bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of Differentiation-Enhanced Photodynamic Therapy for Cancer: Upregulation of Coproporphyrinogen Oxidase by C/EBP Transcription Factors
Authors: Anand Sanjay , Hasan Tayyaba , Maytin Edward V. 
Published: May 2013

Abstract
The efficacy of photodynamic therapy (PDT) for epithelial cancers is increased when PDT is combined with calcitriol (Vit D), a form of differentiation therapy (DT). Here, we describe an underlying mechanism for this effect. Differentiation-promoting agents are known to upregulate CCAAT/enhancer–binding proteins (C/EBP), powerful regulators of cellular differentiation. In subcutaneous A431 tumors in mice, pretreatment with Vit D induced the expression of C/EBPβ isoforms, and of coproporphyrinogen oxidase (CPO), a heme pathway enzyme responsible for the conversion of 5-aminolevulinic acid (ALA) into protoporphyrin IX (PpIX), the principal light-absorbing molecule during PDT. To further investigate this apparent link between C/EBPs and CPO, two cell lines (MEL and LNCaP) were exposed to differentiating agents, and levels of PpIX, C/EBPs, and CPO were measured. Differentiating agents, or transfection of C/EBP expression vectors, increased C/EBP and CPO levels in parallel. Focusing on approximately 1,300 bp of upstream CPO gene promoter, we tested the ability of recombinant C/EBPα, C/EBPβ, C/EBPδ, and C/EBPζ to bind to CPO gene sequences [electrophoretic mobility shift assay (EMSA) assays] and to affect transcriptional activity (luciferase assays). Multiple C/EBP consensus binding sites were identified (15 for mouse, 18 for human). Individual probes representing each site bound to C/EBPs with characteristic affinities (strong, moderate, or weak), but when sites were inactivated in the context of the native promoter, transcriptional activity was reduced nearly equally for strong or weak sites. Cooperative interactions between regularly spaced C/EBP sites seem critical for CPO transcriptional regulation by differentiation therapy. These results provide a mechanistic rationale for DT/PDT combination therapy for cancer. Mol Cancer Ther; 12(8); 1638–50. ©2013 AACR.
Effect of Zileuton and Celecoxib on Urinary LTE4 and PGE-M Levels in Smokers
Authors: Mohebati Arash , Milne Ginger L. , Zhou Xi Kathy , Duffield-Lillico Anna J. , Boyle Jay O. , Knutson Allison , Bosworth Brian P. , Kingsley Philip J. , Marnett Lawrence J. , Brown Powel H. , Akpa Esther G. , Szabo Eva , Dannenberg Andrew J. 
Published: May 2013

AbstractCOX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P &lt; 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P &lt; 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4. Cancer Prev Res; 6(7); 646–55. ©2013 AACR.
Interleukin-6–Signal Transducer and Activator of Transcription-3 Signaling Mediates Aortic Dissections Induced by Angiotensin II via the T-Helper Lymphocyte 17–Interleukin 17 Axis in C57BL/6 Mice
Authors: Ju Xiaoxi , Ijaz Talha , Sun Hong , Ray Sutapa , Lejeune Wanda , Lee Chang , Recinos Adrian , Guo Dong-Chuan , Milewicz Dianna M. , Tilton Ronald G. , Brasier Allan R. 
Published: May 2013

Objective—
Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6–signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II–induced dissections in C57BL/6 mice.

Approach and Results—

Ang II infusion induced aortic dissections and CD4
+
-interleukin 17A (IL-17A)–expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6
−/−
mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II–infused mice with IL-17A–neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A–neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II–mediated aortic dissections occurred independent of blood pressure changes.

Conclusions—
Our results indicate that the IL-6–signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.
Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels
Authors: Motazacker Mohammad Mahdi , Peter Jorge , Treskes Marco , Shoulders Carol C. , Kuivenhoven Jan Albert , Hovingh G. Kees 
Published: May 2013

Objective—
There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes.

Approach and Results—

We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39;
P
=0.019) and normal HDL-C (odds ratio, 1.43;
P
=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23;
P
<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried ≥2 and ≥5 rare variants.

Conclusions—
This study suggests that most extreme HDL-C phenotypes have a polygenic origin.
Regional Density of Cardiologists and Rates of Mortality for Acute Myocardial Infarction and Heart Failure
Authors: Kulkarni Vivek T. , Ross Joseph S. , Wang Yongfei , Nallamothu Brahmajee K. , Spertus John A. , Normand Sharon-Lise T. , Masoudi Frederick A. , Krumholz Harlan M. 
Published: May 2013

Background—
Cardiologists are distributed unevenly across regions of the United States. It is unknown whether patients in regions with fewer cardiologists have worse outcomes after hospitalization for acute myocardial infarction (AMI) or heart failure (HF).

Methods and Results—
Using Medicare administrative claims data from 2010, we examined the relationship between regional density of cardiologists and risk of death after hospitalization for AMI and HF using hospitalizations for pneumonia as a comparison. We defined density as the number of cardiologists divided by population aged≥65 years within hospital referral regions, categorized into quintiles. Among 171 126 admissions for AMI, 352 853 admissions for HF, and 343 053 admissions for pneumonia, we tested associations between density of cardiologists and 30-day and 1-year mortality for each condition. We used 2-level hierarchical logistic regression models that adjusted for characteristics of patients and hospital referral regions. Patients hospitalized for AMI (odds ratios [OR], 1.13; 95% confidence interval [CI], 1.06–1.21) and HF (OR, 1.19; 95% CI, 1.12–1.27) in the lowest quintile of density had modestly higher 30-day mortality risk compared with patients in the highest quintile, unlike patients hospitalized for pneumonia (OR, 1.02; 95% CI, 0.96–1.09). Patients hospitalized for AMI (OR, 1.06; 95% CI, 1.00–1.12) and HF (OR, 1.09; 95% CI, 1.04–1.13) in the lowest quintile had slightly higher 1-year mortality risk, unlike patients hospitalized for pneumonia (OR, 1.00; 95% CI, 0.95–1.05).

Conclusions—
Patients hospitalized for AMI and HF in regions with a low density of cardiologists experienced modestly higher 30-day and 1-year mortality risk, unlike patients with pneumonia.
Prognostic Value of the Index of Microcirculatory Resistance Measured After Primary Percutaneous Coronary Intervention
Authors: Fearon William F. , Low Adrian F. , Yong Andy S. , McGeoch Ross , Berry Colin , Shah Maulik G. , Ho Michael Y. , Kim Hyun-Sook , Loh Joshua P. , Oldroyd Keith G. 
Published: May 2013

Background—
Most methods for assessing microvascular function are not readily available in the cardiac catheterization laboratory. The aim of this study is to determine whether the Index of Microcirculatory Resistance (IMR), measured at the time of primary percutaneous coronary intervention, is predictive of death and rehospitalization for heart failure.

Methods and Results—

IMR was measured immediately after primary percutaneous coronary intervention in 253 patients from 3 institutions with the use of a pressure–temperature sensor wire. The primary end point was the rate of death or rehospitalization for heart failure. The prognostic value of IMR was compared with coronary flow reserve, TIMI myocardial perfusion grade, and clinical variables. The mean IMR was 40.3±32.5. Patients with an IMR >40 had a higher rate of the primary end point at 1 year than patients with an IMR ≤40 (17.1% versus 6.6%;
P
=0.027). During a median follow-up period of 2.8 years, 13.8% experienced the primary end point and 4.3% died. An IMR >40 was associated with an increased risk of death or rehospitalization for heart failure (hazard ratio [HR], 2.1;
P
=0.034) and of death alone (HR, 3.95;
P
=0.028). On multivariable analysis, independent predictors of death or rehospitalization for heart failure included IMR >40 (HR, 2.2;
P
=0.026), fractional flow reserve ≤0.8 (HR, 3.24;
P
=0.008), and diabetes mellitus (HR, 4.4;
P
<0.001). An IMR >40 was the only independent predictor of death alone (HR, 4.3;
P
=0.02).

Conclusions—
An elevated IMR at the time of primary percutaneous coronary intervention predicts poor long-term outcomes.
New Generation of Flow Diverter (Surpass) for Unruptured Intracranial Aneurysms
Authors: De Vries Joost , Boogaarts Jeroen , Van Norden Anouk , Wakhloo Ajay K. 
Published: May 2013

Background and Purpose—
In patients harboring intracranial aneurysms, the major goal in treatment is to prevent bleeding. A new generation of an endoluminal device (Surpass Flow Diverter [Surpass]) was developed to reconstruct parent artery and occlude the aneurysm. We present our clinical and angiographic single-center experience.

Methods—
Patients with a wide range of complex unruptured aneurysms were treated with the Surpass placed in the parent artery and bridging the aneurysm. Clinical and angiographic follow-up were performed at 6 months. Data were prospectively collected.

Results—
Thirty seven patients (mean age, 56 years; range, 32–79), harboring 49 unruptured aneurysms were treated at our center. All except 1 patient were treated with a single device. Successful delivery of the device was achieved in all patients. All 35 nonbifurcation aneurysm necks were covered completely, whereas 14 bifurcation aneurysms were only partially covered. There was no major periprocedural morbidity or mortality. During follow-up, 4 patients (10.4%) experienced transient neurological deficit. One patient (3%) developed a minor stroke at 4-month follow-up with persistent neurological deficit. Twelve patients had neurological symptoms related to their aneurysm and 7 showed improvement of these symptoms during follow-up. At 6-month follow-up, 29 of 31 aneurysms studied that had complete neck coverage showed a complete occlusion (94%) including 1 case with a 95% to 100% occlusion, whereas 5 of the 10 bifurcation aneurysms were occluded.

Conclusions—
Our study shows high safety and efficacy profile of a new generation endoluminal device in treatment of complex intracranial aneurysms. Long-term studies of treated bifurcation aneurysms are needed.
Baseline Cognitive Function, Recurrent Stroke, and Risk of Dementia in Patients With Stroke
Authors: Rist Pamela M. , Chalmers John , Arima Hisatomi , Anderson Craig , MacMahon Stephen , Woodward Mark , Kurth Tobias , Tzourio Christophe 
Published: May 2013

Background and Purpose—
To determine the interrelationships between baseline Mini-Mental State Examination (MMSE) score and risk of overall dementia, post-recurrent stroke dementia, and dementia without recurrent stroke among patients with a history of stroke.

Methods—
Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories: 30, 29–27, 26–24, and <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE score and dementia.

Results—
Of the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 29–28, 1369 had a score of 26–24, and 450 had a score of <24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE score on the risk of dementia without recurrent stroke was much stronger than the impact of MMSE score on the risk of post-recurrent stroke dementia. For those with MMSE score <24, the risk of dementia without recurrent stroke was 47.89 (95% confidence interval, 28.57–80.26), whereas the risk of post-recurrent stroke dementia was only 7.17 (95% confidence interval, 3.70–13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia.

Conclusions—
Patients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.
Accuracy and Clinical Usefulness of Intracerebral Hemorrhage Grading Scores
Authors: Parry-Jones Adrian R. , Abid Kamran A. , Di Napoli Mario , Smith Craig J. , Vail Andy , Patel Hiren C. , King Andrew T. , Tyrrell Pippa J. 
Published: May 2013

Background and Purpose—
Various grading scores to predict survival after intracerebral hemorrhage (ICH) have been described. We aimed to test the accuracy and clinical usefulness of 3 well-known scores (original ICH score, modified ICH score, and ICH grading scale) in a large unselected cohort of typical ICH patients.

Methods—
A total of 1364 ICH cases were referred to our center from January 1, 2008, to October 17, 2010. Clinical details were prospectively recorded, and the first computed tomography brain scan was retrospectively reviewed to determine ICH volume and location and to identify intraventricular hemorrhage. The original ICH, ICH grading scale, and modified ICH score were calculated. Receiver operating characteristic and decision curves for 30-day mortality were generated.

Results—
A total of 1175 patients were included in the final analysis. All 3 scores and the Glasgow Coma Scale (GCS) divided cases into groups with highly significant differences in mortality. The area under the receiver operating characteristic curve was very similar for original ICH (0.861), ICH grading scale (0.874), and GCS (0.872), but was less for modified ICH score (0.824). Age was much less predictive (0.565). Combining GCS with age, log ICH volume, and intraventricular hemorrhage to derive a multifactorial risk of death at 30 days significantly increased the area under the receiver operating characteristic curve (0.897). All scores and GCS demonstrated a similar net benefit for threshold probabilities of 10% to 95%. Above 95%, the net benefit of GCS became inferior to the prognostic scores.

Conclusions—
Although existing grading scores are highly predictive of 30-day mortality, GCS alone was as predictive in our cohort, but age was not.
Nonrelevant Cerebral Atherosclerosis is a Strong Prognostic Factor in Acute Cerebral Infarction
Authors: Kim Jinkwon , Song Tae-Jin , Song Dongbeom , Lee Hye Sun , Nam Chung Mo , Nam Hyo Suk , Kim Young Dae , Heo Ji Hoe 
Published: May 2013

Background and Purpose—
We investigated whether the presence of nonrelevant cerebral atherosclerosis (NRCA) had prognostic value in patients with acute stroke.

Methods—
We compared prognosis in 780 consecutive patients with first-ever acute cerebral infarction who underwent cerebral angiography and diffusion-weighted MRI.

Results—

NRCA was present in 267 patients (34.2%). Multivariate analysis demonstrated that the presence of NRCA was independently associated with less improvement in National Institute of Health Stroke Scale score during the first 7 days (
P
=0.004), and a poor functional outcome (modified Rankin Scale score >2) after 3 months (odds ratio, 2.51; 95% confidence interval, 1.55–4.07). An increase in burden count of NRCA was also associated with poor outcomes.

Conclusions—
The presence and burden count of NRCA were associated with poor neurological outcomes in patients with acute cerebral infarction.
Endovascular Treatment of Intracranial Aneurysms in Elderly Patients
Authors: Sturiale Carmelo L. , Brinjikji Waleed , Murad Mohammad H. , Lanzino Giuseppe 
Published: May 2013

Background and Purpose—
Use of endovascular coiling for treatment of ruptured and unruptured intracranial aneurysms (IAs) in the elderly is increasing. We performed a meta-analysis of the literature examining clinical and angiographic outcomes for treatment of IAs in the elderly.

Methods—
We performed a comprehensive review of the literature from 1995 to 2012, reporting series of patients ≥65 years of age with ruptured or unruptured IAs treated with endovascular approach. Event rates were pooled across studies using random effects meta-analysis.

Results—

A total of 21 studies reporting on 1511 patients were included. Long-term aneurysm occlusion rates were 79% (95% confidence interval [CI], 70%–85%). Perioperative stroke occurred in 4% (95% CI, 3%–6%), with similar rates between patients with ruptured (5%; 95% CI, 3%–7%) and unruptured aneurysms (4%; 95% CI, 1%–14%;
P
=0.68). Intraprocedural rupture occurred in 1% (95% CI, 0%–3%) and 4% (95% CI, 2–6%;
P
=0.04) of patients with unruptured and ruptured aneurysms, respectively. Perioperative mortality rate for patients with ruptured aneurysms was 23% (95% CI, 17%–30%) and 1% (95% CI, 0%–6%) for patients with unruptured aneurysms (
P
<0.01). Rates of good clinical outcome at 1 year were 93% (95% CI, 88%–96%) and 66% (95% CI, 59%–72%) in patients with unruptured and ruptured aneurysms, respectively.

Conclusions—
This study suggests that endovascular treatment of IAs in the elderly is associated with high long-term occlusion rates. Given the morbidity and mortality associated with endovascular treatment of IAs in the elderly, careful patient selection, especially in the case of patients with unruptured aneurysm, is recommended.
Neuroprotection of Ischemic Postconditioning by Downregulating the Postsynaptic Signaling Mediated by Kainate Receptors
Authors: Liu Jing , Xu Qin , Wang Hui , Wang Ran , Hou Xiao-Yu 
Published: May 2013

Background and Purpose—
Ischemic postconditioning, a brief episode of ischemia after a prolonged ischemic insult, has been found to reduce the delayed neuronal loss after stroke. However, the mechanisms underlying such endogenous neuroprotective strategy remain obscure. In this study, we try to explore the excitatory postsynaptic signal events associated with neuroprotective effect of ischemic postconditioning.

Methods—
Global cerebral ischemia was induced for 15 minutes by the 4-vessel occlusion method in male Sprague–Dawley rats. Ischemic postconditioning was conducted 10 minutes later by a single reocclusion for 3 minutes.

Results—
A severe global cerebral ischemia after 5 days of reperfusion destroyed almost all hippocampal CA1 pyramidal neurons. A brief ischemic postconditioning robustly reduced the neuronal loss after ischemia. Preadministration of phosphoinositide 3-kinase inhibitor LY294002 blocked the neuroprotection of postconditioning, whereas mitogen-activated protein kinase kinase 1 inhibitor PD98059 had no effect. Ischemic postconditioning significantly increased the Akt phosphorylation (Ser473). In addition, postconditioning not only perturbed the binding of postsynaptic density protein-95 with glutamatergic kainate receptor subunit 2 and mixed lineage kinase 3 but also suppressed the downstream activation of mixed lineage kinase 3, mitogen-activated protein kinase kinase 7, and c-Jun N-terminal kinase 3. LY294002, but not PD98059, abolished the postconditioning-induced decreases in the assembly of glutamatergic kainate receptor subunit 2–postsynaptic density protein-95–mixed lineage kinase 3 complex and in the mixed lineage kinase 3–c-Jun N-terminal kinase 3 signaling. Akt inhibitor IV, a specific Akt inhibitor, showed the same effects as LY294002.

Conclusions—
Ischemic postconditioning protects neurons against stroke by attenuating the postsynaptic glutamatergic kainate receptor subunit 2–postsynaptic density protein-95–mixed lineage kinase 3–c-Jun N-terminal kinase 3 signal cascade via phosphoinositide 3-kinase–Akt pathway. (Stroke. 2013;44:2031-2035.)