilized cyclin D2 levels, whereas ectopically expressed FBXL2 decreased cyclin D2 lifespan. FBXL2 did not bind a phosphodegron within its substrate, which is typical of other F-box proteins, but uniquely targeted a calmodulin-binding signature within cyclin D2 to facilitate its polyubiquitination. Calmodulin competes with the F-box protein for access to this motif where it bound and protected cyclin D2 from FBXL2. Calmodulin reversed FBXL2-induced G0 phase arrest and attenuated FBXL2-induced apoptosis of lymphoblastoid cells. These results suggest an antiproliferative effect of SCFFBXL2 in lymphoproliferative malignancies.
Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9
Authors: Gleason Michelle K. , Lenvik Todd R. , McCullar Valarie , Felices Martin , O'Brien M. Shea , Cooley Sarah A. , Verneris Michael R. , Cichocki Frank , Holman Carol J. , Panoskaltsis-Mortari Angela , Niki Toshiro , Hirashima Mitsuomi , Blazar Bruce R. , Miller Jeffrey S. 
Published: February 2012

Abstract
NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-γ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3+ population of low-dose IL-12/IL-18–activated primary NK cells significantly increased IFN-γ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-γ production, and Tim-3 cross-linking induced ERK activation and degradation of IκBα. Exposure to Gal-9–expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-γ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-γ production, which has important implications for control of infectious disease and cancer.
Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma
Authors: Nishikawa Hiroyoshi , Maeda Yuka , Ishida Takashi , Gnjatic Sacha , Sato Eiichi , Mori Fumiko , Sugiyama Daisuke , Ito Asahi , Fukumori Yasuo , Utsunomiya Atae , Inagaki Hiroshi , Old Lloyd J. , Ueda Ryuzo , Sakaguchi Shimon 
Published: February 2012

AbstractAdult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1–specific CD8+ T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1–specific CD8+ T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL.
Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function
Authors: Dannull Jens , Schneider Tristan , Lee Walter T. , de Rosa Nicole , Tyler Douglas S. , Pruitt Scott K. 
Published: February 2012

AbstractGeneration of human monocyte–derived dendritic cells (DCs) for cancer vaccination involves ex vivo maturation in the presence of proinflammatory cytokines and prostaglandin E(2) (PGE2). Although the inclusion of PGE2 during maturation is imperative for the induction of DC migration, PGE2 has unfavorable effects on the immunostimulatory capacity of these cells. Like PGE2, leukotrienes (LTs) are potent mediators of DC migration. We therefore sought to characterize the migratory and immunologic properties of DCs that matured in the presence of LTB4, LTC4, LTD4, and PGE2. Here, we demonstrate that DCs matured in the presence of LTC4, but not LTB4 or LTD4, are superior to PGE2-matured DCs in stimulating CD4+ T-cell responses and in inducing antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without concomitant induction or recruitment of regulatory T cells (Tregs). LTC4-matured DCs migrate efficiently through layers of extracellular matrix and secrete higher levels of immunostimulatory IL-12p70 while producing reduced levels of immune-inhibitory IL-10, IL12p40, indoleamine-2,3-dioxidase, and TIMP-1 (tissue inhibitor of matrix metalloproteinases). Intracellular calcium mobilization and receptor antagonist studies reveal that, in contrast to LTD4, LTC4 did not signal through CysLTR1 in DCs. Collectively, our data suggest that LTC4 represents a promising candidate to replace PGE2 in DC maturation protocols for cancer vaccination.
Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?
Authors: Hasselbalch Hans Carl 
Published: February 2012

AbstractThe morbidity and mortality of patients with the chronic Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis are mainly caused by cardiovascular diseases, thrombohemorrhagic complications, and bone marrow failure because of myelofibrosis and leukemic transformation. In the general population, chronic inflammation is considered of major importance for the development of atherosclerosis and cancer. MPNs are characterized by a state of chronic inflammation, which is proposed to be the common denominator for the development of “premature atherosclerosis,” clonal evolution, and second cancer in patients with MPNs. Chronic inflammation may both initiate clonal evolution and catalyze its expansion from early disease stage to the myelofibrotic burnt-out phase. Furthermore, chronic inflammation may also add to the severity of cardiovascular disease burden by accelerating the development of atherosclerosis, which is well described and recognized in other chronic inflammatory diseases. A link between chronic inflammation, atherosclerosis, and second cancer in MPNs favors early intervention at the time of diagnosis (statins and interferon-α2), the aims being to dampen chronic inflammation and clonal evolution and thereby also diminish concurrent disease-mediated chronic inflammation and its consequences (accelerated atherosclerosis and second cancer).
Cervical cancer cell lines expressing NKG2D-ligands are able to down-modulate the NKG2D receptor on NKL cells with functional implications
Authors: Jimenez-Perez Miriam I , Jave-Suarez Luis F , Ortiz-Lazareno Pablo C , Bravo-Cuellar Alejandro , Gonzalez-Ramella Oscar , Aguilar-Lemarroy Adriana , Hernandez-Flores Georgina , Pereira-Suarez Ana L , Daneri-Navarro Adrian , del Toro-Arreola Susana 
Published: February 2012

AbstractBackgroundCervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide. Natural killer (NK) cells play an important role in the defense against viruses, intracellular bacteria and tumors. NKG2D, an activating receptor on NK cells, recognizes MHC class I chain-related molecules, such as MICA/B and members of the ULBP/RAET1 family. Tumor-derived soluble NKG2D-ligands have been shown to down-modulate the expression of NKG2D on NK cells. In addition to the down-modulation induced by soluble NKG2D-ligands, it has recently been described that persistent cell-cell contact can also down-modulate NKG2D expression. The goal of this study was to determine whether the NKG2D receptor is down-modulated by cell-cell contact with cervical cancer cells and whether this down-modulation might be associated with changes in NK cell activity.ResultsWe demonstrate that NKG2D expressed on NKL cells is down-modulated by direct cell contact with cervical cancer cell lines HeLa, SiHa, and C33A, but not with non-tumorigenic keratinocytes (HaCaT). Moreover, this down-modulation had functional implications. We found expression of NKG2D-ligands in all cervical cancer cell lines, but the patterns of ligand distribution were different in each cell line. Cervical cancer cell lines co-cultured with NKL cells or fresh NK cells induced a marked diminution of NKG2D expression on NKL cells. Additionally, the cytotoxic activity of NKL cells against K562 targets was compromised after co-culture with HeLa and SiHa cells, while co-culture with C33A increased the cytotoxic activity of the NKL cells.ConclusionsOur results suggest that differential expression of NKG2D-ligands in cervical cancer cell lines might be associated with the down-modulation of NKG2D, as well as with changes in the cytotoxic activity of NKL cells after cell-cell contact with the tumor cells.
A comparison of two distinct murine macrophage gene expression profiles in response to Leishmania amazonensisinfection
Authors: Probst Christian M , Silva Rodrigo A , B Menezes Juliana P , Almeida Tais F , Gomes Ivana N , Dallabona Andréia C , Ozaki Luiz S , Buck Gregory A , Pavoni Daniela P , Krieger Marco A , T Veras Patrícia S 
Published: February 2012

AbstractBackgroundThe experimental murine model of leishmaniasis has been widely used to characterize the immune response againstLeishmania. CBA mice develop severe lesions, while C57BL/6 present small chronic lesions underL. amazonensisinfection. Employing a transcriptomic approach combined with biological network analysis, the gene expression profiles of C57BL/6 and CBA macrophages, before and afterL. amazonensisinfection in vitro, were compared. These strains were selected due to their different degrees of susceptibility to this parasite.ResultsThe genes expressed by C57BL/6 and CBA macrophages, before and after infection, differ greatly, both with respect to absolute number as well as cell function. Uninfected C57BL/6 macrophages express genes involved in the deactivation pathway of macrophages at lower levels, while genes related to the activation of the host immune inflammatory response, including apoptosis and phagocytosis, have elevated expression levels. Several genes that participate in the apoptosis process were also observed to be up-regulated in C57BL/6 macrophages infected withL. amazonensis, which is very likely related to the capacity of these cells to control parasite infection. By contrast, genes involved in lipid metabolism were found to be up-regulated in CBA macrophages in response to infection, which supports the notion thatL. amazonensisprobably modulates parasitophorous vacuoles in order to survive and multiply in host cells.ConclusionThe transcriptomic profiles of C57BL/6 macrophages, before and after infection, were shown to be involved in the macrophage pathway of activation, which may aid in the control ofL. amazonensisinfection, in contrast to the profiles of CBA cells.