bluuebunny/crossref_metadata_2025_split huggingface dataset:
CBP/p300 Drives the Differentiation of Regulatory T Cells through Transcriptional and Non-Transcriptional Mechanisms
Authors: Castillo Joseph , Wu Esther , Lowe Christopher , Srinivasan Shrividhya , McCord Ron , Wagle Marie-Claire , Jayakar Sangeeta , Edick Melissa Gonzalez , Eastham-Anderson Jeffrey , Liu Bonnie , Hutchinson Katherine E. , Jones Wendell , Stokes Matthew P. , Tarighat Somayeh S. , Holcomb Thomas , Glibicky Andrew , Romero F. Anthony , Magnuson Steven , Huang Shih-Min A. , Plaks Vicki , Giltnane Jennifer M. , Lackner Mark R. , Mounir Zineb 
Published: June 2019

AbstractRegulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of CBP/p300 loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering proinflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring CBP/p300 loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300, with potential clinical implications on alteration of the immune landscape.Significance:This study provides insights into the dynamic role of CBP/p300 in the differentiation of Tregs, with potential clinical implications in the alteration of the immune landscape in follicular lymphoma.
Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia
Authors: Tarlock Katherine , Alonzo Todd A. , Wang Yi-Cheng , Gerbing Robert B. , Ries Rhonda , Loken Michael R. , Pardo Laura , Hylkema Tiffany , Joaquin Jason , Sarukkai Leela , Raimondi Susana C. , Hirsch Betsy , Sung Lillian , Aplenc Richard , Bernstein Irwin , Gamis Alan S. , Meshinchi Soheil , Pollard Jessica A. 
Published: June 2019

Abstract

Purpose:
KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.

Experimental Design:
Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT−)] and mutation location (E8 vs. E17).

Results:
KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT− (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT− patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.

Conclusions:
E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.
Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer
Authors: Brooks Jill M. , Menezes Albert N. , Ibrahim Maha , Archer Lucinda , Lal Neeraj , Bagnall Christopher J. , von Zeidler Sandra V. , Valentine Helen R. , Spruce Rachel J. , Batis Nikolaos , Bryant Jennifer L. , Hartley Margaret , Kaul Baksho , Ryan Gordon B. , Bao Riyue , Khattri Arun , Lee Steven P. , Ogbureke Kalu U.E. , Middleton Gary , Tennant Daniel A. , Beggs Andrew D. , Deeks Jonathan , West Catharine M. L. , Cazier Jean-Baptiste , Willcox Benjamin E. , Seiwert Tanguy Y. , Mehanna Hisham 
Published: June 2019

Abstract

Purpose:
Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxia-immune classifier with potential application in patient prognostication and prediction of response to targeted therapy.

Experimental Design:
A 54-gene hypoxia-immune signature was constructed on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC was used to investigate the utility of a simplified protein signature. The spatial distribution of hypoxia and immune markers was examined using multiplex immunofluorescence staining.

Results:
Unsupervised hierarchical clustering of TCGA dataset (development cohort) identified three patient subgroups with distinct hypoxia-immune phenotypes and survival profiles: hypoxialow/immunehigh, hypoxiahigh/immunelow, and mixed, with 5-year overall survival (OS) rates of 71%, 51%, and 49%, respectively (P = 0.0015). The prognostic relevance of the hypoxia-immune gene signature was replicated in two independent validation cohorts. Only PD-L1 and intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumors were overrepresented in “inflamed” and “immune-desert” microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3+ T cells (r = −0.5464; P = 0.0377), further corroborating the transcription-based classification.

Conclusions:
We developed and validated a hypoxia-immune prognostic transcriptional classifier, which may have clinical application to guide the use of hypoxia modification and targeted immunotherapies for the treatment of HNC.
Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway
Authors: Liu Jie , Zhuang Tao , Pi Jingjiang , Chen Xiaoli , Zhang Qi , Li Ying , Wang Haikun , Shen Yajing , Tomlinson Brian , Chan Paul , Yu Zuoren , Cheng Yu , Zheng Xiangjian , Reilly Muredach , Morrisey Edward , Zhang Lin , Liu Zhongmin , Zhang Yuzhen 
Published: June 2019

Background:
Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms.

Methods:
Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs.

Results:
Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II–induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1–promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs.

Conclusions:
EC-Foxp1 regulates the TGF-β1–endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC–Foxp1–TGF-β1–endothelin-1 pathway might provide a future novel therapy for heart failure.
Time Trends in Race-Ethnic Differences in Do-Not-Resuscitate Orders After Stroke
Authors: Bailoor Kunal , Shafie-Khorassani Fatema , Lank Rebecca J. , Case Erin , Garcia Nelda M. , Lisabeth Lynda D. , Sánchez Brisa N. , Kim Sehee , Morgenstern Lewis B. , Zahuranec Darin B. 
Published: June 2019

Background and Purpose—
Do-not-resuscitate (DNR) orders are common after stroke, though there are limited data on trends over time. We investigated time trends in DNR orders in a community with a large minority population.

Methods—
Cases of ischemic stroke (IS) or intracerebral hemorrhage (ICH) were identified from the BASIC study (Brain Attack Surveillance in Corpus Christi) from June 2007 through October 2016. Cox proportional hazards models were used to assess time to DNR orders, with an interaction term added to allow separate hazard ratios for early (≤24 hours) and late (>24 hours) DNR. Stroke type–specific calendar trends were assessed with an interaction term between calendar year (linear) and stroke type.

Results—

Two thousand six hundred seventy-two cases were included (ICH, 14%). Mean age was 69, 50% were female, and race-ethnicity was Mexican American (58%), non-Hispanic white (37%), and African American (5%). Overall, 16% had a DNR order during the hospitalization. For ICH, DNR orders (early and late) were stable over the study period. However, early DNR orders became more common over time after ischemic stroke (hazard ratio for 2016 versus 2007: 1.89; 95% CI, 1.06–3.39), with no change over time for late DNR orders after ischemic stroke. Mexican Americans (hazard ratio, 0.65; 95% CI, 0.50–0.86) and African Americans (hazard ratio, 0.17; 95% CI, 0.04–0.71) were less likely than non-Hispanic whites to have early DNR orders, though there were no race-ethnic differences in late DNR orders. There was no change in race-ethnic difference in DNR orders over the time of the study (interaction
P
>0.60).

Conclusions—
Despite revised national guidelines cautioning against early DNR orders in ICH, presence of DNR orders after ICH was stable between 2007 and 2016, with only slight increases in early DNR orders after ischemic stroke. Mexican Americans and African Americans remain less likely than non-Hispanic whites to have early DNR orders after stroke.
Short-Term Double Layer Mesh Stent Patency for Emergent or Elective Carotid Artery Stenting
Authors: de Vries Evelien E. , Vonken Evert J. , Kappelle L. Jaap , Toorop Raechel J. , de Borst Gert J. 
Published: June 2019

Background and Purpose—
Novel double layer micromesh stents have recently been introduced for treatment of patients with significant carotid stenosis. Strict evaluation of safety and patency of such novel devices is required both in elective and in emergency interventions. We report a single center experience with double layer mesh stents for carotid artery revascularization.

Methods—
Consecutive patients who underwent carotid artery stenting with a double layer mesh stent between June 2015 and September 2018 in our tertiary vascular referral center were included. Treatment indications were emergent carotid artery stenting for intracranial or extracranial carotid stenosis in patients undergoing intraarterial thrombectomy for acute ischemic stroke in the anterior circulation, or elective carotid artery stenting for significant symptomatic or asymptomatic stenosis. End points were postprocedural thrombotic stent occlusion and procedural stroke or death.

Results—
Fifty-four patients were included; 27 were treated for acute stroke with intracranial and extracranial (tandem) lesions and 27 for elective stenting. Follow-up imaging was available for 9/27 (33%) patients with acute stroke, and 19/27 (70%) electively treated patients. Five stent occlusions occurred, of which 2 were symptomatic with clinical deterioration within one day. Another patient deteriorated on postprocedural day one, but imaging of the carotids was not performed, and the stent turned out occluded on the 30-day duplex. All stent occlusions occurred in patients treated for acute stroke.

Conclusions—
This study suggests that occlusion of novel double layer mesh stents occurs in a considerable proportion of carotid artery stenting procedures performed in the emergency setting for acute stroke, with occlusion-related symptoms in half the cases. Future prospective studies should clarify the role of double layer mesh stents in this high-risk patient population.
When to Stop
Authors: García-Tornel Álvaro , Requena Manuel , Rubiera Marta , Muchada Marian , Pagola Jorge , Rodriguez-Luna David , Deck Matias , Juega Jesus , Rodríguez-Villatoro Noelia , Boned Sandra , Olivé-Gadea Marta , Tomasello Alejandro , Hernández David , Molina Carlos A. , Ribo Marc 
Published: June 2019

Background and Purpose—
Substantial proportion of patients who achieve successful recanalization of acute ischemic stroke due to large vessel occlusion do not achieve good functional outcome. We aim to analyze the effect of number of thrombectomy device passes and degree of the recanalization (by modified Thrombolysis in Cerebral Infarction) on the clinical and functional outcome.

Methods—
Five hundred forty-two consecutive patients underwent mechanical thrombectomy for large vessel occlusion in the anterior circulation at a single tertiary stroke center. Baseline characteristics, number of passes, recanalization degree, clinical outcome at 24 hours (measured by National Institutes of Health Scale score), and functional outcome (measured by modified Rankin Scale at 90 days) were registered. Multivariate analysis was performed to determine the association of number of passes and degree of recanalization with dramatical clinical recovery (final National Institutes of Health Scale score ≤2 or decrease in 8 or more National Institutes of Health Scale score points in 24 hours) and good functional outcome (modified Rankin Scale score ≤2 at 90 days).

Results—

Four hundred fifty-nine patients (84%) achieved successful recanalization (modified Thrombolysis in Cerebral Infarction 2B–3), 213 (39%) of them after first device pass. In the multivariate analysis, first-pass recanalization and modified Thrombolysis in Cerebral Infarction 3 were independent predictors of good functional outcome (odds ratio, 2.5; 95% CI, 1.4–4.5;
P
=0.002 and odds ratio, 2.6 CI; 1.5–4.7;
P
=0.001, respectively) and dramatical clinical recovery (odds ratio, 1.8; 95% CI, 1.1–3;
P
=0.032 and odds ratio, 2.9; 95% CI, 1.7–5.1;
P
<0.001, respectively). Rate of recanalization declined after each pass 39% (213/542), 35% (113/310), 33% (63/190), and 24% (26/154) for passes 1 to 4, respectively and 28% (45/158) for every attempt above 4 passes (
P
<0.001). In patients who achieved recanalization, a linear association between number of passes and good functional outcome was observed: 1 pass (58.6%), 2 passes (50.5%), 3 passes (48.4%), 4 passes (38.5%), or 5 or more passes (25.6%;
P
<0.001) as compared with patients who did not achieve recanalization (16.9%).

Conclusions—
High number of device passes and less degree of recanalization are associated with worse outcome in patients with acute ischemic stroke secondary to large vessel occlusion. Future studies should investigate the optimal number of passes that should be attempted in patients without substantial recanalization.
Complement Inhibition Attenuates Early Erythrolysis in the Hematoma and Brain Injury in Aged Rats
Authors: Wang Ming , Hua Ya , Keep Richard F. , Wan Shu , Novakovic Nemanja , Xi Guohua 
Published: June 2019

Background and Purpose—
Early erythrolysis in the hematoma contributes to brain injury after intracerebral hemorrhage (ICH). This study investigated the effects of N-acetylheparin, a complement inhibitor, and aurin tricarboxylic acid, a membrane attack complex inhibitor, on early erythrolysis, brain iron deposition, and brain injury in aged rats.

Methods—
There were 3 parts in the study. First, aged (18 months old) male Fischer 344 rats had an ICH. The time course of erythrolysis in the hematoma was determined by T2* weighted magnetic resonance imaging, and the expression of CD163 was examined. Second, aged rats had an ICH with N-acetylheparin or vehicle. Rats were euthanized at days 1, 3, and 28 after magnetic resonance imaging (T2-, T2*-weighted, and T2* array) and behavioral tests. Brains were used for immunohistochemistry. Third, aged rats had an ICH with avaurin tricarboxylic acid or vehicle. The rats had magnetic resonance imaging and behavioral tests and were euthanized at day 3. Brains were used for immunohistochemistry.

Results—
Early erythrolysis occurred within the clot in aged F344 rats. There were increased numbers of CD163-positive cells after ICH. Almost all perihematomal CD163-positive cells were microglia/macrophages, while positive neurons were found more distant from the hematoma. Coinjection of N-acetylheparin attenuated erythrolysis, iron accumulation, CD163 expression, microglia activation, brain swelling, and neuronal death in the acute phase, as well as reducing brain atrophy and neurological deficits in the chronic phase. Coinjection of aurin tricarboxylic acid also reduced erythrolysis and ICH-induced brain injury.

Conclusions—
Inhibiting complement activation resulted in less erythrolysis and brain injury after ICH.
Electrocardiomatrix Facilitates Accurate Detection of Atrial Fibrillation in Stroke Patients
Authors: Brown Devin L. , Xu Gang , Belinky Krzyske Alexandra Mary , Buhay Nicholas C. , Blaha Madeline , Wang Michael M. , Farrehi Peter , Borjigin Jimo 
Published: June 2019

Background and Purpose—
Cardiac telemetry is a routine part of inpatient ischemic stroke/transient ischemic attack evaluation to assess for atrial fibrillation (AF). Yet, tools to assist stroke clinicians in the evaluation of the large quantities of telemetry data are limited. The investigators developed a new method to evaluate electrocardiographic signals, electrocardiomatrix, that was applied to stroke unit telemetry data to determine its feasibility, validity, and usefulness. Electrocardiomatrix displays telemetry data in a 3-dimensional matrix that allows for more accurate and less time consuming P-wave analysis.

Methods—
In this single-center, prospective, observational study conducted in a stroke unit, all telemetry data from ischemic stroke and transient ischemic attack patients were collected (April 2017–January 2018) for examination facilitated by electrocardiomatrix. AF>30 seconds was identified through review of electrocardiomatrix-generated matrices by a nonphysician researcher. Electrocardiomatrix results were compared with the clinical team’s medical record documentation of AF identified through telemetry. A study cardiologist reviewed the standard telemetry associated with all AF episodes identified by electrocardiomatrix and each case of disagreement.

Results—
Telemetry data (median 46 hours [interquartile range: 22–90]) were analyzed among 265 unique subjects (88% ischemic stroke). Electrocardiomatrix was successfully applied in 260 (98%) of cases. The positive predictive value of electrocardiomatrix compared with the clinical documentation was 86% overall and 100% among the subset with no prior history of AF. For the 5 false-positive and 5 false-negative cases, expert overview disagreed with the clinical documentation and confirmed the electrocardiomatrix-based diagnosis.

Conclusions—
The application of electrocardiomatrix to stroke unit-acquired telemetry data is feasible and appears to have superior accuracy compared with traditional monitor analysis by noncardiologists.
Eulobomyia, a new replacement name for Lobomyia Woodley &amp; Arnaud (Diptera: Tachinidae)
Authors: WOODLEY NORMAN E. , ARNAUD, JR. PAUL H. 
Published: June 2019

A new genus, Lobomyia Woodley & Arnaud (Diptera: Tachinidae), from the Neotropical Region was recently described by us (Woodley & Arnaud, 2008: 32; type species, Lobomyia neotropica Woodley & Arnaud; published 6 June 2008). At the time the manuscript was being prepared, one of us (NEW) checked available nomenclatural resources to ensure the generic name had not been previously used. However, in the interim, the name Lobomyia was published as a new genus of Diptera, Chironomidae from Japan (Niitsuma, 2007: 105; type species, Lobomyia immaculata Niitsuma; published 15 June 2007). We therefore propose a new replacement name here, Eulobomyia, nom. nov. for Lobomyia Woodley & Arnaud. The gender of the name is feminine.
The Unexpected Rapid Intensification of Tropical Cyclones in Moderate Vertical Wind Shear. Part III: Outflow–Environment Interaction
Authors: Ryglicki David R. , Doyle James D. , Hodyss Daniel , Cossuth Joshua H. , Jin Yi , Viner Kevin C. , Schmidt Jerome M. 
Published: June 2019

Abstract
Interactions between the upper-level outflow of a sheared, rapidly intensifying tropical cyclone (TC) and the background environmental flow in an idealized model are presented. The most important finding is that the divergent outflow from convection localized by the tilt of the vortex serves to divert the background environmental flow around the TC, thus reducing the local vertical wind shear. We show that this effect can be understood from basic theoretical arguments related to Bernoulli flow around an obstacle. In the simulation discussed, the environmental flow diversion by the outflow is limited to 2 km below the tropopause in the 12–14-km (250–150 hPa) layer. Synthetic water vapor satellite imagery confirms the presence of upshear arcs in the cloud field, matching satellite observations. These arcs, which exist in the same layer as the outflow, are caused by slow-moving wave features and serve as visual markers of the outflow–environment interface. The blocking effect where the outflow and the environmental winds meet creates a dynamic high pressure whose pressure gradient extends nearly 1000 km upwind, thus causing the environmental winds to slow down, to converge, and to sink. We discuss these results with respect to the first part of this three-part study, and apply them to another atypical rapid intensification hurricane: Matthew (2016).