bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer
Authors: Deenen Maarten J. , Tol Jolien , Burylo Artur M , Doodeman Valerie D. , de Boer Anthonius , Vincent Andrew , Guchelaar Henk-Jan , Smits Paul H.M. , Beijnen Jos H. , Punt Cornelis J.A. , Schellens Jan H.M. , Cats Annemieke 
Published: April 2011

Abstract
Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine.
Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P &lt; 0.1) or frequently occurring (&gt;1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival.
Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G&gt;A, 2846A&gt;T, and 1236G&gt;A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G&gt;A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G&gt;A and 25% in 2846A&gt;T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)].
Conclusions: DPYD IVS14+1G&gt;A and 2846A&gt;T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.
Extrahepatic Cancer Suppresses Nuclear Receptor–Regulated Drug Metabolism
Authors: Kacevska Marina , Downes Michael R. , Sharma Rohini , Evans Ronald M. , Clarke Stephen J. , Liddle Christopher , Robertson Graham R. 
Published: April 2011

Abstract
Purpose: To determine the mechanisms by which tumors situated in extrahepatic sites can cause profound changes in hepatic drug clearance, contributing to altered drug response and chemotherapy resistance.
Experimental Design: We studied in wild-type or transgenic CYP3A4 reporter mice implanted with the murine Engelbreth–Holm–Swarm sarcoma changes in nuclear receptor and hepatic transcription factor expression and/or function, particularly related to CYP3A gene regulation.
Results: Repression of hepatic CYP3A induction was dramatic and associated with reduced levels of C/EBPβ isoforms, impaired pregnane X receptor, and constitutive androstane receptor function. Unexpectedly, extrahepatic tumors strongly reduced nuclear accumulation of retinoid X receptor alpha (RXRα) in hepatocytes, providing a potential explanation for impaired function of nuclear receptors that rely on RXRα dimerization. Profiling revealed 38 nuclear receptors were expressed in liver with 14 showing between 1.5- and four-fold reduction in expression in livers of tumor-bearing animals, including Car, Trβ, Lxrβ, Pparα, Errα/β, Reverbα/β, and Shp. Altered Pparα and γ induction of target genes provided additional evidence of perturbed hepatic metabolic control elicited by extrahepatic tumors.
Conclusions: Extrahepatic malignancy can affect hepatic drug metabolism by nuclear receptor relocalization and decreased receptor expression and function. These findings could aid the design of intervention strategies to normalize drug clearance and metabolic pathways in cancer patients at risk of chemotherapy-induced toxicity or cancer cachexia. Clin Cancer Res; 17(10); 3170–80. ©2011 AACR.
Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy
Authors: Rosenberg Steven A. , Yang James C. , Sherry Richard M. , Kammula Udai S. , Hughes Marybeth S. , Phan Giao Q. , Citrin Deborah E. , Restifo Nicholas P. , Robbins Paul F. , Wunderlich John R. , Morton Kathleen E. , Laurencot Carolyn M. , Steinberg Seth M. , White Donald E. , Dudley Mark E. 
Published: April 2011

AbstractPurpose: Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We investigated the ability of adoptive cell transfer utilizing autologous tumor-infiltrating lymphocytes (TIL) to mediate durable complete regressions in heavily pretreated patients with metastatic melanoma.Experimental Design: Ninety-three patients with measurable metastatic melanoma were treated with the adoptive transfer of autologous TILs administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential follow-up was 62 months.Results: Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) in the 3 trials using lymphodepleting preparative regimens (chemotherapy alone or with 2 or 12 Gy irradiation) were 49%, 52%, and 72%, respectively. Twenty of the 93 patients (22%) achieved a complete tumor regression, and 19 have ongoing complete regressions beyond 3 years. The actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused cells, the number of CD8+CD27+ cells infused, and the persistence of the infused cells in the circulation at 1 month (all P2 &lt; 0.001).Conclusions: Cell transfer therapy with autologous TILs can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment. Clin Cancer Res; 17(13); 4550–7. ©2011 AACR.
Does Stage II Colorectal Cancer Need to Be Redefined?
Authors: Grothey Axel 
Published: April 2011

Abstract
Detection of guanylyl cyclase C mRNA in lymph nodes of resected stage II colorectal cancer is highly correlated with the risk of tumor recurrence. If validated, these results could have significant implications for the selection of patients for adjuvant therapy in this disease. Clin Cancer Res; 17(10); 3053–5. ©2011 AACR.
Of Timing and Surrogates: A Way Forward for Cancer Chemoprevention
Authors: Thompson Patricia A. , Gerner Eugene W. 
Published: April 2011

Abstract
Cancer chemoprevention strategies are not widely implemented in clinical practice. Targeting biomarkers in patients with elevated risk of developing cancer by means of short-term administration of certain agents may be a strategy to minimize toxicities while maintaining efficacy in clinical trials that can be completed in years rather than decades. Clin Cancer Res; 17(11); 3509–11. ©2011 AACR.
The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance
Authors: Filippova Natalia , Yang Xiuhua , Wang Yimin , Gillespie G. Yancey , Langford Cathy , King Peter H. , Wheeler Crystal , Nabors L. Burt 
Published: April 2011

Abstract
Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3′-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target. Mol Cancer Res; 9(5); 648–59. ©2011 AACR.
The S1103Y Cardiac Sodium Channel Variant Is Associated With Implantable Cardioverter-Defibrillator Events in Blacks With Heart Failure and Reduced Ejection Fraction
Authors: Sun Albert Y. , Koontz Jason I. , Shah Svati H. , Piccini Jonathan P. , Nilsson Kent R. , Craig Damian , Haynes Carol , Gregory Simon G. , Hranitzky Patrick M. , Pitt Geoffrey S. 
Published: April 2011

Background—

Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel
SCN5A
variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction.

Methods and Results—

Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%,
P
=0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73,
P
=<0.01). There was no difference in mortality between carriers and noncarriers.

Conclusions—
This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.
Mechanisms of Acute Mitral Regurgitation in Patients With Takotsubo Cardiomyopathy
Authors: Izumo Masaki , Nalawadi Smruti , Shiota Maiko , Das Jayanta , Dohad Suhail , Kuwahara Eiji , Fukuoka Yoko , Siegel Robert J. , Shiota Takahiro 
Published: April 2011

Background—
Recent studies have suggested acute mitral regurgitation (MR) as a potentially serious complication of takotsubo cardiomyopathy (TTC); however, the mechanism of acute MR in TTC remains unclear. The aim of this study was to elucidate the mechanisms of acute MR in patients with TTC.

Methods and Results—

Echocardiography was used to assess the mitral valve and left ventricular outflow tract (LVOT) pressure gradient in 47 patients with TTC confirmed by coronary angiography and left ventriculography. Mitral valve assessment included coaptation distance, tenting area at mid systole in the long-axis view, and systolic anterior motion of the mitral valve (SAM). Of the study patients, 12 (25.5%) had significant (moderate or severe) acute MR. In patients with acute MR versus those without acute MR, we found lower ejection fraction (31.3±6.2% versus 41.5±10.6%,
P
=0.001) and higher systolic pulmonary artery pressure (49.3±7.4 versus 35.5±8.9 mm Hg,
P
<0.001). Moreover, 6 of the 12 patients with acute MR had SAM, with peak LVOT pressure gradient >20 mm Hg (average peak LVOT pressure gradient, 81.3±35.8 mm Hg). The remaining 6 patients with acute MR revealed significantly greater mitral valve coaptation distance (10.9±1.6 versus 7.8±1.4 mm,
P
<0.001) and tenting area (2.1±0.4 versus 0.95±0.25 cm
2
,
P
<0.001) than those without acute MR. A multivariate analysis revealed that SAM and tenting area were independent predictors of acute MR in patients with TTC (all
P
<0.001).

Conclusions—
SAM and tethering of the mitral valve are independent mechanisms with differing pathophysiology that can lead to acute MR in patients with TTC.
Identification and characterization of a novel transcriptional target of RUNX1/AML1 at the onset of hematopoietic development
Authors: Ferreras Cristina , Lancrin Christophe , Lie-A-Ling Michael , Kouskoff Valerie , Lacaud Georges 
Published: April 2011

AbstractAlthough the critical requirement for the transcription factor RUNX1/AML1 at the onset of hematopoietic development is well established, little is known about its transcriptional targets at this pivotal stage of blood development. Using microarrays, we identified the uncharacterized gene AI467606 as a gene whose expression level is dramatically reduced in the absence of RUNX1. We further demonstrated by chromatin immunoprecipitation and promoter assay a direct regulation of its transcription by RUNX1. Using a bacterial artificial chromosome transgenic approach, we established that AI467606 is expressed during the development of the hematopoietic system in vivo and in vitro and that its expression is detected within the CD41+ population and marks definitive hematopoietic potential. Similarly, in the adult mouse, all hematopoietic cell lineages, except mature erythrocytes, express AI467606. Taken together, these findings indicate that AI467606 is a novel transcriptional target of RUNX1/AML1 at the onset of hematopoietic development that is extensively expressed within the hematopoietic system.
The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow
Authors: Lobov Ivan B. , Cheung Eunice , Wudali Rajeev , Cao Jingtai , Halasz Gabor , Wei Yi , Economides Aris , Lin Hsin C. , Papadopoulos Nicholas , Yancopoulos George D. , Wiegand Stanley J. 
Published: April 2011

AbstractBlood vessel remodeling is crucial to the formation of the definitive vasculature, but little is known about the mechanisms controlling this process. We show that Delta-like ligand 4 (Dll4)/Notch pathway regulates vessel regression in normal pathologic conditions. Genetic and pharmacologic inhibition of Dll4/Notch prevented retinal capillary regression in the oxygen-induced retinopathy (OIR) model and during normal development. Deletion of the Notch-regulated ankyrin repeat protein, a negative regulator of the Notch pathway, produced an opposite phenotype. Inhibition of Dll4/Notch reduced vessel occlusion, maintaining blood flow that is essential for survival of microvessels. Dll4/Notch inhibition up-regulated the expression of vasodilators adrenomedullin and suppressed the expression of vasoconstrictor angiotensinogen. Angiotensin II induced rapid nonperfusion and regression of developing retinal capillaries, whereas Ace1 and AT1 inhibitors and adrenomedullin attenuated vasoobliteration in OIR, indicating that both pathways are involved in modulating vessel remodeling. In contrast, inhibition of vascular endothelial growth factor-A (VEGF-A) did not result in a pervasive loss of retinal capillaries, demonstrating that reduced expression of VEGF-A is not the proximate cause of capillary regression in OIR. Modulation of VEGF-A and DII4/Notch signaling produced distinct changes in blood vessel morphology and gene expression, indicating that these pathways can have largely independent functions in vascular remodeling.
Mouse Ly49G2+ NK cells dominate early responses during both immune reconstitution and activation independently of MHC
Authors: Barao Isabel , Alvarez Maite , Ames Erik , Orr Mark T. , Stefanski Heather E. , Blazar Bruce R. , Lanier Lewis L. , Anderson Stephen K. , Redelman Doug , Murphy William J. 
Published: April 2011

AbstractNatural killer (NK) cell subsets can be defined by the differential expression of inhibitory receptors for MHC class I molecules. Early after congenic HSCT, we found that Ly49G2high single-positive NK cells repopulated, displayed an activated phenotype, and were highly cytolytic. Over time, this subset was replaced with NK cells with a normal pattern of Ly49 expression. Treatment of mice with IL-2 also resulted in the rapid expansion of these Ly49G2high single-positive NK cells. Only the Ly49g (Klra7) Pro1 transcript was highly induced in both HSCT- and IL-2–treated recipients. MHC-independent expansion of the Ly49G2+ subset was also observed after Listeria monocytogenes or mouse cytomegalovirus infection. Our data indicate that during reconstitution after HSCT and various activation stimuli, Ly49G2+ NK cells represent the “first-responder” NK cells, which occur independently of NK-cell licensing via Ly49-MHC interactions. These data suggest that the inhibitory Ly49G2 receptor represents an activation marker on mouse NK cells under various conditions.
Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs
Authors: Buttari Brigitta , Profumo Elisabetta , Capozzi Antonella , Facchiano Francesco , Saso Luciano , Sorice Maurizio , Riganò Rachele 
Published: April 2011

AbstractIn chronic disorders related to endothelial cell dysfunction, plasma β2 glycoprotein I (β2GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why β2GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified β2GPI is able to interact and activate monocyte-derived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that β2GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-β2GPI. AGE-β2GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-κB. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-β2GPI–stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of β2GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction.
Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study
Authors: Nottage Kerri , Lanctot Jennifer , Li Zhenghong , Neglia Joseph P. , Bhatia Smita , Hammond Sue , Leisenring Wendy , Meadows Anna , Srivastava Deokumar , Robison Leslie L. , Armstrong Gregory T. 
Published: April 2011

Abstract
Previous investigations of cancer survivors report that the cumulative incidence of subsequent leukemia plateaus between 10 and 15 years after primary therapy. Risk beyond 15 years has not been comprehensively assessed, primarily because of lack of long-term follow-up. Among 5-year survivors from the Childhood Cancer Survivor Study cohort, 13 pathologically confirmed cases of subsequent leukemia occurred ≥ 15 years after primary malignancy, with a mean latency of 21.6 years (range, 15-32 years). Seven were acute myeloid leukemia (2 acute promyelocytic leukemia with t(15;17), 2 with confirmed preceding myelodysplastic syndrome), 4 acute lymphoblastic leukemia (2 pre-B lineage, 1 T cell, 1 unknown), and 2 other. Two acute myeloid leukemia cases had the 7q− deletion. The standardized incidence ratio was 3.5 (95% confidence interval, 1.9-6.0). Median survival from diagnosis of subsequent leukemia was 2 years. This is the first description of a statistically significant increased risk of subsequent leukemia ≥ 15 years from primary diagnosis of childhood cancer.
Estradiol administration controls eosinophilia through estrogen receptor-α activation during acute peritoneal inflammation
Authors: Douin-Echinard Victorine , Calippe Bertrand , Billon-Galès Audrey , Fontaine Coralie , Lenfant Françoise , Trémollières Florence , Bayard Françis , Guéry Jean-Charles , Arnal Jean-François , Gourdy Pierre 
Published: April 2011

ABSTRACTEstrogens influence the incidence and the course of numerous immune or inflammatory diseases in humans and in experimental models. For instance, estrogens prevent the accumulation of granulocytes in acute inflammatory murine models, but the respective actions on neutrophil and eosinophil trafficking remain to be clarified. We demonstrate here that in a model of TGC-induced sterile peritonitis in ovx mice, chronic E2 administration electively and strongly inhibited peritoneal eosinophil accumulation. E2 decreased BM eosinophil number, contributing to a marked prevention of the TGC-induced eosinophil blood mobilization. These effects on eosinophil mobilization and peritoneal accumulation were abolished in ER-α−/− mice, demonstrating the crucial role of this nuclear receptor. Grafting ER-α−/− mice with ER-α+/+ BM cells restored the suppressive effect of E2 on peritoneal eosinophilia, although the action on eosinophil blood mobilization was still abrogated. We therefore explored additional mechanisms and found that E2 reduced the peritoneal concentrations of key eosinophil prosurvival factors (IL-5, IL-9, and IL-25) and enhanced eosinophil apoptosis during the inflammatory process. Furthermore, this proapoptotic effect of E2 was abrogated in IL-5-overexpressing Tg mice. To conclude, we demonstrate for the first time that ER-α activation by exogenous E2 administration strongly inhibits eosinophil accumulation during acute inflammation in a nonreproductive target site for estrogen through combined actions on eosinophil mobilization and apoptosis. This specific, suppressive effect of chronic E2 replacement therapy on eosinophils has to be integrated to further understand the evolution of eosinophil-associated diseases in menopausal women.