bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe Hepatitis Promotes Hepatocellular Carcinoma Recurrence via NF-κB Pathway-Mediated Epithelial–Mesenchymal Transition after Resection
Authors: Wu Ting-Jung , Chang Shih-Shin , Li Chia-Wei , Hsu Yi-Hsin , Chen Tse-Ching , Lee Wei-Chen , Yeh Chau-Ting , Hung Mien-Chie 
Published: December 2015

Abstract
Purpose: Surgical resection is considered as a curative treatment modality for hepatocellular carcinoma; however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of the risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to hepatocellular carcinoma progression.
Experimental Design: In this study, we used a cytokine array to identify important cytokines whose levels are increased in liver microenvironment with severe hepatitis. We evaluated the morphologic changes, migration and invasion ability, and signal transduction in hepatocellular carcinoma cells with or without inflammatory cytokine in vitro. Finally, we analyzed the NF-κB signal pathway in tumor specimens from 232 patients with hepatocellular carcinoma by immunohistochemical staining.
Results: The proinflammatory cytokine TNFα was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNFα promoted hepatocellular carcinoma cancer cell migration, invasion, and epithelial–mesenchymal transition (EMT) by upregulating the transcriptional regulator, Snail. We identified Snail as a direct target gene downstream of the TNFα-mediated canonical NF-κB activation. In addition, tumor recurrence-free survival of hepatocellular carcinoma patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression.
Conclusions: Our results establish a signaling axis that explains how inflammatory tumor microenvironment promotes hepatocellular carcinoma recurrence and metastasis. These findings suggest that controlling liver inflammation and/or targeting NF-κB–mediated Snail expression may be a potential therapeutic strategy to prevent hepatocellular carcinoma recurrence after hepatectomy. Clin Cancer Res; 22(7); 1800–12. ©2015 AACR.
Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF
Authors: Hechtman Jaclyn F. , Zehir Ahmet , Yaeger Rona , Wang Lu , Middha Sumit , Zheng Tao , Hyman David M. , Solit David , Arcila Maria E. , Borsu Laetitia , Shia Jinru , Vakiani Efsevia , Saltz Leonard , Ladanyi Marc 
Published: December 2015

Abstract
Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.
Implications: Targetable kinase alterations were identified in a subset of advanced colorectal carcinoma patients, preferentially associated with wild-type RAS/RAF, and may predict poor response to standard anti-EGFR therapy. Mol Cancer Res; 14(3); 296–301. ©2015 AACR.
Targeting CDK4 and CDK6: From Discovery to Therapy
Authors: Sherr Charles J. , Beach David , Shapiro Geoffrey I. 
Published: December 2015

AbstractBiochemical and genetic characterization of D-type cyclins, their cyclin D–dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4 over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein–dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.Significance: Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses the discovery of these CDKs and their regulators, as well as translation of CDK4/6 biology to positive clinical outcomes and development of rational combinatorial therapies. Cancer Discov; 6(4); 353–67. ©2015 AACR.
Sixty-Four–Section Cardiac Computed Tomography in Mechanical Prosthetic Heart Valve Dysfunction
Authors: Gündüz Sabahattin , Özkan Mehmet , Kalçik Macit , Gürsoy Ozan Mustafa , Astarcioğlu Mehmet Ali , Karakoyun Süleyman , Aykan Ahmet Çağri , Biteker Murat , Gökdeniz Tayyar , Kaya Hasan , Yesin Mahmut , Duran Nilüfer Ekşi , Sevinç Deniz , Güneysu Tahsin 
Published: December 2015

Background—
Distinguishing pannus and thrombus in patients with prosthetic valve dysfunction is essential for the selection of proper treatment. We have investigated the utility of 64-slice multidetector computed tomography (MDCT) in distinguishing between pannus and thrombus, the latter amenable to thrombolysis.

Methods and Results—

Sixty-two (23 men, mean age 44±14 years) patients with suspected mechanical prosthetic valve dysfunction assessed by transesophageal echocardiography were included in this prospective observational trial. Subsequently, MDCT was performed before any treatment was started. Periprosthetic masses were detected by MDCT in 46 patients, and their attenuation values were measured as Hounsfield Units (HU). Patients underwent thrombolysis unless contraindicated, and those with a contraindication or failed thrombolysis underwent surgery. A mass which was completely lysed or surgically detected as a clot was classified as thrombus, whereas a mass which was surgically detected as tissue overgrowth was classified as pannus. A definitive diagnosis could be achieved in 37 patients with 39 MDCT masses (22 thrombus and 17 pannus). The mean attenuation value of 22 thrombotic masses was significantly lower than that in 17 pannus (87±59 versus 322±122;
P
<0.001). Area under the receiver operating characteristic curve was 0.96 (95% confidence interval: 0.91–0.99;
P
<0.001), and a cutoff point of HU≥145 provided high sensitivity (87.5%) and specificity (95.5%) in discriminating pannus from thrombus. Complete lysis was more common for masses with HU<90 compared with those with HU 90 to 145 (100% versus 42.1%;
P
=0.007).

Conclusions—
Sixty-four slice MDCT is helpful in identifying masses amenable to thrombolysis in patients with prosthetic valve dysfunction. A high (HU≥145) attenuation suggests pannus overgrowth, whereas a lower value is associated with thrombus formation. A higher attenuation (HU>90) is associated with reduced lysis rates.
Impaired Right, Left, or Biventricular Function and Resting Oxygen Saturation Are Associated With Mortality in Eisenmenger Syndrome
Authors: Jensen Annette S. , Broberg Craig S. , Rydman Riikka , Diller Gerhard-Paul , Li Wei , Dimopoulos Konstantinos , Wort Stephen J. , Pennell Dudley J. , Gatzoulis Michael A, , Babu-Narayan Sonya V. 
Published: December 2015

Background—
Patients with Eisenmenger syndrome (ES) have better survival, despite similar pulmonary vascular pathology, compared with other patients with pulmonary arterial hypertension. Cardiovascular magnetic resonance (CMR) is useful for risk stratification in idiopathic pulmonary arterial hypertension, whereas it has not been evaluated in ES. We studied CMR together with other noninvasive measurements in ES to evaluate its potential role as a noninvasive risk stratification test.

Methods and Results—

Between 2003 and 2005, 48 patients with ES, all with a post-tricuspid shunt, were enrolled in a prospective, longitudinal, single-center study. All patients underwent a standardized baseline assessment with CMR, blood test, echocardiography, and 6-minute walk test and were followed up for mortality until the end of December 2013. Twelve patients (25%) died during follow-up, mostly from heart failure (50%). Impaired ventricular function (right or left ventricular ejection fraction) was associated with increased risk of mortality (lowest quartile: right ventricular ejection fraction, <40%; hazard ratio, 4.4 [95% confidence interval, 1.4–13.5];
P
=0.01 and left ventricular ejection fraction, <50%; hazard ratio, 6.6 [95% confidence interval, 2.1–20.8];
P
=0.001). Biventricular impairment (lowest quartile left ventricular ejection fraction, <50% and right ventricular ejection fraction, <40%) conveyed an even higher risk of mortality (hazard ratio, 8.0 [95% confidence interval, 2.5–25.1];
P
=0.0004). No other CMR or noninvasive measurement besides resting oxygen saturation (hazard ratio, 0.90 [0.83–0.97]/%;
P
=0.007) was associated with mortality.

Conclusions—
Impaired right, left, or biventricular systolic function derived from baseline CMR and resting oxygen saturation are associated with mortality in adult patients with ES. CMR is a useful noninvasive tool, which may be incorporated in the risk stratification assessment of ES during lifelong follow-up.
Coronary Artery Calcium Progression and Atrial Fibrillation
Authors: O’Neal Wesley T. , Efird Jimmy T. , Qureshi Waqas T. , Yeboah Joseph , Alonso Alvaro , Heckbert Susan R. , Nazarian Saman , Soliman Elsayed Z. 
Published: December 2015

Background—
Coronary artery calcium (CAC) measured at a single time point has been associated with an increased risk for atrial fibrillation (AF). It is unknown whether CAC progression over time carries a similar risk.

Methods and Results—

This analysis included 5612 participants (mean age: 62±10; 52% women; 39% whites; 27% blacks; 20% Hispanics; 12% Chinese Americans) from the Multi-Ethnic Study of Atherosclerosis. Phantom-adjusted Agatston scores for baseline and follow-up measurements were used to compute change in CAC per year (≤0, 1–100, 101–300, and >300 U/year). AF was ascertained by review of hospital discharge records and from Medicare claims data through December 31, 2010. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between CAC progression and AF. Over a median follow-up of 5.6 years (25th, 75th percentiles=5.1, 6.8), a total of 203 (3.6%) incident AF cases were detected. Any CAC progression (>0/year) was associated with an increased risk for AF (HR=1.55, 95% CI=1.10, 2.19), and the risk increased with higher levels of CAC progression (≤0/year: HR=1.0 [reference]; 1–100/year: HR=1.47, 95% CI=1.03, 2.09; 101–300/year: HR=1.92, 95%CI=1.15, 3.20; >300/year: HR=3.23, 95%CI=1.48, 7.05). An interaction was observed by age with the association of CAC progression with AF being stronger for younger (<61 years: HR=3.53, 95% CI=1.29, 9.69) compared with older (≥61 years: HR=1.42, 95% CI=0.99, 2.04) participants (
P
interaction=0.037).

Conclusions—
CAC progression during an average of 5 to 6 years of follow-up is associated with an increased risk for AF.
Comparison of Atherosclerotic Calcification in Major Vessel Beds on the Risk of All-Cause and Cause-Specific Mortality
Authors: Bos Daniel , Leening Maarten J.G. , Kavousi Maryam , Hofman Albert , Franco Oscar H. , Lugt Aad van der , Vernooij Meike W. , Ikram M. Arfan 
Published: December 2015

Background—
Atherosclerosis is a major contributor to global morbidity and mortality. Although atherosclerosis is a systemic disease, its burden varies considerably across vessel beds, which may translate into differences in mortality risk.

Methods and Results—
From 2003 to 2006, a sample of 2408 elderly participants (mean age, 69.6±6.7 years; 52.4% female) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. Mortality follow-up was complete until January 1, 2012. We investigated associations of calcification in each vessel bed with mortality using Cox regression, adjusting for age, sex, and cardiovascular risk factors. Next, all vessel beds were included into 1 model to investigate independency of associations. Finally, we investigated the predictive value of calcification beyond the predictors included in the Pooled Cohort equations. During 15 775 person-years of follow-up, 283 participants died. Larger calcification volumes in all vessels were related to higher risks of all-cause mortality, cardiovascular, and noncardiovascular mortality, independent of cardiovascular risk factors. Most prominent associations were found for aortic arch calcification and cardiovascular mortality (age- and sex-adjusted hazard ratio per 1-SD increase 2.72 [95% confidence interval, 1.85–4.02]), independent of calcification elsewhere (hazard ratio, 1.75 (95% confidence interval, 1.13–2.72]). Calcification in any vessel improved prediction for all 3 outcomes.

Conclusions—
Atherosclerotic load in major vessel beds is associated with an increased risk of death. In particular, aortic arch calcification volume yields unique information with regard to mortality in addition to atherosclerosis in other vessel beds.
Heart Failure Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin
Authors: Connors Lawreen H. , Sam Flora , Skinner Martha , Salinaro Francesco , Sun Fangui , Ruberg Frederick L. , Berk John L. , Seldin David C. 
Published: December 2015

Background—
Heart failure caused by wild-type transthyretin amyloidosis (ATTRwt) is an underappreciated cause of morbidity and mortality in the aging population. The aims of this study were to examine features of disease and to characterize outcomes in a large ATTRwt cohort.

Methods and Results—

Over 20 years, 121 patients with ATTRwt were enrolled in a prospective, observational study. Median age at enrollment was 75.6 years (range, 62.6–87.8 years); 97% of patients were white. The median survival, measured from biopsy diagnosis, was 46.69 months (95% confidence interval, 41.95–56.77); 78% of deaths were attributable to cardiac causes. By Kaplan–Meier analysis, 5-year survival was 35.7% (95% confidence interval, 25–46). Impaired functional capacity (mean V
o
2
max, 13.5 mL·kg
−1
·min
−1
) and atrial fibrillation (67%) were common clinical features. Multivariate predictors of reduced survival were elevated serum brain natriuretic peptide (482±337 pg/mL) and uric acid (8.2±2.6 mg/dL), decreased left ventricular ejection fraction (50% median; range, 10%–70%), and increased relative wall thickness (0.75±0.19).

Conclusions—
In this series of patients with biopsy-proven ATTRwt, poor functional capacity and atrial arrhythmias were common clinical features. Elevated brain natriuretic peptide and uric acid, decreased left ventricular ejection fraction, and increased relative wall thickness were associated with limited survival of only 35.7% at 5 years for the group as a whole. These data establish the natural history of ATTRwt, provide statistical basis for the design of future interventional clinical trials, and highlight the need for more sensitive diagnostic tests and disease-specific treatments for this disease.
Repolarization Alternans and Ventricular Arrhythmia in a Repaired Tetralogy of Fallot Animal Model
Authors: Chiu Shuenn‐Nan , Tsai Chia‐Ti , Lin Lian‐Yu , Huang Shu‐Chien , Chen Yih‐Sharng , Wang Jou‐Kou , Wu Mei‐Hwan , Lai Ling‐Ping , Lin Jiunn‐Lee 
Published: December 2015

Background

Ventricular arrhythmia is an important cause of late death in patients with repaired tetralogy of Fallot (
rTOF
). By using an
rTOF
canine model, we investigated the role of repolarization alternans and its electrophysiological mechanisms.

Methods and Results

Six dogs received right ventricular outflow tract (
RVOT
) transannular patch, pulmonary valve destruction, and right bundle branch ablation to simulate
rTOF
. After 1 year, we performed high‐resolution dual‐voltage and calcium optical mapping to record action potentials and calcium transients on the excised right ventricular outflow tract wedges. Another 6 dogs without operation served as control. The
rTOF
group was more susceptible to action potential duration alternans (
APD
‐
ALT
) and spatially discordant
APD
‐
ALT
than control (threshold for
APD
‐
ALT
: 516±36 vs 343±36 ms;
P
=0.017; threshold for discordant
APD
‐
ALT
: 387±30 vs 310±14 ms;
P
=0.046). We detected 2 episodes of ventricular tachycardia in the
rTOF
group, but none in the control. Expressions of Kv4.3 and
KC
h
IP
2 decreased in the
rTOF
group. Expression of connexin 43 also decreased in the
rTOF
group with a corresponding decrease of conduction velocity and might contribute to spatially discordant
APD
‐
ALT
. We also found distinct electrophysiological features of the
RVOT
, including biphasic relationship between magnitude of
APD
‐
ALT
and pacing cycle length, uncoupling of
APD
‐
ALT
, and calcium transients alternans, and shortened
APD
, but unchanged,
APD
restitution in
rTOF
.

Conclusions

We demonstrated novel electrophysiological properties of the
RVOT
. In an
rTOF
model, the
RVOT
exhibits increased susceptibility to temporal and spatially discordant
APD
‐
ALT
, which was not totally dependent on calcium transient alternans.
Can Link Analysis Be Applied to Identify Behavioral Patterns in Train Recorder Data?
Authors: Strathie Ailsa , Walker Guy H. 
Published: December 2015

Objective: A proof-of-concept analysis was conducted to establish whether link analysis could be applied to data from on-train recorders to detect patterns of behavior that could act as leading indicators of potential safety issues. Background: On-train data recorders capture data about driving behavior on thousands of routine journeys every day and offer a source of untapped data that could be used to offer insights into human behavior. Method: Data from 17 journeys undertaken by six drivers on the same route over a 16-hr period were analyzed using link analysis, and four key metrics were examined: number of links, network density, diameter, and sociometric status. Results: The results established that link analysis can be usefully applied to data captured from on-vehicle recorders. The four metrics revealed key differences in normal driver behavior. These differences have promising construct validity as leading indicators. Conclusion: Link analysis is one method that could be usefully applied to exploit data routinely gathered by on-vehicle data recorders. It facilitates a proactive approach to safety based on leading indicators, offers a clearer understanding of what constitutes normal driving behavior, and identifies trends at the interface of people and systems, which is currently a key area of strategic risk. Application: These research findings have direct applications in the field of transport data monitoring. They offer a means of automatically detecting patterns in driver behavior that could act as leading indicators of problems during operation and that could be used in the proactive monitoring of driver competence, risk management, and even infrastructure design.
Effects of whole body vibration on muscle spasticity for people with central nervous system disorders: a systematic review
Authors: Huang Meizhen , Liao Lin-Rong , Pang Marco YC 
Published: December 2015

Objectives: To examine the effects of whole-body vibration on spasticity among people with central nervous system disorders. Methods: Electronic searches were conducted using CINAHL, Cochrane Library, MEDLINE, Physiotherapy Evidence Database, PubMed, PsycINFO, SPORTDiscus and Scopus to identify randomized controlled trials that investigated the effect of whole-body vibration on spasticity among people with central nervous system disorders (last search in August 2015). The methodological quality and level of evidence were rated using the PEDro scale and guidelines set by the Oxford Centre for Evidence-Based Medicine. Results: Nine trials with totally 266 subjects (three in cerebral palsy, one in multiple sclerosis, one in spinocerebellar ataxia, and four in stroke) fulfilled all selection criteria. One study was level 1b (PEDro⩾6 and sample size>50) and eight were level 2b (PEDro<6 or sample size ⩽50). All three cerebral palsy trials (level 2b) reported some beneficial effects of whole-body vibration on reducing leg muscle spasticity. Otherwise, the results revealed no consistent benefits on spasticity in other neurological conditions studied. There is little evidence that change in spasticity was related to change in functional performance. The optimal protocol could not be identified. Many reviewed studies were limited by weak methodological and reporting quality. Adverse events were minor and rare. Conclusion: Whole-body vibration may be useful in reducing leg muscle spasticity in cerebral palsy but this needs to be verified by future high quality trials. There is insufficient evidence to support or refute the notion that whole-body vibration can reduce spasticity in stroke, spinocerebellar ataxia or multiple sclerosis.
Diabetes Self-Care Activities and Health-Related Quality-of-Life of individuals with Type 1 Diabetes Mellitus in Shantou, China
Authors: Lin Kun , Yang Xiaoping , Yin Guoshu , Lin Shaoda 
Published: December 2015

Objective To assess diabetes self-care behaviours and health-related quality-of-life (HRQoL) in people with type 1 diabetes mellitus (T1DM), in China. Methods Individuals with T1DM underwent face-to-face interviews over a 7-day questionnaire period. The Summary of Diabetes Self-Care Activities (SDSCA) was used to assess self-care behaviours. EQ-5D-3L was used to quantify HRQoL. Results Of self-care activities, individuals ( n = 322) were most likely to adhere to treatment and least likely to perform foot care. A total of 78.9% of participants did not examine their feet and 33.9% of participants did not monitor blood glucose during the questionnaire period. Moderate/severe anxiety or depression was reported by 28.6% of participants; 23.9% reported moderate/severe pain or discomfort. The individual’s level of diabetes education, insulin injection regimen and HbA1c were independently associated with total SDSCA score. Household income and age were independently associated with EQ-5D index. Conclusions Enhancing diabetes education in individuals and implementing strict insulin regimens could improve self-care behaviours in people with T1DM in China.