bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
Authors: Dethlefsen Christine , Hansen Louise S. , Lillelund Christian , Andersen Christina , Gehl Julie , Christensen Jesper F. , Pedersen Bente K. , Hojman Pernille 
Published: September 2017

Abstract
Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise–conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1nu mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of β-adrenergic signaling in MCF-7 cells, indicating that catecholamines were the responsible exercise factors. Both epinephrine (EPI) and norepinephrine (NE) could directly inhibit breast cancer cell viability, as well as tumor growth in vivo. EPI and NE activate the tumor suppressor Hippo signaling pathway, and the suppressive effect of exercise-conditioned serum was found to be mediated through phosphorylation and cytoplasmic retention of YAP and reduced expression of downstream target genes, for example, ANKRD1 and CTGF. In parallel, tumor-bearing mice with access to running wheels showed reduced growth of MCF-7 (–36%, P &lt; 0.05) and MDA-MB-231 (–66%, P &lt; 0.01) tumors and, for the MCF-7 tumor, increased regulation of the Hippo signaling pathway. Taken together, our findings offer a mechanistic explanation for exercise-dependent suppression of breast cancer cell growth. Cancer Res; 77(18); 4894–904. ©2017 AACR.
ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma
Authors: Ndoye Abibatou , Budina-Kolomets Anna , Kugel Curtis H. , Webster Marie R. , Kaur Amanpreet , Behera Reeti , Rebecca Vito W. , Li Ling , Brafford Patricia A. , Liu Qin , Gopal Y.N. Vashisht , Davies Michael A. , Mills Gordon B. , Xu Xiaowei , Wu Hong , Herlyn Meenhard , Nicastri Michael C. , Winkler Jeffrey D. , Soengas Maria S. , Amaravadi Ravi K. , Murphy Maureen E. , Weeraratna Ashani T. 
Published: September 2017

Abstract
Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873–85. ©2017 AACR.
Defining Optimal Triage Strategies for hrHPV Screen–Positive Women—An Evaluation of HPV 16/18 Genotyping, Cytology, and p16/Ki-67 Cytoimmunochemistry
Authors: Stanczuk Grazyna A. , Baxter Gwen J. , Currie Heather , Forson William , Lawrence James R. , Cuschieri Kate , Wilson Allan , Patterson Lynne , Govan Lynn , Black Janice , Palmer Tim , Arbyn Marc 
Published: September 2017

Abstract
Background: Several options for the triage of high-risk HPV screen–positive (hrHPV+) women were assessed.
Methods: This study incorporated CIN2+ cases and controls, all of whom tested hrHPV+ and whose results of liquid-based cytology (LBC), HPV16/18 genotyping, and p16/Ki67 cytoimmunochemistry were available. Sensitivity and specificity for the CIN2+ of these triage tests were evaluated.
Results: Absolute sensitivities of HPV 16/18 typing, LBC, and p16/Ki-67 cytoimmunochemistry for CIN2+ detection were 61.7%, 68.3%, and 85.0% for women with hrHPV+ clinician-taken samples. Respective specificities were 70.5%, 89.1%, and 76.7%. The absolute accuracy of the triage tests was similar for women with a hrHPV+ self-sample. P16/Ki-67 cyto-immunochemistry was significantly more sensitive than LBC although significantly less specific.
Conclusions: All three single-test triage options, if positive, exceed the threshold of 20% risk at which colposcopy would be indicated. However, none of them conferred a post-test probability of CIN2+ &lt;2%; which would permit routine recall. P16/Ki-67 cytoimmunochemistry on HPV16/18 negative women had a post-test probability of CIN2+ of 1.7% and 0.6% if also LBC negative.
Impact: This is one of the few studies to directly compare the performance of triage strategies of hrHPV+ women, in isolation and combinations. It is the only study assessing triage strategies in women who test hrHPV+ in self-taken vaginal samples. A combined triage option that incorporated HPV 16/18 typing prior to p16/ki-67 cytoimmunochemistry in HPV 16/18–negative women yielded a post-test probability of CIN2+ of &gt;20%, whereas women who tested negative had a probability of CIN2+ of &lt;2%. Cancer Epidemiol Biomarkers Prev; 26(11); 1629–35. ©2017 AACR.
Initial Clinical Experience With a New Automated Antitachycardia Pacing Algorithm
Authors: Yee Raymond , Fisher John D. , Birgersdotter-Green Ulrika , Smith Timothy W. , Kenigsberg David N. , Canby Robert , Jackson Troy , Taepke Robert , DeGroot Paul 
Published: September 2017

Background:
Antitachycardia pacing (ATP) in implantable cardioverter-defibrillators (ICD) decreases patient shock burden but has recognized limitations. A new automated ATP (AATP) based on electrophysiological first principles was designed. The study objective was to assess the feasibility and safety of AATP in ambulatory ICD patients.

Methods and Results:
Enrolled patients had dual chamber or cardiac resynchronization therapy ICDs, history of ≥1 ICD-treated ventricular tachycardias (VT)/ventricular fibrillation episode, or a recorded, sustained monomorphic VT. Detection was set to ventricular fibrillation number of intervals to detect=24/32, VT number of intervals to detect≥16, and a fast VT zone of 240 to 320 ms. AATP prescribed the components and delivery of successive ATP sequences in real time, using the same settings for all patients. ICD datalogs were uploaded every ≈3 months, at unscheduled visits, exit, and death. Episodes and adverse events were adjudicated by separate committees. Results were adjusted (generalized estimating equations) for multiple episodes. AATP was downloaded into the ICDs of 144 patients (121 men), aged 67.4±11.9 years, left ventricular ejection fraction 33.1±13.6% (n=137), and treated 1626 episodes in 49 patients during 14.5±5.1 months of follow-up. Datalogs permitted adjudication of 702 episodes, including 669 sustained monomorphic VT, 20 polymorphic VT, 10 supraventricular tachycardia, and 3 malsensing episodes. AATP terminated 39 of 69 (59% adjusted) sustained monomorphic VT in the fast VT zone, 509 of 590 (85% adjusted) in the VT zone, and 6 of 10 in the ventricular fibrillation zone. No supraventricular tachycardias converted to VT or ventricular fibrillation. No anomalous AATP behavior was observed.

Conclusions:
The new AATP algorithm safely generated ATP sequences and controlled therapy progression in all zones without need for individualized programing.
Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping
Authors: Haldar Shouvik K. , Magtibay Karl , Porta-Sanchez Andreu , Massé Stéphane , Mitsakakis Nicholas , Lai Patrick F.H. , Azam Mohammed Ali , Asta John , Kusha Marjan , Dorian Paul , Ha Andrew C.T. , Chauhan Vijay , Deno D. Curtis , Nanthakumar Kumaraswamy 
Published: September 2017

Background:

Low-voltage–guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (V
pp
) from variations in wavefront direction relative to electrode orientation and from fractionation and collision events. We aim to compare bipole V
pp
with novel omnipolar peak-to-peak voltages (V
max
) in sinus rhythm (SR) and AF.

Methods and Results:

A high-density fixed multielectrode plaque was placed on the epicardial surface of the left atrium in dogs. Horizontal and vertical orientation bipolar EGMs, followed by omnipolar EGMs, were obtained and compared in both SR and AF. Bipole orientation has significant impact on bipolar EGM voltages obtained during SR and AF. In SR, vertical values were on average 66±119% larger than horizontal (
P
=0.004). In AF, vertical values were on average 31±96% larger than horizontal (
P
=0.07). Omnipole V
max
values were 99.9±125% larger than both horizontal (99.9±125%;
P
<0.001) and vertical (41±78%;
P
<0.0001) in SR and larger than both horizontal (76±109%;
P
<0.001) and vertical (52±70%;
P
value <0.0001) in AF. Vector field analysis of AF wavefronts demonstrates that omnipolar EGMs can account for collision and fractionation and record EGM voltages unaffected by these events.

Conclusions:
Omnipolar EGMs can extract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation, compared with contemporary bipolar techniques.
Role of Admission Troponin‐T and Serial Troponin‐T Testing in Predicting Outcomes in Severe Sepsis and Septic Shock
Authors: Vallabhajosyula Saraschandra , Sakhuja Ankit , Geske Jeffrey B. , Kumar Mukesh , Poterucha Joseph T. , Kashyap Rahul , Kashani Kianoush , Jaffe Allan S. , Jentzer Jacob C. 
Published: September 2017

Background
Troponin‐T elevation is seen commonly in sepsis and septic shock patients admitted to the intensive care unit. We sought to evaluate the role of admission and serial troponin‐T testing in the prognostication of these patients.

Methods and Results

This was a retrospective cohort study from 2007 to 2014 on patients admitted to the intensive care units at the Mayo Clinic with severe sepsis and septic shock. Elevated admission troponin‐T and significant delta troponin‐T were defined as ≥0.01 ng/mL and ≥0.03 ng/mL in 3 hours, respectively. The primary outcome was in‐hospital mortality. Secondary outcomes included 1‐year mortality and lengths of stay. During this 8‐year period, 944 patients met the inclusion criteria with 845 (90%) having an admission troponin‐T ≥0.01 ng/mL. Serial troponin‐T values were available in 732 (78%) patients. Elevated admission troponin‐T was associated with older age, higher baseline comorbidity, and severity of illness, whereas significant delta troponin‐T was associated with higher severity of illness. Admission log
10
troponin‐T was associated with unadjusted in‐hospital (odds ratio 1.6;
P
=0.003) and 1‐year mortality (odds ratio 1.3;
P
=0.04), but did not correlate with length of stay. Elevated delta troponin‐T and log
10
delta troponin‐T were not significantly associated with any of the primary or secondary outcomes. Admission log
10
troponin‐T remained an independent predictor of in‐hospital mortality (odds ratio 1.4;
P
=0.04) and 1‐year survival (hazard ratio 1.3;
P
=0.008).

Conclusions
In patients with sepsis and septic shock, elevated admission troponin‐T was associated with higher short‐ and long‐term mortality. Routine serial troponin‐T testing did not add incremental prognostic value in these patients.
Reversal of Arterial Stiffness and Maladaptative Arterial Remodeling After Kidney Transplantation
Authors: Karras Alexandre , Boutouyrie Pierre , Briet Marie , Bozec Erwan , Haymann Jean‐Philippe , Legendre Christophe , McMahon Lawrence P. , Delahousse Michel 
Published: September 2017

Background

Chronic kidney disease is characterized by stiffening, thinning, dilatation, and increased circumferential wall stress of large arteries, associated with increased cardiovascular risk. Kidney transplantation (
KT
) reverses many pathological features of chronic kidney disease and improves life expectancy; however, longitudinal studies exploring the impact of
KT
on recipient large arteries are scarce.

Methods and Results

This study was designed to appraise arterial changes following
KT
. Carotid‐femoral pulse wave velocity, carotid remodeling (circumferential wall stress and carotid internal diameter), and stiffness were measured in 161 consecutive recipients receiving either a living (n=49) or a deceased (n=112) donor allograft, at 3 and 12 months after transplantation. Mean pulse wave velocity decreased from 10.8 m/s (95% confidence interval, 10.5–11.2 m/s) (at month 3) to 10.1 m/s (95% confidence interval, 9.8–10.5 m/s) (at month 12) (
P
<0.001). After multivariate adjustment, pulse wave velocity reduction from month 3 to month 12 was significantly larger in the living donor allograft
KT
(
P
<0.001). Circumferential wall stress decreased, 70 kPa (95% confidence interval, 68–72 kPa) to 64 kPa (95% confidence interval, 62–67 kPa), as well as carotid internal diameter and carotid stiffness (
P
<0.001 for all). Reductions in circumferential wall stress, diameter, and stiffness were significantly larger in the living donor allograft
KT
(
P
<0.001). When deceased donor allograft patients were classified into standard and expanded criteria donors, changes in both pulse wave velocity and circumferential wall stress were blunted in expanded criteria donors. Changes were independent of graft function and blood pressure changes.

Conclusions

Large‐artery stiffness and maladaptive carotid artery remodeling of chronic kidney disease is partially reversed within 12 months of
KT
and appears unrelated to renal function. Improvements were independently associated with live organ donation. Our data suggest that expanded criteria donors may hamper vascular recovery.
Inorganic Nitrate in Angina Study: A Randomized Double‐Blind Placebo‐Controlled Trial
Authors: Schwarz Konstantin , Singh Satnam , Parasuraman Satish K. , Rudd Amelia , Shepstone Lee , Feelisch Martin , Minnion Magdalena , Ahmad Shakil , Madhani Melanie , Horowitz John , Dawson Dana K. , Frenneaux Michael P. 
Published: September 2017

Background
In this double‐blind randomized placebo‐controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.

Methods and Results

Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2‐week washout period before crossing over to the other treatment (n=34 placebo‐nitrate, n=36 nitrate‐placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm
ST
depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm
ST
segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds,
P
=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds,
P
=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] μmol/L,
P
<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L,
P
=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation.

Conclusions
Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
02078921. Eudra
CT
number: 2012‐000196‐17.
White Matter Hyperintensity Volume and Outcome of Mechanical Thrombectomy With Stentriever in Acute Ischemic Stroke
Authors: Atchaneeyasakul Kunakorn , Leslie-Mazwi Thabele , Donahue Kathleen , Giese Anne-Katrin , Rost Natalia S. 
Published: September 2017

Background and Purpose—
Finding of white matter hyperintensity (WMH) has been associated with an increased risk of parenchymal hematoma and poor clinical outcomes after mechanical thrombectomy using old-generation endovascular devices. Currently, no data exist with regard to the risk of mechanical thrombectomy using stentriever devices in patients with significant WMH. We hypothesized that WMH volume will not affect the hemorrhagic and clinical outcome in patients with acute ischemic stroke undergoing thrombectomy using new-generation devices.

Methods—
A retrospective cohort of consecutive acute ischemic stroke patients >18-year-old receiving mechanical thrombectomy with stentriever devices at a single academic center was examined. WMH volume was assessed by a semiautomated volumetric analysis on T2 fluid attenuated inversion recovery–magnetic resonance imaging. Outcomes included the rate of any intracerebral hemorrhage, 90-day modified Rankin Score (mRS), the rate of good outcome (discharge mRS ≤2), and the rate of successful reperfusion (thrombolysis in cerebral ischemia score 2b or 3).

Results—

Between June 2012 and December 2015, 56 patients with acute ischemic stroke met the study criteria. Median WMH volume was 6.76 cm
3
(4.84–16.09 cm
3
). Increasing WMH volume did not significantly affect the odds of good outcome (odds ratio [OR], 0.811; 95% confidence interval [CI], 0.456–1.442), intracerebral hemorrhage (OR, 1.055; 95% CI, 0.595–1.871), parenchymal hematoma (OR, 0.353; 95% CI, 0.061–2.057), successful recanalization (OR, 1.295; 95% CI, 0.704–2.383), or death (OR, 1.583; 95% CI, 0.84–2.98).

Conclusions—
Mechanical thrombectomy using stentrievers seems to be safe in selected patients with acute ischemic stroke with large vessel occlusion, nonwithstanding the severity of WMH burden in this population. Larger prospective studies are warranted to validate these findings.
Minocycline in Acute Cerebral Hemorrhage
Authors: Fouda Abdelrahman Y. , Newsome Andrea S. , Spellicy Samantha , Waller Jennifer L. , Zhi Wenbo , Hess David C. , Ergul Adviye , Edwards David J. , Fagan Susan C. , Switzer Jeffrey A. 
Published: September 2017

Background and Purpose—
Minocycline is under investigation as a neurovascular protective agent for stroke. This study evaluated the pharmacokinetic, anti-inflammatory, and safety profile of minocycline after intracerebral hemorrhage.

Methods—
This study was a single-site, randomized controlled trial of minocycline conducted from 2013 to 2016. Adults ≥18 years with primary intracerebral hemorrhage who could have study drug administered within 24 hours of onset were included. Patients received 400 mg of intravenous minocycline, followed by 400 mg minocycline oral daily for 4 days. Serum concentrations of minocycline after the last oral dose and biomarkers were sampled to determine the peak concentration, half-life, and anti-inflammatory profile.

Results—

A total of 16 consecutive eligible patients were enrolled, with 8 randomized to minocycline. Although the literature supports a time to peak concentration (T
max
) of 1 hour for oral minocycline, the T
max
was estimated to be at least 6 hours in this cohort. The elimination half-life (available on 7 patients) was 17.5 hours (SD±3.5). No differences were observed in inflammatory biomarkers, hematoma volume, or perihematomal edema. Concentrations remained at neuroprotective levels (>3 mg/L) throughout the dosing interval in 5 of 7 patients.

Conclusions—
In intracerebral hemorrhage, a 400 mg dose of minocycline was safe and achieved neuroprotective serum concentrations. However, oral administration led to delayed absorption in these critically ill patients and should not be used when rapid, high concentrations are desired. Given the safety and pharmacokinetic profile of minocycline in intracerebral hemorrhage and promising data in the treatment of ischemic stroke, intravenous minocycline is an excellent candidate for a prehospital treatment trial.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01805895.
Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia
Authors: Zhang Yiru , Catts Vibeke Sørensen , Shannon Weickert Cynthia 
Published: September 2017

Objective: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. Method: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. Results: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = −1.077, p = 0.285) or GCLC mRNA expression ( t(71) = −0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = −0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. Discussion: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins.