bluuebunny/crossref_metadata_2025_split huggingface dataset:
Important roles of endothelial caveolin-1 in endothelium-dependent hyperpolarization and ischemic angiogenesis in mice
Authors: Ito Akiyo , Shiroto Takashi , Godo Shigeo , Saito Hiroki , Tanaka Shuhei , Ikumi Yosuke , Kajitani Shoko , Satoh Kimio , Shimokawa Hiroaki 
Published: February 2019

Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. We have previously demonstrated that endothelium-derived H2O2 is an endothelium-dependent hyperpolarization (EDH) factor and that loss of endothelial caveolin-1 reduces EDH/H2O2 in the microcirculation. Caveolin-1 (Cav-1) is a scaffolding/regulatory protein that interacts with diverse signaling pathways, including angiogenesis. However, it remains unclear whether endothelial Cav-1 plays a role in ischemic angiogenesis by modulating EDH/H2O2. In the present study, we thus addressed this issue in a mouse model of hindlimb ischemia using male endothelium-specific Cav-1 (eCav-1) knockout (KO) mice. In isometric tension experiments with femoral arteries from eCav-1-KO mice, reduced EDH-mediated relaxations to acetylcholine and desensitization of sodium nitroprusside-mediated endothelium-independent relaxations were noted ( n = 4~6). An ex vivo aortic ring assay also showed that the extent of microvessel sprouting was significantly reduced in eCav-1-KO mice compared with wild-type (WT) littermates ( n = 12 each). Blood flow recovery at 4 wk assessed with a laser speckle flowmeter after femoral artery ligation was significantly impaired in eCav-1-KO mice compared with WT littermates ( n = 10 each) and was associated with reduced capillary density and muscle fibrosis in the legs ( n = 6 each). Importantly, posttranslational protein modifications by reactive nitrogen species and ROS, as evaluated by thiol glutathione adducts and nitrotyrosine, respectively, were both increased in eCav-1-KO mice ( n = 6~7 each). These results indicate that endothelial Cav-1 plays an important role in EDH-mediated vasodilatation and ischemic angiogenesis through posttranslational protein modifications by nitrooxidative stress in mice in vivo. NEW & NOTEWORTHY Although increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of cardiovascular diseases, the importance of physiological ROS has also been emerging. The present study provides a line of novel evidence that endothelial caveolin-1 plays important roles in endothelium-dependent hyperpolarization and ischemic angiogenesis in hindlimb ischemia in mice through posttranslational protein modifications by reactive nitrogen species and ROS in mice in vivo.
The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
Authors: Liu Tong , Jiang Le , Tavana Omid , Gu Wei 
Published: February 2019

Abstract

Although cell-cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, nonapoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers.

Significance:
This study identifies OTUB1 as a key regulator of ferroptosis and implicates it as a potential target in cancer therapy.
See related commentary by Gan, p. 1749
Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia
Authors: Jia Bei , Zhao Chenchen , Rakszawski Kevin L. , Claxton David F. , Ehmann W. Christopher , Rybka Witold B. , Mineishi Shin , Wang Ming , Shike Hiroko , Bayerl Michael G. , Sivik Jeffrey M. , Schell Todd D. , Drabick Joseph J. , Hohl Raymond J. , Zheng Hong 
Published: February 2019

Abstract

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics.

Significance:
These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.
Epigenetic Drift in Colorectal Cancer—It's Probably Later Than You Think
Authors: Sapienza Carmen 
Published: February 2019

Abstract
The analysis of age-related methylation changes in patients with colorectal cancer indicates that tumors have their origins earlier in life than previously suspected. The implication is that healthy lifestyle modifications designed to prevent colorectal cancer should be adopted early in life.
See related article by Luebeck et al., p. 495
Genetic Variation in Steroid and Xenobiotic Metabolizing Pathways and Enterolactone Excretion Before and After Flaxseed Intervention in African American and European American Women
Authors: Chang Huiru , Yao Song , Tritchler David , Hullar Meredith A. , Lampe Johanna W. , Thompson Lilian U. , McCann Susan E. 
Published: February 2019

Abstract

Background:
Metabolism and excretion of the phytoestrogen enterolactone (ENL), which has been associated with breast cancer risk, may be affected by variation in steroid hormone and xenobiotic-metabolizing genes.

Methods:
We conducted a randomized, crossover flaxseed intervention study in 252 healthy, postmenopausal women [137 European ancestry (EA) and 115 African ancestry (AA)] from western New York. Participants were randomly assigned to maintain usual diet or consume 10 g/day ground flaxseed for 6 weeks. After a 2-month washout period, participants crossed over to the other diet condition for an additional 6 weeks. Urinary ENL excretion was measured by gas chromatography-mass spectrometry and 70 polymorphisms in 29 genes related to steroid hormone and xenobiotic metabolism were genotyped. Mixed additive genetic models were constructed to examine association of genetic variation with urinary ENL excretion at baseline and after the flaxseed intervention.

Results:
SNPs in several genes were nominally (P &lt; 0.05) associated with ENL excretion at baseline and/or after intervention: ESR1, CYP1B1, COMT, CYP3A5, ARPC1A, BCL2L11, SHBG, SLCO1B1, and ZKSCAN5. A greater number of SNPs were associated among AA women than among EA women, and no SNPs were associated in both races. No SNP–ENL associations were statistically significant after correction for multiple comparisons.

Conclusions:
Variation in several genes related to steroid hormone metabolism was associated with lignan excretion at baseline and/or after flaxseed intervention among postmenopausal women.

Impact:
These findings may contribute to our understanding of the differences observed in urinary ENL excretion among AA and EA women and thus hormone-related breast cancer risk.
Simultaneous Measurement of 92 Serum Protein Biomarkers for the Development of a Multiprotein Classifier for Ovarian Cancer Detection
Authors: Skubitz Amy P.N. , Boylan Kristin L.M. , Geschwind Kate , Cao Qing , Starr Timothy K. , Geller Melissa A. , Celestino Joseph , Bast Robert C. , Lu Karen H. , Koopmeiners Joseph S. 
Published: February 2019

Abstract
The best known ovarian cancer biomarker, CA125, is neither adequately sensitive nor specific for screening the general population. By using a combination of proteins for screening, it may be possible to increase the sensitivity and specificity over CA125 alone. In this study, we used Proseek Multiplex Oncology II plates to simultaneously measure the expression of 92 cancer-related proteins in serum using proximity extension assays. This technology combines the sensitivity of the PCR with the specificity of antibody-based detection methods, allowing multiplex biomarker detection and high-throughput quantification. We analyzed 1 μL of sera from each of 61 women with ovarian cancer and compared the values obtained with those from 88 age-matched healthy women. Principle component analysis and unsupervised hierarchical clustering separated the ovarian cancer patients from the healthy, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with clinical values for CA125. We identified 52 proteins that differed significantly (P &lt; 0.006) between ovarian cancer and healthy samples, several of which are novel serum biomarkers for ovarian cancer. In total, 40 proteins had an estimated area under the ROC curve of 0.70 or greater, suggesting their potential to serve as biomarkers for ovarian cancer. CA125 alone achieved a sensitivity of 93.4% at a specificity of 98%. By adding the Oncology II values for five proteins to CA125 in a multiprotein classifier, we increased the assay sensitivity to 98.4% at a specificity of 98%, thereby improving the sensitivity and specificity of CA125 alone.
Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer
Authors: Lo Winifred , Parkhurst Maria , Robbins Paul F. , Tran Eric , Lu Yong-Chen , Jia Li , Gartner Jared J. , Pasetto Anna , Deniger Drew , Malekzadeh Parisa , Shelton Thomas E. , Prickett Todd , Ray Satyajit , Kivitz Scott , Paria Biman C. , Kriley Isaac , Schrump David S. , Rosenberg Steven A. 
Published: February 2019

Abstract
Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here, we report the identification and characterization in one patient of T-cell receptors (TCRs) recognizing mutated p53 p.R175H, which is shared among a subset of patients with cancer. Tumor-infiltrating lymphocytes were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer. HLA-A*0201–restricted recognition of mutated p53 p.R175H was identified, and the minimal peptide epitope was HMTEVVRHC. Reactive T cells were isolated by tetramer sorting, and three TCRs were identified. These TCRs mediated recognition of commercially available ovarian cancer, uterine carcinoma, and myeloma cell lines, as well as an NIH patient–derived esophageal adenocarcinoma line that endogenously expressed p53 p.R175H and HLA-A*0201. They also mediated recognition of p53 p.R175H+ colon, breast, and leukemia cell lines after transduction with a retrovirus encoding HLA-A*0201. This work demonstrates that common shared mutated epitopes such as those found in p53 can elicit immunogenic responses and that the application of ACT may be extended to patients with any cancer histology that expresses both HLA-A*0201 and the p53 p.R175H mutation.
Onde andará a bicha melancólica?
Authors: Duarte Filho Ricardo 
Published: February 2019

O presente artigo pretende discutir como a presença de uma melancolia queer pode gerar novas possibilidades criadoras. Para tal, pretendo discorrer brevemente sobre as ideias de melancolia como falta e fantasmagoria e então as contrapor à ideia da melancolia como produção e estetização, especialmente como suscitadas pelo filme brasileiro Doce Amianto (2013), de Guto Parente e Uirá dos Reis. O artigo argumenta que a bicha melancólica, por recusar o seu presente através de sua estetização melancólica, possibilita a criação de novas formas de vida para o sujeito queer e como essa visão possibilitaria instigantes escolhas estéticas dentro do campo cinematográfico.
Palavras-chaves: artifício; cinema brasileiro contemporâneo; cinema queer; melancolia.
Submillisievert Multiphasic Coronary Computed Tomography Angiography for Pediatric Patients With Congenital Heart Diseases
Authors: Le Roy Julien , Vernhet Kovacsik Hélène , Zarqane Hamid , Vincenti Marie , Abassi Hamouda , Lavastre Kathleen , Mura Thibault , Lacampagne Alain , Amedro Pascal 
Published: February 2019

Background:
The use of coronary computed tomography (CT) angiography in children with coronary artery anomalies is increasing. However, it remains technically demanding and the need to adapt acquisition parameters to a patient’s cardiac characteristics has not yet been addressed. The aim of the study was to prospectively assess the feasibility of personalized multiphasic coronary CT angiography for pediatric patients.

Methods:
Fifty pediatric patients (mean age 6.1±4.9 years) with coronary artery anomalies underwent a coronary CT angiography on a wide detector single-source CT equipment. Fifteen different acquisition patterns were used to trigger the acquisition at the best theoretical moment within the cardiac cycle. The appropriate pattern was automatically selected based on the patient’s heart rate and heart rate variability, derived from the patient’s ECG. Two independent radiologists qualitatively evaluated images.

Results:

All acquisitions fully answered the clinical question for a mean effective dose of 0.97±0.34 mSv. Image quality qualified as good or excellent in 94% of cases (47/50). No examination was considered as not assessable but 6% (3/50) were scored as adequate for diagnosis. For these 3 patients, motion artifacts were the main cause of average image quality. No significant visual differences were reported between the different coronary arteries (mean score of 3.6 on a 4-point scale). No correlation between image quality and cardiac parameters were reported (
r
=−0.19 and
r
=0.00, respectively for heart rate and heart rate variability).

Conclusions:
Personalized multiphasic coronary CT angiography acquisitions could be performed with diagnostic quality for a dose equivalent of <4 months of natural background irradiation.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03194763.
Association of International Normalized Ratio Stability and Bleeding Outcomes Among Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention
Authors: Kerneis Mathieu , Yee Megan K. , Mehran Roxana , Nafee Tarek , Bode Christoph , Halperin Jonathan L. , Peterson Eric D. , Verheugt Freek W.A. , Wildgoose Peter , van Eickels Martin , Lip Gregory Y.H. , Cohen Marc , Fox Keith A.A. , Gibson C. Michael 
Published: February 2019

Background:
Among atrial fibrillation patients undergoing percutaneous coronary intervention enrolled in PIONEER AF-PCI (An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), it is unclear if the observed reduction in bleeding events with rivaroxaban regimens is consistent across a range of the international normalized ratio (INR) among subjects administrated Vitamin K antagonist (VKA)-triple therapy. This analysis compares the occurrence of clinically significant bleeding between rivaroxaban and VKA strategies, according to INR stability of subjects administrated VKA.

Methods and Results:

A total of 2124 atrial fibrillation patients undergoing percutaneous coronary intervention were randomized to 3 groups: rivaroxaban 15 mg od plus a P2Y
12
inhibitor (group 1, n=709); rivaroxaban 2.5 mg bid plus dual antiplatelet therapy (group 2, n=709); and warfarin plus dual antiplatelet therapy (group 3, n=706). Subjects assigned to the VKA group were stratified according to time in therapeutic range and time spent with an INR >3. Kaplan-Meier estimates were calculated for clinically significant bleeding through 1 year and hazard ratios were derived using Cox Proportional Hazards models. Among group 3, 93.4% of the participants had a time in therapeutic range available (mean time in therapeutic range=65.0±24.8%). Both groups 1 and 2 were associated with a reduction in clinically significant bleeding compared with subjects in group 3, regardless of the time in therapeutic range (hazard ratio ranges=0.53–0.71 and 0.57–0.76; respectively,
P
<0.05 for all). Rivaroxaban strategies were associated with a reduction in clinically significant bleeding compared with VKA regardless of the proportion of time spent with an INR >3 (hazard ratio ranges=0.59–0.67 and 0.42–0.69;
P
<0.05 for all).

Conclusions:
Among atrial fibrillation patients undergoing percutaneous coronary intervention, rivaroxaban-based therapy was superior to warfarin plus dual antiplatelet therapy in lowering bleeding outcomes regardless of the INR stability.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01830543.
Intracardiac Delineation of Septal Conduction in Left Bundle-Branch Block Patterns
Authors: Upadhyay Gaurav A. , Cherian Tharian , Shatz Dalise Y. , Beaser Andrew D. , Aziz Zaid , Ozcan Cevher , Broman Michael T. , Nayak Hemal M. , Tung Roderick 
Published: February 2019

Background:
Septal activation in patients with left bundle-branch block (LBBB) patterns has not been described previously. We performed detailed intracardiac mapping of left septal conduction to assess for the presence and level of complete conduction block (CCB) in the His-Purkinje system. Response to His bundle pacing was assessed in patients with and without CCB in the left bundle.

Methods:
Left septal mapping was performed with a linear multielectrode catheter in consecutive patients with LBBB pattern referred for device implantation (n=38) or substrate mapping (n=47). QRS width, His duration, His-ventricular (HV) intervals, and septal conduction patterns were analyzed. The site of CCB was localized to the level of the left-sided His fibers (left intrahisian) or left bundle branch. Patients with ventricular activation preceded by Purkinje potentials were categorized as having intact Purkinje activation.

Results:
A total of 88 left septal conduction recordings were analyzed in 85 patients: 72 LBBB block pattern and 16 controls (narrow QRS, n=11; right bundle-branch block, n=5). Among patients with LBB block pattern, CCB within the proximal left conduction system was observed in 64% (n=46) and intact Purkinje activation in the remaining 36% (n=26). Intact Purkinje activation was observed in all controls. The site of block in patients with CCB was at the level of the left His bundle in 72% and in the proximal left bundle branch in 28%. His bundle pacing corrected wide QRS in 54% of all patients with LBBB pattern and 85% of those with CCB (94% left intrahisian, 62% proximal left bundle-branch). No patients with intact Purkinje activation demonstrated correction of QRS with His bundle pacing. CCB showed better predictive value (positive predictive value 85%, negative predictive value 100%, sensitivity 100%) than surface ECG criteria for correction with His bundle pacing.

Conclusions:
Heterogeneous septal conduction was observed in patients with surface LBBB pattern, ranging from no discrete block to CCB. When block was present, we observed pathology localized within the left-sided His fibers (left intrahisian block), which was most amenable to corrective His bundle pacing by recruitment of latent Purkinje fibers. ECG criteria for LBBB incompletely predicted CCB, and intracardiac data might be useful in refining patient selection for resynchronization therapy.
Subseasonal Weather Prediction in a Global Convection-Permitting Model
Authors: Weber Nicholas J. , Mass Clifford F. 
Published: February 2019

AbstractAlthough accurate weather and climate prediction beyond one to two weeks is of great value to society, the skill of such extended prediction is limited in current operational global numerical models, whose coarse horizontal grid spacing necessitates the parameterization of atmospheric processes. Of particular concern is the parameterization of convection and specifically convection in the tropics, which impacts global weather at all time scales through atmospheric teleconnections. Convection-permitting models, which forego convective parameterization by explicitly resolving cumulus-scale motions using fine (1–4 km) horizontal grid spacing, can improve global prediction at extended time scales by more faithfully simulating tropical convection and associated teleconnections. This study demonstrates that convection-permitting resolution in a global numerical model can improve both the statistical features of tropical precipitation and extended predictive skill in the tropics and midlatitudes. Comparing four monthlong global simulations with 3-km grid spacing to coarser-resolution simulations that parameterize convection reveals that convection-permitting simulations improve tropical precipitation rates and the diurnal cycle of tropical convection. The propagation of the Madden–Julian oscillation was better predicted in three of the four 3-km simulations; these three runs also featured more skillful prediction of weekly extratropical circulation anomalies, particularly during week 3 of each forecast. These results, though based on a small sample of four cases, demonstrate that convection-permitting global modeling can benefit extended atmospheric prediction and offers the potential for improved operational subseasonal forecast skill.