bluuebunny/crossref_metadata_2025_split huggingface dataset:
Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome
Authors: GuhaThakurta Debraj , Sheikh Nadeem A. , Fan Li-Qun , Kandadi Harini , Meagher T. Craig , Hall Simon J. , Kantoff Philip W. , Higano Celestia S. , Small Eric J. , Gardner Thomas A. , Bailey Kate , Vu Tuyen , DeVries Todd , Whitmore James B. , Frohlich Mark W. , Trager James B. , Drake Charles G. 
Published: February 2015

Abstract
Purpose: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen).
Experimental Design: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels.
Results: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P &lt; 0.01), but not control. IgG responses (≥2-fold elevation posttreatment) occurred in ≥25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T–treated patients from IMPACT (P ≤ 0.05).
Conclusions: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. Clin Cancer Res; 21(16); 3619–30. ©2015 AACR.
See related commentary by Hellstrom and Hellstrom, p. 3581
Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials
Authors: Rafii Saeed , Roda Desamparados , Geuna Elena , Jimenez Begona , Rihawi Karim , Capelan Marta , Yap Timothy A. , Molife L. Rhoda , Kaye Stanley B. , de Bono Johann S. , Banerji Udai 
Published: February 2015

AbstractPurpose: Novel antitumor therapies against the PI3K–AKT–mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown.Experimental Design: In this retrospective case–control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K–AKT–mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K–AKT–mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K–AKT–mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapies.Results: The incidence of all grade infection was significantly higher with all single-agent PI3K–AKT–mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9–9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K–AKT–mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1–12.4; P = 0.02). Also, the combination of PI3K–AKT–mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0–11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0–7.6; P = 0.03) infection when compared with single-agent PI3K–AKT–mTOR inhibitors.Conclusions: Inhibitors of the PI3K–AKT–mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K–AKT–mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K–AKT–mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents. Clin Cancer Res; 21(8); 1869–76. ©2015 AACR.
Autologous Dermal Fibroblast Injections Slow Atrioventricular Conduction and Ventricular Rate in Atrial Fibrillation in Swine
Authors: Tondato Fernando , Zeng Hong , Goodchild Traci , Ng Fu Siong , Chronos Nicolas , Peters Nicholas S. 
Published: February 2015

Background—
Nonpharmacological ventricular rate control in atrial fibrillation (AF) without producing atrioventricular (AV) block remains a clinical challenge. We investigated the hypothesis that autologous dermal fibroblast (ADF) injection into the AV nodal area would reduce ventricular response during AF without causing AV block.

Methods and Results—

Fourteen pigs underwent electrophysiology study before, immediately, and 28 days after ≈200 million cultured ADFs (n=8) or saline (n=6) were injected under electroanatomical guidance in the AV nodal area, with continuous 28-day ECG recording. In the ADF group at 28 days postinjection, there were prolongations of PR interval (after versus before: 130±13 versus 113±14 ms,
P
=0.04), of AH interval during both sinus rhythm (92±13 versus 76.8±8 ms,
P
<0.01) and atrial pacing at 400 ms (102±13 versus 91±9 ms,
P
<0.01), and of AV node Wenckebach cycle length (230±19 versus 213±24 ms,
P
<0.01), with no changes in the control group. The RR interval during induced AF 28 days after injections was 24% longer in ADF-treated group compared with controls (488±120 versus 386±116 ms,
P
<0.001). Histological analysis revealed presence of ADF-labeled cells in the AV nodal area at 28 days. Transient accelerated junctional rhythm during injections, and transient nocturnal Mobitz I AV conduction occurred early postinjection in both groups.

Conclusions—
Cells survived for 4 weeks and significantly slowed AV conduction and ventricular rate in acutely induced AF. Critically, despite a large number of injections in the AV nodal area and marked effects on AV conduction, AV block did not occur. Further studies are necessary to determine the clinical feasibility and safety of this strategy for ventricular rate control in AF.
Baseline Distribution of Participants With Depression and Impaired Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial
Authors: Hamo Carine E. , Heitner John F. , Pfeffer Marc A. , Kim Hae-Young , Kenwood Christopher T. , Assmann Susan F. , Solomon Scott D. , Boineau Robin , Fleg Jerome L. , Spertus John A. , Lewis Eldrin F. 
Published: February 2015

Background—
Previous studies have demonstrated the psychosocial effect of heart failure in patients with reduced ejection fraction. However, the effects on patients with preserved ejection fraction have not yet been elucidated. This study aimed to determine the baseline characteristics of participants with heart failure with preserved ejection fraction as it relates to impaired quality of life (QOL) and depression, identify predictors of poor QOL and depression, and determine the correlation between QOL and depression.

Methods and Results—
Among patients enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT), 3400 patients completed the Kansas City Cardiomyopathy Questionnaire, 3395 patients completed European QOL 5D Visual Analog Scale, and 1431 patients in United States and Canada completed the Patient Health Questionnaire-9. The mean summary score on the Kansas City Cardiomyopathy Questionnaire was 54.8, and on European QOL 5D Visual Analog Scale, it was 60.3; 27% of patients had moderate to severe depression. Factors associated with better Kansas City Cardiomyopathy Questionnaire and European QOL 5D Visual Analog Scale via multiple logistic regression analysis were American region, older age, no history of angina pectoris or asthma, no use of hypoglycemic agent, more activity level, and lower New York Heart Association class. Factors associated with depression via multiple logistic regression analysis included younger age, female sex, comorbid angina, chronic obstructive pulmonary disease, use of a hypoglycemic agent, lower activity level, higher New York Heart Association class, and selective serotonin reuptake inhibitor use. There were significant correlations between each of the QOL scores and depression.

Conclusions—
Patients with heart failure with preserved ejection fraction, who were younger had higher New York Heart Association class or comorbid angina pectoris, had lower activity levels, lived in Eastern Europe or were taking hypoglycemic agents, were more likely to have impaired QOL and depression.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00094302.
Quantifying the Utility of Taking Pills for Cardiovascular Prevention
Authors: Hutchins Robert , Viera Anthony J. , Sheridan Stacey L. , Pignone Michael P. 
Published: February 2015

Background—
The decrease in utility attributed to taking pills for cardiovascular prevention can have major effects on the cost-effectiveness of interventions but has not been well studied. We sought to measure the utility of daily pill-taking for cardiovascular prevention.

Methods and Results—
We conducted a cross-sectional Internet-based survey of 1000 US residents aged ≥30 in March 2014. We calculated utility values, using time trade-off as our primary method and standard gamble and willingness-to-pay techniques as secondary analyses. Mean age of respondents was 50 years. Most were female (59%) and white (63%); 28% had less than a college degree; and 79% took ≥1 pills daily. Mean utility using the time trade-off method was 0.990 (95% confidence interval, 0.988–0.992), including ≈70% not willing to trade any amount of time to avoid taking a preventive pill daily. Using the standard gamble method, mean utility was 0.991 (0.989–0.993), with 62% not willing to risk any chance of death. Respondents were willing to pay an average of $1445 to avoid taking a pill daily, which translated to a mean utility of 0.994 (0.940–0.997), including 41% unwilling to pay any amount. Time trade-off–based utility varied by age (decreasing utility as age increased), sex, race, numeracy, difficulty with obtaining pills, and number of pills taken per day but did not vary by education level, literacy, or income.

Conclusions—
Mean utility for taking a pill daily for cardiovascular prevention is ≈0.990 to 0.994.
Local Association Between Endothelial Dysfunction and Intimal Hyperplasia: Relevance in Peripheral Artery Disease
Authors: Heinen Yvonne , Stegemann Emilia , Sansone Roberto , Benedens Kolja , Wagstaff Rabea , Balzer Jan , Rassaf Tienush , Lauer Thomas , Kelm Malte , Heiss Christian 
Published: February 2015

Background

Endothelial dysfunction is a key factor in the development of atherosclerosis. Commonly, endothelial function is determined in the brachial artery, whereas patients with peripheral artery disease (
PAD
) present with lower limb atherosclerosis. We hypothesized that in
PAD,
a segmental or local association exists between endothelial dysfunction and atherosclerotic structural changes.

Methods and Results

We used ultrasound to study endothelial function as flow‐mediated vasodilation, intima media thickness, and local stiffness of the superficial femoral artery (
SFA
) and brachial artery (
BA
).
PAD
patients with symptomatic
SFA
or below‐the‐knee disease were compared with age‐matched patients without
PAD
and young healthy controls.
PAD
patients with
SFA
or below‐the‐knee disease exhibited endothelial dysfunction of the proximal
SFA
(flow‐mediated vasodilation: 3.9±0.6%, 3.7±0.6%) compared with healthy controls (7.4±1.0%) and patients without
PAD
(5.4±0.6%). Brachial artery flow‐mediated vasodilation values were not different in
PAD
patients with
SFA
or below‐the‐knee disease compared with patients without
PAD
, but they were significantly lower than those of healthy controls. Endothelial dysfunction correlated with increased intima media thickness or plaque thickness at the site of flow‐mediated vasodilation measurement across vascular sites. In
PAD
patients with
SFA
disease,
SFA
flow‐mediated vasodilation was further impaired within and distal to stenosis (prestenosis 3.9±0.6%, intrastenosis 2.3±0.7%, poststenosis 2.5±0.6%) and recovered within 24 hours after
SFA
balloon angioplasty to prestenotic values but not to the brachial artery or
SFA
values in patients without
PAD
or controls.

Conclusion

A close association exists between local endothelial function and atherosclerotic structural remodeling, suggesting that in
PAD
, local and segmental factors—in addition to systemic factors—influence local endothelial function. Our data point toward a pathophysiological role for lower extremity endothelial dysfunction in
PAD
.
Impact of Perioperative Infarcts After Cardiac Surgery
Authors: Patel Nikil , Horsfield Mark A. , Banahan Caroline , Janus Justyna , Masters Katie , Morlese John , Egan Vincent , Chung Emma M.L. 
Published: February 2015

Background and Purpose—
Brain injury after cardiac surgery is a serious concern for patients and their families. The purpose of this study was to use 3-T fluid attenuated inversion recovery MRI to characterize new and preexisting cerebral ischemic lesions in patients undergoing cardiac surgery and to test whether the accumulation of new ischemic lesions adversely affects cognition.

Methods—
Digital comparison of before and after fluid attenuated inversion recovery MRI images was performed for 77 cardiac surgery patients. The burden of preexisting versus new ischemic lesions was quantified and compared with the results of baseline and postoperative neuropsychological testing.

Results—

After surgery, new lesions were identified in 31% of patients, averaging 0.5 lesions per patient (67 mm
3
[0.004%] of brain tissue). Patients with preexisting lesions were 10× more likely to receive new lesions after surgery than patients without preexisting lesions. Preexisting ischemic lesions were observed in 64% of patients, averaging 19.4 lesions (1542 mm
3
[0.1%] of brain tissue). New lesions in the left hemisphere were significantly smaller and more numerous (29 lesions; median volume, 44 mm
3
; volume range, 5–404 mm
3
) than those on the right (10 lesions; median volume, 128 mm
3
; volume range, 13–1383 mm
3
), which is consistent with a cardioembolic source of particulate emboli. Overall, the incidence of postoperative cognitive decline was 46% and was independent of whether new lesions were present.

Conclusions—
New lesions after cardiac surgery added a small (≈4%) contribution to the burden of preexisting cerebrovascular disease and did not seem to affect cognitive function.

Clinical Trial Registration—

URL:
http://public.ukcrn.org.uk
. Unique identifier: UKCRN ID: 11702.
Association Between Socioeconomic Deprivation and Functional Impairment After Stroke
Authors: Chen Ruoling , Crichton Siobhan , McKevitt Christopher , Rudd Anthony G. , Sheldenkar Anita , Wolfe Charles D.A. 
Published: February 2015

Background and Purpose—
Previous findings of the association between socioeconomic deprivation and functional impairment after stroke are inconsistent. There is a lack of data on long-term association. We assessed the association and differences by age, sex, prestroke comorbidities, and stroke phenotypes.

Methods—
We examined data from the South London Stroke Register cohort of 1995 to 2011, recording all first-ever strokes in patients of all ages in South London. A total of 2104 patients were alive at 3 months after stroke. Socioeconomic deprivation was measured using the index of multiple deprivation based on patient postcodes, and functional impairment after stroke was defined as a Barthel index of <15.

Results—

At 3 months after stroke, 643 patients had functional impairment (30.6%; 95% confidence interval, 28.6%–32.5%). Compared with the first quartile of index of multiple deprivation (the least deprived), multivariate-adjusted odds ratios for functional impairment in patients with the second, third, and fourth quartiles were 1.29 (95% confidence interval, 0.94–1.76), 1.33 (0.97–1.82), and 1.78 (1.31–2.43), overall
P
=0.004. The association was significant in patients aged ≥65 years (corresponding odds ratios were 1.49 [1.02–2.17], 1.21 [0.83–1.75], and 1.94 [1.34–2.81];
P
=0.003); in women,
P
=0.008, in patients who do not have prestroke comorbidities,
P
=0.009, and in patients with ischemic stroke,
P
<0.001, but not significant in their counterpart patients. There were similar patterns of the associations of socioeconomic deprivation with impairment at 3 years after stroke.

Conclusions—
There are significant inequalities in short- and long-term functional recovery after stroke. General socioeconomic improvement, targeting groups at high risk of functional impairment is likely to reduce inequality in functional recovery after stroke.
How Sustained Is 24-Hour Diffusion-Weighted Imaging Lesion Reversal?
Authors: Soize Sebastien , Tisserand Marie , Charron Sylvain , Turc Guillaume , Ben Hassen Wagih , Labeyrie Marc-Antoine , Legrand Laurence , Mas Jean-Louis , Pierot Laurent , Meder Jean-François , Baron Jean-Claude , Oppenheim Catherine 
Published: February 2015

Background and Purpose—
Here, we assessed how sustained is reversal of the acute diffusion lesion (RAD) observed 24 hours after intravenous thrombolysis, and the relationships between RAD fate and early neurological improvement.

Methods—

We analyzed 155 consecutive patients thrombolyzed intravenously 152 minutes (median) after stroke onset and who underwent 3 MR sessions: 1 before and 2 after treatment (median times from onset, 25.6 and 54.3 hours, respectively). Using voxel-based analysis of diffusion-weighted imaging (DWI)
1
, DWI
2
, and DWI
3
lesions on coregistered image data sets, we assessed the outcome of RAD voxels (hyperintense on DWI
1
but not on DWI
2
) as transient or sustained on DWI
3
, and their relationships with early neurological improvement, defined as ΔNational Institutes of Health Stroke Scale ≥8 or National Institutes of Health Stroke Scale ≤1 at 24 hours.
T
max
and apparent diffusion coefficient values were compared between sustained and transient RAD voxels.

Results—

The median (interquartile range) baseline National Institutes of Health Stroke Scale and DWI
1
lesion volume were 11 (7–18) mL and 15.6 (6.0–50.9) mL, respectively. The median (interquartile range) RAD volume on DWI
2
was 2.8 (1.1–6.6) mL, of which 70% was sustained on DWI
3
. Sixteen (10.3%) patients had sustained RAD ≥10 mL. As compared with transient RAD voxels, sustained RAD voxels had nonsignificantly higher baseline apparent diffusion coefficient values (median [interquartile range], 793 [717–887] versus 777 [705–869]×10
−6
mm
2
·s
−1
, respectively;
P
=0.08) and significantly better perfusion (
T
max
, mean±SD, 6.3±3.2 versus 7.8±4.0 s;
P
<0.001). At variance with transient RAD, the volume of sustained RAD was associated with early neurological improvement in multivariate analysis (odds ratio, 1.08; 95% confidence interval, [1.01–1.17], per 1-mL increase;
P
=0.03).

Conclusions—
After thrombolysis, over two-thirds of the DWI lesion reversal captured on 24-hour follow-up MR is sustained. Sustained DWI lesion reversal volume is a strong imaging correlate of early neurological improvement.
Check on Foreign Debt Agreements in the Jordanian Legal System
Authors: Shabeeb Lina Abdallah Khalil , Aljaghoub Mahasen 
Published: February 2015

The system of checks and balances, adopted by the Jordanian Constitution is highly
weakened by the High Tribunal’s interpretation of Article 33 (addressing international
relations) in Decision number 1/1962; especially regarding foreign debt agreements,
where such agreements, entered into by the Executive Power, are, almost always,
excluded from the approval of the National Assembly.
Unfortunately, the 2011 Constitutional Reform missed a golden opportunity to
amend this Article; therefore, the alternative would be for the Constitutional Court,
the successor of the High Tribunal, to present a different approach, especially since
the authorities supporting the Tribunal’s decision can be revised to present a different
interpretation that allows a better check over foreign debt, which has been rising
recently to alarming levels.
The best candidate to initiate this change is the National Assembly, especially the
Chamber of Deputies, either by submitting a request to the Court to this effect, or by
carrying a legislative reform amending the Public Debt Management Law from the one
side and, from the other side, drafting a law for the check over the Executive Power’s role
in conducting external agreements in general, and foreign debt agreements, in particular;
a law that balances the relations between the two Powers, regarding their financial
functions, and enhances the democratization of the Jordanian System.
A revision of Boreantrops Kits &amp; Marshall (Diptera: Sphaeroceridae: Archiborborinae)
Authors: KITS JOEL H. , MARSHALL STEPHEN A. 
Published: February 2015

Boreantrops Kits & Marshall is a recently described genus of flies in the family Sphaeroceridae. Species occur from Brazil and Bolivia north to northern Mexico, mostly in humid montane environments. Two species were included in the genus when originally described, B. calceatus (Duda) and B. mexicanus (Steyskal). Here we revise the genus to include 32 species, including the following 30 new species: B. albipes, B. alytothrix, B. apterus, B. auranticeps, B. avignis, B. boliviensis, B. challabamba, B. costaricensis, B. cryptopygium, B. durango, B. emarginatus, B. friburguensis, B. guatemalensis, B. hispidus, B. hondurensis, B. inbio, B. longiphallus, B. masneri, B. machinator, B. oaxacensis, B. peruvianus, B. pollex, B. punctipennis, B. subemarginatus, B. subfoveolatus, B. suchixtepecensis, B. talamanca, B. wayqecha, B. zacapa, B. zamora. A key is provided for all known species.