bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
Authors: Baselga José , Lewis Phillips Gail D. , Verma Sunil , Ro Jungsil , Huober Jens , Guardino Alice E. , Samant Meghna K. , Olsen Steve , de Haas Sanne L. , Pegram Mark D. 
Published: February 2016

Abstract
Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study.
Experimental Design: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.
Results: Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1–treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.
Conclusions: Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755–63. ©2016 AACR.
Everything Old Is New Again: Using Nelfinavir to Radiosensitize Rectal Cancer
Authors: Meyn Raymond E. , Krishnan Sunil , Skinner Heath D. 
Published: February 2016

Abstract
Repurposing agents approved for other indications to radiosensitize tumors may be advantageous. The study by Hill and colleagues utilizes nelfinavir, an HIV protease inhibitor (PI), in combination with radiotherapy in rectal cancer in a prospective study. This combination may improve tumor perfusion and regression compared with radiotherapy alone. Clin Cancer Res; 22(8); 1834–6. ©2016 AACR.
See related article by Hill et al., p. 1922
Therapeutic Guide for mTOuRing through the Braided Kidney Cancer Genomic River
Authors: Voss Martin H. , Hsieh James J. 
Published: February 2016

Abstract
mTORC1 inhibitors were first approved for the use in metastatic kidney cancer. However, observed treatment benefit was highly heterogeneous among patients. Through case-based cancer genomic sequencing of therapeutic outliers, we can begin to appreciate the convergent evolution of given cancer pathways/phenotypes beyond genes in kidney cancer, like a braided river. Clin Cancer Res; 22(10); 2320–2. ©2016 AACR.
See related article by Kwiatkowski et al., p. 2445
In Vitro and In Vivo Studies of a New Class of Anticancer Molecules for Targeted Radiotherapy of Cancer
Authors: Wang Chun-Rong , Mahmood Javed , Zhang Qin-Rong , Vedadi Ali , Warrington Jenny , Ou Ning , Bristow Robert G. , Jaffray David A. , Lu Qing-Bin 
Published: February 2016

Abstract
There is a compelling need to develop anticancer therapies that target cancer cells and tissues. Arising from innovative femtomedicine studies, a new class of non–platinum-based halogenated molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells in treatments of multiple cancers has been discovered. This article reports the first observation of the radiosensitizing effects of such compounds in combination with ionizing radiation for targeted radiotherapy of a variety of cancers. We present in vitro and in vivo studies focused on combination with radiotherapy of cervical, ovarian, head and neck, and lung cancers. Our results demonstrate that treatments of various cancer cells in vitro and in vivo mouse xenograft models with such compounds led to enhanced efficiencies in radiotherapy, while the compounds themselves induced no or little radiotoxicity toward normal cells or tissues. These compounds are therefore effective radiosensitizers that can be translated into clinical trials for targeted radiotherapy of multiple types of cancer. This study also shows the potential of femtomedicine to bring breakthroughs in understanding fundamental biologic processes and to accelerate the discovery of novel drugs for effective treatment or prevention of a variety of cancers. Mol Cancer Ther; 15(4); 640–50. ©2016 AACR.
β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation
Authors: Kallifatidis Georgios , Munoz Daniel , Singh Rajendra Kumar , Salazar Nicole , Hoy James J. , Lokeshwar Bal L. 
Published: February 2016

Abstract
The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand–independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7–EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/amphiregulin) and G-protein–coupled receptor signaling. An alternate signaling mechanism involving β-arrestin-2 (ARRB2/β-AR2) was examined by manipulating the levels of β-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of β-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, β-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of β-AR2–expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of β-AR2 enhanced this nuclear translocation. These results demonstrate that β-AR2 is a negative regulator of CXCR7/Src/EGFR–mediated mitogenic signaling.
Implications: This study reveals that β-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR–mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493–503. ©2016 AACR.
Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
Authors: Vandeveer Amanda J. , Fallon Jonathan K. , Tighe Robert , Sabzevari Helen , Schlom Jeffrey , Greiner John W. 
Published: February 2016

Abstract
Bacillus Calmette–Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P &lt; 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452–62. ©2016 AACR.
Cardiac Resynchronization Therapy
Authors: Sridhar Arun Raghav Mahankali , Yarlagadda Vivek , Parasa Sravanthi , Reddy Yeruva Madhu , Patel Dhavalkumar , Lakkireddy Dhanunjaya , Wilkoff Bruce L. , Dawn Buddhadeb 
Published: February 2016

Background—
The use of cardiac resynchronization therapy (CRT) has increased significantly since its initial approval in 2001 for use in patients with advanced heart failure. However, trends in utilization of CRT have not been systematically characterized.

Methods and Results—

We used the Nationwide Inpatient Sample database to identify all patients with CRT implantation during 2002 to 2010. The overall trends in CRT device implantation, patient characteristics, and outcomes were examined in detail and compared among demographic subgroups. During 2002 to 2010, a total of 374 202 CRT procedures were recorded. Significant and persistent gender and racial disparities favoring men (71.4%) and white (79.6%), respectively, were noted in all years. The highest number of CRT devices were implanted in the 65- to 84-year age group (64.6%), with significant increase in number of CRT implants in older patients ≥85 years over the years (
P
=0.02). The CRT-associated in-hospital mortality improved from 1.08% in 2003 to 0.70% in 2010 (
P
=0.03). The correlates of higher mortality included males (0.93% versus 0.71% in females;
P
=0.04) and older age (age ≥85 years had 1.5% mortality versus 0.8% for age <85 year;
P
<0.001). The mean hospital length of stay for CRT decreased, while mean CRT-associated hospital charges increased progressively over the years. Factors associated with higher charges were gender (males>females), older age, and greater comorbidities.

Conclusions—
CRT implantation is a relatively safe procedure that has become safer in higher risk patients. However, significant disparities in CRT utilization exist in certain demographic subgroups, and these disparities have persisted across the years.
Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function
Authors: Iantorno Micaela , Hays Allison G. , Schär Michael , Krishnaswamy Rupa , Soleimanifard Sahar , Steinberg Angela , Stuber Matthias , Gerstenblith Gary , Weiss Robert G. 
Published: February 2016

Background—
Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE.

Methods and Results—

Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (
R
=0.91) and blood flow (
R
=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-
l
-arginine (
P
<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (
P
=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease.

Conclusions—
MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health.
Duration of Prehospital Resuscitation Efforts After Out-of-Hospital Cardiac Arrest
Authors: Nagao Ken , Nonogi Hiroshi , Yonemoto Naohiro , Gaieski David F. , Ito Noritoshi , Takayama Morimasa , Shirai Shinichi , Furuya Singo , Tani Sigemasa , Kimura Takeshi , Saku Keijiro 
Published: February 2016

Background—
During out-of-hospital cardiac arrest, it is unclear how long prehospital resuscitation efforts should be continued to maximize lives saved.

Methods and Results—

Between 2005 and 2012, we enrolled 282 183 adult patients with bystander-witnessed out-of-hospital cardiac arrest from the All-Japan Utstein Registry. Prehospital resuscitation duration was calculated as the time interval from call receipt to return of spontaneous circulation in cases achieving prehospital return of spontaneous circulation or from call receipt to hospital arrival in cases not achieving prehospital return of spontaneous circulation. In each of 4 groups stratified by initial cardiac arrest rhythm (shockable versus nonshockable) and bystander resuscitation (presence versus absence), we calculated minimum prehospital resuscitation duration, defined as the length of resuscitation efforts in minutes required to achieve ≥99% sensitivity for the primary end point, favorable 30-day neurological outcome after out-of-hospital cardiac arrest. Prehospital resuscitation duration to achieve prehospital return of spontaneous circulation ranged from 1 to 60 minutes. Longer prehospital resuscitation duration reduced the likelihood of favorable neurological outcome (adjusted odds ratio, 0.84; 95% confidence interval, 0.838–0.844). Although the frequency of favorable neurological outcome was significantly different among the 4 groups, ranging from 20.0% (shockable/bystander resuscitation group) to 0.9% (nonshockable/bystander resuscitation group;
P
<0.001), minimum prehospital resuscitation duration did not differ widely among the 4 groups (40 minutes in the shockable/bystander resuscitation group and the shockable/no bystander resuscitation group, 44 minutes in the nonshockable/bystander resuscitation group, and 45 minutes in the nonshockable/no bystander resuscitation group).

Conclusions—
On the basis of time intervals from the shockable arrest groups, prehospital resuscitation efforts should be continued for at least 40 minutes in all adults with bystander-witnessed out-of-hospital cardiac arrest.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: 000009918.
Understanding women who self-harm: Predictors and long-term outcomes in a longitudinal community sample
Authors: Stanford Sarah , Jones Michael P , Loxton Deborah J 
Published: February 2016

Objective: There is growing awareness of the range of psychosocial, lifestyle, and sociodemographic factors related to self-harm, however this research is often limited by using cross-sectional or convenience samples. And while we generally assume that young adults who self-harm experience poorer long-term outcomes, longitudinal research is needed. This paper builds on prior research using a large, representative, longitudinal sample. Methods: 5765 Australian women completed 5 surveys (age 18–23 to 31–36). Six-month self-harm was measured by self-report. We had two aims: firstly to predict future self-harm, separately for women with and without prior self-harm. Secondly, to identify outcomes 3 and 6 years following self-harm. Results: Six-month self-harm prevalence was 2.5%. Predictors among women without recent self-harm included depression, dieting behaviours, number of male sexual partners, and abuse. Among women with recent or current self-harm, predictors were number of dieting behaviours, tiredness of life, and stress. Women who self-harmed reported poorer outcomes, namely greater difficulties in relationships at 3- and 6-year follow-up. Conclusions: Longitudinal risk factors for self-harm differed depending on prior self-harm status, and included depression, dieting behaviours, tiredness of life and stress. These factors may serve as warning signs for new or continued self-harm. This study offers new insight into long-term outcomes up to six years after self-harm, particularly with relationships.
Preparing for community development practice: A Delphi study of Canadian occupational therapists
Authors: Leclair Leanne L. , Ashcroft Morgan L. , Canning Tamara L. , Lisowski Marla A. 
Published: February 2016

Background. Increasingly, community development is recognized as an important process for occupational therapy practice. However, occupational therapists working in community development report feeling unprepared. Purpose. This study aimed to identify the knowledge, skills, and experiences that occupational therapists need for practice in community development. Method. Using the Delphi technique, the researchers developed statements from the Round 1 ( n = 8) responses of occupational therapists involved in community development practice or scholarship. Rounds 2 ( n = 14) and 3 ( n = 12) sought to establish consensus among the occupational therapists on the areas of focus. Findings. Participants rated the importance of 64 statements grouped into 11 domains. After three rounds, researchers eliminated six statements by analyzing the median, interquartile range, and percentage of agreement. Participants reached consensus on 58 statements. Implications. Many of the competencies identified were relevant to all areas of practice, while others were specific to community development, suggesting a need for specialized education and training in this area. The results provide information that can be used to enhance the preparation of occupational therapists for practice in community development.
Fasting serum insulin levels and insulin resistance are associated with blood rheology in Japanese young adults without diabetes
Authors: Yoshida Kensuke , Kimura Takao , Aoki Tomoyuki , Tsunekawa Katsuhiko , Araki Osamu , Shoho Yoshifumi , Nara Makoto , Sumino Hiroyuki , Murakami Masami 
Published: February 2016

Objectives To evaluate fasting serum insulin levels and insulin resistance, and their association with blood rheology, in Japanese young adults without diabetes. Methods Blood samples were analysed and blood rheology was estimated using haematological parameters. Whole blood passage time was measured using a Hitachi MC-FAN© microchannel array flow analyser. Results Out of 151 subjects (mean age, 24.1 ± 1.5 years), fasting serum insulin levels and insulin resistance (using homeostasis model assessment-estimated insulin resistance [HOMA-IR]), were positively correlated with longer whole blood passage times and higher values for haematocrit (Hct), haemoglobin (Hb), fibrinogen, body weight, body mass index (BMI), triglycerides, and low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, and were negatively correlated with HDL-C. Whole blood passage time correlated with body weight, BMI, LDL-C/HDL-C ratio, Hct, Hb, white blood cell (WBC) count, platelet count, fibrinogen, fasting serum insulin levels, and HOMA-IR. Multiple regression analysis revealed that whole blood passage time was independently associated with Hct, fibrinogen levels, and WBC count. Conclusions Fasting serum insulin levels and insulin resistance were associated with blood rheology, and may influence blood rheology by modulating haematological parameters and lipid parameters in young adults without diabetes.
Altered Visual Adaptation to Body Shape in Eating Disorders: Implications for Body Image Distortion
Authors: Mohr Harald M. , Rickmeyer Constanze , Hummel Dennis , Ernst Mareike , Grabhorn Ralph 
Published: February 2016

Previous research has shown that after adapting to a thin body, healthy participants (HP) perceive pictures of their own bodies as being fatter and vice versa. This aftereffect might contribute to the development of perceptual body image disturbances in eating disorders (ED). In the present study, HP and ED completed a behavioral experiment to rate manipulated pictures of their own bodies after adaptation to thin or fat body pictures. After adapting to a thin body, HP judged a thinner than actual body picture to be the most realistic and vice versa, resembling a typical aftereffect. ED only showed such an adaptation effect when they adapted to fat body pictures. The reported results indicate a relationship between body image distortion in ED and visual body image adaptation. It can be suspected that due to a pre-existing, long-lasting adaptation to thin body shapes in ED, an additional visual adaption to thin body shapes cannot be induced. Hence this pre-existing adaptation to thin body shapes could induce perceptual body image distortions in ED.