bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomere Length in Peripheral Blood Leukocytes and Lung Cancer Risk: A Large Case–Control Study in Caucasians
Authors: Sanchez-Espiridion Beatriz , Chen Meng , Chang Joe Y. , Lu Charles , Chang David W. , Roth Jack A. , Wu Xifeng , Gu Jian 
Published: March 2014

Abstract
Telomere dysfunction is a crucial event in malignant transformation and tumorigenesis. Telomere length in peripheral blood leukocytes has been associated with lung cancer risk, but the relationship has remained controversial. In this study, we investigated whether the association might be confounded by study of different histological subtypes of lung cancer. We measured relative telomere lengths in patients in a large case–control study of lung cancer and performed stratified analyses according to the two major histologic subtypes [adenocarcinoma and squamous cell carcinoma (SCC)]. Notably, patients with adenocarcinoma had longer telomeres than controls, whereas patients with SCC had shorter telomeres compared with controls. Long telomeres were associated with increased risk of adenocarcinoma, with the highest risk associated with female sex, younger age (&lt;60 years), and lighter smoking (&lt;30 pack-years). In contrast, long telomeres were protective against SCC, particularly in male patients. Our results extend the concept that telomere length affects risk of lung cancer in a manner that differs with histologic subtype. Cancer Res; 74(9); 2476–86. ©2014 AACR.
Gastric Cancer: Descriptive Epidemiology, Risk Factors, Screening, and Prevention
Authors: Karimi Parisa , Islami Farhad , Anandasabapathy Sharmila , Freedman Neal D. , Kamangar Farin 
Published: March 2014

Abstract
Less than a century ago, gastric cancer was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, gastric cancer remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of gastric cancer, including its incidence, survival, mortality, and trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serologic markers and histological precursor lesions of gastric cancer and early detection of gastric cancer using these markers are reviewed. Finally, we discuss prevention strategies and provide suggestions for further research. Cancer Epidemiol Biomarkers Prev; 23(5); 700–13. ©2014 AACR.
Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies
Authors: Zhang Weiguo , Gao Chen , Konopleva Marina , Chen Ye , Jacamo Rodrigo O. , Borthakur Gautam , Cortes Jorge E. , Ravandi Farhad , Ramachandran Abhijit , Andreeff Michael 
Published: March 2014

Abstract
Purpose: FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy.
Experimental Design: Acquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD–mutated AML patient samples.
Results: We identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines.
Conclusions: These combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML. Clin Cancer Res; 20(9); 2363–74. ©2014 AACR.
Nullifying the CDKN2AB Locus Promotes Mutant K-ras Lung Tumorigenesis
Authors: Schuster Katja , Venkateswaran Niranjan , Rabellino Andrea , Girard Luc , Peña-Llopis Samuel , Scaglioni Pier Paolo 
Published: March 2014

Abstract
Lung cancer commonly displays a number of recurrent genetic abnormalities, and about 30% of lung adenocarcinomas carry activating mutations in the Kras gene, often concomitantly with inactivation of tumor suppressor genes p16INK4A and p14ARF of the CDKN2AB locus. However, little is known regarding the function of p15INK4B translated from the same locus. To determine the frequency of CDKN2AB loss in human mutant KRAS lung cancer, The Cancer Genome Atlas (TCGA) database was interrogated. Two-hit inactivation of CDKN2A and CDKN2B occurs frequently in patients with mutant KRAS lung adenocarcinoma. Moreover, p15INK4B loss occurs in the presence of biallelic inactivation of p16INK4A and p14ARF, suggesting that p15INK4B loss confers a selective advantage to mutant KRAS lung cancers that are p16INK4A and p14ARF deficient. To determine the significance of CDKN2AB loss in vivo, genetically engineered lung cancer mouse models that express mutant Kras in the respiratory epithelium were utilized. Importantly, complete loss of CDKN2AB strikingly accelerated mutant Kras–driven lung tumorigenesis, leading to loss of differentiation, increased metastatic disease, and decreased overall survival. Primary mutant Kras lung epithelial cells lacking Cdkn2ab had increased clonogenic potential. Furthermore, comparative analysis of mutant Kras;Cdkn2a null with Kras;Cdkn2ab null mice and experiments with mutant KRAS;CDKN2AB–deficient human lung cancer cells indicated that p15INK4B is a critical tumor suppressor. Thus, the loss of CDKN2AB is of biologic significance in mutant KRAS lung tumorigenesis by fostering cellular proliferation, cancer cell differentiation, and metastatic behavior.
Implications: These findings indicate that mutant Kras;Cdkn2ab null mice provide a platform for accurately modeling aggressive lung adenocarcinoma and testing therapeutic modalities. Mol Cancer Res; 12(6); 912–23. ©2014 AACR.
Molecular Profiling of Premalignant Lesions in Lung Squamous Cell Carcinomas Identifies Mechanisms Involved in Stepwise Carcinogenesis
Authors: Ooi Aik T. , Gower Adam C. , Zhang Kelvin X. , Vick Jessica L. , Hong Longsheng , Nagao Brian , Wallace W. Dean , Elashoff David A. , Walser Tonya C. , Dubinett Steven M. , Pellegrini Matteo , Lenburg Marc E. , Spira Avrum , Gomperts Brigitte N. 
Published: March 2014

Abstract
Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium; therefore, studying these lesions is critical for understanding lung carcinogenesis. Previous microarray and sequencing studies designed to discover early biomarkers and therapeutic targets for lung SCC had limited success identifying key driver events in lung carcinogenesis, mostly due to the cellular heterogeneity of patient samples examined and the interindividual variability associated with difficult to obtain airway premalignant lesions and appropriate normal control samples within the same patient. We performed RNA sequencing on laser-microdissected representative cell populations along the SCC pathologic continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. This is the first gene expression profiling study of airway premalignant lesions with patient-matched SCC tumor samples. Our results provide much needed information about the biology of premalignant lesions and the molecular changes that occur during stepwise carcinogenesis of SCC, and it highlights a novel approach for identifying some of the earliest molecular changes associated with initiation and progression of lung carcinogenesis within individual patients. Cancer Prev Res; 7(5); 487–95. ©2014 AACR.
Kussmaul Physiology in Patients With Heart Failure
Authors: Nadir Adnan M. , Beadle Roger , Lim Hoong Sern 
Published: March 2014

Background—
A paradoxical inspiratory rise in right atrial pressure (in contrast to the normal fall during inspiration), Kussmaul sign, has been described in congestive heart failure (CHF). However, the clinical and hemodynamic characteristics and clinical outcomes of patients with CHF and Kussmaul physiology have not been studied.

Methods and Results—

This is a single-center study of consecutive ambulant patients with CHF (New York Heart Association class III/IV) referred for assessment for heart transplantation between November 2011 and April 2013. Kussmaul physiology was defined as inspiratory rise in right atrial pressure during right heart catheterization. Clinical, biochemical, echocardiographic, and hemodynamic correlates were studied and outcomes assessed in patients with or without Kussmaul physiology after a mean follow-up of 379±227 days. Ninety ambulant patients (age, 53±12 years; 86% men) with CHF were studied. Kussmaul physiology was demonstrated in 39 (43%) patients, and it was associated with higher pulmonary pressures and lower cardiac index and pulmonary capacitance (all
P
<0.05). Patients with Kussmaul physiology were more likely to be treated with higher doses of diuretics, while higher filling pressures, N-terminal pro–B natriuretic peptide levels, and hyponatremia reflected greater neurohormonal activation. Echocardiography revealed greater left and right ventricular dimensions/volumes, restrictive transmitral filling pattern, and lower left ventricular ejection fraction and lower tricuspid annular plane systolic excursion. Peak oxygen uptake was low and comparable in both groups, but ventilation slope was higher in patients with Kussmaul physiology who also had a higher incidence of post-transplant right ventricular failure and overall mortality (
P
<0.05).

Conclusions—
Kussmaul physiology is common in patients with CHF referred for heart transplantation and is associated with adverse cardiopulmonary hemodynamics. As a result of the latter, Kussmaul physiology is associated with poorer clinical outcomes. Kussmaul physiology may be useful during assessment of right heart function and pulmonary pressures before transplantation.
Cardiac Magnetic Resonance Parameters Predict Transplantation-Free Survival in Patients With Fontan Circulation
Authors: Rathod Rahul H. , Prakash Ashwin , Kim Yuli Y. , Germanakis Ioannis E. , Powell Andrew J. , Gauvreau Kimberlee , Geva Tal 
Published: March 2014

Background—
Several clinical risk factors for death and heart transplantation have been identified in patients with Fontan circulation. It is unknown whether cardiac magnetic resonance (CMR) measurements of ventricular size and function are independently associated with these outcomes and further improve risk stratification.

Methods and Results—

Data on patients with Fontan circulation who had a CMR study from January 2002 to January 2011 were retrospectively reviewed. The end point was time to death or listing for heart transplantation after the CMR study. The median age of the 215 patients was 18.3 years (25th, 75th percentiles: 14, 26) with a median age at Fontan of 3.6 years (2.3, 7.1). During a median post-CMR follow-up period of 4.1 years (2.6, 6.2), 24 patients (11%) reached the end point: 20 deaths, 3 transplantations, and 1 transplantation listing. In a multivariable Cox regression model with clinical parameters only, protein-losing enteropathy was associated with death or listing for transplant. A multivariable model, including clinical and CMR parameters, showed that in addition to protein-losing enteropathy, ventricular indexed end-diastolic volume >125 mL/body surface area raised to the 1.3 power was associated with the endpoint. A likelihood-ratio test comparing the 2 models showed that the addition of indexed end-diastolic volume resulted in a significantly improved end point prediction (
P
<0.001)—
C
-index increased from 0.63 to 0.79.

Conclusions—
CMR-derived ventricular indexed end-diastolic volume is an independent predictor of death or transplant in patients late after the Fontan operation and adds incremental value over clinical symptoms alone for risk stratification.
Hospital Quality Improvement Initiative for Patients With Acute Coronary Syndromes in China
Authors: Du Xin , Gao Runlin , Turnbull Fiona , Wu Yangfeng , Rong Ye , Lo Serigne , Billot Laurent , Hao Zhixin , Ranasinghe Isuru , Iedema Rick , Kong Lingzhi , Hu Dayi , Lin Shuguang , Shen Weifeng , Huang Dejia , Yang Yuejing , Ge Junbo , Han Yaling , Lv Shuzheng , Ma Aiqun , Gao Wei , Patel Anushka 
Published: March 2014

Background—
Substantial evidence-practice gaps exist in the management of acute coronary syndromes (ACS) in China. Clinical pathways are tools for improving ACS quality of care but have not been rigorously evaluated.

Methods and Results—
Between October 2007 and August 2010, a quality improvement program was conducted in 75 hospitals throughout China with mixed methods evaluation in a cluster randomized, controlled trial. Eligible hospitals were level 2 or level 3 centers routinely admitting >100 patients with ACS per year. Hospitals were assigned immediate implementation of the American Heart Association/American College of Cardiology guideline based clinical pathways or commencement of the intervention 12 months later. Outcomes were several key performance indicators reflecting the management of ACS. The key performance indicators were measured 12 months after commencement in intervention hospitals and compared with baseline data in control hospitals, using data collected from 50 consecutive patients in each hospital. Pathway implementation was associated with an increased proportion of patients discharged on appropriate medical therapy, with nonsignificant improvements or absence of effects on other key performance indicators.

Conclusions—
Among hospitals in China, the use of a clinical pathway for the treatment of ACS compared with usual care improved secondary prevention treatments, but effectiveness was otherwise limited. An accompanying process evaluation identified several health system barriers to more successful implementation.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au/default.aspx
. Unique identifier: ACTRN12609000491268.
System Barriers to the Evidence-Based Care of Acute Coronary Syndrome Patients in China
Authors: Ranasinghe Isuru , Rong Ye , Du Xin , Wang Yangfang , Gao Runlin , Patel Anushka , Wu Yangfeng , Iedema Rick , Hao Zhixin , Hu Dayi , Turnbull Fiona 
Published: March 2014

Background—
Organizational and wider health system factors influence the implementation and success of interventions. Clinical Pathways in Acute Coronary Syndromes 2 is a cluster randomized trial of a clinical pathway–based intervention to improve acute coronary syndrome care in hospitals in China. We performed a qualitative evaluation to examine the system-level barriers to implementing clinical pathways in the dynamic healthcare environment of China.

Methods and Results—
A qualitative descriptive analysis of 40 in-depth interviews with health professionals conducted in a sample of 10 hospitals purposively selected to explore barriers to implementation of the intervention. Qualitative data were analyzed using the Framework method. In-depth interviews identified 5 key system-level barriers to effective implementation: (1) leadership support for implementing quality improvement, (2) variation in the capacity of clinical services and quality improvement resources, (3) fears of patient disputes and litigation, (4) healthcare funding constraints and high out-of-pocket expenses, and (5) patient-related factors.

Conclusions—
System-level barriers affect the ability of acute coronary syndrome clinical pathways to change practice. Addressing these barriers in the context of current and planned national health system reform will be critical for future improvements in the management of acute coronary syndromes, and potentially other hospitalized conditions, in China.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au/default.aspx
. Register. Unique identifier: ACTRN12609000491268.
Prohibitin Viral Gene Transfer Protects Hippocampal CA1 Neurons From Ischemia and Ameliorates Postischemic Hippocampal Dysfunction
Authors: Kurinami Hitomi , Shimamura Munehisa , Ma Tao , Qian Liping , Koizumi Kenzo , Park Laibaik , Klann Eric , Manfredi Giovanni , Iadecola Costantino , Zhou Ping 
Published: March 2014

Background and Purpose—
Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional.

Methods—
A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin.

Results—

Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome
c
release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent.

Conclusions—
These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.
Prothrombin G20210A Mutation Is Associated With Young-Onset Stroke
Authors: Jiang Baijia , Ryan Kathleen A. , Hamedani Ali , Cheng Yuching , Sparks Mary J. , Koontz Deborah , Bean Christopher J. , Gallagher Margaret , Hooper W. Craig , McArdle Patrick F. , O’Connell Jeffrey R. , Stine O. Colin , Wozniak Marcella A. , Stern Barney J. , Mitchell Braxton D. , Kittner Steven J. , Cole John W. 
Published: March 2014

Background and Purpose—
Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case–control population and additionally performed a meta-analysis.

Methods—
From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case–control studies (n=2305 cases <55 years) was also performed with and without GEOS data.

Results—

Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9–6.5;
P
=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2–28.1;
P
=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4–5.1;
P
=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1–1.9;
P
=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1–2.0;
P
=0.005).

Conclusions—
The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication.
Market Equilibrium and the Environmental Effects of Tax Adjustments in China's Automobile Industry
Authors: Xiao Junji , Ju Heng 
Published: March 2014

Abstract
This paper explores the effects of consumption-tax and fuel-tax adjustments in the Chinese automobile industry. Applying the model and simulation method of Berry, Levinson, and Pakes (1995), we conduct a comparative static analysis of equilibrium prices and sales, fuel consumption, and social welfare before and after tax adjustments. For the first time, we compare the progressivity of both taxes. Our empirical findings suggest that the fuel tax is effective in decreasing fuel consumption at the expense of social welfare, while the consumption tax does not significantly affect either fuel consumption or social welfare.
Convective Cells in Altocumulus Observed with a High-Resolution Radar
Authors: Schmidt Jerome M. , Flatau Piotr J. , Yates Robert D. 
Published: March 2014

Abstract
Very-high-resolution Doppler radar observations are used together with aircraft measurements to document the dynamic and thermodynamic structure of a dissipating altocumulus cloud system associated with a deep virga layer. The cloud layer circulation is shown to consist of shallow vertical velocity couplets near cloud top and a series of subkilometer-scale Rayleigh–Bénard-like cells that extend vertically through the depth of the cloud layer. The subcloud layer was observed to contain a number of narrow virga fall streaks that developed below the more dominant Rayleigh–Bénard updraft circulations in the cloud layer. These features were discovered to be associated with kilometer-scale horizontally orientated rotor circulations that formed along the lateral flanks of the streaks collocated downdraft circulation. The Doppler analysis further reveals that a layer mean descent was present throughout both the cloud and subcloud layers. This characteristic of the circulation is analyzed with regard to the diabatic and radiative forcing on horizontal length scales ranging from the Rayleigh–Bénard circulations to the overall cloud layer width. In particular, linear analytical results indicate that a deep and broad mesoscale region of subsidence is quickly established in middle-level cloud layers of finite width when a layer-wide horizontal gradient in the cloud-top radiative cooling rate is present. A conceptual model summarizing the primary observed and inferred circulation features of the altocumulus layer is presented.