bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival
Authors: Santegoets Saskia J. , van Ham Vanessa J. , Ehsan Ilina , Charoentong Pornpimol , Duurland Chantal L. , van Unen Vincent , Höllt Thomas , van der Velden Lilly-Ann , van Egmond Sylvia L. , Kortekaas Kim E. , de Vos van Steenwijk Peggy J. , van Poelgeest Mariëtte I.E. , Welters Marij J.P. , van der Burg Sjoerd H. 
Published: September 2018

Abstract

Purpose:
The tumor immune microenvironment determines clinical outcome. Whether the original tissue in which a primary tumor develops influences this microenvironment is not well understood.

Experimental Design:
We applied high-dimensional single-cell mass cytometry [Cytometry by Time-Of-Flight (CyTOF)] analysis and functional studies to analyze immune cell populations in human papillomavirus (HPV)–induced primary tumors of the cervix (cervical carcinoma) and oropharynx (oropharyngeal squamous cell carcinoma, OPSCC).

Results:
Despite the same etiology of these tumors, the composition and functionality of their lymphocytic infiltrate substantially differed. Cervical carcinoma displayed a 3-fold lower CD4:CD8 ratio and contained more activated CD8+CD103+CD161+ effector T cells and less CD4+CD161+ effector memory T cells than OPSCC. CD161+ effector cells produced the highest cytokine levels among tumor-specific T cells. Differences in CD4+ T-cell infiltration between cervical carcinoma and OPSCC were reflected in the detection rate of intratumoral HPV-specific CD4+ T cells and in their impact on OPSCC and cervical carcinoma survival. The peripheral blood mononuclear cell composition of these patients, however, was similar.

Conclusions:
The tissue of origin significantly affects the overall shape of the immune infiltrate in primary tumors.
Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Fan Ping , Abderrahman Balkees , Chai Tina S. , Yerrum Smitha , Jordan V. Craig 
Published: September 2018

Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression. Activation of PPARγ by a specific agonist, pioglitazone, selectively blocked the induction of TNFα expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFα expression by pioglitazone was mainly mediated by transrepression of nuclear factor-κB (NF-κB) DNA-binding activity. A novel finding was that NF-κB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-κB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPARγ by siRNA or the PPARγ antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-κB–dependent TNFα and oxidative stress. For the first time, we demonstrated that PPARγ is a growth signal and has potential to modulate NF-κB activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPARγ therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.
Outcomes After Implantable Cardioverter-Defibrillator Generator Replacement for Primary Prevention of Sudden Cardiac Death
Authors: Madhavan Malini , Waks Jonathan W. , Friedman Paul A. , Kramer Daniel B. , Buxton Alfred E. , Noseworthy Peter A. , Mehta Ramila A. , Hodge David O. , Higgins Angela Y. , Webster Tracy L. , Witt Chance M. , Cha Yong-Mei , Gersh Bernard J. 
Published: September 2018

Background—
The effectiveness of implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death in patients with an ejection fraction (EF) ≤35% and clinical heart failure is well established. However, outcomes after replacement of the ICD generator in patients with recovery of EF to >35% and no previous therapies are not well characterized.

Methods and Results—

Between 2001 and 2011, generator replacement was performed at 2 tertiary medical centers in 253 patients (mean age, 68.3±12.7 years; 82% men) who had previously undergone ICD placement for primary prevention but subsequently never received appropriate ICD therapy. EF had recovered to >35% in 72 of 253 (28%) patients at generator replacement. During median (quartiles) follow-up of 3.3 (1.8–5.3) years after generator replacement, 68 of 253 (27%) experienced appropriate ICD therapy. Patients with EF ≤35% were more likely to experience ICD therapy compared with those with EF >35% (12% versus 5% per year; hazard ratio, 3.57;
P
=0.001). On multivariable analysis, low EF predicted appropriate ICD therapy after generator replacement (hazard ratio, 1.96 [1.35–2.87] per 10% decrement;
P
=0.001). Death occurred in 25% of patients 5 years after generator replacement. Mortality was similar in patients with EF ≤35% and >35% (7% versus 5% per year; hazard ratio, 1.10;
P
=0.68). Atrial fibrillation (3.24 [1.63–6.43];
P
<0.001) and higher blood urea nitrogen (1.28 [1.14–1.45] per increase of 10 mg/dL;
P
<0.001) were associated with mortality.

Conclusions—
Although approximately one fourth of patients with a primary prevention ICD and no previous therapy have EF >35% at the time of generator replacement, these patients continue to be at significant risk for appropriate ICD therapy (5% per year). These data may inform decisions on ICD replacement.
Patient, Provider, and Practice Characteristics Associated With Sacubitril/Valsartan Use in the United States
Authors: DeVore Adam D. , Hill C. Larry , Thomas Laine , Sharma Puza P. , Albert Nancy M. , Butler Javed , Patterson J. Herbert , Spertus John A. , Williams Fredonia B. , Duffy Carol I. , McCague Kevin , Hernandez Adrian F. , Fonarow Gregg C. 
Published: September 2018

Background
Current guidelines recommend sacubitril/valsartan for patients with heart failure with reduced ejection fraction, but the rate of adoption in the United States has been slow.

Methods and Results

Using data from CHAMP-HF (Change the Management of Patients With Heart Failure), we described current sacubitril/valsartan use and identified patient, provider, and practice characteristics associated with its use. We considered patients to be on sacubitril/valsartan if they were prescribed it before enrollment or initiated on it at the baseline visit. We excluded patients with a contraindication to sacubitril/valsartan and practices with <10 patients enrolled. Of 4216 patients from 121 sites, 616 (15%) were prescribed sacubitril/valsartan, 2506 (59%) an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), and 1094 (26%) neither. Patients prescribed sacubitril/valsartan were younger (63 years versus 66 years ACE inhibitor/ARB versus 69 years neither,
P
<0.001), less likely to have chronic kidney disease (15% versus 17% ACE inhibitor/ARB versus 30% neither,
P
<0.001), more likely to have cardiac resynchronization therapy (12% versus 7% ACE inhibitor/ARB versus 7% neither,
P
<0.001), and had lower ejection fraction (27% versus 30% ACE inhibitor/ARB versus 30% neither,
P
<0.001). Larger practices, based on number of cardiologists and advanced practice providers, were associated with the highest sacubitril/valsartan use. After multivariable adjustment, the number of advanced practice providers was associated with sacubitril/valsartan use (adjusted odds ratio,1.08; 95% CI, 1.03–1.14).

Conclusions
Despite current guideline recommendations, adoption of sacubitril/valsartan remains low. Provider and practice characteristics associated with sacubitril/valsartan use were related to general practice size and were not associated with practice characteristics specific for heart failure. Further research is needed to identify strategies for effective quality improvement interventions in chronic heart failure with reduced ejection fraction.
Regional Strain by Cardiac Magnetic Resonance Imaging Improves Detection of Right Ventricular Scar Compared With Late Gadolinium Enhancement on a Multimodality Scar Evaluation in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Zghaib Tarek , Ghasabeh Mounes Aliyari , Assis Fabrizio R. , Chrispin Jonathan , Keramati Ali , Misra Satish , Berger Ronald , Calkins Hugh , Kamel Ihab , Nazarian Saman , Zimmerman Stefan , Tandri Harikrishna 
Published: September 2018

Background:
Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy characterized by fibrofatty replacement of right ventricular myocardium resulting in reentrant ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) can noninvasively measure regional abnormalities using tissue-tracking strain as well as late gadolinium enhancement (LGE). In this study, we examine arrhythmogenic substrate using regional CMR strain, LGE, and electroanatomic mapping (EAM) in arrhythmogenic right ventricular cardiomyopathy patients presenting for VT ablation.

Methods and Results:

Twenty-one patients underwent right ventricular endocardial EAM, whereas 17 underwent epicardial EAM, to detect dense scar (<0.5 mV) as well as CMR study within 12 months. Quantitative regional strain analysis was performed in all 21 patients, although the presence of LGE was visually examined in 17 patients. Strain was lower in segments with dense scar on endocardial and epicardial EAM (−9.7±4.1 versus −7.3±4.0, and −9.8±2.8 versus −7.6±3.8;
P
<0.05), in segments with LGE scar (−9.9±4.4 versus −6.0±3.6;
P
=0.001), and at VT culprit sites (−7.4±3.7 versus −10.1±4.1;
P
<0.001), compared with the rest of right ventricular. On patient-clustered analysis, a unit increase in strain was associated with 21% and 18% decreased odds of scar on endocardial and epicardial EAM, respectively, 17% decreased odds of colocalizing VT culprit site, and 43% decreased odds of scar on LGE-CMR (
P
<0.05 for all). LGE and EAM demonstrated poor agreement with κ=0.18 (endocardial, n=17) and κ=0.06 (epicardial, n=13). Only 8 (15%) VT termination sites exhibited LGE.

Conclusions:
Regional myocardial strain on cine CMR improves detection of arrhythmogenic VT substrate compared with LGE. This may enhance diagnostic accuracy of CMR in arrhythmogenic right ventricular cardiomyopathy without the need for invasive procedures and facilitate the planning of VT ablation procedures.
Current Society of Thoracic Surgeons Model Reclassifies Mortality Risk in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Kumar Arnav , Sato Kimi , Narayanswami Jyoti , Banerjee Kinjal , Andress Krystof , Lokhande Chetan , Mohananey Divyanshu , Anumandla Anil Kumar , Khan Abdur Rahman , Sawant Abhishek C. , Menon Vivek , Krishnaswamy Amar , Tuzcu E. Murat , Jaber Wael A. , Mick Stephanie , Svensson Lars G. , Kapadia Samir R. 
Published: September 2018

Background:
The Society of Thoracic Surgeons (STS) scores are used to screen patients for transcatheter aortic valve replacement (TAVR). The STS scores were also used to risk stratify patients in major TAVR trials. This study evaluates the reclassification of predicted risk of mortality by the currently available online STS score calculator compared with the 2008 STS risk model in patients undergoing TAVR.

Methods and Results:

All patients who underwent TAVR from 2006 to 2016 were included in the study. The STS scores for all included patients were calculated by applying the 2008 STS risk model and again using the current STS online calculator. Among 1209 patients who underwent TAVR, 30-day mortality was 27 (2.2%). The overall predicted risk of mortality estimated by using the current online STS risk calculator was significantly lower than the 2008 STS risk model (6.3±4.4 vs 7.3±4.9;
P
<0.001). A total of 235 (19%) patients were reclassified into a lower risk category per the current STS risk model. In a multivariable logistic regression analysis, patients with persistent atrial fibrillation (odds ratio, 1.4; 95% CI, 1.0–1.9;
P
=0.03), chronic heart failure (odds ratio, 6.0; 95% CI, 3.8–10.1;
P
<0.001), and New York Heart Association class IV heart failure (odds ratio, 2.4; 95% CI, 1.3–4.4;
P
=0.007) were more likely to be reclassified into a lower risk category per the current STS risk model.

Conclusions:
The current STS calculation method produces significantly lower predicted risk of mortality than the 2008 calculator, more pronounced in patients with certain comorbid conditions. These results should be considered while evaluating data from prior studies of TAVR.
Micronutrient Deficiency Independently Predicts Time to Event in Patients With Heart Failure
Authors: Lennie Terry A. , Andreae Christina , Rayens Mary Kay , Song Eun Kyeung , Dunbar Sandra B. , Pressler Susan J. , Heo Seongkum , Kim JinShil , Moser Debra K. 
Published: September 2018

Background
Dietary micronutrient deficiencies have been shown to predict event‐free survival in other countries but have not been examined in patients with heart failure living in the United States. The purpose of this study was to determine whether number of dietary micronutrient deficiencies in patients with heart failure was associated with shorter event‐free survival, defined as a combined end point of all‐cause hospitalization and death.

Methods and Results

Four‐day food diaries were collected from 246 patients with heart failure (age: 61.5±12 years; 67% male; 73% white; 45% New York Heart Association [NYHA] class
III
/
IV
) and analyzed using Nutrition Data Systems for Research. Micronutrient deficiencies were determined according to methods recommended by the Institute of Medicine. Patients were followed for 1 year to collect data on all‐cause hospitalization or death. Patients were divided according to number of dietary micronutrient deficiencies at a cut point of ≥7 for the
high deficiency
category versus <7 for the
no to moderate deficiency
category. In the full sample, 29.8% of patients experienced hospitalization or death during the year, including 44.3% in the high‐deficiency group and 25.1% in the no/moderate group. The difference in survival distribution was significant (log rank,
P
=0.0065). In a Cox regression, micronutrient deficiency category predicted time to event with depression,
NYHA
classification, comorbidity burden, body mass index, calorie and sodium intake, and prescribed angiotensin‐converting enzyme inhibitors, diuretics, or β‐blockers included as covariates.

Conclusions
This study provides additional convincing evidence that diet quality of patients with heart failure plays an important role in heart failure outcomes.
Clinical Significance of Get With the Guidelines–Heart Failure Risk Score in Patients With Chronic Heart Failure After Hospitalization
Authors: Suzuki Satoshi , Yoshihisa Akiomi , Sato Yu , Kanno Yuki , Watanabe Shunsuke , Abe Satoshi , Sato Takamasa , Oikawa Masayoshi , Kobayashi Atsushi , Yamaki Takayoshi , Kunii Hiroyuki , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika 
Published: September 2018

Background

The Get With the Guidelines–Heart Failure (
GWTG
‐
HF
) risk score was developed using American Heart Association
GWTG
‐
HF
program data and predicts in‐hospital mortality in patients with acute heart failure (HF). We aimed to clarify the prognostic impacts of the
GWTG
‐
HF
risk score in patients with HF after discharge.

Methods and Results

We examined the
GWTG
‐
HF
score in 1452 patients with HF, who were admitted to our hospital and discharged after treatment, by calculating 7 predetermined variables. We divided all subjects into 3 groups according to the
GWTG
‐
HF
risk score (low, moderate, and high score groups). The plasma B‐type natriuretic peptide level significantly increased with increasing
GWTG
‐
HF
risk score severity (median values of B‐type natriuretic peptide: 167.0 in low, 260.7 in moderate, and 418.2 pg/mL in high score groups). We followed up all subjects after discharge, and there were 347 (23.9%) all‐cause deaths and 407 (28.0%) cardiac events in follow‐up periods. A Kaplan‐Meier survival curve demonstrated that event rates of all‐cause death and cardiovascular events, including worsening
HF
and cardiac death, significantly increased with increasing
GWTG
‐
HF
risk score severity in all subjects, and also in 749 patients with HF with preserved ejection fraction (ejection fraction ≥50%) and 703 patients with HF with reduced ejection fraction (ejection fraction <50%) patients. The multivariable Cox proportional hazard regression analysis demonstrated that the
GWTG
‐
HF
risk score was one of the significant predictors of all‐cause mortality and cardiac events (all‐cause mortality: hazard ratio, 1.537, 95% confidence interval, 1.172–2.023; cardiac events: hazard ratio, 1.584, 95% confidence interval, 1.344–1.860, per 10‐point increase of
GWTG
‐
HF
score).

Conclusions

The
GWTG
‐
HF
risk score is a useful multivariable score model for several years after hospitalization in patients with HF in a Japanese population.
Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability
Authors: Vila Cuenca Marc , Ferrantelli Evelina , Meinster Elisa , Pouw Stephan M. , Kovačević Igor , de Menezes Renee X. , Niessen Hans W. , Beelen Robert H.J. , Hordijk Peter L. , Vervloet Marc G. 
Published: September 2018

Background

Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (
CKD
). Supplementation with active vitamin D has been proposed to have vasoprotective potential in
CKD
, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.

Methods and Results

In a combined rat model of
CKD
with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the
CKD
model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.

Conclusions

Our results demonstrate that paricalcitol attenuates the
CKD
‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.
Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy
Authors: Frustaci Andrea , Verardo Romina , Grande Claudia , Galea Nicola , Piselli Pierluca , Carbone Iacopo , Alfarano Maria , Russo Matteo Antonio , Chimenti Cristina 
Published: September 2018

Background

Glycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy (
FDCM
).

Methods and Results

Myocarditis, defined as
CD
3
+
T lymphocytes >7/mm
2
associated with necrosis of glycolipid‐laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with
FDCM
: 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with
FDCM
(38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes.
CD
3
+
cells/mm
2
correlated with myocyte necrosis, antimyosin autoantibody titer, and
MWT
(
P
<0.001,
r
=0.79;
P
<0.001,
r
=0.84;
P
<0.001,
r
=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4.

Conclusions

Myocarditis is detectable at histology in up to 56% of patients with
FDCM
. It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of
FDCM
and resistance to enzyme replacement therapy.
Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice
Authors: Shen Yuntian , Yan Baihui , Zhao Qiang , Wang Zhuoran , Wu Jiangbo , Ren Jiafa , Wang Wei , Yu Shu , Sheng Huaxin , Crowley Steven D. , Ding Fei , Paschen Wulf , Yang Wei 
Published: September 2018

Background

The mechanisms underlying worse outcome at advanced age after cardiac arrest (
CA
) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after
CA
, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after
CA
.

Methods and Results

Young (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to
CA
and cardiopulmonary resuscitation (
CPR
). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level.
CA
/
CPR
‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring
mRNA
and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After
CA
/
CPR
, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after
CA
/
CPR
in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after
CA
improved outcome.

Conclusions

Results suggest that impaired activation of prosurvival pathways contributes to worse outcome after
CA
/
CPR
in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after
CA
/
CPR
may represent a promising therapeutic strategy.