bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS Mutations
Authors: Yao Yung-mae M. , Donoho Gregory P. , Iversen Philip W. , Zhang Youyan , Van Horn Robert D. , Forest Amelie , Novosiadly Ruslan D. , Webster Yue Wang , Ebert Philip , Bray Steven , Ting Jason C. , Aggarwal Amit , Henry James R. , Tiu Ramon V. , Plowman Gregory D. , Peng Sheng-Bin 
Published: June 2017

Abstract
Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models.
Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial.
Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.
Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547–60. ©2017 AACR.
Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer
Authors: Hu Qianghua , Hisamatsu Takeshi , Haemmerle Monika , Cho Min Soon , Pradeep Sunila , Rupaimoole Rajesha , Rodriguez-Aguayo Cristian , Lopez-Berestein Gabriel , Wong Stephen T.C. , Sood Anil K. , Afshar-Kharghan Vahid 
Published: June 2017

Abstract
Purpose: Transforming growth factor β1 (Tgfβ1) plays an important role in cancer. Most of Tgfβ1 in plasma is from platelets; thus, we studied whether platelet Tgfβ1 has any role in the progression of ovarian cancer, and whether this role is limited to metastasis or also involves the growth of primary tumors.
Experimental Design: We compared the growth of murine ovarian cancer cell-induced tumors in platelet-specific Tgfβ1-deficient mice and wild-type mice. Using resected tumor nodules, we studied the effect of platelet Tgfβ1 on neoangiogenesis and on platelet extravasation into tumors. To investigate the effect of Tgfβ1 at different stages of ovarian cancer, we reduced expression of Tgfβ1 receptor (its TgfβR1 component) in tumors at different time points after injection of cancer cells, and compared the final tumor size.
Results: Lack of platelet Tgfβ1 in mice reduced tumor growth, neoangiogenesis, and platelet extravasation. Ovarian cancer tumors in platelet-specific Tgfβ1-deficient mice reached less than half of their size in wild-type littermates. Knockdown of TgfβR1 on cancer cells in the first 2 weeks after their injection reduced tumor growth, but was less effective if initiated after 3 weeks.
Conclusions: We showed that platelet Tgfβ1 increased the growth of primary tumors in murine models of ovarian cancer. We also showed that inhibition of TgfβR1 is more effective in reducing the growth of ovarian cancer if initiated earlier. Our results supported a therapeutic benefit in preventing platelet activation, degranulation, and release of Tgfβ1 in ovarian cancer. Clin Cancer Res; 23(18); 5611–21. ©2017 AACR.
ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types
Authors: Chüeh Anderly C. , Tse Janson W.T. , Dickinson Michael , Ioannidis Paul , Jenkins Laura , Togel Lars , Tan BeeShin , Luk Ian , Davalos-Salas Mercedes , Nightingale Rebecca , Thompson Matthew R. , Williams Bryan R.G. , Lessene Guillaume , Lee Erinna F. , Fairlie Walter D. , Dhillon Amardeep S. , Mariadason John M. 
Published: June 2017

Abstract

Purpose:
Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.

Experimental Design:
Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.

Results:
We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.

Conclusions:
These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.
CPT1A
Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders
Authors: Skotte Line , Koch Anders , Yakimov Victor , Zhou Sirui , Søborg Bolette , Andersson Mikael , Michelsen Sascha W. , Navne Johan E. , Mistry Jacqueline M. , Dion Patrick A. , Pedersen Michael L. , Børresen Malene L. , Rouleau Guy A. , Geller Frank , Melbye Mads , Feenstra Bjarke 
Published: June 2017

Background—
Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders.

Methods and Results—

Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in
CPT1A
, was strongly associated with markers of
n
-3 fatty acid metabolism, including degree of unsaturation (
P
=1.16×10
−
34
), levels of polyunsaturated fatty acids,
n
-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (
P
=2.35×10
−
15
,
P
=4.02×10
−
19
, and
P
=7.92×10
−
27
). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (
P
=1.04×10
−
9
). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779.

Conclusion—

Our study shows that a common
CPT1A
missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.
Endothelial Senescence Contributes to Heart Failure With Preserved Ejection Fraction in an Aging Mouse Model
Authors: Gevaert Andreas B. , Shakeri Hadis , Leloup Arthur J. , Van Hove Cor E. , De Meyer Guido R.Y. , Vrints Christiaan J. , Lemmens Katrien , Van Craenenbroeck Emeline M. 
Published: June 2017

Background—
Because of global aging, the prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise. Although HFpEF pathophysiology remains incompletely understood, endothelial inflammation is stated to play a central role. Cellular senescence is a process of cellular growth arrest linked with aging and inflammation. We used mice with accelerated aging to investigate the role of cellular senescence in HFpEF development.

Methods and Results—
Senescence-accelerated mice (SAM, n=18) and control mice with normal senescence (n=15) were fed normal chow or a high-fat, high-salt diet (WD). Vascular and cardiac function was assessed at 8, 16, and 24 weeks of age. At 24 weeks, both SAM on WD (SAM-WD) and SAM on regular diet displayed endothelial dysfunction, as evidenced by impaired acetylcholine-induced relaxation of aortic segments and reduced basal nitric oxide. At week 24, SAM-WD had developed HFpEF, characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, and interstitial fibrosis. Also, exercise capacity was reduced and lung weight increased. Cardiovascular inflammation and senescence were assessed by immunohistochemical and immunofluorescence staining of hearts and aortas. SAM-WD showed increased endothelial inflammation (intercellular adhesion molecule 1 expression) and increased endothelial senescence (acetyl-p53/CD31 costaining). The latter correlated with diastolic function and intercellular adhesion molecule 1 expression.

Conclusions—
SAM develop endothelial dysfunction. Adding a high-salt, high-fat diet accelerates endothelial senescence and instigates endothelial inflammation. This coincides with hemodynamic and structural changes typical of HFpEF. Targeting endothelial senescence could be a new therapeutic avenue in HFpEF.
Success, Failure, and Transparency in Biomarker-Based Drug Development
Authors: Hey Spencer Phillips , Franklin Jessica M. , Avorn Jerry , Kesselheim Aaron S. 
Published: June 2017

Background—
Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use.

Methods and Results—
We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors’ recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points.

Conclusions—
Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs.
Epidemiology, Endovascular Treatment, and Prognosis of Cerebral Venous Thrombosis: US Center Study of 152 Patients
Authors: Salottolo Kristin , Wagner Jeffrey , Frei Donald F. , Loy David , Bellon Richard J. , McCarthy Kathryn , Jensen Judd , Fanale Christopher , Bar‐Or David 
Published: June 2017

Background
Cerebral venous thrombosis is a rare cause of stroke that poses diagnostic, therapeutic, and prognostic challenges. Mainstay treatment is systemic anticoagulation, but endovascular treatment is increasingly advocated. Our objectives were to describe the epidemiology, treatment, and prognosis of 152 patients with cerebral venous thrombosis.

Methods and Results

This was a retrospective study of consecutive cerebral venous thrombosis cases from 2006 to 2013 at a comprehensive stroke center through hospital discharge. Predictors of full recovery (modified Rankin Scale scores 0–1) were analyzed with multiple logistic regression and presented as adjusted odds ratios (
AORs
) with 95% confidence intervals (
CIs
). The population was young (average age: 42 years), majority female (69%), and commonly presenting with cerebral edema (63%), and 72% were transferred in. All patients received systemic anticoagulation; 49% (n=73) required endovascular treatment. Reasons for requiring endovascular treatment included cerebral edema, herniation, or hemorrhagic infarct (n=38); neurologic decline (n=17); rethrombosis, persistent occlusion, or clot propagation (n=10); extensive clot burden (n=7); and persistent headache despite anticoagulation (n=1). There were 7 (10%) procedural complications. Recanalization was successful (61%), partial (30%), and unsuccessful (9%). Overall, 60% fully recovered. Positive predictors of full recovery included hormonal etiology, particularly for patients who were transferred in (
AOR
: 7.06 [95% CI, 2.27–21.96], interaction
P
=0.03) and who had migraine history (
AOR
: 4.87 [95% CI, 1.01–23.50],
P
=0.05), whereas negative predictors of full recovery were cerebral edema (
AOR
: 0.11 [95% CI, 0.04–0.34],
P
<0.001) and motor weakness (
AOR
: 0.28 [95% CI, 0.09–0.96],
P
=0.04).

Conclusions
As one of the largest cohort studies, our findings suggest that cerebral edema, history of migraine, and hormonal etiology were prognostic and that endovascular treatment might be a safe and effective treatment for cerebral venous thrombosis when conventional management is inadequate.
Ticagrelor and Eptifibatide Bolus Versus Ticagrelor and Eptifibatide Bolus With 2‐Hour Infusion in High‐Risk Acute Coronary Syndromes Patients Undergoing Early Percutaneous Coronary Intervention
Authors: Marian Moazez J. , Alli Oluseun , Al Solaiman Firas , Brott Brigitta C. , Sasse Mark , Leesar Tara , Prabhu Sumanth D. , Leesar Massoud A. 
Published: June 2017

Background

In patients with non‐
ST
‐segment elevation acute coronary syndromes, inhibition of platelet aggregation (
IPA
) with a potent P2Y
12
inhibitor, ticagrelor, was inferior to tirofiban infusion at 2 hours, indicating that glycoprotein
II
b/
III
a inhibitors are still needed. Ticagrelor and eptifibatide bolus only may maximally inhibit platelet aggregation and decrease bleeding, but
IPA
with ticagrelor and eptifibatide bolus versus 2‐hour infusion is unknown.

Methods and Results

A total of 70 P2Y
12
‐naïve patients, with high‐risk non‐
ST
‐segment elevation acute coronary syndromes, were randomized to ticagrelor and eptifibatide bolus (group 1) versus ticagrelor and eptifibatide bolus with 2‐hour infusion (group 2). Levels of
IPA
with
ADP
, thrombin receptor‐activating peptide, collagen, and high on‐treatment platelet reactivity were measured by light transmission aggregometry at baseline and at 2, 6, and 24 hours after percutaneous coronary intervention in both groups. The primary end point,
IPA
with
ADP
20 μmol/L at 2 hours, was 99.59±0.43% in group 1 versus 99.88±1.0% in group 2 (
P
<0.001 for noninferiority). High on‐treatment platelet reactivity with
ADP
was zero at 2, 6, and 24 hours in both groups.
IPA
levels with
ADP
, thrombin receptor‐activating peptide, and collagen were significantly higher at 2 and 6 hours than at 24 hours in both groups. Periprocedural myocardial infarction was not significantly different between the groups. Hemoglobin level was significantly less at 24 hours versus baseline in group 2 (13.35±1.8 versus 12.38±1.8 g/dL, respectively;
P
<0.01).

Conclusions
Ticagrelor and eptifibatide bolus maximally inhibited platelet aggregation at 2 hours, which was associated with no significant hemoglobin drop after percutaneous coronary intervention. This obviates the need for eptifibatide 2‐hour infusion and might decrease bleeding complications.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01919723.
Exercise‐Related Out‐of‐Hospital Cardiac Arrest Among the General Population in the Era of Public‐Access Defibrillation: A Population‐Based Observation in Japan
Authors: Kiyohara Kosuke , Nishiyama Chika , Kiguchi Takeyuki , Nishiuchi Tatsuya , Hayashi Yasuyuki , Iwami Taku , Kitamura Tetsuhisa 
Published: June 2017

Background

Exercise can trigger sudden cardiac arrest. Early initiation of cardiopulmonary resuscitation and automated external defibrillator use by laypersons could maximize the survival rate following exercise‐related out‐of‐hospital cardiac arrest (
OHCA
).

Methods and Results

OHCA
data between 2005 and 2012 were obtained from a prospective population‐based
OHCA
registry in Osaka Prefecture. Patients with
OHCA
of presumed cardiac origin and occurring before emergency medical service personnel arrival were included. The incidence trends of exercise‐related
OHCA
over the 8‐year study period were assessed. Among patients with bystander‐witnessed, exercise‐related
OHCA
, the trends in the initiation of bystander cardiopulmonary resuscitation, public‐access defibrillation, and outcome were evaluated. The primary outcome was 1‐month survival with favorable neurological outcome, defined as cerebral performance category 1 or 2. During the study period, 0.7% of
OHCAs
of cardiac origin (222/31 030) were exercise related. The incidence of exercise‐related
OHCA
increased from 1.8 (per million population per year) in 2005 to 4.3 in 2012. Of these, 83.8% (186/222) were witnessed by bystanders. Among the patients with bystander‐witnessed, exercise‐related
OHCA
, the proportion that received bystander cardiopulmonary resuscitation (50.0% in 2005 and 86.2% in 2012) and public‐access defibrillation (7.1% in 2005 and 62.1% in 2012) significantly increased during the study period. Furthermore, the rate of 1‐month survival with favorable neurological outcome among these patients significantly improved (from 28.6% in 2005 to 58.6% in 2012).

Conclusions

The incidence rate of exercise‐related
OHCA
was low in the study population. The increase in bystander cardiopulmonary resuscitation and public‐access defibrillation rates were associated with improved outcome among patients with bystander‐witnessed, exercise‐related
OHCA
.
The Mud and the Water: Towards a History of a Simile in Kabbalah
Authors: Idel Moshe 
Published: June 2017

Abstract
The present study surveys a series of kabbalistic antecedents of a simile for the presence of the roots of evil in the pre-emanationalist stage, as formulated in Lurianic Kabbalah. What has been conceived by scholars as a cathartic explanation characteristic of Lurianism, and even an esoteric aspect of this Kabbalah, turns to be quite an exoteric teaching shared by several kabbalists since the 13th century.
Randomised controlled trial of a healthy lifestyle intervention among smokers with psychotic disorders: Outcomes to 36 months
Authors: Baker Amanda L , Richmond Robyn , Kay-Lambkin Frances J , Filia Sacha L , Castle David , Williams Jill M , Lewin Terry J , Clark Vanessa , Callister Robin , Palazzi Kerrin 
Published: June 2017

Objective: People living with psychotic disorders (schizophrenia spectrum and bipolar disorders) have high rates of cardiovascular disease risk behaviours, including smoking, physical inactivity and poor diet. We report cardiovascular disease risk, smoking cessation and other risk behaviour outcomes over 36 months following recruitment into a two-arm randomised controlled trial among smokers with psychotic disorders. Methods: Participants ( N = 235) drawn from three sites were randomised to receive nicotine replacement therapy plus (1) a Healthy Lifestyles intervention delivered over approximately 9 months or (2) a largely telephone-delivered intervention (designed to control for nicotine replacement therapy provision, session frequency and other monitoring). The primary outcome variables were 10-year cardiovascular disease risk and smoking status, while the secondary outcomes included weekly physical activity, unhealthy eating, waist circumference, psychiatric symptomatology, depression and global functioning. Results: Significant reductions in cardiovascular disease risk and smoking were detected across the 36-month follow-up period in both intervention conditions, with no significant differences between conditions. One-quarter (25.5%) of participants reported reducing cigarettes per day by 50% or more at multiple post-treatment assessments; however, few (8.9%) managed to sustain this across the majority of time points. Changes in other health behaviours or lifestyle factors were modest; however, significant improvements in depression and global functioning were detected over time in both conditions. Participants experiencing worse ‘social discomfort’ at baseline (e.g. anxiety, mania, poor self-esteem and social disability) had on average significantly worse global functioning, lower scores on the 12-Item Short Form Health Survey physical scale and significantly greater waist circumference. Conclusion: Although the telephone-delivered intervention was designed as a comparison condition, it achieved excellent retention and comparable outcomes. Telephone-delivered smoking cessation support may potentially help to reduce smoking rates among people with psychotic disorders. Discomfort in social situations may also be a useful target for future health interventions, addressing confidence and social skills, and promoting social networks that reduce inactivity.