bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib-Induced Unfolded Protein Response Increases Oncolytic HSV-1 Replication Resulting in Synergistic Antitumor Effects
Authors: Yoo Ji Young , Hurwitz Brian S. , Bolyard Chelsea , Yu Jun-Ge , Zhang Jianying , Selvendiran Karuppaiyah , Rath Kellie S. , He Shun , Bailey Zachary , Eaves David , Cripe Timothy P. , Parris Deborah S. , Caligiuri Michael A. , Yu Jianhua , Old Matthew , Kaur Balveen 
Published: May 2014

Abstract
Background: Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic herpes simplex virus-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for antitumor efficacy.
Experimental Design: The synergistic interaction between oHSV and bortezomib was calculated using Chou–Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western blot assays were used to evaluate induction of estrogen receptor (ER) stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Antitumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan–Meier curves and two-sided log-rank test.
Results: Combination treatment with bortezomib and oHSV (34.5ENVE), displayed strong synergistic interaction in ovarian cancer, head and neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK, and IRE1α (Western blot analysis) and the UPR (induction of hsp40, 70, and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (P &lt; 0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced antitumor efficacy in multiple different tumor models in vivo.
Conclusions: The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib-induced UPR and warrants future clinical testing in patients. Clin Cancer Res; 20(14); 3787–98. ©2014 AACR.
EW-7197, a Novel ALK-5 Kinase Inhibitor, Potently Inhibits Breast to Lung Metastasis
Authors: Son Ji Yeon , Park So-Yeon , Kim Sol-Ji , Lee Seon Joo , Park Sang-A. , Kim Min-Jin , Kim Seung Won , Kim Dae-Kee , Nam Jeong-Seok , Sheen Yhun Yhong 
Published: May 2014

Abstract
Advanced tumors produce an excessive amount of transforming growth factor β (TGFβ), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFβ therapeutics for cancer. We synthesized a novel small-molecule TGFβ receptor I kinase (activin receptor–like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 inhibited Smad/TGFβ signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic–grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFβ-treated breast cancer cells and 4T1 orthotopic–grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic–grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor–bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy. Mol Cancer Ther; 13(7); 1704–16. ©2014 AACR.
Regulation of SRC Kinases by microRNA-3607 Located in a Frequently Deleted Locus in Prostate Cancer
Authors: Saini Sharanjot , Majid Shahana , Shahryari Varahram , Tabatabai Z. Laura , Arora Sumit , Yamamura Soichiro , Tanaka Yuichiro , Dahiya Rajvir , Deng Guoren 
Published: May 2014

Abstract
Genomic studies suggest that deletions at chromosome (chr) 5q region (particularly chr5q14-q23) are frequent in prostate cancer, implicating this region in prostate carcinogenesis. However, the genes within this region are largely unknown. Here, we report for the first time the widespread attenuation of miR-3607, an miRNA gene located at chr5q14 region, in prostate cancer. Expression analyses of miR-3607 in a clinical cohort of prostate cancer specimens showed that miR-3607 is significantly attenuated and low miR-3607 expression is correlated with tumor progression and poor survival outcome in prostate cancer. Our analyses suggest that miR-3607 expression may be a clinically significant parameter with an associated diagnostic potential. We examined the functional significance of miR-3607 in prostate cancer cell lines and found that miR-3607 overexpression led to significantly decreased proliferation, apoptosis induction, and decreased invasiveness. Furthermore, our results suggest that miR-3607 directly represses oncogenic SRC family kinases LYN and SRC in prostate cancer. In view of our results, we propose that miR-3607 plays a tumor-suppressive role in prostate cancer by regulating SRC kinases that in turn regulates prostate carcinogenesis. To our knowledge, this is the first report that: (i) identifies a novel role for miR-3607 located in a frequently deleted region of prostate cancer and (ii) defines novel miRNA-mediated regulation of SRC kinases in prostate cancer. Because SRC kinases play a central role in prostate cancer progression and metastasis and are attractive targets, this study has potential implications in the design of better therapeutic modalities for prostate cancer management. Mol Cancer Ther; 13(7); 1952–63. ©2014 AACR.
The PARP Inhibitors, Veliparib and Olaparib, Are Effective Chemopreventive Agents for Delaying Mammary Tumor Development in BRCA1-deficient Mice
Authors: To Ciric , Kim Eun-Hee , Royce Darlene B. , Williams Charlotte R. , Collins Ryan M. , Risingsong Renee , Sporn Michael B. , Liby Karen T. 
Published: May 2014

Abstract
Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1Co/Co;MMTV-Cre;p53+/−) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. Cancer Prev Res; 7(7); 698–707. ©2014 AACR.
Circulating microparticles in carriers of prothrombin G20210A mutation
Authors: Campello Elena , Spiezia Luca , Radu Claudia , Gavasso Sabrina , Zerbinati Patrizia , Woodhams Barry , Simioni Paolo 
Published: May 2014

SummaryFactor V Leiden (FVL) and prothrombin gene mutation G20210A (PTM) are the two most common genetic polymorphisms known to predispose carriers to venous thromboembolism (VTE). A recent study in FVL carriers showed that circulating levels of microparticles (MP) may contribute to their thrombogenic profile. To further elucidate the prothrombotic state linked to genetic thrombophilia, we extended this study to carriers of PTM. The plasma level of annexin V-MP, endothelial- MP (EMP), platelet-MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) was measured in 124 carriers of PTM (105 heterozygous and 19 homozygous) and in 120 age- and gender-matched healthy individuals. Heterozygous and homozygous carriers of PTM showed significantly increased levels of annexin V-MP (2930 [1440–4646] MP/μl and 3064 [2412–4906] MP/μl, respectively) and significantly shorter PPL clotting time (54 [46–67] sec and 55 [46–64] sec) compared to controls (1728 [782–2122] MP/μl and 71 [61–75] sec, respectively; p<0.01). Similarly, heterozygous and homozygous subjects presented with significantly higher levels of EMP, PMP and TF+ than controls (p<0.05). PTM carriers with a VTE history had significantly higher MP numbers and activity than controls. No significant difference was seen between carriers with and without a VTE history. We conclude that the higher levels of circulating MP found in PTM carriers may play a role in the development of VTE possibly by increasing thrombin generation. Further studies are needed to better define the role of MP as triggering factors for the thrombotic complications characterizing mild genetic thrombophilic defects.
Evaluation of Interval Times From Onset to Reperfusion in Patients Undergoing Endovascular Therapy in the Interventional Management of Stroke III Trial
Authors: Goyal Mayank , Almekhlafi Mohammed A. , Fan Liqiong , Menon Bijoy K. , Demchuk Andrew M. , Yeatts Sharon D. , Hill Michael D. , Tomsick Thomas , Khatri Pooja , Zaidat Osama O. , Jauch Edward C. , Eesa Muneer , Jovin Tudor G. , Broderick Joseph P. 
Published: May 2014

Background—
Meaningful delays occurred in the Interventional Management of Stroke (IMS) III trial. Analysis of the work flow will identify factors contributing to the in-hospital delays.

Methods and Results—
In the endovascular arm of the IMS III trial, the following time intervals were calculated: stroke onset to emergency department arrival; emergency department to computed tomography (CT); CT to intravenous tissue plasminogen activator start; intravenous tissue plasminogen activator start to randomization; randomization to groin puncture; groin puncture to thrombus identification; thrombus identification to start of endovascular therapy; and start of endovascular therapy to reperfusion. The effects of enrollment time, CT angiography use, interhospital transfers, and intubation on work flow were evaluated. Delays occurred notably in the time intervals from intravenous tissue plasminogen activator initiation to groin puncture (median 84 minutes) and start of endovascular therapy to reperfusion (median 85 minutes). The CT to groin puncture time was significantly shorter during working hours than after. Times from emergency department to reperfusion and groin puncture to reperfusion decreased over the trial period. Patients with CT angiography had shorter emergency department to reperfusion and onset to reperfusion times. Transfer of patients resulted in a longer onset to reperfusion time compared with those treated in the same center. Age, sex, National Institutes of Health Stroke Scale score, and intubation did not affect delays.

Conclusions—
Important delays were identified before reperfusion in the IMS III trial. Delays decreased as the trial progressed. Use of CT angiography and endovascular treatment in the same center were associated with time savings. These data may help in optimizing work flow in current and future endovascular trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00359424.
Electrocardiographic Precordial ST‐Segment Deviations and the Risk of Cardiovascular Death: Results From the Copenhagen ECG Study
Authors: Rasmussen Peter Vibe , Nielsen Jonas Bille , Pietersen Adrian , Graff Claus , Lind Bent , Struijk Johannes Jan , Olesen Morten Salling , Haunsø Stig , Køber Lars , Svendsen Jesper Hastrup , Holst Anders Gaarsdal 
Published: May 2014

Background

We sought to perform a study assessing the association between electrocardiographic
ST
‐segment deviations and cardiovascular death (
CVD
), in relation to sex and age (≥ and <65 years), in a large primary care population without overt ischemic heart disease.

Methods and Results

Using computerized analysis of
ECG
s from 285 194 persons, we evaluated the association between precordial
ST
‐segment deviations and the risk of
CVD
. All data on medication, comorbidity, and outcomes were retrieved from
D
anish registries. After a median follow‐up period of 5.8 years, there were 6679 cardiovascular deaths. Increasing
ST
‐depression was associated with an increased risk of
CVD
in almost all of the precordial leads, with the most robust association seen in lead V5 to V6.
ST
‐elevations in lead V2 to V6 were associated with increased risk of
CVD
in young women, but not in men. However,
ST
‐elevations in V1 increased the risk for both genders and age groups, exemplified by a
HR
of 1.80 (95%
CI
[1.19 to 2.74],
P
=0.005) for men <65 years with
ST
‐elevations ≥150 μV versus a nondeviating
ST
‐segment (−50 μV to +50 μV). In contrast, for men <65 years,
ST
‐elevations in lead V2 to V3 conferred a decreased risk of
CVD
with a
HR
of 0.77 (95%
CI
[0.62 to 0.96],
P
<0.001) for
ST
‐elevations ≥150 μV in V2.

Conclusion

We found that
ST
‐depressions were associated with a dose‐responsive increased risk of
CVD
in nearly all the precordial leads.
ST
‐elevations conferred an increased risk of
CVD
in women and with regard to lead V1 also in men. However,
ST
‐elevations in V2 to V3 were associated with a decreased risk of
CVD
in young men.
Carotid Intima‐Media Thickness is Associated With Incident Heart Failure Among Middle‐Aged Whites and Blacks: The Atherosclerosis Risk in Communities Study
Authors: Effoe Valery S. , Rodriguez Carlos J. , Wagenknecht Lynne E. , Evans Gregory W. , Chang Patricia P. , Mirabelli Maria C. , Bertoni Alain G. 
Published: May 2014

Background

Increased carotid intima‐media thickness (
IMT
) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid
IMT
in heart failure (
HF
) risk determination.

Methods and Results

Mean far wall carotid
IMT
, measured by B‐mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of
HF
at baseline.
HF
was defined using
ICD
‐9 428 and
ICD
‐10 I‐50 codes from hospitalization records and death certificates. The association between carotid
IMT
and incident
HF
was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major
CVD
risk factors, and interim
CHD
. There were 2008 incident
HF
cases over a median follow‐up of 20.6 years (8.1 cases per 1000 person‐years). Mean
IMT
was higher in those with
HF
than in those without (0.81 mm±0.23 versus 0.71 mm±0.17,
P
<0.001). Unadjusted rate of
HF
for the fourth compared with the first quartile of
IMT
was 15.4 versus 3.9 per 1000 person‐years;
P
<0.001. In multivariable analysis, after adjustment, each standard deviation increase in
IMT
was associated with incident
HF
(
HR
1.20 [95%
CI
: 1.16 to 1.25]). After adjustment, the top quartile of
IMT
was associated with
HF
(
HR
1.60 [95%
CI
: 1.37 to 1.87]). Results were similar across race and gender groups.

Conclusions

Increasing carotid
IMT
is associated with incident
HF
in middle‐aged whites and blacks, beyond risks explained by major
CVD
risk factors and
CHD
. This suggests that carotid
IMT
may be associated with
HF
through mechanisms different from myocardial ischemia or infarction.
Cyclooxygenases 1 and 2 Differentially Regulate Blood Pressure and Cerebrovascular Responses to Acute and Chronic Intermittent Hypoxia: Implications for Sleep Apnea
Authors: Beaudin Andrew E. , Pun Matiram , Yang Christina , Nicholl David D. M. , Steinback Craig D. , Slater Donna M. , Wynne‐Edwards Katherine E. , Hanly Patrick J. , Ahmed Sofia B. , Poulin Marc J. 
Published: May 2014

Background

Obstructive sleep apnea (
OSA
) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (
IH
)‐induced inflammation. Cyclooxygenase (
COX
)‐formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (
CBF
), but their role in blood pressure and
CBF
responses to
IH
is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to
IH
.

Methods and Results

Twelve healthy, male participants underwent three, 6‐hour
IH
exposures. For 4 days before each
IH
exposure, participants ingested a placebo, indomethacin (nonselective
COX
inhibitor), or Celebrex
®
(selective
COX
‐2 inhibitor) in a double‐blind, randomized, crossover study design. Pre‐ and post‐
IH
blood pressure,
CBF
, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated
OSA
patients (n=33). Nonselective
COX
inhibition increased pre‐
IH
blood pressure (
P
≤0.04) and decreased pre‐
IH CBF
(
P
=0.04) while neither physiological variable was affected by
COX
‐2 inhibition (
P
≥0.90). Post‐
IH
,
MAP
was elevated (
P
≤0.05) and
CBF
was unchanged with placebo and nonselective
COX
inhibition. Selective
COX
‐2 inhibition abrogated the
IH
‐induced
MAP
increase (
P
=0.19), but resulted in lower post‐
IH CBF
(
P
=0.01). Prostanoids were unaffected by
IH
, except prostaglandin E
2
was elevated with the placebo (
P
=0.02). Finally,
OSA
patients had elevated blood pressure (
P
≤0.4) and
COX
‐1 formed thromboxane A
2
concentrations (
P
=0.02).

Conclusions

COX
‐2 and
COX
‐1 have divergent roles in modulating vascular responses to acute and chronic
IH
. Moreover,
COX
‐1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in
OSA
.

Clinical Trial Registration

URL:
www.clinicaltrials.gov
. Unique identifier: NCT01280006
Viewing Mount Laurel from Mount Zion: Theological Reflections on Social Integration
Authors: Brown Kevin , Stoddart Eric 
Published: May 2014

AbstractRacial segregation continues to be a staple of us social arrangements. However, the absence of a normative dimension to this phenomenon has allowed the value of segregation, or its conceptual opposite, integration to be determined by market forces. The result is that segregation is understood as an economic problem whose adverse effects can be ameliorated through efforts to integrate. We identify two primary problems with this approach. First, this conception risks bracketing out moral considerations related to exclusion. Secondly, under this paradigm, the rightness of integration is related to its consequence. In contrast, we argue for an inherent value to residential integration in itself and that a theological conception of relational autonomy can contribute to a more rich, morally engaged and motivating understanding of integration.
A Closed Marketplace: Religious Claims in the Public Square
Authors: Reynolds Terrence 
Published: May 2014

AbstractThis article argues that the rules governing religious contributions to public debates are unnecessarily restrictive and grounded in a faulty understanding of the nature of all truth claims. After critically assessing the current limits on arguments made in the public domain, this study analyses the Ramsey Colloquium’s statement on ‘The Homosexual Movement’ as a paradigmatic illustration of the difficulties that accompany the public proclamation of religious convictions. It suggests that the rules currently governing cultural conversations marginalize distinctive religious contributions and call into question the reality of a genuine marketplace of ideas.
Further Sensitivities of Orographic Precipitation to Terrain Geometry in Idealized Simulations
Authors: Watson Campbell D. , Lane Todd P. 
Published: May 2014

Abstract
This study examines how variations to the nondimensional mountain height Ĥ and the horizontal aspect ratio β of a straight ridge and a concave ridge influence orographic precipitation. An idealized three-dimensional model is used to simulate a moist flow impinging upon these two ridges with Ĥ = 0.66–2.0 and β = 1.0–8.0. The concave ridge generates substantially more precipitation than the straight ridge via an established precipitation-enhancing funneling mechanism near the ridge vertex when the flow is unblocked. Based on previous work, it was hypothesized that when the approaching flow becomes blocked, the strength of the precipitation enhancement by the concave ridge relative to the straight ridge becomes negligible. This study reveals that, if Ĥ is sufficiently large to induce flow reversal on the windward slope, then a secondary circulation develops that is strengthened by the concave ridge with a subsequent enhancement of precipitation. It is also shown that the competing effects of the ridge length and width render the strength of the precipitation enhancement largely insensitive to β. A flow regime diagram for the straight ridge and the concave ridge is also constructed to illustrate the sensitivity of the critical Ĥ value for flow regime transition to changes in the terrain geometry; variations to the low-level relative humidity are also explored.
Some Observing System Simulation Experiments with a Hybrid 3DEnVAR System for Storm-Scale Radar Data Assimilation
Authors: Gao Jidong , Stensrud David J. 
Published: May 2014

AbstractA hybrid three-dimensional ensemble–variational data assimilation (3DEnVAR) algorithm is developed based on the 3D variational data assimilation (3DVAR) and ensemble Kalman filter (EnKF) programs with the Advanced Regional Prediction System (ARPS). The method uses the extended control variable approach to combine the static and ensemble-derived flow-dependent forecast error covariances. The method is applied to the assimilation of simulated data from two radars for a supercell storm. Some sensitivity experiments are performed to answer questions about how flow-dependent covariance estimated from the forecast ensemble can be best used in the hybrid 3DEnVAR scheme. When the ensemble size is relatively small (with 5 or 10 ensemble members), it is found that experiments with a weaker weighting value for the ensemble covariance leads to better analysis results. Even when severe sampling errors exist, introducing ensemble-estimated covariances into the variational method still benefits the analysis. For reasonably large ensemble sizes (50–100 members), a stronger relative weighting (>0.8) for the ensemble covariance leads to better analyses from the hybrid 3DEnVAR. In addition, the sensitivity experiments also indicate that the best results are obtained when the number of the augmented control variables is a function of three spatial dimensions and ensemble members, and is the same for all analysis variables.