bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2
Authors: Pont Margot J. , van der Lee Dyantha I. , van der Meijden Edith D. , van Bergen Cornelis A.M. , Kester Michel G.D. , Honders Maria W. , Vermaat Martijn , Eefting Matthias , Marijt Erik W.A. , Kielbasa Szymon M. , Hoen Peter A.C. 't , Falkenburg J.H. Frederik , Griffioen Marieke 
Published: March 2016

Abstract
Purpose: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT.
Experimental Design: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity.
Results: T-cell clones were isolated for two HLA-B*15:01–restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1. For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01–binding peptide, which was validated as hematopoietic MiHA by T-cell experiments.
Conclusions: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185–96. ©2016 AACR.
Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance
Authors: Malorni Luca , Giuliano Mario , Migliaccio Ilenia , Wang Tao , Creighton Chad J. , Lupien Mathieu , Fu Xiaoyong , Hilsenbeck Susan G. , Healy Nuala , De Angelis Carmine , Mazumdar Abhijit , Trivedi Meghana V. , Massarweh Suleiman , Gutierrez Carolina , De Placido Sabino , Jeselsohn Rinath , Brown Myles , Brown Powel H. , Osborne C. Kent , Schiff Rachel 
Published: March 2016

Abstract
The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.
Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470–81. ©2016 AACR.
Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti–PD-1 Therapy
Authors: Greenplate Allison R. , Johnson Douglas B. , Roussel Mikael , Savona Michael R. , Sosman Jeffrey A. , Puzanov Igor , Ferrell P. Brent , Irish Jonathan M. 
Published: March 2016

Abstract
Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti–PD-1 agent. Myeloid blasts comprised &lt;1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474–80. ©2016 AACR.
Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein
Authors: Reyes-Soffer Gissette , Millar John S. , Ngai Colleen , Jumes Patricia , Coromilas Ellie , Asztalos Bela , Johnson-Levonas Amy O. , Wagner John A. , Donovan Daniel S. , Karmally Wahida , Ramakrishnan Rajasekhar , Holleran Stephen , Thomas Tiffany , Dunbar Richard L. , deGoma Emil M. , Rafeek Hashmi , Baer Amanda L. , Liu Yang , Lassman Michael E. , Gutstein David E. , Rader Daniel J. , Ginsberg Henry N. 
Published: March 2016

Objective—
Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP.

Approach and Results—

Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%;
P
<0.001) and apoA-I levels (29.5%;
P
<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%;
P
=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (
P
<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (
P
<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%,
P
<0.001) with no change in CETP production rate.

Conclusions—
ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.
Leukocyte Calpain Deficiency Reduces Angiotensin II–Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice
Authors: Howatt Deborah A. , Balakrishnan Anju , Moorleghen Jessica J. , Muniappan Latha , Rateri Debra L. , Uchida Haruhito A. , Takano Jiro , Saido Takaomi C. , Chishti Athar H. , Baud Laurent , Subramanian Venkateswaran 
Published: March 2016

Objective—
Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)–derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice.

Approach and Results—

To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low-density lipoprotein receptor
−/−
mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII.

Conclusions—
The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.
Cocaine Use and Risk of Ischemic Stroke in Young Adults
Authors: Cheng Yu-Ching , Ryan Kathleen A. , Qadwai Saad A. , Shah Jay , Sparks Mary J. , Wozniak Marcella A. , Stern Barney J. , Phipps Michael S. , Cronin Carolyn A. , Magder Laurence S. , Cole John W. , Kittner Steven J. 
Published: March 2016

Background and Purpose—
Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use.

Methods—
A population-based case–control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders.

Results—
Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age–sex–race adjusted odds ratio, 6.4; 95% confidence interval, 2.2–18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8–35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7–16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7–19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event.

Conclusions—
Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS.
Astrocyte-Derived Pentraxin 3 Supports Blood–Brain Barrier Integrity Under Acute Phase of Stroke
Authors: Shindo Akihiro , Maki Takakuni , Mandeville Emiri T. , Liang Anna C. , Egawa Naohiro , Itoh Kanako , Itoh Naoki , Borlongan Mia , Holder Julie C. , Chuang Tsu Tshen , McNeish John D. , Tomimoto Hidekazu , Lok Josephine , Lo Eng H. , Arai Ken 
Published: March 2016

Background and Purpose—
Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood–brain barrier dysfunction during the acute phase of ischemic stroke.

Methods—
In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood–brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor–mediated endothelial permeability.

Results—
During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor–induced endothelial permeability.

Conclusions—
Astrocytes in peri-infarct areas upregulate PTX3, which may support blood–brain barrier integrity by regulating vascular endothelial growth factor–related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood–brain barrier function after ischemic stroke.
Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes
Authors: Asciutto Giuseppe , Wigren Maria , Fredrikson Gunilla Nordin , Mattisson Ingrid Yao , Grönberg Caitriona , Alm Ragnar , Björkbacka Harry , Dias Nuno V. , Edsfeldt Andreas , Gonçalves Isabel , Nilsson Jan 
Published: March 2016

Background and Purpose—
Treatment with IgG against the malondialdehyde (MDA)-modified apolipoprotein B-100 epitope p45 reduces atherosclerosis in experimental models. This study investigated the association between p45 IgG autoantibodies and plaque inflammation in subjects with advanced cardiovascular disease.

Methods—
Native and MDA-p45 IgG levels were analyzed by ELISA in 349 carotid endarterectomy patients. In a subcohort of 195 subjects, endarterectomy samples were analyzed by immunohistochemistry and ELISA to determine plaque constituents and inflammation. Peripheral blood mononuclear cells were isolated from healthy donors.

Results—
Patients with preoperative events of neurological ischemia had lower levels of native p45 IgG. Low levels of MDA-p45 IgG were associated with increased risk of postoperative cardiovascular death during a mean follow-up of 54 months. High plasma levels of native p45 IgG were associated with increased plaque content of collagen and smooth muscle cell growth factors, as well as with lower levels of proinflammatory cytokines. Exposure of peripheral blood mononuclear cells from healthy donors to recombinant MDA-p45 IgG in presence of oxidized low-density lipoprotein reduced the expression of tumor necrosis factor-α and stimulated release of smooth muscle cell growth factors.

Conclusions—
This study confirms previous experimental findings of anti-inflammatory properties of apolipoprotein B-100 p45 antibodies and provides the first clinical evidence of associations between p45 IgG autoantibody levels and atherosclerotic plaque inflammation, plaque repair as well as prevalent and incident cardiovascular events in carotid endarterectomy patients. These findings suggest the possibility that treatment with anti-p45 antibodies may have beneficial effects in advanced cardiovascular disease.
Effects of Arterial Stiffness on Brain Integrity in Young Adults From the Framingham Heart Study
Authors: Maillard Pauline , Mitchell Gary F. , Himali Jayandra J. , Beiser Alexa , Tsao Connie W. , Pase Matthew P. , Satizabal Claudia L. , Vasan Ramachandran S. , Seshadri Sudha , DeCarli Charles 
Published: March 2016

Background and Purpose—
Previous work from the Framingham Heart Study suggests that brain changes because of arterial aging may begin in young adulthood and that such changes precede cognitive deficits. The objective of this study was to determine the association of arterial stiffness with measures of white matter and gray matter (GM) integrity in young adults.

Methods—
One thousand nine hundred three participants from the Framingham Heart Study Third Generation (mean age, 46±8.7 years) had complete tonometry measurements and brain magnetic resonance imaging (T1-weighted and diffusion tensor imaging). Tonometry measures included carotid-femoral pulse wave velocity, augmentation index, carotid-brachial pressure amplification, and central pulse pressure. Fractional anisotropy and GM density images were computed from diffusion tensor imaging and T1 images. Registration to a common anatomic template enabled voxel-based linear regressions relating measures of fractional anisotropy and GM to tonometry measures, adjusting for relevant covariables.

Results—

Higher carotid-femoral pulse wave velocity was associated with lower regional fractional anisotropy, including the corpus callosum and the corona radiata (8.7 and 8.6 cc, respectively,
P
<0.001), as well as lower GM density in the thalamus region (0.9 cc,
P
<0.001). Analyses did not reveal significant associations between other tonometry measures and fractional anisotropy or GM.

Conclusions—
Among young healthy adults, higher aortic stiffness was associated with measures of reduced white matter and GM integrity in areas implicated in cognitive decline and Alzheimer’s disease. Greater aortic stiffness may result in subclinical vascular brain injury at ages much younger than previously described.
Cue-related Temporal Factors Modulate Movement-related Beta Oscillatory Activity in the Human Motor Circuit
Authors: Heinrichs-Graham Elizabeth , Arpin David J. , Wilson Tony W. 
Published: March 2016

Abstract
In humans, there is a strong beta (15–30 Hz) event-related desynchronization (ERD) that begins before movement, which has been tentatively linked to motor planning operations. The dynamics of this response are strongly modulated by whether a pending movement is cued and the inherent parameters of the cue. However, previous studies have focused on the information content of cues and not on parameters such as the timing of the cue relative to other events. Variations in such timing are critical, as they directly impact the amount of time that participants have to plan pending movements. In this study, participants performed finger-tapping sequences during magnetoencephalography, and we manipulated the amount of time (i.e., “long” vs. “short”) between the presentation of the to-be-executed sequence and the cue to initiate the sequence. We found that the beta ERD was stronger immediately after the cue to move in the contralateral postcentral gyrus and bilateral parietal cortices during the short compared with long planning time condition. During movement execution, the beta ERD was stronger in the premotor cortex and the SMA in the short relative to long condition. Finally, peak latency in the SMA significantly correlated with RT, such that the closer the peak beta ERD was to the cue to move, the quicker the participant responded. The results of this study establish that peri-movement beta ERD activity across the cortical motor circuit is highly sensitive to cue-related temporal factors, with a direct link to motor performance.
“How Did I Make It?”: Uncertainty about Own Motor Performance after Inhibition of the Premotor Cortex
Authors: Bolognini Nadia , Zigiotto Luca , Carneiro Maíra Izzadora Souza , Vallar Giuseppe 
Published: March 2016

Abstract
Optimal motor performance requires the monitoring of sensorimotor input to ensure that the motor output matches current intentions. The brain is thought to be equipped with a “comparator” system, which monitors and detects the congruence between intended and actual movement; results of such a comparison can reach awareness. This study explored in healthy participants whether the cathodal transcranial direct current stimulation (tDCS) of the right premotor cortex (PM) and right posterior parietal cortex (PPC) can disrupt performance monitoring in a skilled motor task. Before and after tDCS, participants underwent a two-digit sequence motor task; in post-tDCS session, single-pulse TMS (sTMS) was applied to the right motor cortex, contralateral to the performing hand, with the aim of interfering with motor execution. Then, participants rated on a five-item questionnaire their performance at the motor task. Cathodal tDCS of PM (but not sham or PPC tDCS) impaired the participants' ability to evaluate their motor performance reliably, making them unconfident about their judgments. Congruently with the worsened motor performance induced by sTMS, participants reported to have committed more errors after sham and PPC tDCS; such a correlation was not significant after PM tDCS. In line with current computational and neuropsychological models of motor control and awareness, the present results show that a mechanism in the PM monitors and compares intended versus actual movements, evaluating their congruence. Cathodal tDCS of the PM impairs the activity of such a “comparator,” disrupting self-confidence about own motor performance.