bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic parameters for ramp versus step incremental cycle ergometer tests
Authors: Zuniga Jorge M. , Housh Terry J. , Camic Clayton L. , Bergstrom Haley C , Traylor Daniel A. , Schmidt Richard J. , Johnson Glen O. 
Published: November 2012

The purpose of this study was to examine mean differences and the patterns of responses for oxygen uptake ([Formula: see text]O2), heart rate (HR), and rating of perceived exertion (RPE) for ramp (15 W·min–1) versus step (30 W increments every 2 min) incremental cycle ergometer tests. Fourteen subjects (age and body mass of 23.2 ± 3.1 (mean ± SD ) years and 71.1 ± 10.1 kg, respectively) visited the laboratory on separate occasions. Two-way repeated measures ANOVAs with appropriate follow-up procedures, as well as paired t tests, were used to analyze the data. In addition, polynomial regression analyses were used to determine the patterns of responses for each dependent variable for the ramp and step tests. The ramp protocol resulted in lower mean [Formula: see text]O2 and HR values at the common power outputs than the step protocol with no differences in RPE. The increased amount of work performed during the step (total work = 75.83 kJ) versus ramp (total work = 65.60 kJ) tests at the common power outputs may have contributed to the greater [Formula: see text]O2 and HR values. The polynomial regression analyses showed that most subjects had the same patterns of responses for the ramp and step incremental tests for HR (86%) and RPE (93%) but different patterns for [Formula: see text]O2 (71%). The findings from the present study suggested that the protocol selection for an incremental cycle ergometer test can affect the mean values for [Formula: see text]O2 and HR, as well as the [Formula: see text]O2 – power output relationship.
Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer
Authors: Wojtalla Anna , Fischer Barbara , Kotelevets Nataliya , Mauri Francesco A. , Sobek Jens , Rehrauer Hubert , Wotzkow Carlos , Tschan Mario P. , Seckl Michael J. , Zangemeister-Wittke Uwe , Arcaro Alexandre 
Published: November 2012

Abstract
Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types.
Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA.
Results: Overexpression of the PI3K isoforms p110-α and p110-β and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-α with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-β was less effective. Inhibition of p110-α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-α inhibition profoundly affected the balance of pro- and antiapoptotic Bcl-2 family proteins. Finally, p110-α inhibition led to impaired SCLC tumor formation and vascularization in vivo.
Conclusion: Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC. Clin Cancer Res; 19(1); 96–105. ©2012 AACR.
Variation in Precursor Lesions of Pancreatic Cancer among High-Risk Groups
Authors: Potjer Thomas P. , Schot Ingrid , Langer Peter , Heverhagen Johannes T. , Wasser Martin N.J.M. , Slater Emily P. , Klöppel Günter , Morreau Hans M. , Bonsing Bert A. , de Vos tot Nederveen Cappel Wouter H. , Bargello Mathias , Gress Thomas M. , Vasen Hans F.A. , Bartsch Detlef K. 
Published: November 2012

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups.
Experimental Design: Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0–127 months) or 36 months (0–110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery.
Results: Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable.
Conclusion: In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group. Clin Cancer Res; 19(2); 442–9. ©2012 AACR.
Secrets of Drug Resistance in NSCLC Exposed by New Molecular Definition of EMT
Authors: Neel Dana S. , Bivona Trever G. 
Published: November 2012

Abstract
Non–small cell lung carcinoma (NSCLC) metastasis and drug resistance has been associated with epithelial-to-mesenchymal transition (EMT). This study reports the development of a robust gene expression signature of EMT in NSCLC and reveals new insights into the key molecular events that underlie EMT and drug resistance in NSCLC. Clin Cancer Res; 19(1); 3–5. ©2012 AACR.
MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Authors: Mitra Anirban K. , Zillhardt Marion , Hua Youjia , Tiwari Payal , Murmann Andrea E. , Peter Marcus E. , Lengyel Ernst 
Published: November 2012

Abstract
Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit.
Significance: The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. Cancer Discov; 2(12); 1100–8. ©2012 AACR.
Read the Commentary on this article by Chou and Werb, p. 1078
This article is highlighted in the In This Issue feature, p. 1065
Elucidating Distinct Roles for NF1 in Melanomagenesis
Authors: Maertens Ophélia , Johnson Bryan , Hollstein Pablo , Frederick Dennie T. , Cooper Zachary A. , Messiaen Ludwine , Bronson Roderick T. , McMahon Martin , Granter Scott , Flaherty Keith , Wargo Jennifer A. , Marais Richard , Cichowski Karen 
Published: November 2012

Abstract
BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal–regulated kinase pathways. As such, Nf1/Braf–mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal–regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.
Significance: This study elucidates the mechanism by which NF1 mutations cooperate with different BRAF mutations in melanomagenesis and shows that NF1/neurofibromin loss may desensitize tumors to BRAF inhibitors. Cancer Discov; 3(3); 338–49. ©2012 AACR.
See related commentary by Gibney and Smalley, p. 260
This article is highlighted in the In This Issue feature, p. 239
Estrogen Receptor–Mediated Regulation of MicroRNA Inhibits Proliferation of Vascular Smooth Muscle Cells
Authors: Zhao Jin , Imbrie Gregory A. , Baur Wendy E. , Iyer Lakshmanan K. , Aronovitz Mark J. , Kershaw Tanya B. , Haselmann Greta M. , Lu Qing , Karas Richard H. 
Published: November 2012

Objective—
Estradiol (E2) regulates gene transcription by activating estrogen receptor-α and estrogen receptor-β. Many of the genes regulated by E2 via estrogen receptors are repressed, yet the molecular mechanisms that mediate E2-induced gene repression are currently unknown. We hypothesized that E2, acting through estrogen receptors, regulates expression of microRNAs (miRs) leading to repression of expression of specific target genes.

Methods and Results—
Here, we report that E2 significantly upregulates the expression of 26 miRs and downregulates the expression of 6 miRs in mouse aorta. E2-mediated upregulation of one of these miRs, miR-203, was chosen for further study. In cultured vascular smooth muscle cells (VSMC), E2-mediated upregulation of miR-203 is mediated by estrogen receptor-α (but not estrogen receptor-β) via transcriptional upregulation of the primary miR. We demonstrate that the transcription factors Zeb-1 and AP-1 play critical roles in mediating E2-induced upregulation of miR-203 transcription. We show further that miR-203 mediates E2-induced repression of Abl1, and p63 protein abundance in VSMC. Finally, knocking-down miR-203 abolishes E2-mediated inhibition of VSMC proliferation, and overexpression of miR-203 inhibits cultured VSMC proliferation, but not vascular endothelial cell proliferation.

Conclusion—
Our findings demonstrate that E2 regulates expression of miRs in the vasculature and support the estrogen receptors-dependent induction of miRs as a mechanism for E2-mediated gene repression. Furthermore, our findings demonstrate that miR-203 contributes to E2-induced inhibition of VSMC proliferation and highlight the potential of miR-203 as a therapeutic agent in the treatment of proliferative cardiovascular diseases.
Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors
Authors: Saremi Aramesh , Schwenke Dawn C. , Buchanan Thomas A. , Hodis Howard N. , Mack Wendy J. , Banerji MaryAnn , Bray George A. , Clement Stephen C. , Henry Robert R. , Kitabchi Abbas E. , Mudaliar Sunder , Ratner Robert E. , Stentz Frankie B. , Musi Nicolas , Tripathy Devjit , DeFronzo Ralph A. , Reaven Peter D. 
Published: November 2012

Objective—
To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes.

Methods and Results—

CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (
P
=0.01) lower with pioglitazone treatment (4.76×10
–3
mm/year; 95% CI: 2.39×10
–3
–7.14×10
–3
mm/year) compared with placebo (9.69×10
–3
mm/year; 95% CI: 7.24×10
–3
–12.15×10
–3
mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA
1c
, fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (
P
<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.

Conclusion—
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
Association Between Interleukin-6 Levels and First-Ever Cerebrovascular Events in Patients With Vascular Risk Factors
Authors: Miwa Kaori , Tanaka Makiko , Okazaki Shuhei , Furukado Shigetaka , Sakaguchi Manabu , Mochizuki Hideki , Kitagawa Kazuo 
Published: November 2012

Objective—
The objective of this study was to examine the association of inflammatory markers with risk of first-ever cerebrovascular events (CVEs), while simultaneously evaluating subclinical vascular disease.

Methods and Results—

We enrolled 464 outpatients who had vascular risk factors without any preexisting cardiovascular disease. We examined the presence of silent lacunar infarction (SLI) by magnetic resonance imaging; carotid intima-media thickness by ultrasound; and measured high-sensitivity C-reactive protein, interleukin (IL)-6, and IL-18 at baseline, and assessed their associations with CVEs using Cox proportional hazards models of 4.8±2.6 years follow-up. We further calculated measures of reclassification and discrimination. In age- and sex-adjusted analysis, IL-6, but neither high-sensitivity C-reactive protein nor IL-18, was associated with CVEs. The association remained significant after adjustment for conventional risk factors, intima-media thickness, and SLI (hazard ratios: 1.80, per 1-SD increase in log IL-6,
P
=0.03). Compared with the patients with below median IL-6 without SLI, those with above median IL-6 and SLI had a higher risk of CVEs (hazard ratios: 4.14,
P
=0.0014). The combination of IL-6 and SLI resulted in the net reclassification improvement of 14.3% (
P
=0.04), and the integrated discrimination improvement gain of 2.1% (
P
=0.05).

Conclusion—
IL-6 levels were independently associated with CVEs and could improve reclassification in those with SLI.
Pulse Steroid Therapy Inhibits Murine Subglottic Granulation
Authors: Ghosh Ankona , Philiponis Genevieve , Lee Jennifer Y. , Leahy Kevin P. , Singhal Sunil , Cohen Noam A. , Mirza Natasha 
Published: November 2012

ObjectiveUsing a functional model of airway granulation tissue in subglottic stenosis, we investigated changes in inflammatory markers within granulation tissue in response to intraperitoneal dexamethasone injections. Changes in inflammatory markers will allow us to identify potential targets for immunological therapy.Study DesignInstitutional Animal Care and Use Committee–approved animal study.SettingPhiladelphia Veterans Administration Medical Center animal research facility.Subjects and MethodsLaryngotracheal complexes of donor mice underwent direct airway injury and were transplanted into subcutaneous tissue of 19 recipient mice in 2 groups: steroid treated and untreated, with sample sizes of 10 and 9, respectively. The steroid‐treated arm received intraperitoneal injection of dexamethasone for 3 weeks. Laryngotracheal complexes were then harvested, and granulation formation was measured. The messenger RNA (mRNA) expression of transforming growth factor (TGF)–β1 and interleukin (IL)–1 was quantified.ResultsAt 3 weeks posttransplantation, there were statistically significant differences in observable granulation formation as well as mRNA expression of TGF‐β1 and IL‐1β in all groups within the steroid treated arm as compared with the untreated arm.ConclusionsSystemic steroids have been used to prevent formation of granulation tissue and subglottic stenosis. However, the study of the immunologic markers and the corresponding changes with steroid treatment has not been well studied in animal models. Using a previously described novel murine model, we begin to delineate inflammatory markers that can be applied for potential therapeutic targets.
A meta-analytic review of relationship maintenance and its correlates
Authors: Ogolsky Brian G. , Bowers Jill R. 
Published: November 2012

This meta-analysis examines the five factors from the Relational Maintenance Strategies Measure (RMSM, i.e., positivity, openness, assurances, social networks, and sharing tasks) and their associations with satisfaction, commitment, control mutuality, love, liking, and relationship duration. Across 35 studies ( N = 12,273 participants), results showed positive correlations between the maintenance factors and the relational correlates except relationship duration, which was negatively associated with positivity and assurances and unassociated with openness, social networks, and sharing tasks. Moderator analyses showed differences in effect sizes depending upon measure (i.e., RMSM or a revision), reporter (i.e., perceptions of partner’s maintenance or individuals’ own enactment of maintenance), and biological sex. Effect sizes were generally larger for women than men and when studies used the RMSM and perceptions of the partner’s maintenance.
Self-disclosure mediates the effects of gender orientation and homophobia on the relationship quality of male same-sex friendships
Authors: Morman Mark T. , Schrodt Paul , Tornes Michael J. 
Published: November 2012

This study tested the degree to which self-disclosure mediates the effects of gender orientation and homophobia on relational satisfaction, closeness, and commitment in men’s same-sex friendships. Participants included 211 men from the southwest region of the US, who reported on either geographically close ( n = 107) or long distance same-sex friendships ( n = 104). Results indicated that self-disclosure mediates the positive effect of femininity on satisfaction, closeness, and commitment in men’s same-sex friendships. Self-disclosure also mediates the negative, indirect effects of homophobia on all three relational outcomes. Tests of structural invariance provided no evidence to suggest that the indirect effects of femininity and homophobia on all three relational outcomes vary as a function of geographic distance.
Neuropathic cancer pain: Prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative–Computerised Symptom Assessment study
Authors: Rayment Clare , Hjermstad Marianne J , Aass Nina , Kaasa Stein , Caraceni Augusto , Strasser Florian , Heitzer Ellen , Fainsinger Robin , Bennett Michael I ,   On behalf of the European Palliative Care Research Collaborative (EPCRC)
Published: November 2012

Background: Neuropathic pain causes greater pain intensity and worse quality of life than nociceptive pain. There are no published data that confirm this in the cancer population. Aim: We hypothesised that patients with neuropathic cancer pain had more intense pain, experienced greater suffering and were treated with more analgesics than those with nociceptive cancer pain, and a neuropathic pain screening tool, painDETECT, would perform as well in those with cancer pain as is reported in those with non-cancer pain. Design: The data were obtained from an international cross-sectional observational study. Setting/Participants: A total of 1051 patients from inpatients and outpatients, with incurable cancer completed a computerised assessment on symptoms, function and quality of life. In all, 17 centres within eight countries participated. Medical data were recorded by physicians. Pain type was a clinical diagnosis recorded on the Edmonton Classification System for Cancer Pain. Results: Of the patients, 670 had pain: 534 with nociceptive pain, 113 with neuropathic pain and 23 were unclassified. Patients with neuropathic cancer pain were significantly more likely to be receiving oncological treatment, strong opioids and adjuvant analgesia and have a reduced performance status. They reported worse physical, cognitive and social function. Sensitivity and specificity of painDETECT for identifying neuropathic cancer pain was less accurate than when used in non-cancer populations. Conclusions: Neuropathic cancer pain is associated with a negative impact on daily living and greater analgesic requirements than nociceptive cancer pain. Validated assessment methods are needed to enable early identification of neuropathic cancer pain, leading to more appropriate treatment and reduced burden on patients.