bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing risk with e-based support for adherence to lifestyle change in hypertension (REACH): protocol for a multicentred randomised controlled trial
Authors: Nolan Robert P , Liu Sam , Feldman Ross , Dawes Martin , Barr Susan , Lynn Hazel , Gwardy-Sridhar Femida , Thomas Scott G , Goodman Jack , Oh Paul , Kaczorowski Janusz , Chessex Caroline , Hachinski Vladimir , Shoemaker Kevin 
Published: August 2013

IntroductionWeb-based lifestyle counselling designed to improve adherence to self-management behaviours for diet, exercise and medication has been shown to reduce blood pressure (BP). However, the long-term clinical outcome of these interventions is not established. Our aim was to establish whether an e-counselling program is independently associated with improved clinical outcomes over a 12-month period, as defined by the following criteria: (1) reduction of systolic BP, diastolic BP, pulse pressure and associated risk factors for cardiovascular events; and (2) adherence to self-management behaviour (diet, exercise, smoke-free living and prescribed medication).Methods and analysisReducing risk with e-based support for adherence to lifestyle change in hypertension is a two-parallel group, double-blind randomised controlled trial that will utilise a two (Groups: e-counselling vs control) by three (assessment intervals: baseline, 4-month and 12-month outcome) design. BP, lipoprotein cholesterol, physical activity and dietary behaviours and psychological distress will be measured at each assessment. We plan to recruit 528 participants (35–74 years of age) diagnosed with stage 1 or 2 hypertension (systolic BP, 140–180 mm Hg; diastolic BP 90–110 mm Hg) from three major cities (Toronto, London, Vancouver) and one rural area (Grey Bruce region) across Canada between February 2012 and July 2015. Controls will receive general educational e-messages on heart healthy living and the e-counselling group will receive tailored e-messages that are matched to their stage of readiness for change. For both groups, e-messages will be sent proactively on a weekly basis during months 1–4, then bi-weekly during months 5–8 and then monthly during months 9–12.Ethics and disseminationEthical approval has been obtained from all recruitment sites. This will be one of the first studies to evaluate the long-term efficacy of preventive e-counselling strategies for cardiovascular disease prevention in patients with hypertension. Findings from this study will be used to guide the ongoing development of e-counselling services.Trial RegistrationClinicaltrial.govNCT01541540;http://clinicaltrials.gov/ct2/show/NCT01541540.
Integrin αvβ3 and Fibronectin Upregulate Slug in Cancer Cells to Promote Clot Invasion and Metastasis
Authors: Knowles Lynn M. , Gurski Lisa A. , Engel Charlotte , Gnarra James R. , Maranchie Jodi K. , Pilch Jan 
Published: August 2013

Abstract
The blood clotting cascade is selectively involved in lung metastasis, but the reason for this selectivity is unclear. Here, we show that tumor cells that metastasize predominantly to the lung, such as renal cell carcinoma (RCC) and soft tissue sarcoma (STS), have an inherent capacity to generate extensive invadopodia when embedded in a blood clot. Compared with other metastatic cancer cells tested, RCC and STS cells exhibited increased levels of expression of fibronectin and an activated form of the integrin αvβ3, which coordinately supported the generation of an elaborate fibronectin matrix and actin stress fibers in fibrin-embedded tumor cells. Together, fibronectin and αvβ3 induced upregulation of the transcription factor Slug, which mediates epithelial–mesenchymal transition as well as fibrin invasion and lung metastasis. This mechanism is clinically significant, because primary cancer cells from patients with metastatic RCC strongly invaded fibrin and this correlated with fibronectin matrix formation and Slug expression. In contrast, tumor cells from patients with localized RCC were largely noninvasive. Together, our findings establish that activated integrin αvβ3 and fibronectin promote lung metastasis by upregulating Slug, defining a mechanism through which cancer cells can colonize blood clots in the lung vasculature. Cancer Res; 73(20); 6175–84. ©2013 AACR.
Increased Proliferative Background in Healthy Women with BRCA1/2 Haploinsufficiency Is Associated with High Risk for Breast Cancer
Authors: Nisman Benjamin , Kadouri Luna , Allweis Tanir , Maly Bella , Hamburger Tamar , Gronowitz Simon , Peretz Tamar 
Published: August 2013

Abstract
Previous studies indicated that BRCA haploinsufficiency was associated with activation of the EGF receptor (EGFR) signaling pathway and increased proliferative activity in mammary epithelial cells of healthy women. We hypothesized that these processes might be reflected in the expression of serologic soluble EGFR (sEGFR) and thymidine kinase 1 (TK1) activity, which signal the initial and final steps of the proliferative pathway, respectively. We found that healthy carriers of BRCA1/2 mutations (n = 80) showed a significantly higher TK1 activity than age-matched controls (P = 0.0003), and TK1 activity was similar in women with BRCA1 and BRCA2 mutations (P = 0.74). The sEGFR concentration was significantly higher in women with BRCA1 than in controls and BRCA2 mutation (P = 0.013 and 0.002, respectively). During follow-up, four of 80 BRCA1/2 mutation carriers developed breast cancer. These women showed a significantly higher TK1 activity and somewhat higher sEGFR concentrations than the other 76 BRCA1/2 carriers (P = 0.04 and 0.09, respectively). All tumors were negative for ovarian hormone receptors, but showed a high EGFR expression. This study was limited by the short-term follow-up (mean, 27 months; range, 5–45), which resulted in a small sample size. Women with BRCA1 and BRCA2 mutations that had undergone risk-reducing bilateral salpingo-oophorectomy (BSO) showed significantly lower sEGFR compared with those without surgery (P = 0.007 and 0.038, respectively). Larger, prospective studies are warranted to investigate whether TK1 and sEGFR measurements may be useful for identifying healthy BRCA1/2 carriers with high risk of developing breast cancer; moreover, sEGFR measurements may serve as effective tools for assessing risk before and after BSO. Cancer Epidemiol Biomarkers Prev; 22(11); 2110–5. ©2013 AACR.
The Use of Metformin and Colorectal Cancer Incidence in Patients with Type II Diabetes Mellitus
Authors: Smiechowski Brielan , Azoulay Laurent , Yin Hui , Pollak Michael N. , Suissa Samy 
Published: August 2013

Abstract
Background: Experimental studies have suggested that metformin may decrease the incidence of colorectal cancer in patients with type II diabetes. However, previous observational studies have reported contradictory results, which are likely due to important methodologic limitations. Thus, the objective of this study was to assess whether the use of metformin is associated with the incidence of colorectal cancer in patients with type II diabetes.
Methods: A cohort study of patients newly treated with non-insulin antidiabetic agents was assembled using the United Kingdom Clinical Practice Research Datalink. A nested case–control analysis was conducted, where all incident cases of colorectal cancer occurring during follow-up were identified and randomly matched with up to 10 controls. Conditional logistic regression was used to estimate adjusted rate ratios (RR) of colorectal cancer associated with ever use, and cumulative duration of use of metformin. All models accounted for latency and were adjusted for relevant potential confounding factors.
Results: Overall, ever use of metformin was not associated with the incidence of colorectal cancer [RR: 0.93; 95% confidence interval (CI), 0.73–1.18]. Similarly, no dose–response relationship was observed in terms of cumulative duration of use.
Conclusions: The use of metformin was not associated with the incidence of colorectal cancer in patients with type II diabetes.
Impact: The results of this study do not support the launch of metformin randomized controlled trials for the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 22(10); 1877–83. ©2013 AACR.
Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer
Authors: Gucalp Ayca , Tolaney Sara , Isakoff Steven J. , Ingle James N. , Liu Minetta C. , Carey Lisa A. , Blackwell Kimberly , Rugo Hope , Nabell Lisle , Forero Andres , Stearns Vered , Doane Ashley S. , Danso Michael , Moynahan Mary Ellen , Momen Lamia F. , Gonzalez Joseph M. , Akhtar Arooj , Giri Dilip D. , Patil Sujata , Feigin Kimberly N. , Hudis Clifford A. , Traina Tiffany A. 
Published: August 2013

AbstractPurpose: Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer.Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) &gt; 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) &gt; 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer.Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed.Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. Clin Cancer Res; 19(19); 5505–12. ©2013 AACR.
New Strategies in Neuroblastoma: Therapeutic Targeting of MYCN and ALK
Authors: Barone Giuseppe , Anderson John , Pearson Andrew D.J. , Petrie Kevin , Chesler Louis 
Published: August 2013

AbstractClinical outcome remains poor in patients with high-risk neuroblastoma, in which chemoresistant relapse is common following high-intensity conventional multimodal therapy. Novel treatment approaches are required. Although recent genomic profiling initiatives have not revealed a high frequency of mutations in any significant number of therapeutically targeted genes, two exceptions, amplification of the MYCN oncogene and somatically acquired tyrosine kinase domain point mutations in anaplastic lymphoma kinase (ALK), present exciting possibilities for targeted therapy. In contrast with the situation with ALK, in which a robust pipeline of pharmacologic agents is available from early clinical use in adult malignancy, therapeutic targeting of MYCN (and MYC oncoproteins in general) represents a significant medicinal chemistry challenge that has remained unsolved for two decades. We review the latest approaches envisioned for blockade of ALK activity in neuroblastoma, present a classification of potential approaches for therapeutic targeting of MYCN, and discuss how recent developments in targeting of MYC proteins seem to make therapeutic inhibition of MYCN a reality in the clinic. Clin Cancer Res; 19(21); 5814–21. ©2013 AACR.
Intratumoral Anti-CTLA-4 Therapy: Enhancing Efficacy While Avoiding Toxicity
Authors: Marabelle Aurélien , Kohrt Holbrook , Levy Ronald 
Published: August 2013

Abstract
Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe autoimmune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peritumoral delivery of low doses of this immunomodulatory drug can trigger a systemic antitumor immune response while preventing the toxicity against other organs. Clin Cancer Res; 19(19); 5261–3. ©2013 AACR.
Synergistic Targeting of PI3K/AKT Pathway and Androgen Receptor Axis Significantly Delays Castration-Resistant Prostate Cancer ProgressionIn Vivo
Authors: Thomas Christian , Lamoureux Francois , Crafter Claire , Davies Barry R. , Beraldi Eliana , Fazli Ladan , Kim Soojin , Thaper Daksh , Gleave Martin E. , Zoubeidi Amina 
Published: August 2013

AbstractThe progression to castration-resistant prostate cancer (CRPC) correlates with gain-of-function of the androgen receptor (AR) and activation of AKT. However, as single agents, AR or AKT inhibitors result in a reciprocal feedback loop. Therefore, we hypothesized that combination of an AKT inhibitor with an antiandrogen might result in a more profound, long-lasting remission of CRPC. Here, we report that the AKT inhibitor AZD5363 potently inhibits proliferation and induces apoptosis in prostate cancer cell lines expressing the AR and has anticancer activity in vivo in androgen-sensitive and castration-resistant phases of the LNCaP xenograft model. However, we found that the effect of castration-resistant tumor growth inhibition and prostate-specific antigen (PSA) stabilization is transient and resistance occurs with increasing PSA after approximately 30 days of treatment. Mechanistically, we found that single agent AZD5363 induces increase of AR binding to androgen response element, AR transcriptional activity, and AR-dependent genes such as PSA and NKX3.1 expression. These effects were overcome by the combination of AZD5363 with the antiandrogen bicalutamide, resulting in synergistic inhibition of cell proliferation and induction of apoptosis in vitro, and prolongation of tumor growth inhibition and PSA stabilization in CRPC in vivo. This study provides a preclinical proof-of-concept that combination of an AKT inhibitor with antiandrogen results in prolonged disease stabilization in a model of CRPC. Mol Cancer Ther; 12(11); 2342–55. ©2013 AACR.
Hsp90 Inhibitors Promote p53-Dependent Apoptosis through PUMA and Bax
Authors: He Kan , Zheng Xingnan , Zhang Lin , Yu Jian 
Published: August 2013

Abstract
Hsp90 is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promise in solid and hematologic malignancies, which likely involves degradation of client oncoproteins in a cell-type–specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53, at lesser extent, abrogated 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17-AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17-AAG analog 17-DMAG in xenografts. These results show an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor–induced killing of p53 wild-type cells, and have important implications for their clinical applications. Mol Cancer Ther; 12(11); 2559–68. ©2013 AACR.
RETRACTED: Combining PARP-1 Inhibition and Radiation in Ewing Sarcoma Results in Lethal DNA Damage
Authors: Lee Hae-June , Yoon Changhwan , Schmidt Benjamin , Park Do Joong , Zhang Alexia Y. , Erkizan Hayriye V. , Toretsky Jeffrey A. , Kirsch David G. , Yoon Sam S. 
Published: August 2013

Abstract
Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5–1 μmol/L vs. &gt;5 μmol/L) and to radiation (IC50 2–4 Gy vs. &gt;6 Gy). PARP-1 inhibition with short hairpin RNA (shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36–54 vs. 26–28) and sustained DNA damage at 24 hours (24–29 vs. 6–8). This DNA damage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-N-MC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1–dependent manner. Mol Cancer Ther; 12(11); 2591–600. ©2013 AACR.
Examining the Association between Oral Health and Oral HPV Infection
Authors: Bui Thanh Cong , Markham Christine M. , Ross Michael Wallis , Mullen Patricia Dolan 
Published: August 2013

Abstract
Oral human papillomavirus (HPV) infection is the cause of 40% to 80% of oropharyngeal cancers; yet, no published study has examined the role of oral health in oral HPV infection, either independently or in conjunction with other risk factors. This study examined the relation between oral health and oral HPV infection and the interactive effects of oral health, smoking, and oral sex on oral HPV infection. Our analyses comprised 3,439 participants ages 30 to 69 years for whom data on oral HPV and oral health were available from the nationally representative 2009–2010 National Health and Nutrition Examination Survey. Results showed that higher unadjusted prevalence of oral HPV infection was associated with four measures of oral health, including self-rated oral health as poor-to-fair [prevalence ratio (PR) = 1.56; 95% confidence interval (CI), 1.25–1.95], indicated the possibility of gum disease (PR = 1.51; 95% CI, 1.13–2.01), reported use of mouthwash to treat dental problems in the past week (PR = 1.28; 95% CI, 1.07–1.52), and higher number of teeth lost (Ptrend = 0.035). In multivariable logistic regression models, oral HPV infection had a statistically significant association with self-rated overall oral health (OR = 1.55; 95% CI, 1.15–2.09), independent of smoking and oral sex. In conclusion, poor oral health was an independent risk factor of oral HPV infection, irrespective of smoking and oral sex practices. Public health interventions may aim to promote oral hygiene and oral health as an additional measure to prevent HPV-related oral cancers. Cancer Prev Res; 6(9); 917–24. ©2013 AACR.
Procoagulant reactivity to laboratory acute mental stress in Africans and Caucasians, and its relation to depressive symptoms: The SABPA Study
Authors: Hamer Mark , Malan Nico T. , Scheepers Kobus , Meiring Muriel , Malan Leonè , Känel Roland von 
Published: August 2013

SummaryThe risk of cardiovascular disease is dramatically increasing in Africans (black). The prothrombotic stress response contributes to atherothrombotic disease and is modulated by depressive symptoms. We examined coagulation reactivity to acute mental stress and its relation to psychological well-being in Africans relative to Caucasians (white). A total of 102 African and 165 Caucasian school teachers underwent the Stroop Color-Word Conflict test. Circulating levels of von Willebrand factor (VWF) antigen, fibrinogen, and D-dimer were measured before and after the Stroop. Cardiovascular reactivity measures were also obtained. All participants completed the Patient Health Questionnaire-9 and the General Health Questionnaire-28 for the assessment of depressive symptoms and total psychological distress, respectively. After controlling for covariates, resting levels of VWF, fibrinogen, and D-dimer were higher in Africans than in Caucasians (all p-values ≤0.006). Depressive symptoms and psychological distress were not significantly associated with resting coagulation measures. Stress reactivity in VWF (p<0.001) and fibrinogen (p=0.016), but not in D-dimer (p=0.27), were decreased in Africans relative to Caucasians with Africans showing greater reactivity of total peripheral resistance (p=0.017). Depressive symptoms, but not general psychological distress, were associated with greater VWF increase (p=0.029) and greater fibrinogen decrease (p=0.030) in Africans relative to Caucasians. In conclusion, Africans showed greater hypercoagulability at rest but diminished procoagulant reactivity to acute mental stress when compared with Caucasians. Ethnic differences in the vascular adrenergic stress response might partially explain this finding. Depressive symptoms were associated with exaggerated VWF reactivity in Africans relative to Caucasians. The clinical implications of these findings for Africans need further study.
Use of Hydralazine‐Isosorbide Dinitrate Combination in African American and Other Race/Ethnic Group Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction
Authors: Golwala Harsh B. , Thadani Udho , Liang Li , Stavrakis Stavros , Butler Javed , Yancy Clyde W. , Bhatt Deepak L. , Hernandez Adrian F. , Fonarow Gregg C. 
Published: August 2013

Background

Hydralazine‐isosorbide dinitrate (H‐
ISDN
) therapy is recommended for
A
frican
A
merican patients with moderate to severe heart failure with reduced ejection fraction (<40%) (
HF
r
EF
), but use, temporal trends, and clinical characteristics associated with H‐
ISDN therapy
in clinical practice are unknown.

Methods and Results

An observational analysis of 54 622 patients admitted with
HF
r
EF
and discharged home from 207 hospitals participating in the Get With The Guidelines–
H
eart
F
ailure registry from April 2008 to March 2012 was conducted to assess prescription, trends, and predictors of use of H‐
ISDN
among eligible patients. Among 11 185
A
frican
A
merican patients eligible for H‐
ISDN
therapy, only 2500 (22.4%) received H‐
ISDN
therapy at discharge. In the overall eligible population, 5115 of 43 498 (12.6%) received H‐
ISDN
at discharge. Treatment rates increased over the study period from 16% to 24% among
A
frican
A
mericans and from 10% to 13% among the entire
HF
r
EF
population. In a multivariable model, factors associated with H‐
ISDN
use among the entire cohort included younger age; male sex;
A
frican
A
merican/Hispanic ethnicity; and history of diabetes, hypertension, anemia, renal insufficiency, higher systolic blood pressure, and lower heart rate. In
A
frican
A
merican patients, these factors were similar; in addition, being uninsured was associated with lower use.

Conclusions

Overall, few potentially eligible patients with
HF
r
EF
are treated with H‐
ISDN
, and among
A
frican‐
A
mericans fewer than one‐fourth of eligible patients received guideline‐recommended H‐
ISDN
therapy. Improved ways to facilitate use of H‐
ISDN
therapy in
A
frican
A
merican patients with
HF
r
EF
are needed.