bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nicotine and Carcinogen Exposure after Water Pipe Smoking in Hookah Bars
Authors: St. Helen Gideon , Benowitz Neal L. , Dains Katherine M. , Havel Christopher , Peng Margaret , Jacob Peyton 
Published: May 2014

Abstract
Background: Water pipe tobacco smoking is spreading globally and is increasingly becoming popular in the United States, particularly among young people. Although many perceive water pipe smoking to be relatively safe, clinical experimental studies indicate significant exposures to tobacco smoke carcinogens following water pipe use. We investigated biomarkers of nicotine intake and carcinogen exposure from water pipe smoking in the naturalistic setting of hookah bars.
Methods: Fifty-five experienced water pipe users were studied before and after smoking water pipe in their customary way in a hookah bar. Urine samples were analyzed for nicotine, cotinine, the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and mercapturic acid metabolites of volatile organic compounds (VOC).
Results: We found an average 73-fold increase in nicotine, 4-fold increase in cotinine, 2-fold increase in NNAL, and 14% to 91% increase in VOC mercapturic acid metabolites immediately following water pipe smoking. We saw moderate to high correlations between changes in tobacco-specific biomarkers (nicotine, cotinine, and NNAL) and several mercapturic acid metabolites of VOCs.
Conclusion: Water pipe smoking in a hookah bar is associated with significant nicotine intake and carcinogen exposure.
Impact: Given the significant intake of nicotine and carcinogens, chronic water pipe use could place users at increased risk of cancer and other chronic diseases. Cancer Epidemiol Biomarkers Prev; 23(6); 1055–66. ©2014 AACR.
PIK3R3 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Colorectal Cancer
Authors: Wang Guihua , Yang Xi , Li Chuan , Cao Xiaonian , Luo Xuelai , Hu Junbo 
Published: May 2014

Abstract
Class IA PI3K plays an essential role in the invasion and metastasis of cancer. However, the mechanisms and specific functions of PI3K isoforms in tumor invasion and metastasis are not fully understood. We evaluated the role of PIK3R3, a PI3K regulatory subunit encoded by the PIK3R3 gene, in colorectal cancer invasion and metastasis. Clinical specimens and cell lines data show that the expression level of PIK3R3 is associated with colorectal cancer metastasis. Overexpression of PIK3R3 increases tumor migration and invasion in vitro and promotes metastasis of colorectal cancers in vivo. Furthermore, we investigated that the overexpression of PIK3R3 depends on SNAI2, inducing significant epithelial-to-mesenchymal transition (EMT). Downregulation of PIK3R3 reverses this process, which possibly contributes to the enhanced invasive and metastasizing abilities of colorectal cancer cells. In this study, we found that PIK3R3 plays an important role in colorectal cancer metastasis and might be a potential and specific target for therapies against metastatic colorectal cancer. Mol Cancer Ther; 13(7); 1837–47. ©2014 AACR.
STAT3-Activated GM-CSFRα Translocates to the Nucleus and Protects CLL Cells from Apoptosis
Authors: Li Ping , Harris David , Liu Zhiming , Rozovski Uri , Ferrajoli Alessandra , Wang Yongtao , Bueso-Ramos Carlos , Hazan-Halevy Inbal , Grgurevic Srdana , Wierda William , Burger Jan , O'Brien Susan , Faderl Stefan , Keating Michael , Estrov Zeev 
Published: May 2014

Abstract
Here, it was determined that chronic lymphocytic leukemia (CLL) cells express the α subunit, but not the β subunit, of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR/CSF2R). GM-CSFRα was detected on the surface, in the cytosol, and in the nucleus of CLL cells via confocal microscopy, cell fractionation, and GM-CSFRα antibody epitope mapping. Because STAT3 is frequently activated in CLL and the GM-CSFRα promoter harbors putative STAT3 consensus binding sites, MM1 cells were transfected with truncated forms of the GM-CSFRα promoter, then stimulated with IL6 to activate STAT3 and to identify STAT3-binding sites. Chromatin immunoprecipitation (ChIP) and an electoromobility shift assay (EMSA) confirmed STAT3 occupancy to those promoter regions in both IL6-stimulated MM1 and CLL cells. Transfection of MM1 cells with STAT3-siRNA or CLL cells with STAT3-shRNA significantly downregulated GM-CSFRα mRNA and protein levels. RNA transcripts, involved in regulating cell survival pathways, and the proteins KAP1 (TRIM28) and ISG15 coimmunoprecipitated with GM-CSFRα. GM-CSFRα–bound KAP1 enhanced the transcriptional activity of STAT3, whereas GM-CSFRα-bound ISG15 inhibited the NF-κB pathway. Nevertheless, overexpression of GM-CSFRα protected MM1 cells from dexamethasone-induced apoptosis, and GM-CSFRα knockdown induced apoptosis in CLL cells, suggesting that GM-CSFRα provides a ligand-independent survival advantage.
Implications: Constitutively, activation of STAT3 induces the expression of GM-CSFRα that protects CLL cells from apoptosis, suggesting that inhibition of STAT3 or GM-CSFRα may benefit patients with CLL. Mol Cancer Res; 12(9); 1267–82. ©2014 AACR.
Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance
Authors: Guda Kishore , Fink Stephen P. , Milne Ginger L. , Molyneaux Neil , Ravi Lakshmeswari , Lewis Susan M. , Dannenberg Andrew J. , Montgomery Courtney G. , Zhang Shulin , Willis Joseph , Wiesner Georgia L. , Markowitz Sanford D. 
Published: May 2014

Abstract
HPGDand SLCO2A1 genes encode components of the prostaglandin catabolic pathway, with HPGD encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD-null mice show increased prostaglandin E2 (PGE2), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We, here, characterize a family with digital clubbing and early-onset colon neoplasia. Whole-exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in 3 males with digital clubbing. Two of these males further demonstrated notably early-onset colon neoplasia, 1 with an early-onset colon cancer and another with an early-onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M, whereas, female mutation carriers were in the normal range. Furthermore, in the male proband, urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD-null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early-onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man. Cancer Prev Res; 7(8); 805–12. ©2014 AACR.
PTEN-Deficient Tumors Depend on AKT2 for Maintenance and Survival
Authors: Chin Y. Rebecca , Yuan Xin , Balk Steven P. , Toker Alex 
Published: May 2014

Abstract
Loss of PTEN is a common event in many cancers and leads to hyperactivation of the PI3K–AKT signaling pathway. The mechanisms by which AKT isoforms mediate signaling to phenotypes associated with PTEN inactivation in cancer have not been defined. Here, we show that AKT2 is exclusively required for PTEN-deficient prostate tumor spheroid maintenance, whereas AKT1 is dispensable. shRNA silencing of AKT2 but not AKT1 promotes regression of prostate cancer xenografts. Mechanistically, we show that AKT2 silencing upregulates p21 and the proapoptotic protein BAX and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of AKT2 in mediating prostate tumor maintenance. Moreover, AKT2 is also exclusively required for the maintenance and survival of other PTEN-deficient solid tumors, including breast cancer and glioblastoma. These findings identify a specific function for AKT2 in mediating survival of PTEN-deficient tumors and provide a rationale for developing therapeutics targeting AKT2.
Significance: Depletion of AKT2, but not AKT1, induces potent tumor regression in PTEN-deficient prostate cancer xenografts, concomitant with upregulation of p21, which may serve as a potential biomarker for screening AKT2 activity in clinical samples. The specific role of AKT2 in tumor maintenance provides a rationale for the development of isoform-specific inhibitors for patients with PTEN-deficient cancers. Cancer Discov; 4(8); 942–55. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 855
Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping
Authors: Lou Qing , Hansen Brian J. , Fedorenko Olga , Csepe Thomas A. , Kalyanasundaram Anuradha , Li Ning , Hage Lori T. , Glukhov Alexey V. , Billman George E. , Weiss Raul , Mohler Peter J. , Györke Sándor , Biesiadecki Brandon J. , Carnes Cynthia A. , Fedorov Vadim V. 
Published: May 2014

Background—
Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF.

Methods and Results—

We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 μmol/L) markedly prolonged postpacing SAN conduction time in HF by 206±99 milliseconds (versus 66±21 milliseconds in controls;
P
=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (
P
=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1±28.9 versus 1.5±1.3 seconds;
P
<0.001). Furthermore, 10 μmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (
P
=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 μmol/L theophylline/1 μmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47±19%) and surrounding atrial myocardium (by 90±40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38±4% versus 23±4%;
P
<0.001).

Conclusions—
In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.
Association Between Antipsychotic Use and Risk of Acute Myocardial Infarction
Authors: Lin Shuai-Ting , Chen Cheng-Chung , Tsang Hin-Yeung , Lee Chee-Siong , Yang Pinchen , Cheng Kai-Da , Li Dian-Jeng , Wang Chin-Jen , Hsieh Yung-Chi , Yang Wei-Cheng 
Published: May 2014

Background—
Antipsychotic medications have been increasingly and more widely prescribed despite continued uncertainty about their association with the incidence of acute myocardial infarction (AMI).

Methods and Results—

We investigated the risk of AMI associated with antipsychotic treatment in 56 910 patients with schizophrenia, mood disorders, or dementia first hospitalized or visiting an emergency room for AMI in 1999 to 2009. A case-crossover design was used to compare the distributions of antipsychotic exposure for the same patient across 1 to 30 and 91 to 120 days just before the AMI event. Adjustments were made for comedications and outpatient visits. The adjusted odds ratio of AMI risk was 2.52 (95% confidence interval, 2.37–2.68) for any antipsychotics, 2.32 (95% confidence interval, 2.17–2.47) for first-generation antipsychotics, and 2.74 (95% confidence interval, 2.49–3.02) for second-generation antipsychotics. The risk significantly increased (
P
<0.001) with elevations in dosage and in short-term use (≤30 days). Male patients, elderly patients, and patients with dementia were at significantly increased risk (all
P
<0.001). Physically healthier patients with no preexisting diabetes mellitus, hypertension, or dyslipidemia were at significantly greater risk (
P
<0.001), largely because they had been exposed to higher doses of antipsychotics (
P
<0.001). A study of the selected binding of antipsychotics to 14 neurotransmitter receptors revealed only dopamine type 3 receptor antagonism to be significantly associated with AMI risk (adjusted odds ratio, 2.59; 95% confidence interval, 2.43–2.75;
P
<0.0001).

Conclusions—
Antipsychotic use may be associated with a transient increase in risk for AMI, possibly mediated by dopamine type 3 receptor blockades. Further education on drug safety and research into the underlying biological mechanisms are needed.
Efficacy of Long Detection Interval Implantable Cardioverter-Defibrillator Settings in Secondary Prevention Population
Authors: Kloppe Axel , Proclemer Alessandro , Arenal Angel , Lunati Maurizio , Martìnez Ferrer José Bautista , Hersi Ahmad , Gulaj Marcin , Wijffels Maurits C.E.F. , Santi Elisabetta , Manotta Laura , Mangoni Lorenza , Gasparini Maurizio 
Published: May 2014

Background—
Three trials demonstrated recently that a long detection window reduces implantable cardioverter-defibrillator (ICD) therapy in primary prevention patients. Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) was the only trial that enrolled both primary and secondary prevention patients.

Methods and Results—

Of the 1902 patients enrolled in the ADVANCE III trial, 477 received a defibrillator for secondary prevention; 248 patients were randomly assigned to a long detection setting (30 of 40 intervals) and 229 to the nominal setting (18 of 24 intervals) for ventricular arrhythmias with cycle length ≤320 ms. Eight-five percent of patients were men, with a mean age of 65±12 years, a previous history of ventricular fibrillation in 37% of the cases, and a mean ejection fraction of 38±13%. The ICD device mix was 37% single chamber, 47% dual chamber, and 16% triple chamber. Over a median period of 12 months, the long detection period was associated with a 25% reduction in the number of overall therapies (115.6 versus 86.8 per 100 patient-years; incidence rate ratio, 0.75; 95% confidence interval, 0.61–0.93;
P
=0.008) and a 34% reduction in the number of shocks (rate per 100 patient-years, 51.2 versus 38.1; incidence rate ratio, 0.66; 95% confidence interval, 0.48–0.89;
P
=0.007). Appropriate therapies (89.7 versus 67.7; incidence rate ratio, 0.77; 95% confidence interval, 0.60–0.97;
P
=0.029) and appropriate shocks (37.1 versus 28.1; incidence rate ratio, 0.64; 95% confidence interval, 0.45–0.93;
P
=0.018) were also reduced.

Conclusions—
ADVANCE III is the first randomized trial to assess a long detection window setting in ICDs in both primary and secondary prevention populations and demonstrates a reduction of overall therapies and shocks in the subgroup of secondary prevention patients. These data suggest that even the secondary prevention population may benefit from programming that combines a long detection period with antitachycardia pacing during charging.

Clinical Trial Registration—

URL:
http://www/clinicaltrials.gov
. Unique identifier: NCT00617175.
Haptoglobin 2‐2 Genotype is Not Associated With Cardiovascular Risk in Subjects With Elevated Glycohemoglobin—Results From the Bruneck Study
Authors: Pechlaner Raimund , Kiechl Stefan , Willeit Peter , Demetz Egon , Haun Margot , Weger Siegfried , Oberhollenzer Friedrich , Kronenberg Florian , Bonora Enzo , Weiss Günter , Willeit Johann 
Published: May 2014

Background

Haptoglobin (Hp) is an abundant plasma protein with antioxidant properties. The Hp 2‐2 genotype has previously been linked to coronary heart disease risk in individuals with elevated glycosylated hemoglobin (HbA
1c
). We investigated the association of Hp and HbA
1c
with cardiovascular disease (
CVD
) in the longitudinal, population‐based Bruneck Study.

Methods and Results

Hp genotype was determined by polymerase chain reaction according to standard procedures and HbA
1c
concentration by a Diabetes Control and Complications Trial‐aligned assay. HbA
1c
was measured in 1995, 2000, and 2005. Occurrence of the combined
CVD
endpoint of myocardial infarction or stroke was recorded between 1995 and 2010. Outcome analyses employed the Cox proportional hazards model with HbA
1c
category as time‐varying covariate. At baseline in 1995, 806 subjects (male sex, 49.3%; age, mean±standard deviation, 62.70±11.08 years) were included. During follow‐up, 123 subjects experienced at least 1
CVD
event (48 suffered myocardial infarction, 68 stroke, and 7 both). Among subjects with HbA
1c
≥6.5% (≥48 mmol/mol), those with the Hp 2‐2 genotype did not show an elevated risk of incident
CVD
compared with those with other genotypes (age‐ and sex‐adjusted hazard ratio [95%
CI
], 0.47 [0.19, 1.13],
P
=0.092) and a null association was also observed in subjects with HbA
1c
<6.5% (1.10 [0.75, 1.62],
P
=0.629) (
P
for interaction=0.082).

Conclusions

Subjects with the Hp 2‐2 genotype and elevated HbA
1c
compared with subjects with other Hp genotypes and elevated HbA
1c
did not show increased
CVD
risk.
The Retention of Manual Flying Skills in the Automated Cockpit
Authors: Casner Stephen M. , Geven Richard W. , Recker Matthias P. , Schooler Jonathan W. 
Published: May 2014

Objective: The aim of this study was to understand how the prolonged use of cockpit automation is affecting pilots’ manual flying skills. Background: There is an ongoing concern about a potential deterioration of manual flying skills among pilots who assume a supervisory role while cockpit automation systems carry out tasks that were once performed by human pilots. Method: We asked 16 airline pilots to fly routine and nonroutine flight scenarios in a Boeing 747-400 simulator while we systematically varied the level of automation that they used, graded their performance, and probed them about what they were thinking about as they flew. Results: We found pilots’ instrument scanning and manual control skills to be mostly intact, even when pilots reported that they were infrequently practiced. However, when pilots were asked to manually perform the cognitive tasks needed for manual flight (e.g., tracking the aircraft’s position without the use of a map display, deciding which navigational steps come next, recognizing instrument system failures), we observed more frequent and significant problems. Furthermore, performance on these cognitive tasks was associated with measures of how often pilots engaged in task-unrelated thought when cockpit automation was used. Conclusion: We found that while pilots’ instrument scanning and aircraft control skills are reasonably well retained when automation is used, the retention of cognitive skills needed for manual flying may depend on the degree to which pilots remain actively engaged in supervising the automation.
The clinical impact of orthotic correction of lower limb rotational deformities in children with cerebral palsy: a randomized controlled trial
Authors: Abd El-Kafy Ehab Mohamed 
Published: May 2014

Objective: This study aimed to evaluate the effectiveness of a static ground reaction ankle foot orthosis and strapping system on improving gait parameters in children with spastic diplegic cerebral palsy. Setting: The current study was conducted at the physical therapy faculty of Cairo University, Egypt. Subjects: This study included 57 children of both sexes, aged 6 to 8 years. Study design: Three-armed randomized control trial. Intervention: Participants in all groups received a traditional neuro-developmental physical therapy program that included standing and gait training exercises. Children in group A performed the training program without any orthotic management, in group B with the TheraTogs™ strapping system, and in group C with the TheraTogs™ strapping system and static ground reaction ankle foot orthoses. Children underwent treatment for two hours daily, except on weekends, for twelve successive weeks. Main measure: Gait speed, cadence, stride length, and hip and knee flexion angles in the mid-stance phase were evaluated pre-and post-treatment using a three-dimensional motion analysis system (pre-reflex system). Results: Statistically significant differences were recorded among the three groups post-treatment in gait speed, cadences, and stride length. The P-values for these variable differences were 0.03, 0.011, and 0.001 respectively. Significant post-treatment differences were also recorded for bilateral hip-and knee-flexion angles. For all measured parameters, better significant results were registered for group C than for the other groups. Conclusion: Orthotic intervention composed of a static ground reaction ankle foot orthosis combined with the TheraTogs™ strapping system improves gait more than conventional treatment with or without TheraTogs™ in children with spastic diplegic cerebral palsy.