bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing the clinical-effectiveness and cost-effectiveness of an internet-delivered Acceptance and Commitment Therapy (ACT) intervention with a waiting list control among adults with chronic pain: study protocol for a randomised controlled trial
Authors: Hayes Sara , Hogan Michael , Dowd Haulie , Doherty Edel , O'Higgins Siobhan , Nic Gabhainn Saoirse , MacNeela Padraig , Murphy Andrew W , Kropmans Thomas , O'Neill Ciaran , Newell John , McGuire Brian E 
Published: July 2014

IntroductionInternet-delivered psychological interventions among people with chronic pain have the potential to overcome environmental and economic barriers to the provision of evidence-based psychological treatment in the Irish health service context. While the use of internet-delivered cognitive–behavioural therapy programmes has been consistently shown to have small-to-moderate effects in the management of chronic pain, there is a paucity in the research regarding the effectiveness of an internet-delivered Acceptance and Commitment Therapy (ACT) programme among people with chronic pain. The current study will compare the clinical-effectiveness and cost-effectiveness of an online ACT intervention with a waitlist control condition in terms of the management of pain-related functional interference among people with chronic pain.Methods and analysisParticipants with non-malignant pain that persists for at least 3 months will be randomised to one of two study conditions. The experimental group will undergo an eight-session internet-delivered ACT programme over an 8-week period. The control group will be a waiting list group and will be offered the ACT intervention after the 3-month follow-up period. Participants will be assessed preintervention, postintervention and at a 3-month follow-up. The primary outcome will be pain-related functional interference. Secondary outcomes will include: pain intensity, depression, global impression of change, acceptance of chronic pain and quality of life. A qualitative evaluation of the perspectives of the participants regarding the ACT intervention will be completed after the trial.Ethics and disseminationThe study will be performed in agreement with the Declaration of Helsinki and is approved by the National University of Ireland Galway Research Ethics Committee (12/05/05). The results of the trial will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals.Trial registration numberISRCTN18166896.
Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson's disease with dementia: a prospective study
Authors: Stubendorff Kajsa , Larsson Victoria , Ballard Clive , Minthon Lennart , Aarsland Dag , Londos Elisabet 
Published: July 2014

ObjectiveTo investigate the effect on survival of treatment with memantine in patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD).Methods75 patients with DLB and PDD were included in a prospective double-blinded randomised placebo-controlled trial (RCT) of memantine, of whom long-term follow-up was available for 42. Treatment response was recorded 24 weeks from baseline and measured by Clinical Global Impression of Change (CGIC). The participants were grouped as responders (CGIC 1–3) or non-responders (CGIC 4–7). The 24-week RCT was followed by open-label treatment and survival was recorded at 36 months.ResultsAfter 36-month follow-up, patients in the memantine group had a longer length of survival compared with patients in the placebo group (log rank x²=4.02, p=0.045). Within the active treatment group, survival analysis 36 months from baseline showed that the memantine responders, based on CGIC, had higher rates of survival compared with the non-responders (log rank x²=6.595, p=0.010). Similar results were not seen in the placebo group.ConclusionsEarly treatment with memantine and a positive clinical response to memantine predicted longer survival in patients with DLB and PDD. This suggests a possible disease-modifying effect and also has implications for health economic analysis. However, owing to the small study sample, our results should merely be considered as generating a hypothesis which needs to be evaluated in larger studies.Trial registration numberISRCTN89624516.
Doctors admitted to a Physicians’ Health Program: a comparison of self-referrals versus directed referrals
Authors: Braquehais María Dolores , Valero Sergi , Bel Miquel Jordi , Navarro María Cecilia , Matalí Josep Lluís , Nasillo Viviana , Padrós Jaume , Arteman Antoni , Bruguera Eugeni , Casas Miquel 
Published: July 2014

ObjectiveTo compare the profile of doctors with mental disorders admitted to a Physicians’ Health Program (PHP) depending on their type of referral.DesignRetrospective chart review.MethodWe analysed 1545 medical records of doctors admitted to the Barcelona PHP (PAIMM) from 1 February 1998 to 31 December 2012.ResultsMost doctors (83.2%) were self-referred to the programme. Patients non-self-referred were older (=55 vs=49.6 years; t=6.96, p<0.01) than those self-referred and there were more men (68.3%) than women (45.8%; OR=0.39; 95% CI 0.29 to 0.52). Self-referrals were more frequent among patients with non-addictive disorders (84.6% vs 15.4%; OR=4.52; 95% CI 3.23 to 28.45). Self-referred patients needed less inpatient admissions (16.8% vs30.9%; OR=2.22; 95% CI 1.63 to 3.01) and the length of their treatment episodes was shorter (=24.3 vs = 32.4 months; t=3.34; p<0.01). Logistic regression showed a significant model (χ2=67.52; df=3; p<0.001). Age, gender and diagnosis were statistically associated with type of referral to the programme.ConclusionsType of referral to a PHP may be influenced not only by sick doctors’ personal traits but also by each programme's design and how it is perceived by service users. Our findings should be taken into account when designing treatment and preventive interventions for this professional group.
PTEN Deficiency Mediates a Reciprocal Response to IGFI and mTOR Inhibition
Authors: Patel Mukund , Gomez Nicholas C. , McFadden Andrew W. , Moats-Staats Billie M. , Wu Sam , Rojas Andres , Sapp Travis , Simon Jeremy M. , Smith Scott V. , Kaiser-Rogers Kathleen , Davis Ian J. 
Published: July 2014

Abstract
Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.
Implications: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials. Mol Cancer Res; 12(11); 1610–20. ©2014 AACR.
Viral Oncogene Expression in the Stem/Progenitor Cell Compartment of the Mouse Intestine Induces Adenomatous Polyps
Authors: Sáenz Robles Maria Teresa , Chong Jean Leon , Koivisto Christopher , Trimboli Anthony , Liu Huayang , Leone Gustavo , Pipas James M. 
Published: July 2014

Abstract
Genetic and epigenetic events that alter gene expression and/or protein function or localization are thought to be the primary mechanism that drives tumorigenesis and governs the clinical behavior of cancers. Yet, a number of studies have shown that the effects of oncogene expression or tumor suppressor ablation are highly dependent on cell type. The molecular basis for this cell-type specificity and how it contributes to tumorigenesis are unknown. Here, expression of a truncated SV40 large T antigen in murine intestinal crypts promoted the formation of numerous adenomatous polyps in the colon and small intestine. In contrast, when the same T-antigen construct is expressed in villous enterocytes, the consequences are limited to hyperplasia and dysplasia. The T-antigen–induced polyps show high levels of the proto-oncogene c-Myc protein even though there is no transport of β-catenin to the nucleus. Targeting the expression of viral oncogenes to intestinal crypts or villi provides a murine model system for studying cell-type specific effects in tumorigenesis, and is particularly relevant to the study of APC/β-catenin–independent pathways contributing to the generation of intestinal polyps.
Implications: This mouse model system describes the formation of colon polyps in the absence of Wnt/β-catenin signaling. Mol Cancer Res; 12(10); 1355–64. ©2014 AACR.
Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer
Authors: Yao Ke , Chen Hanyong , Liu Kangdong , Langfald Alyssa , Yang Ge , Zhang Yi , Yu Dong Hoon , Kim Myoung Ok , Lee Mee-Hyun , Li Haitao , Bae Ki Beom , Kim Hong-Gyum , Ma Wei-Ya , Bode Ann M. , Dong Ziming , Dong Zigang 
Published: July 2014

Abstract
Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. Cancer Prev Res; 7(9); 958–67. ©2014 AACR.
Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Authors: Chonghaile Triona Ni , Roderick Justine E. , Glenfield Cian , Ryan Jeremy , Sallan Stephen E. , Silverman Lewis B. , Loh Mignon L. , Hunger Stephen P. , Wood Brent , DeAngelo Daniel J. , Stone Richard , Harris Marian , Gutierrez Alejandro , Kelliher Michelle A. , Letai Anthony 
Published: July 2014

AbstractAcute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.Significance: ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials. Cancer Discov; 4(9); 1074–87. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 973
Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-Negative Melanoma: Long-term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival
Authors: Carson William E. , Unger Joseph M. , Sosman Jeffrey A. , Flaherty Lawrence E. , Tuthill Ralph J. , Porter Mark J. , Thompson John A. , Kempf Raymond A. , Othus Megan , Ribas Antoni , Sondak Vernon K. 
Published: July 2014

AbstractAssociations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37–1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2– and/or HLA-Cw3–expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. Cancer Immunol Res; 2(10); 981–7. ©2014 AACR.
Prediction of Asymptomatic Carotid Artery Stenosis in the General Population
Authors: de Weerd Marjolein , Greving Jacoba P. , Hedblad Bo , Lorenz Matthias W. , Mathiesen Ellisiv B. , O’Leary Daniel H. , Rosvall Maria , Sitzer Matthias , de Borst Gert Jan , Buskens Erik , Bots Michiel L. 
Published: July 2014

Background and Purpose—
Because of a low prevalence of severe carotid stenosis in the general population, screening for presence of asymptomatic carotid artery stenosis (ACAS) is not warranted. Possibly, for certain subgroups, screening is worthwhile. The present study aims to develop prediction rules for the presence of ACAS (>50% and >70%).

Methods—
Individual participant data from 4 population-based cohort studies (Malmö Diet and Cancer Study, Tromsø Study, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study; totaling 23 706 participants) were pooled. Multivariable logistic regression was performed to determine which variables predict presence of ACAS (>50% and >70%). Calibration and discrimination of the models were assessed, and bootstrapping was used to correct for overfitting.

Results—

Age, sex, history of vascular disease, systolic and diastolic blood pressure, total cholesterol/high-density lipoprotein ratio, diabetes mellitus, and current smoking were predictors of stenosis (>50% and >70%). The calibration of the model was good confirmed by a nonsignificant Hosmer and Lemeshow test for moderate (
P
=0.59) and severe stenosis (
P
=0.07). The models discriminated well between participants with and without stenosis, with an area under the receiver operating characteristic curve corrected for over optimism of 0.82 (95% confidence interval, 0.80–0.84) for moderate stenosis and of 0.87 (95% confidence interval, 0.85–0.90) for severe stenosis. The regression coefficients of the predictors were converted into a score chart to facilitate practical application.

Conclusions—
A clinical prediction rule was developed that allows identification of subgroups with high prevalence of moderate (>50%) and severe (>70%) ACAS. When confirmed in comparable cohorts, application of the prediction rule may lead to a reduction in the number needed to screen for ACAS.
Different Doses of Recombinant Tissue-Type Plasminogen Activator for Acute Stroke in Chinese Patients
Authors: Chao A-Ching , Liu Ching-Kuan , Chen Chih-Hung , Lin Huey-Juan , Liu Chung-Hsiang , Jeng Jiann-Shing , Hu Chaur-Jong , Chung Chih-Ping , Hsu Hung-Yi , Sheng Wen-Yung , Hu Han-Hwa 
Published: July 2014

Background and Purpose—
The relationship between the dose of recombinant tissue-type plasminogen activator (r-tPA) and its safety/efficacy for ischemic stroke has not been well evaluated in the East Asian population. We assessed the safety/efficacy of different doses of r-tPA for acute ischemic stroke in Chinese patients.

Methods—
A total of 1004 eligible patients were classified according to the dose of r-tPA received for managing acute ischemic stroke: 0.9 mg/kg (n=422), 0.8 mg/kg (n=202), 0.7 mg/kg (n=199), and 0.6 mg/kg (n=181). The safety outcome was symptomatic intracerebral hemorrhage and death within 3 months. The efficacy outcome was good functional outcome (modified Rankin Scale ≤1) at 3 months.

Results—

There was a significant trend for symptomatic intracerebral hemorrhage with age (
P
=0.002). With multivariate logistic regression analysis, a dose of 0.9 mg/kg was a predictor of symptomatic intracerebral hemorrhage (
P
=0.0109), and a dose ≤0.65 mg/kg was a predictor of good functional outcome (
P
=0.0369). In patients aged 71 to 80 years, there was a significant trend of increasing symptomatic intracerebral hemorrhage (
P
=0.0130) and less good functional outcome (
P
=0.0179) with increasing doses of r-tPA. There was also a trend of increasing mortality (
P
=0.0971) at 3 months in these patients.

Conclusions—
These results did not support the dose of 0.9 mg/kg of r-tPA being optimal for all patients in the East Asian population. In elderly patients (71–80 years), a lower dose of 0.6 mg/kg is associated with a better outcome. Confirmation of the results through randomized trial is required.
Cryptogenic Subtype Predicts Reduced Survival Among Cancer Patients With Ischemic Stroke
Authors: Navi Babak B. , Singer Samuel , Merkler Alexander E. , Cheng Natalie T. , Stone Jacqueline B. , Kamel Hooman , Iadecola Costantino , Elkind Mitchell S.V. , DeAngelis Lisa M. 
Published: July 2014

Background and Purpose—
Cryptogenic stroke is common in patients with cancer. Autopsy studies suggest that many of these cases may be because of marantic endocarditis, which is closely linked to cancer activity. We, therefore, hypothesized that among patients with cancer and ischemic stroke, those with cryptogenic stroke would have shorter survival.

Methods—
We retrospectively analyzed all adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary care cancer center from 2005 through 2009. Two neurologists determined stroke mechanisms by consensus. Patients were diagnosed with cryptogenic stroke if no specific mechanism could be determined. The diagnosis of marantic endocarditis was restricted to patients with cardiac vegetations on echocardiography or autopsy and negative blood cultures. Patients were followed until July 31, 2012, for the primary outcome of death. Kaplan–Meier statistics and the log-rank test were used to compare survival between patients with cryptogenic stroke and patients with known stroke mechanisms. Multivariate Cox proportional hazard analysis evaluated the association between cryptogenic stroke and death after adjusting for potential confounders.

Results—

Among 263 patients with cancer and ischemic stroke, 133 (51%) were cryptogenic. Median survival in patients with cryptogenic stroke was 55 days (interquartile range, 21–240) versus 147 days (interquartile range, 33–735) in patients with known stroke mechanisms (
P
<0.01). Cryptogenic stroke was independently associated with death (hazard ratio, 1.64; 95% confidence interval, 1.25–2.14) after adjusting for age, systemic metastases, adenocarcinoma histology, and functional status.

Conclusions—
Cryptogenic stroke is independently associated with reduced survival in patients with active cancer and ischemic stroke.
Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells
Authors: Wang Yin , Liu Yan , Tang Fei , Bernot Kelsie M. , Schore Reuven , Marcucci Guido , Caligiuri Michael A. , Zheng Pan , Liu Yang 
Published: July 2014

Key Points
Echinomycin can selectively kill the leukemia-initiating cell in relapsed AML without normal stem cell toxicity. In vivo delivery of echinomycin can induce long-term complete remission in a murine model of relapsed AML.
Decreased lung function precedes severe respiratory syncytial virus infection and post-respiratory syncytial virus wheeze in term infants
Authors: Zomer-Kooijker Kim , Uiterwaal Cuno S.P.M. , van der Gugten Anne C. , Wilbrink Berry , Bont Louis J. , van der Ent Cornelis K. 
Published: July 2014

It is unknown why respiratory syncytial virus (RSV) causes mild disease in some children and severe disease, requiring hospitalisation, in others. We aimed to assess whether diminished premorbid lung function in healthy term infants predisposes to hospitalisation during RSV bronchiolitis, and to post-RSV wheeze.In a prospective birth cohort study of unselected term healthy children, neonatal lung function was measured before the age of 2 months (n=2133). From birth through the first year of life, respiratory symptoms were recorded in a diary, and general practitioner consultations and hospitalisations were documented. In a subgroup (n=417) repeated nose and throat swabs were collected for PCR to detect RSV infections.Median neonatal respiratory system compliance (Crs) was significantly lower (41.2versus47.4 mL·kPa−1, p=0.03) and resistance (Rrs) was higher (8.2versus6.3 kPa·s·L−1, p=0.10) in hospitalised RSV patients (n=18) compared with nonhospitalised RSV-positive infants (n=84). Every 10 mL·kPa−1increase inCrswas associated with 55% less post-RSV wheeze (OR 0.56, 95% CI 0.35–0.90), and each kPa·s·L−1increase inRrswas associated with 42% more post-RSV wheeze, which was only marginally explained by pre-RSV wheeze or severity of the RSV disease.This unselected birth cohort study shows for the first time that decreased lung function at birth predisposes to severe RSV disease, and to post-RSV wheeze.