bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canonical Androstenedione Reduction Is the Predominant Source of Signaling Androgens in Hormone-Refractory Prostate Cancer
Authors: Fankhauser Matthew , Tan Yuen , Macintyre Geoff , Haviv Izhak , Hong Matthew K.H. , Nguyen Anne , Pedersen John S. , Costello Anthony J. , Hovens Christopher M. , Corcoran Niall M. 
Published: April 2014

AbstractPurpose: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression.Experimental Design: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography–mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset.Results: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the “backdoor” or “5-α dione” pathway.Conclusions: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC. Clin Cancer Res; 20(21); 5547–57. ©2014 AACR.
Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis
Authors: Charles Roch-Philippe , Silva Jillian , Iezza Gioia , Phillips Wayne A. , McMahon Martin 
Published: April 2014

Abstract
Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3′-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we previously developed a model of PTC. However, as in humans, BRAFV600E-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CAH1047R is unable to drive transformation on its own, when combined with BRAFV600E in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAFV600E cooperates with either PIK3CAH1074R or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma.
Implications: This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma. Mol Cancer Res; 12(7); 979–86. ©2014 AACR.
Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer
Authors: Bruegl Amanda S. , Djordjevic Bojana , Batte Brittany , Daniels Molly , Fellman Bryan , Urbauer Diana , Luthra Rajyalakshmi , Sun Charlotte , Lu Karen H. , Broaddus Russell R. 
Published: April 2014

Abstract
Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO)–codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch syndrome (PLS). In this cohort, 10.5% of patients were designated as PLS based on tumor testing. The sensitivity and specificity of the SGO criteria to identify these same cases were 32.6% [95% confidence interval (CI), 19.2–48.5] and 77% (95% CI, 72.7–81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and PLS groups. A simplified cost-effectiveness analysis demonstrated that the SGO clinical criteria and universal tissue testing strategies had comparable costs per patient with PLS identified. In conclusion, the SGO criteria successfully identify PLS cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of patients with PLS who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch syndrome. Cancer Prev Res; 7(7); 686–97. ©2014 AACR.
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Authors: Konieczkowski David J. , Johannessen Cory M. , Abudayyeh Omar , Kim Jong Wook , Cooper Zachary A. , Piris Adriano , Frederick Dennie T. , Barzily-Rokni Michal , Straussman Ravid , Haq Rizwan , Fisher David E. , Mesirov Jill P. , Hahn William C. , Flaherty Keith T. , Wargo Jennifer A. , Tamayo Pablo , Garraway Levi A. 
Published: April 2014

Abstract
Most melanomas harbor oncogenic BRAFV600 mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAFV600-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail to respond. Here, we show that RAF inhibitor–sensitive and inhibitor-resistant BRAFV600-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-κB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-κB–high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF-κB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF-κB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAFV600-mutant melanoma.
Significance: Although most BRAFV600-mutant melanomas are sensitive to RAF and/or MEK inhibitors, a subset fails to respond to such treatment. This study characterizes a transcriptional cell state distinction linked to MITF and NF-κB that may modulate intrinsic sensitivity of melanomas to MAPK pathway inhibitors. Cancer Discov; 4(7); 816–27. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 745
Effect of the Restitution Properties of Cardiac Tissue on the Repeatability of Entrainment Mapping Response
Authors: Derejko Paweł , Podziemski Piotr , Żebrowski Jan Jacek , Walczak Franciszek , Szumowski Łukasz Jan 
Published: April 2014

Background—
The difference between the postpacing interval (PPI) and the tachycardia cycle length (TCL; PPI−TCL) is a useful tool in mapping macro-reentrant tachycardias. However, entrainment pacing causes some perturbation of the conduction velocity within the tachycardia circuit, which may affect the repeatability and consequently the accuracy of the measurement of PPI−TCL. The aim of this study was to assess PPI−TCL repeatability both in vivo and in silico.

Methods and Results—
In the experimental part, entrainment pacing was performed twice at each of the 124 tested sites for 30 patients undergoing radiofrequency ablation of atrial and ventricular re-entrant arrhythmias. A similar protocol was used in a simplified computer model of the cardiac tachycardia circuit in a 2-dimensional tissue strip using a Fenton–Karma model of cardiac tissue. In vivo, in the case of fast tachycardias (<350 ms), PPI−TCL variability observed was doubled compared with slow tachycardias (>350 ms; 95% Limits of Agreement ranged from −21.4 to 21.6 ms for TCL<350 ms and from −10.8 to 11.5 ms for TCL>350 ms). Simulations show that this increase of variability may be because of the oscillations of the conduction velocity inside the tachycardia circuits. The effect of the restitution properties of cardiac tissue on the outcome of entrainment pacing is discussed.

Conclusions—
PPI−TCL is characterized by a high repeatability with the differences between the results for individual stimulations of ≤20 ms. The variability of this parameter is significantly lower in the case of slow tachycardias.
Prevalence and Prognostic Value of Concealed Structural Abnormalities in Patients With Apparently Idiopathic Ventricular Arrhythmias of Left Versus Right Ventricular Origin
Authors: Nucifora Gaetano , Muser Daniele , Masci Pier Giorgio , Barison Andrea , Rebellato Luca , Piccoli Gianluca , Daleffe Elisabetta , Toniolo Mauro , Zanuttini Davide , Facchin Domenico , Lombardi Massimo , Proclemer Alessandro 
Published: April 2014

Background—
Routine diagnostic work-up occasionally does not identify any abnormality among patients with monomorphic ventricular arrhythmias (VAs) of left ventricular (LV) origin. Aim of this study was to investigate the value of cardiac MRI (cMRI) for the diagnostic work-up and prognostication of these patients.

Methods and Results—

Forty-six consecutive patients (65% males; mean age, 44±15 years) with monomorphic VAs of LV origin and negative routine diagnostic work-up were included. Seventy-four consecutive patients (60% males; mean age, 40±17 years) with apparently idiopathic monomorphic VAs of right ventricular origin served as control group. Both groups underwent comprehensive cMRI study and were followed-up for a median of 14 months (25th–75th percentiles, 7–37 months). The outcome event was an arrhythmic composite end point of sudden cardiac death or nonfatal episode of ventricular fibrillation or sustained ventricular tachycardia requiring external cardioversion or appropriate implantable cardioverter defibrillator therapy. The 2 groups of patients did not differ in age (
P
=0.14) and sex (
P
=0.57). No significant difference was observed between patients with VAs of LV origin and VAs of right ventricular origin about biventricular volumes and systolic function. cMRI demonstrated myocardial structural abnormalities in 19 (41%) patients with VAs of LV origin versus 4 (5%) patients with VAs of right ventricular origin (
P
<0.001). The outcome event occurred in 9 patients; myocardial structural abnormalities on cMRI were significantly related to the outcome event (hazard ratio, 41.6; 95% confidence interval, 5.2–225.0;
P
<0.001).

Conclusions—
Myocardial structural changes are detected by cMRI in a non-negligible proportion of patients with apparently idiopathic monomorphic VAs of LV origin and are associated with worse outcome.
Real-Time Magnetic Resonance Assessment of Septal Curvature Accurately Tracks Acute Hemodynamic Changes in Pediatric Pulmonary Hypertension
Authors: Pandya Bejal , Quail Michael A. , Steeden Jennifer A. , McKee Andrea , Odille Freddy , Taylor Andrew M. , Schulze-Neick Ingram , Derrick Graham , Moledina Shahin , Muthurangu Vivek 
Published: April 2014

Background—
This study assesses the relationship between septal curvature and mean pulmonary artery pressure and indexed pulmonary vascular resistance in children with pulmonary hypertension. We hypothesized that septal curvature could be used to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics.

Methods and Results—

Fifty patients with a median age of 6.7 years (range, 0.45–16.5 years) underwent combined cardiac catheterization and cardiovascular magnetic resonance. The majority had idiopathic pulmonary arterial hypertension (n=30); the remaining patients had pulmonary hypertension associated with repaired congenital heart disease (n=17) or lung disease (n=3). Mean pulmonary artery pressure and pulmonary vascular resistance were acquired at baseline and during vasodilation. Septal curvature was measured using real-time cardiovascular magnetic resonance. There was a strong correlation between mean pulmonary artery pressure and
SC
min
at baseline and during vasodilator testing (
r
=–0.81 and –0.85, respectively;
P
<0.01). A strong linear relationship also existed between pulmonary vascular resistance and minimum septal curvature indexed to cardiac output both at baseline and during vasodilator testing (
r
=–0.88 and –0.87, respectively;
P
<0.01). Change in septal curvature metrics moderately correlated with absolute change in mean pulmonary artery pressure and pulmonary vascular resistance, respectively (
r
=0.58 and –0.74;
P
<0.01). Septal curvature metrics were able to identify vasoresponders with a sensitivity of 83% (95% confidence interval, 0.36–0.99) and a specificity of 91% (95% confidence interval, 0.77–0.97), using the Sitbon criteria. Idiopathic pulmonary arterial hypertension subgroup analysis revealed 3 responders with Δ
SC
min
values of 0.523, 0.551, and 0.568. If the middle value of 0.551 is taken as a cutoff, the approximate sensitivity would be 67% and the specificity would be 93%.

Conclusions—
Septal curvature metrics are able to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics during vasodilator testing. This suggests that septal curvature could be used for continuing assessment of load in pulmonary hypertension.
Nuclear Localization of α1A‐Adrenergic Receptors Is Required for Signaling in Cardiac Myocytes: An “Inside‐Out” α1‐AR Signaling Pathway
Authors: Wu Steven C. , Dahl Erika F. , Wright Casey D. , Cypher Andrew L. , Healy Chastity L. , O'Connell Timothy D. 
Published: April 2014

Background
Recent studies indicate that α1‐adrenergic receptors (α1‐ARs) are cardioprotective by preventing cardiac myocyte death and augmenting contractility in heart failure. Although G‐protein‐coupled receptors are assumed to localize to and signal at the plasma membrane, we previously demonstrated that endogenous α1‐ARs localize to the nuclei in adult cardiac myocytes. However, the functional consequence of this nuclear localization remains unclear. Here, we attempted to reconcile nuclear localization of α1‐ARs with their physiologic function by examining α1‐AR‐induced contractility in adult cardiac myocytes.

Methods and Results
By measuring shortening in unloaded, cultured adult cardiac myocytes, we found that the α1A‐subtype regulated contractility through phosphorylation of cardiac troponin I (cTnI) at the protein kinase C (PKC) site, threonine 144. Reconstitution of an α1A‐subtype nuclear localization mutant in cardiac myocytes lacking α1‐ARs failed to rescue nuclear α1A‐mediated phosphorylation of cTnI and myocyte contractility. Leptomycin B, the nuclear export inhibitor, also blocked α1A‐mediated phosphorylation of cTnI. These data indicate that α1‐AR signaling originates in the nucleus. Consistent with these observations, we localized the α1A‐subtype to the inner nuclear membrane, identified PKCα, δ, and ε in the nucleus, and found that α1‐ARs activate PKCδ in nuclei isolated from adult cardiac myocytes. Finally, we found that a PKCδ nuclear localization mutant blunted α1‐induced phosphorylation of cTnI.

Conclusions
Together, our data identify a novel, “inside‐out” nuclear α1A‐subtype/PKCδ/cTnI‐signaling pathway that regulates contractile function in adult cardiac myocytes. Importantly, these data help resolve the discrepancy between nuclear localization of α1‐ARs and α1‐AR‐mediated physiologic function.
The Association of Albuminuria With Tubular Reabsorption of Uric Acid: Results From a General Population Cohort
Authors: Scheven Lieneke , Joosten Michel M. , de Jong Paul E. , Bakker Stephan J. L. , Gansevoort Ron T. ,   For the PREVEND study group
Published: April 2014

Background
Elevated albuminuria as well as an increased serum uric acid concentration is associated with poor cardiovascular outcome. We questioned whether these 2 variables (albuminuria and serum uric concentration) may be interrelated via tubular uric acid reabsorption.

Methods and Results

Included were 7688 participants of the
PREVEND
Study, an observational, general population‐based cohort study. Linear regression analyses were used to test associations of baseline albuminuria with baseline serum uric acid concentration and tubular uric acid reabsorption (calculated as [100−fractional uric acid excretion]%). Cox regression analyses were used to study the association of baseline serum uric acid and albuminuria with incident cardiovascular morbidity and mortality. In cross‐sectional analyses, albuminuria was associated positively with serum uric acid concentration, both crude and after adjustment for potential confounders (both
P
<0.001). Albuminuria was found to be associated positively with tubular uric acid reabsorption, again both crude and after adjustment for potential confounders (both
P
<0.001). In longitudinal analyses during a median follow‐up of 10.5 years, 702 cardiovascular events occurred. After adjusting for cardiovascular risk factors, both albuminuria and serum uric acid were associated with incident cardiovascular events (Hazard Ratios 1.09 [1.03 to 1.17],
P
=0.01 and 1.19 [1.09 to 1.30],
P
<0.001, respectively). A significant interaction between these variables was present (
P
<0.001), consistent with high serum uric acid being less predictive for cardiovascular morbidity and mortality in the presence of high albuminuria and vice versa.

Conclusions
Albuminuria is strongly associated with tubular uric acid reabsorption, and consequently with serum uric acid concentration. This phenomenon may explain in part why albuminuria is associated with cardiovascular outcome.
The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Observational Follow‐Up Study: Benefits of RAS Blockade With Olmesartan Treatment Are Sustained After Study Discontinuation
Authors: Menne Jan , Ritz Eberhard , Ruilope Luis M. , Chatzikyrkou Christos , Viberti Giancarlo , Haller Hermann 
Published: April 2014

Background

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (
OM
) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria.

Methods and Results

One thousand seven hundred and fifty‐eight
ROADMAP
patients (placebo arm: 877;
OM
arm: 881) participated in the observational follow up (
OFU
) with an average of 3.3 years. They received standard medical care and micro‐ and macrovascular events were documented. During observational follow‐up 62.9% and 60.1% in the former
OM
and placebo group, respectively, received treatment with a
RAS
blocking agent. During the
OFU
period the systolic blood pressure (
SBP
) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during
ROADMAP
had a higher incidence of cardio‐ and cerebrovascular events (
OR
1.77,
CI
1.03 to 3.03,
P
=0.039) during the
OFU
period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former
OM
group (8 [0.9%] versus 23 [2.6%],
OR
: 0.34,
CI
0.15 to 0.78,
P
=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%],
OR
: 0.23,
CI
0.06 to 0.85,
P
=0.027) was reduced and there was a trend of reduced cardio‐/cerebrovascular events (
OM
versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2
CV
events) were reported in former placebo patients versus 3 (0.3%) (non‐
CV
events) in former
OM
patients.

Conclusions

Development of microalbuminuria is a valid marker for future
CV
events.
RAS
blockade with Olmesartan might cause sustained reduction (legacy effect) of micro‐ and macrovascular events.
Door‐to‐Puncture: A Practical Metric for Capturing and Enhancing System Processes Associated With Endovascular Stroke Care, Preliminary Results From the Rapid Reperfusion Registry
Authors: Sun Chung‐Huan J. , Ribo Marc , Goyal Mayank , Yoo Albert J. , Jovin Tudor , Cronin Carolyn A. , Zaidat Osama , Nogueira Raul , Nguyen Thanh , Hussain M. Shazam , Menon Bijoy K. , Mehta Brijesh , Jindal Gaurav , Horev Anat , Norbash Alexander , Leslie‐Mazwi Thabele , Wisco Dolora , Gupta Rishi 
Published: April 2014

Background

In 2011, the Brain Attack Coalition proposed door‐to‐treatment times of 2 hours as a benchmark for patients undergoing intra‐arterial therapy (
IAT
). We designed the Rapid Reperfusion Registry to capture the percentage of stroke patients who meet the target and its impact on outcomes.

Methods and Results

This is a retrospective analysis of anterior circulation patients treated with
IAT
within 9 hours of symptom onset. Data was collected from December 31, 2011 to December 31, 2012 at 2 centers and from July 1, 2012 to December 31, 2012 at 7 centers. Short “Door‐to‐Puncture” (D2P) time was hypothesized to be associated with good patient outcomes. A total of 478 patients with a mean age of 68±14 years and median National Institutes of Health Stroke Scale (NIHSS) of 18 (
IQR
14 to 21) were analyzed. The median times for
IAT
delivery were 234 minutes (
IQR
163 to 304) for “last known normal‐to‐groin puncture” time (
LKN
‐to‐
GP
) and 112 minutes (
IQR
68 to 176) for D2P time. The overall good outcome rate was 39.7% for the entire cohort. In a multivariable model adjusting for age,
NIHSS
, hypertension, diabetes, reperfusion status, and symptomatic hemorrhage, both short
LKN
‐to‐
GP
(
OR
0.996; 95%
CI
[0.993 to 0.998];
P
<0.001) and short D2P times (
OR
0.993, 95%
CI
[0.990 to 0.996];
P
<0.001) were associated with good outcomes. Only 52% of all patients in the registry achieved the targeted D2P time of 2 hours.

Conclusions

The time interval of D2P presents a clinically relevant time frame by which system processes can be targeted to streamline the delivery of
IAT
care nationally. At present, there is much opportunity to enhance outcomes through reducing D2P.