bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer
Authors: Yu Ziyang , Chen Sen , Sowalsky Adam G. , Voznesensky Olga S. , Mostaghel Elahe A. , Nelson Peter S. , Cai Changmeng , Balk Steven P. 
Published: January 2014

Abstract
Purpose: Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer; CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.
Experimental Design: Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.
Results: AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (&lt;1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.
Conclusions: AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain. Clin Cancer Res; 20(6); 1590–600. ©2014 AACR.
Novel ATP-Competitive MEK Inhibitor E6201 Is Effective against Vemurafenib-Resistant Melanoma Harboring the MEK1-C121S Mutation in a Preclinical Model
Authors: Narita Yusuke , Okamoto Kiyoshi , Kawada Megumi Ikemori , Takase Kazuma , Minoshima Yukinori , Kodama Kotaro , Iwata Masao , Miyamoto Norimasa , Sawada Kohei 
Published: January 2014

Abstract
Many clinical cases of acquired resistance to the BRAF inhibitor vemurafenib have recently been reported. One of the causes of this acquired resistance is the BRAF downstream kinase point mutation MEK1-C121S. This mutation confers resistance to not only vemurafenib, but also to the allosteric MEK inhibitor selumetinib (AZD6244). Here, we investigated the pharmacologic activities and effectiveness of the novel MEK inhibitor E6201 against BRAF (v-raf murine sarcoma viral oncogene homolog B1)-V600E mutant melanoma harboring the MEK1-C121S mutation. A cell-free assay confirmed that E6201 is an ATP-competitive MEK inhibitor, meaning it has a different binding mode with MEK compared with allosteric MEK inhibitors. E6201 is more effective against BRAF-V600E mutant melanoma compared with BRAF wild-type melanoma based on MEK inhibition. We found that the acquired MEK1-C121S mutation in BRAF-V600E mutant melanoma conferred resistance to both vemurafenib and selumetinib but not E6201. The effectiveness of E6201 in this preclinical study is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable to influence the MAPK pathway inhibitory activity. These results support further clinical investigation of E6201. Mol Cancer Ther; 13(4); 823–32. ©2014 AACR.
Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells
Authors: Eritja Nuria , Domingo Mónica , Dosil Maria Alba , Mirantes Cristina , Santacana Maria , Valls Joan , Llombart-Cussac Antonio , Matias-Guiu Xavier , Dolcet Xavier 
Published: January 2014

Abstract
Mutations in fibroblast growth factor receptor 2 (FGFR2) have been recently described as a molecular-specific feature in endometrial carcinomas and the presence of activated FGFR2 mutations is associated with poor prognosis. For that reason, inhibition of FGFR2 could be a therapeutic target in the treatment of endometriod carcinomas. In this work, we investigated the antitumoral activity of dovitinib (a multiple kinase inhibitor) in human endometrial cancer cell (ECC) lines. We found that dovitinib caused cell growth arrest, loss of clonogenic growth, and cell-cycle arrest in FGFR2-mutated ECCs in in vitro and in vivo experiments. Next, we investigated the mechanistic basis of dovitinib effects. We could determine that dovitinib modified expression levels of well-known key cell-cycle regulatory proteins that induce cellular senescence. To further investigate the role of dovitinib, we analyzed its effect on estrogen receptor α (ER-α) expression. Surprisingly, we discovered that dovitinib enhances ER-α expression in FGFR2-mutant ECCs. Because blocking one signaling pathway is often not sufficient to cause total tumor regression and the effectiveness of individual inhibitors is often short-lived, we examined the impact of targeting FGFR2 with dovitinib in combination with a selective ER antagonist, fulvestrant (ICI182.780). Combination of dovitinib plus ICI182.780 resulted in a significantly higher inhibition of cell growth than dovitinib treatment alone. These findings suggest that combinatory therapies using dovitinib plus ICI182.780 treatment can be truly effective in patients with endometrial carcinomas carrying FGFR2 mutations. Mol Cancer Ther; 13(4); 776–87. ©2014 AACR.
Benign Breast and Gynecologic Conditions, Reproductive and Hormonal Factors, and Risk of Thyroid Cancer
Authors: Braganza Melissa Z. , Berrington de González Amy , Schonfeld Sara J. , Wentzensen Nicolas , Brenner Alina V. , Kitahara Cari M. 
Published: January 2014

AbstractThe higher incidence of thyroid cancer in women compared with men suggests an influence of sex steroid hormones in the etiology of this malignancy. We investigated a comprehensive set of potential indicators of lifetime sex steroid hormone exposure in relation to thyroid cancer risk. Using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, which enrolled 70,047 women, 50 to 78 years old, we prospectively examined associations of self-reported history of benign breast and gynecologic conditions, reproductive factors, and exogenous sex hormone use with thyroid cancer risk. Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated in models using age as the time metric. During follow-up (median, 11 years), 127 women were diagnosed with first primary thyroid cancer. Older age at natural menopause (≥55 vs. &lt;50 years; HR, 2.24; 95% CI, 1.20–4.18), greater estimated lifetime number of ovulatory cycles (≥490 vs. &lt;415 cycles; HR, 2.40; 95% CI, 1.33–4.30), greater number of live births (≥5 vs. 1–2; HR, 1.72; 95% CI, 1.05–2.82), and history of uterine fibroids (HR, 1.72; 95% CI, 1.18–2.50) were associated with an increased risk of thyroid cancer. Earlier age at menarche, greater number of reproductive years, history of a tubal ligation, and history of ovarian cysts were nonsignificantly associated with increased thyroid cancer risk. No associations were observed for oral contraceptive use, menopausal hormone therapy, or history of benign breast disease or endometriosis. In general, we found that factors reflecting a greater length of exposure to endogenous hormones, particularly during the reproductive years, were associated with risk of postmenopausal thyroid cancer. Cancer Prev Res; 7(4); 418–25. ©2014 AACR.
Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy
Authors: Tersteeg Claudia , de Maat Steven , De Meyer Simon F. , Smeets Michel W.J. , Barendrecht Arjan D. , Roest Mark , Pasterkamp Gerard , Fijnheer Rob , Vanhoorelbeke Karen , de Groot Philip. G. , Maas Coen 
Published: January 2014

Background—
Von Willebrand factor (VWF) multimer size is controlled through continuous proteolysis by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type I motif, member 13). This prevents spontaneous platelet agglutination and microvascular obstructions. ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura, in which life-threatening episodes of microangiopathy damage kidneys, heart, and brain. Enigmatically, a complete ADAMTS13 deficiency does not lead to continuous microangiopathy. We hypothesized that plasmin, the key enzyme of the fibrinolytic system, serves as a physiological backup enzyme for ADAMTS13 in the degradation of pathological platelet–VWF complexes.

Methods and Results—

Using real-time microscopy, we determined that plasmin rapidly degrades platelet–VWF complexes on endothelial cells in absence of ADAMTS13, after activation by urokinase-type plasminogen activator or the thrombolytic agent streptokinase. Similarly, plasmin degrades platelet–VWF complexes in platelet agglutination studies. Plasminogen directly binds to VWF and its A1 domain in a lysine-dependent manner, as determined by enzyme-linked immunosorbent assay. Plasma levels of plasmin–α
2
-antiplasmin complexes increase with the extent of thrombocytopenia in patients with acute episodes of thrombotic thrombocytopenic purpura, independent of ADAMTS13 activity. This indicates that plasminogen activation takes place during microangiopathy. Finally, we show that the thrombolytic agent streptokinase has therapeutic value for
Adamts13
−/−
mice in a model of thrombotic thrombocytopenic purpura.

Conclusions—
We propose that plasminogen activation on endothelial cells acts as a natural backup for ADAMTS13 to degrade obstructive platelet–VWF complexes. Our findings indicate that thrombolytic agents may have therapeutic value in the treatment of microangiopathies and may be useful to bypass inhibitory antibodies against ADAMTS13 that cause thrombotic thrombocytopenic purpura.
IL‐6 Regulates Extracellular Matrix Remodeling Associated With Aortic Dilation in a Fibrillin‐1 Hypomorphic mgR/mgR Mouse Model of Severe Marfan Syndrome
Authors: Ju Xiaoxi , Ijaz Talha , Sun Hong , LeJeune Wanda , Vargas Gracie , Shilagard Tuya , Recinos Adrian , Milewicz Dianna M. , Brasier Allan R. , Tilton Ronald G. 
Published: January 2014

Background
Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin‐6 (IL‐6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin‐deficient mice (mgR/mgR).

Methods and Results

MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7±0.1 and 1.3±0.1 for mgR/mgR versus wild‐type mice, respectively;
P
<0.001). IL‐6 signaling was increased in mgR/mgR aortas measured by increases in IL‐6 and SOCS3 mRNA transcripts (
P
<0.05) and in cytokine secretion of IL‐6, MCP‐1, and GM‐CSF (
P
<0.05). To investigate the role of IL‐6 signaling, we generated mgR homozygous mice with IL‐6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial‐adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase‐9 and had significantly reduced aortic dilation (1.0±0.1 versus 1.6±0.2 mm change from baseline, DKO versus mgR/mgR,
P
<0.05) that did not affect rupture and survival.

Conclusion
Activation of IL‐6‐STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP‐9 activity, aggravating extracellular matrix degradation.
Prevention Opportunities for Oral Contraceptive–Associated Ischemic Stroke
Authors: Ryan Kathleen A. , Cole John W. , Saslow Keely , Mitchell Braxton D. , McArdle Patrick F. , Sparks Mary J. , Cheng Yu-Ching , Kittner Steven J. 
Published: January 2014

Background and Purpose—
Literature suggests a small increased risk of ischemic stroke with oral contraception (OC) use. We evaluated the association of stroke and OC use in women on the basis of whether they recalled being advised by a physician not to use OC or to discontinue OC use because of the presence of stroke risk modifiers, and whether such advice resulted in behavioral change.

Methods—
A total of 572 women (224 strokes and 348 controls) aged 15 to 49 years were interviewed about OC use and risk modifiers, including cigarette smoking and headaches, among others.

Results—
The adjusted odds ratio for OC use and stroke was 2.00 (95% confidence interval, 1.29–3.09). The association of OC use with stroke was stronger in women that reported receiving doctor’s advice against OC use because of the presence of other stroke risk modifiers (odds ratio, 3.12; 95% confidence interval, 1.62–6.00) than in women who did not recall receiving such advice (odds ratio, 1.31; 95%confidence interval, 0.71–2.43). Of 256 women who recalled being advised by their doctor not to start OC or to discontinue OC use because of the presence of other stroke risk modifiers, 24% were still on OC at the time of stroke or interview.

Conclusions—
We confirm that certain medical conditions increase the risk of stroke during OC use and demonstrate the importance of physician counseling in those using OC in the setting of concurrent high-risk conditions and the need for improved patient compliance with such counseling.
Homocysteine as a Predictor of Early Neurological Deterioration in Acute Ischemic Stroke
Authors: Kwon Hyung-Min , Lee Yong-Seok , Bae Hee-Joon , Kang Dong-Wha 
Published: January 2014

Background and Purpose—
Hyperhomocysteinemia is a well-known risk factor for vascular disease. However, its action, mechanism, and role in the acute phase of stroke have not been determined. We tried to determine whether an association existed between elevated serum homocysteine levels and early neurological deterioration (END) in patients with acute ischemic stroke.

Methods—
We performed a secondary analysis from the Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial, which was a double-blinded, randomized, multicenter trial, assessing the noninferiority of cilostazol over aspirin within 48 hours of an acute ischemic stroke. END was defined as an increase of ≥1 point in motor power or an increase of ≥2 points in the total National Institute of Health Stroke Scale score within 7 days.

Results—

The mean (±SD) serum homocysteine level was 11.4±4.7 μmol/L. Of the 396 patients studied, 57 (14.4%) patients worsened during the 7 days after inclusion. Most (68%) of the END cases occurred within the first 24 hours after treatment. High levels (>10.3 μmol/L) of serum homocysteine were independent predictors for END (third quartile odds ratio, 3.45; 95% confidence intervals, 1.25–9.50;
P
=0.016; fourth quartile odds ratio, 3.36; 95% confidence intervals 1.18–9.52;
P
=0.023) in multivariate analysis.

Conclusions—
Patients with acute stroke with elevated serum homocysteine levels are at an increased risk for END.
Cloud and Radiative Balance Changes in Response to ENSO in Observations and Models
Authors: Radley Claire , Fueglistaler Stephan , Donner Leo 
Published: January 2014

AbstractThe authors use observations and four GFDL AGCMs to analyze the relation between variations in spatial patterns and area-averaged quantities in the top-of-the-atmosphere radiative fluxes, cloud amount, and precipitation related to El Niño over the period 1979–2008. El Niño is associated with an increase in tropical average sea surface temperature of order +0.1 K (with a maxima of +0.5 K), large local anomalies of +2 K (maxima +6 K), and tropical tropospheric warming of +0.5 K (maxima +1 K). The authors find that model-to-observation biases in the base state translate into corresponding biases in anomalies in response to El Niño. The pattern and amplitude of model biases in reflected shortwave (SW) and outgoing longwave radiation (OLR) follows expectations based on their biases in cloud amount: models with a positive cloud amount bias, compared to observations, have too strong local responses to El Niño in cloud amount, SW, OLR, and precipitation.Tropical average OLR increases in response to El Niño in observations and models [correlation coefficients (r) with Niño-3.4 index in the range 0.4–0.6]. Weaker correlations are found for SW (r: −0.6 to 0), cloud amount (r: −0.2 to +0.1), and precipitation (r: −0.2 to 0). Compositing El Niño events over the period 2001–07 yields similar results. These results are consistent with El Niño periods being warmer due to a heat pulse from the ocean, and a weak response in clouds and their radiative effect. These weak responses occur despite a large rearrangement in the spatial structure of the tropical circulation, and despite substantial differences in the mean state of observations and models.
Spatial Analyses of the 2011 Joplin Tornado Mortality: Deaths by Interpolated Damage Zones and Location of Victims
Authors: Kanti Paul Bimal , Stimers Mitchel 
Published: January 2014

Abstract
On 22 May 2011, a massive tornado tore through a densely populated section of Joplin, Missouri, killing 162 people. The EF5 tornado was the deadliest single tornado to occur in the United States since modern record keeping began in 1950, surpassing the tornado of 8 June 1953, which claimed 116 lives in Flint, Michigan. The Joplin tornado death toll was also far higher than the average annual number of deaths caused by tornadoes in the United States between 2000 and 2011. This study analyzed Joplin deaths by damage zone and place of death. Tabular data collected primarily from secondary sources revealed the number of deaths and death rates differ significantly by zone of destruction. The central zone (labeled as “catastrophic”) had the most deaths, with the number decreasing systematically in both directions from the center of that zone. The results of this study further show that more people died in nonresidential buildings in Joplin than is usual in a U.S. tornado event, calling into question how well such structures protect occupants. Finally, the lack of basements in residential and other structures most likely contributed greatly to the high death toll, although the degree remains uncertain. Several recommendations are offered to reduce future U.S. tornado fatalities.
A comparison of ethical issues in nursing practice across nursing units
Authors: Park Mihyun , Jeon Sang Hee , Hong Hyun-Ja , Cho Sung-Hyun 
Published: January 2014

Background: The complexity and variety of ethical issues in nursing is always increasing, and those issues lead to special concerns for nurses because they have critical impacts on nursing practice. Research objectives: The purpose of this study was to gather comprehensive information about ethical issues in nursing practice, comparing the issues in different types of nursing units including general units, oncology units, intensive care units, operating rooms, and outpatient departments. Research design: The study used a descriptive research design. Ethics/human rights issues encountered by nurses in their daily nursing practice were identified by using the Ethical Issues Scale. Participants: The study sample included 993 staff nurses working in a university hospital in South Korea. Ethical considerations: This study was approved by the University Institutional Review Board. Completed questionnaires were returned sealed with signed informed consent. Findings: The most frequently and disturbingly encountered issues across nursing units were “conflicts in the nurse–physician relationship,” “providing care with a possible risk to your health,” and “staffing patterns that limit patient access to nursing care.” The findings of this study showed that nurses from different nursing units experienced differences in the types or frequency of ethical issues. In particular, intensive care units had the greatest means of all the units in all three component scales including end-of-life treatment issues, patient care issues, and human rights issues. Discussion: Nurses experienced various ethical challenges in their daily practice. Of the ethical issues, some were distinctively and frequently experienced by nurses in a specific unit. Conclusion: This study suggested that identifying and understanding specific ethical issues faced by nurses in their own areas may be an effective educational approach to motivate nurses and to facilitate nurses’ reflection on their experiences.
Revisiting the Convergence Hypothesis of Tourism Markets: Evidence from South Africa
Authors: Solarin Sakiru Adebola 
Published: January 2014

The purpose of this article is to examine the convergence hypothesis in South Africa’s tourism markets over the period January 2000–December 2011. To check the existence of convergence, the study follows existing papers by applying a unit root test on the difference series and a cointegration test on the original series of visitor arrivals. Premised on geographical dimension, we further investigate cluster-based convergence within African and overseas source markets in South Africa. The results provide evidence for long-run convergence in tourism markets. Furthermore, the findings of cluster-based convergence provide greater support for the convergence within African and overseas source markets, respectively. These findings imply that previous policies aimed at boosting total visitor arrivals in South Africa have been successful, and maintaining such (or similar) strategies may continue to enhance international visitor arrivals in the country. JEL Classification: L83, O47, O55
Australia and the system of arbitration in Singapore
Authors: Leggett Chris , Stewart Gordon 
Published: January 2014

AbstractThe purpose of this article is to record and analyse the historical circumstances in which Singapore complemented its legacy of British-type collective bargaining with the compulsory arbitration system long practiced in Australia. It notes the role of Australians (particularly one Australian industrial relations scholar at the University of Malaya) in the inception and adoption of industrial arbitration in Singapore. It seeks to identify, analyse, explain and assess the extent of the subsequent divergence of Singapore’s regulatory industrial relations regime from that of Australia since the 1960s. In doing so, it contributes to Asia-Pacific labour history and adds to the literature on international and comparative labour relations with its focus on cross-national influences on national industrial relations regimes.