bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Nonpump Function of Sodium Iodide Symporter in Thyroid Cancer via Cross-talk with PTEN Signaling
Authors: Feng Fang , Yehia Lamis , Ni Ying , Chang Yi Seok , Jhiang Sissy Meihua , Eng Charis 
Published: September 2018

AbstractThe sodium iodide symporter (NIS) is a classical iodide pump typically localized within the cell plasma membrane in thyroid cells, where NIS expression is believed to ensure success of mainstay radioiodide therapy in thyroid cancers. Although radioiodide uptake is generally reduced in thyroid cancer tissue, intracellular nonmembranous NIS has been reported to increase, suggesting that NIS serves a pump-independent function. Thyroid cancer is one of the major component cancers of Cowden syndrome, a subset of which is caused by germline mutations in PTEN. In this study, we explored the noncanonical tumorigenic role of NIS in thyroid cancer cells in relation to PTEN signaling. PTEN knockdown in thyroid cancer cell lines stabilized intracellular NIS protein by promoting an interaction with NIS-LARG (leukemia-associated RhoA guanine exchange factor). Increased protein levels of cytoplasmic NIS enhanced RhoA activation and resulted in a promigration tumorigenic phenotype. Inhibition of NIS glycosylation through activation of the PI3K/AKT/mTOR signaling pathway contributed to mislocalization of NIS in the cytoplasm, facilitating its nonpump tumorigenic function through an interaction with LARG, which predominantly localized in the cytoplasm. Moreover, PTEN or PI3K/AKT/mTOR signaling could affect DPAGT1, a glycosylating enzyme involved in the initial step of N-linked glycosylation, to inhibit glycosylation of NIS. In summary, our results elucidate a pump-independent, protumorigenic role for NIS in thyroid cancer via its cross-talk with PTEN signaling.Significance: A novel pump-independent protumorigenic role of nonmembranous NIS challenges the presumption that radioiodine treatment of thyroid cancer is ineffective when transmembrane NIS is not expressed. Cancer Res; 78(21); 6121–33. ©2018 AACR.
Compartmentalized Structure of the Moderator Band Provides a Unique Substrate for Macroreentrant Ventricular Tachycardia
Authors: Walton Richard D. , Pashaei Ali , Martinez Marine E. , Constantin Marion , Duchateau Josselin , Bear Laura , Cros Caroline , Pascarel-Auclerc Caroline , Guo Yunbo , Benoist David , Dubes Virginie , Faye Ndeye Rokhaya , Chaigne Sebastien , Dupuis Sebastien , Détaille Dominique , Pourtau Line , Pasdois Philippe , Brette Fabien , Rogier Julien , Labrousse Louis , Hocini Mélèze , Vigmond Edward J. , Haïssaguerre Michel , Bernus Olivier 
Published: September 2018

Background
Papillary muscles are an important source of ventricular tachycardia (VT). Yet little is known about the role of the right ventricular (RV) endocavity structure, the moderator band (MB). The aim of this study was to determine the characteristics of the MB that may predispose to arrhythmia substrates.

Methods
Ventricular wedge preparations with intact MBs were studied from humans (n=2) and sheep (n=15; 40–50 kg). RV endocardium was optically mapped, and electrical recordings were measured along the MB and septum. S1S2 pacing of the RV free wall, MB, or combined S1-RV S2-MB sites were assessed. Human (n=2) and sheep (n=4) MB tissue constituents were assessed histologically.

Results

The MB structure was remarkably organized as 2 excitable, yet uncoupled compartments of myocardium and Purkinje. In humans, action potential duration heterogeneity between MB and RV myocardium was found (324.6±12.0 versus 364.0±8.4 ms;
P
<0.0001). S1S2-MB pacing induced unidirectional propagation via MB myocardium, permitting sustained macroreentrant VT. In sheep, the incidence of VT for RV, MB, and S1-RV S2-MB pacing was 1.3%, 5.1%, and 10.3%. Severing the MB led to VT termination, confirming a primary arrhythmic role. Inducible preparations had shorter action potential duration in the MB than RV (259.3±45.2 versus 300.7±38.5 ms;
P
<0.05), whereas noninducible preparations showed no difference (312.0±30.3 versus 310.0±24.6 ms, respectively).

Conclusions
The MB presents anatomic and electrical compartmentalization between myocardium and Purkinje fibers, providing a substrate for macroreentry. The vulnerability to sustain VT via this mechanism is dependent on MB structure and action potential duration gradients between the RV free wall and MB.
Activation Mapping With Integration of Vector and Velocity Information Improves the Ability to Identify the Mechanism and Location of Complex Scar-Related Atrial Tachycardias
Authors: Anter Elad , Duytschaever Mattias , Shen Changyu , Strisciuglio Teresa , Leshem Eran , Contreras-Valdes Fernando M. , Waks Jonathan W. , Zimetbaum Peter J. , Kumar Kapil , Spector Peter S. , Lee Adam , Gerstenfeld Edward P. , Nakar Elad , Bar-Tal Meir , Buxton Alfred E. 
Published: September 2018

Background:
Activation mapping of scar-related atrial tachycardias (ATs) can be difficult to interpret because of inaccurate time annotation of complex electrograms and passive diastolic activity. We examined whether integration of a vector map can help to describe patterns of propagation to better explain the mechanism and location of ATs.

Methods:
The investigational mapping algorithm calculates vectors and applies physiological constraints of electrical excitation in human atrial tissue to determine the arrhythmia source and circuit. Phase I consisted of retrospective evaluation in 35 patients with ATs. Phase II consisted of prospective validation in 20 patients with ATs. Macroreentry was defined as a continuous propagation in a circular path >30 mm; localized reentry was defined as a circular path ≤30 mm; a focal source had a centrifugal spread from a point source.

Results:
In phase I, standard activation mapping identified 28 of 40 ATs (70%): 25 macroreentry and 3 focal tachycardias. In the remaining 12 ATs, the mechanism and location could not be identified by activation and required entrainment or empirical ablation for termination (radiofrequency time, 17.3±6.6 minutes). In comparison, the investigational algorithm identified 37 of 40 (92.5%) ATs, including 5 macroreentry, 3 localized reentry, and 1 focal AT not identified by standard mapping. It also predicted the successful termination site of all 37 of 40 ATs. In phase II, the investigational algorithm identified 12 macroreentry, 6 localized reentry, and 2 focal tachycardias that all terminated with limited ablation (3.2±1.7 minutes). It identified 3 macroreentry, 3 localized reentry, and 1 focal AT not well characterized by standard mapping. The diagnosis of localized reentry was supported by highly curved vectors, resetting with increasing curve and termination with limited ablation (22±6 s).

Conclusions:
Activation mapping integrating vectors can help determine the arrhythmia mechanism and identify its critical components. It has particular value for identifying complex macroreentrant circuits and for differentiating a focal source from a localized reentry.
Impact of Baseline Hemodynamics on the Effects of a Transcatheter Interatrial Shunt Device in Heart Failure With Preserved Ejection Fraction
Authors: Wessler Jeffrey , Kaye David , Gustafsson Finn , Petrie Mark C. , Hasenfuβ Gerd , Lam Carolyn S.P. , Borlaug Barry A. , Komtebedde Jan , Feldman Ted , Shah Sanjiv J. , Burkhoff Daniel ,   on behalf of the REDUCE-LAP-HF Trial Investigators and Advisors
Published: September 2018

Background
Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects.

Methods and Results

REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg;
P
=0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg;
P
=0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP)
baseline
(
r
2
=0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP)
baseline
(
P
=0.001). Hemodynamics of patients with EF ≥50% and those with EF <50% responded similarly to IASD.

Conclusions
In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01913613.
A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy
Authors: Sharma Umesh C. , Sonkawade Swati D. , Spernyak Joseph A. , Sexton Sandra , Nguyen Juliane , Dahal Suraj , Attwood Kristopher M. , Singh Anurag K. , van Berlo Jop H. , Pokharel Saraswati 
Published: September 2018

Background:
Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways.

Methods and Results:

After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by
Mac-2
gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the
Mac-2
gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure.

Conclusions:
Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.
IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Van Tassell Benjamin W. , Trankle Cory R. , Canada Justin M. , Carbone Salvatore , Buckley Leo , Kadariya Dinesh , Del Buono Marco G. , Billingsley Hayley , Wohlford George , Viscusi Michele , Oddi-Erdle Claudia , Abouzaki Nayef A. , Dixon Dave , Biondi-Zoccai Giuseppe , Arena Ross , Abbate Antonio 
Published: September 2018

Background
Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction.

Methods and Results

Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (V
o
2
), ventilatory efficiency (V
E
/V
co
2
slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak V
o
2
or V
E
/V
co
2
slope between groups at baseline. Peak V
o
2
was not changed after 12 weeks of anakinra (from 13.6 [11.8–18.0] to 14.2 [11.2–18.5] mL·kg
−1
·min
−1
,
P
=0.89), or placebo (14.9 [11.7–17.2] to 15.0 [13.8–16.9] mL·kg
−1
·min
−1
,
P
=0.40), without significant between-group differences in changes at 12 weeks (−0.4 [95% CI, −2.2 to +1.4],
P
=0.64). V
E
/V
co
2
slope was also unchanged with anakinra (from 28.3 [27.2–33.0] to 30.5 [26.3–32.8],
P
=0.97) or placebo (from 31.6 [27.3–36.9] to 31.2 [27.8–33.4],
P
=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, −1.8 to +4.3],
P
=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline (
P
=0.026 and
P
=0.022 versus placebo [between-group analysis], respectively).

Conclusions

Treatment with anakinra for 12 weeks failed to improve peak V
o
2
and V
E
/V
co
2
slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02173548.
Tropoelastin
Authors: Phinikaridou Alkystis , Lacerda Sara , Lavin Begoña , Andia Marcelo E. , Smith Alberto , Saha Prakash , Botnar René M. 
Published: September 2018

Background:
Elastolysis and ineffective elastogenesis favor the accumulation of tropoelastin, rather than cross-linked elastin, in atherosclerotic plaques. We developed gadolinium-labeled tropoelastin-specific magnetic resonance contrast agents for tropoelastin imaging in animal models.

Methods and Results:

Two peptides, VVGSPSAQDEASPLS and YPDHVQYTHY, were selected to target tropoelastin. In vitro binding, relaxivity, and biodistribution experiments enabled characterization of the probes and selecting the best candidate for in vivo magnetic resonance imaging. Magnetic resonance imaging was performed in atherosclerotic apolipoprotein E–deficient mice and New Zealand white rabbits with stable and rupture-prone plaques using a gadolinium-labeled tropoelastin-specific magnetic resonance contrast agent. In addition, human carotid endarterectomy specimens were imaged ex vivo. The VVGSPSAQDEASPLS-based probe discriminated between tropoelastin and cross-linked elastin (64%±7% versus 1%±2%;
P
=0.001), had high in vitro relaxivity in solution (r
1-free
=11.7±0.6 [mmol/L]
−1
s
−1
, r
1-bound to tropoelastin
=44±1 [mmol/L]
−
1
s
−
1
), and favorable pharmacokinetics. In vivo mice vascular enhancement (4 weeks=0.13±0.007 mm
2
, 8 weeks=0.22±0.01 mm
2
, 12 weeks=0.33±0.01 mm
2
;
P
<0.001) and R
1
relaxation rate (4 weeks=[0.90±0.01]/s, 8 weeks=[1.40±0.03]/s, 12 weeks=[1.87±0.04]/s;
P
<0.001) increased with atherosclerosis progression after gadolinium-labeled tropoelastin-specific magnetic resonance contrast agent injection. Conversely, statin-treated (0.13±0.01 mm
2
; R
1
=[1.37±0.03]/s) and control (0.10±0.005 mm
2
; R
1
=[0.87±0.05]/s) mice showed less enhancement. Rupture-prone rabbit plaques had higher R
1
relaxation rate compared with stale plaques (R
1
=[2.26±0.1]/s versus R
1
=[1.43±0.02]/s;
P
=0.001) after administration of the gadolinium-labeled tropoelastin-specific magnetic resonance contrast agent that allowed detection of rupture-prone plaques with high sensitivity (84.4%) and specificity (92.3%). Increased vascular R
1
relaxation rate was observed in carotid endarterectomy plaques after soaking (R
1pre
=[1.1±0.26]/s versus R
1post
=[3.0±0.1]/s;
P
=0.01). Ex vivo analyses confirmed the magnetic resonance imaging findings and showed uptake of the contrast agent to be specific for tropoelastin.

Conclusions:
Magnetic resonance imaging of tropoelastin provides a novel biomarker for atherosclerotic plaque progression and instability.
Drug-Eluting Versus Bare-Metal Stent Implantation With or Without Cilostazol in the Treatment of the Superficial Femoral Artery
Authors: Miura Takashi , Miyashita Yusuke , Soga Yoshimitsu , Hozawa Koji , Doijiri Tatsuki , Ikeda Uichi , Kuwahara Koichiro ,   on behalf of the DEBATE in SFA Investigators
Published: September 2018

Background:
New-generation bare-metal nitinol (BNS) and drug-eluting stents have improved long-term outcomes in patients undergoing endovascular therapy for femoropopliteal lesions. Furthermore, cilostazol reduces in-stent restenosis (ISR) after first-generation BNS implantation for femoropopliteal lesions.

Methods and Results:

We studied 255 patients with femoropopliteal lesions treated at 25 cardiovascular centers. Patients were randomly assigned to the BNS group (Misago stent implantation without cilostazol), BNS with cilostazol group (Misago stent implantation with cilostazol), or drug-eluting stents group (Zilver PTX stent implantation without cilostazol). Primary end point was 1-year restenosis noted using duplex ultrasound (peak systolic velocity ratio, >2.0). Secondary end point was major adverse limb events (limb-related death, target lesion revascularization, major amputation, and major bleeding). During the 1-year follow-up, 12 patients (4.7%) died and 237 (92.9%) had relevant ultrasound findings. The 1-year ISR rate did not differ significantly among the BNS, BNS with cilostazol, and drug-eluting stents groups (28.4% versus 12.2% versus 21.0%;
P
=0.052). Although the 1-year ISR rate was significantly lower in the BNS with cilostazol group than in the BNS group, it was similar to that in the drug-eluting stents group (
P
=0.16). Major adverse limb event was significantly higher in the BNS group (16.9% versus 6.5% versus 6.3%;
P
=0.034); however, target lesion revascularization and major bleeding were similar (9.7% versus 5.1% versus 3.6%;
P
=0.25, 4.8% versus 1.2% versus 2.4%;
P
=0.37, respectively).

Conclusions:
Misago stent implantation with cilostazol showed a comparable 1-year ISR rate with Zilver PTX. Cilostazol reduced the 1-year ISR rate after endovascular therapy when used with new-generation BNS.

Clinical Trial Registration:

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: UMIN 000010071.
Population‐Based Study of Incidence of Acute Abdominal Aortic Aneurysms With Projected Impact of Screening Strategy
Authors: Howard Dominic P. J. , Banerjee Amitava , Fairhead Jack F. , Handa Ashok , Silver Louise E. , Rothwell Peter M. ,   the Oxford Vascular Study
Published: September 2018

Background

Current abdominal aortic aneurysm (
AAA
) screening in men age 65 might have limited impact on overall
AAA
death rates if incidence is moving to older ages. Up‐to‐date population‐based studies of age‐specific incidence, risk factors, and outcome of acute
AAA
are needed to inform screening policy.

Methods and Results

In a prospective, population‐based study (Oxfordshire,
UK
, 2002–2014), the incidence and outcome of acute
AAA
events were determined. Based on population projections and current incidence trends, the impact of screening strategies in the
UK
was estimated. Over the 12‐year period, 103 incident acute
AAA
events occurred in the study population of 92 728. Incidence/100 000/year was 55 in men ages 65 to 74 years, but increased to 112 at 75 to 85 and 298 at ≥85, with 66.0% of all events occurring at age ≥75 years. Incidence at ages 65 to 74 was highest in male smokers (274), with 96.4% of events in men <75 years occurring in ever‐smokers. Extrapolating rates to the
UK
population, using trial evidence of screening efficacy, the current
UK
screening program would prevent 5.6% of aneurysm‐related deaths (315 200 scans/year: 1426/death prevented, 121/year‐of‐life saved). Screening only male smokers age 65 and then all men at age 75 would prevent 21.1% of deaths (247 900 scans/year; 297/death prevented, 34/year‐of‐life saved). By 2030, 91.0% of deaths will occur at age ≥75, 61.6% at ≥85, and 28.6% in women.

Conclusions

Given that two thirds of acute
AAA
occurred at ≥75 years of age, screening older age groups should be considered. Screening nonsmokers at age 65 is likely to have very little impact on
AAA
event rates.
Optimal Lifestyle Components in Young Adulthood Are Associated With Maintaining the Ideal Cardiovascular Health Profile Into Middle Age
Authors: Gooding Holly C. , Shay Christina M. , Ning Hongyan , Gillman Matthew W. , Chiuve Stephanie E. , Reis Jared P. , Allen Norrina B. , Lloyd‐Jones Donald M. 
Published: September 2018

Background

Middle‐aged adults with ideal blood pressure, cholesterol, and glucose levels exhibit substantially lower cardiovascular mortality than those with unfavorable levels. Four healthy lifestyle components—optimal body weight, diet, physical activity, and not smoking—are recommended for cardiovascular health (
CVH
). This study quantified associations between combinations of healthy lifestyle components measured in young adulthood and loss of the ideal
CVH
profile into middle age.

Methods and Results

Analyses included 2164 young adults in the Coronary Artery Risk Development in Young Adults study with the ideal
CVH
profile (defined as untreated blood pressure <120/80 mm Hg, total cholesterol <200 mg/
dL
, fasting blood glucose <100 mg/
dL
, and absence of cardiovascular disease) at baseline. Cox proportional hazards regression models estimated hazard ratios for loss of the ideal
CVH
profile over 25 years according to 4 individual and 16 combinations of optimal healthy lifestyle components measured in young adulthood: body mass index, physical activity, nonsmoking status, and diet quality. Models were adjusted for age, sex, race, education, study center, and baseline blood pressure, cholesterol, and glucose. Eighty percent (n=1737) of participants lost the ideal
CVH
profile by middle age; loss was greatest for young adults with no optimal healthy lifestyle components at baseline. Relative to young adults with no optimal healthy lifestyle components, those with all 4 were less likely to lose the ideal
CVH
profile (hazard ratio 0.59, 95%
CI
0.44–0.80). Combinations that included optimal body mass index and nonsmoking status were each associated with lower risk.

Conclusions

Optimal body mass index and not smoking in young adulthood were protective against loss of the ideal
CVH
profile through middle age. Importance of diet and physical activity may be included through their effects on healthy weight.