bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of arthritis-induced bone erosion by a CRAC channel antagonist
Authors: Blair Harry C , Soboloff Jonathan , Robinson Lisa J , Tourkova Irina L , Larrouture Quitterie C , Witt Michelle R , Holaskova Ida , Schafer Rosana , Elliott Meenal , Hirsch Raphael , Barnett John B 
Published: January 2016

ObjectiveWe have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis.MethodsCollagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured.ResultsAssays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12–17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals.ConclusionsDCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits.
Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)
Authors: Karlovich Chris , Goldman Jonathan W. , Sun Jong-Mu , Mann Elaina , Sequist Lecia V. , Konopa Krzysztof , Wen Wei , Angenendt Philipp , Horn Leora , Spigel David , Soria Jean-Charles , Solomon Benjamin , Camidge D. Ross , Gadgeel Shirish , Paweletz Cloud , Wu Lin , Chien Sean , O'Donnell Patrick , Matheny Shannon , Despain Darrin , Rolfe Lindsey , Raponi Mitch , Allen Andrew R. , Park Keunchil , Wakelee Heather 
Published: January 2016

Abstract
Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.
Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.
Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P &lt; 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.
Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386–95. ©2016 AACR.
miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1
Authors: Sakaguchi Masazumi , Hisamori Shigeo , Oshima Nobu , Sato Fumiaki , Shimono Yohei , Sakai Yoshiharu 
Published: January 2016

Abstract
miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM+/CD44+/CD66a−) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.
Implications: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs. Mol Cancer Res; 14(4); 354–62. ©2016 AACR.
Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1
Authors: Kent Oliver A. , Mendell Joshua T. , Rottapel Robert 
Published: January 2016

Abstract
Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. miRNAs are small noncoding RNAs that regulate gene expression by binding sequences within the 3′UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to the expression of oncogenic KRAS and activity of the MAPK pathway. miR-31 is highly expressed in patient-derived xenografts and a panel of pancreatic and colorectal cancer cells harboring activating KRAS mutations. The miR-31 host gene is a large noncoding RNA that correlates with miR-31 expression and enabled identification of the putative miR-31 promoter. Using luciferase reporters, a minimal RAS-responsive miR-31 promoter was found to drive robust luciferase activity dependent on expression of mutant KRAS and the transcription factor ELK1. Furthermore, ELK1 interacts directly with the endogenous miR-31 promoter in a MAPK-dependent manner. Expression of enforced miR-31 significantly enhanced invasion and migration of multiple pancreatic cancer cells resulting from the activation of RhoA through regulation of the miR-31 target gene RASA1. Importantly, acute knockdown of RASA1 phenocopied enforced miR-31 expression on the migratory behavior of pancreatic cancer cells through increased RhoA activation.
Implications: Oncogenic KRAS can activate Rho through the miR-31–mediated regulation of RASA1 indicating miR-31 acts as a KRAS effector to modulate invasion and migration in pancreatic cancer. Mol Cancer Res; 14(3); 267–77. ©2016 AACR.
Bivalirudin Is Associated With Improved In-Hospital Outcomes Compared With Heparin in Percutaneous Vascular Interventions
Authors: Kimmelstiel Carey , Pinto Duane , Aronow Herbert D. , Weintraub Andrew R. , Dangas George , Fan Weihong , Prats Jayne , Deliargyris Efthymios N. , Katzen Barry T. 
Published: January 2016

Background—
Peripheral vascular interventions are increasingly preferred for the treatment of patients with symptomatic peripheral arterial disease because they are associated with similar clinical outcomes and lower morbidity than open surgical procedures. The objective of this study was to assess the comparative effectiveness of procedural anticoagulation with bivalirudin compared with unfractionated heparin in patients undergoing peripheral vascular interventions.

Methods and Results—

This was a retrospective, observational study using the Premier Hospital administrative database. We examined 23 934 consecutive patients undergoing lower extremity peripheral vascular interventions between January 2008 and December 2012 who were treated with either bivalirudin or unfractionated heparin. In-hospital end points included death, myocardial infarction, transfusion, stroke, amputation, and the composite end points of major adverse cardiovascular events, and net adverse clinical events. Propensity score matching was performed to control for baseline imbalances and yielded 3649 matched pairs. After propensity score matching, patients treated with bivalirudin had lower in-hospital event rates with significantly lower mortality (odds ratio, 0.40;
P
=0.017), need for blood product transfusion (odds ratio, 0.74;
P
=0.009), major adverse cardiovascular events (odds ratio, 0.64;
P
=0.003), and net adverse clinical events (odds ratio, 0.72;
P
<0.001). These associations were observed consistently across clinically relevant subgroups.

Conclusions—
In patients undergoing peripheral vascular interventions, procedural anticoagulation with bivalirudin may result in more favorable in-hospital outcomes compared with unfractionated heparin, the current standard of care. These observations will require prospective confirmation in a randomized, controlled trial.
Body Mass Index, Abdominal Fatness, and Heart Failure Incidence and Mortality
Authors: Aune Dagfinn , Sen Abhijit , Norat Teresa , Janszky Imre , Romundstad Pål , Tonstad Serena , Vatten Lars J. 
Published: January 2016

Background—
Obesity has been associated with increased risk of heart failure, but whether overweight also increases risk is unclear. It is also unclear whether abdominal adiposity is more strongly associated with heart failure risk than general adiposity. We conducted a systematic review and meta-analysis of prospective studies to clarify the strength and shape of the dose-response relationship between general and abdominal adiposity and the risk of heart failure.

Methods and Results—

PubMed and Embase databases were searched up to October 10, 2014. Summary relative risks were calculated using random-effects models. A total of 28 studies (27 publications) were included. Twenty-three prospective studies with >15 905 incident cases among 647 388 participants were included in the analysis of body mass index and heart failure incidence, and 4 studies were included for heart failure mortality. The summary relative risk for a 5-unit increment in body mass index was 1.41 (95% confidence interval, 1.34–1.47;
I
2
=83%) for heart failure incidence and 1.26 (95% confidence interval, 0.85–1.87;
I
2
=95%) heart failure mortality. Although the test for nonlinearity was significant (
P
<0.0001), this appeared to be attributable to a threshold at a body mass index of ≈23 to 24 kg/m
2
; however, there was evidence of increased risk even in the overweight body mass index range. The summary relative risk for a 10-cm increase in waist circumference was 1.29 (95% confidence interval, 1.21–1.37;
I

2

=89%) and per 0.1-unit increase in waist-to-hip ratio was 1.29 (95% confidence interval, 1.13–1.47;
I
2
=82%).

Conclusion—
Overweight and obesity and abdominal adiposity are associated with increased risk of heart failure.
N-Terminal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity
Authors: Ndumele Chiadi E. , Matsushita Kunihiro , Sang Yingying , Lazo Mariana , Agarwal Sunil K. , Nambi Vijay , Deswal Anita , Blumenthal Roger S. , Ballantyne Christie M. , Coresh Josef , Selvin Elizabeth 
Published: January 2016

Background—
Obesity is a risk factor for heart failure (HF) but is associated with lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories.

Methods and Results—

We followed up 12 230 ARIC participants free of prior HF at baseline (visit 2, 1990–1992) with BMI ≥18.5 kg/m
2
. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (
r
=−0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall, even among those with severe obesity (BMI ≥35 kg/m
2
; improvement in C statistic, 0.032; 95% confidence interval, 0.011–0.053). However, given the higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP of 100 to <200 pg/mL, the average 10-year HF risk was <5% among normal-weight individuals but >10% among the severely obese.

Conclusions—
Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information on the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population.
Atrial Fibrillation Begets Heart Failure and Vice Versa
Authors: Santhanakrishnan Rajalakshmi , Wang Na , Larson Martin G. , Magnani Jared W. , McManus David D. , Lubitz Steven A. , Ellinor Patrick T. , Cheng Susan , Vasan Ramachandran S. , Lee Douglas S. , Wang Thomas J. , Levy Daniel , Benjamin Emelia J. , Ho Jennifer E. 
Published: January 2016

Background—
Atrial fibrillation (AF) and heart failure (HF) frequently coexist and together confer an adverse prognosis. The association of AF with HF subtypes has not been well described. We sought to examine differences in the temporal association of AF and HF with preserved versus reduced ejection fraction.

Methods and Results—

We studied Framingham Heart Study participants with new-onset AF or HF between 1980 and 2012. Among 1737 individuals with new AF (mean age, 75±12 years; 48% women), more than one third (37%) had HF. Conversely, among 1166 individuals with new HF (mean age, 79±11 years; 53% women), more than half (57%) had AF. Prevalent AF was more strongly associated with incident HF with preserved ejection fraction (multivariable-adjusted hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.48–3.70; no AF as referent) versus HF with reduced ejection fraction (HR, 1.32; 95% CI, 0.83–2.10), with a trend toward difference between HF subtypes (
P
for difference=0.06). Prevalent HF was associated with incident AF (HR, 2.18; 95% CI, 1.26–3.76; no HF as referent). The presence of both AF and HF portended greater mortality risk compared with neither condition, particularly among individuals with new HF with reduced ejection fraction and prevalent AF (HR, 2.72; 95% CI, 2.12–3.48) compared with new HF with preserved ejection fraction and prevalent AF (HR, 1.83; 95% CI, 1.41–2.37;
P
for difference=0.02).

Conclusions—
AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF. AF precedes and follows HF with both preserved and reduced ejection fraction, with some differences in temporal association and prognosis. Future studies focused on underlying mechanisms of these dual conditions are warranted.
Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes
Authors: Altieri Paola , Barisione Chiara , Lazzarini Edoardo , Garuti Anna , Bezante Gian Paolo , Canepa Marco , Spallarossa Paolo , Tocchetti Carlo Gabriele , Bollini Sveva , Brunelli Claudio , Ameri Pietro 
Published: January 2016

Background
Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long‐term anthracycline cardiomyopathy.

Methods and Results

H9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β‐estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β‐estradiol, counteracted doxorubicin‐elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin‐induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor
LY
294002, and the nitric oxide synthase inhibitor L‐
NG
‐nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of
AKT
and nitric oxide synthase 3. In H9c2 cells, doxorubicin‐stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline‐containing chemotherapy. Remarkably, these effects were also inhibited by testosterone.

Conclusions

Testosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase,
AKT
, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls.
Globalization of the Automotive Industry: Is Indonesia Missing Out?
Authors: Soejachmoen Moekti P. 
Published: January 2016

International trade in automotive and auto parts has grown rapidly during the last two decades but Southeast Asia's largest economy, Indonesia, is lagging behind in its export performance. This paper uses a comparative perspective in examining Indonesia's role in automotive production networks in the context of the contemporary debate on opportunities for reaping gains from economic globalization through engagement in global production sharing. This research aims to answer two questions; the first addresses the determinants of a country's participation in the global production network, the second asks why Indonesia is being left behind in global production networks. Our analysis is based on the Jones and Kierzkowski fragmentation theory. The unbalanced panel trade data for 98 countries for the period 1988–2007 are estimated using the least square dummy variable method. The results show that in Asian countries, foreign direct investment openness is the most important determinant followed by trade cost, trade openness, competitiveness, and labor quality. Indonesia is being left behind for a number of reasons, such as restrictive foreign investment policies, higher trade costs and remaining high protection in the automotive sector in terms of tariff and non-tariff measure, and a low education level that hampers the absorption capacity in technology.
Device Life of Two Generations of Provox Voice Prostheses
Authors: Thylur David S. , Villegas Brenda Capobres , Fisher Laurel M. , Sinha Uttam K. , Kokot Niels 
Published: January 2016

Background: Tracheoesophageal voice prostheses are invaluable for speech rehabilitation in patients who have received total laryngectomy, but device failure impedes communication and creates psychosocial and financial burdens. This study compares the Provox 2 and Provox Vega voice prostheses on the parameter of device life. Methods: This was a retrospective observational study of 21 patients with 181 device replacements at an academic tertiary care medical center. Disparity in device life and factors that may influence device life were analyzed. Results: The mean device life for Provox 2, at 115.6 days (SE = 5.8), was longer than for Provox Vega, at 65.1 days (SE = 7.5) ( P < .001). Conclusions: Device longevity was greater for Provox 2 over Provox Vega. These results will facilitate the design of prospective studies to assess reasons for variations in device life between patients and device types.
Myeloperoxidase-Antineutrophil Cytoplasmic Antibody–Positive Otitis Media and Rhinosinusitis With Pathological Features of Immunoglobulin G4-Related Disease
Authors: Ohno Keiko , Matsuda Yoko , Arai Tomio , Sugihara Takahiko , Iga Shoko , Kimura Yurika 
Published: January 2016

Background: Immunoglobulin G4-related disease (IgG4-RD) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have different clinical and pathological features. However, differentiation between these 2 disorders is sometimes difficult. Objective: To report a case involving a patient with characteristics of both IgG4-RD and AAV. Methods: Case report with literature review. Results: We report a case of myeloperoxidase-ANCA–positive otitis media and rhinosinusitis with pathological features of IgG4-RD in a 73-year-old man. The patient was first clinically suspected to have granulomatosis with polyangiitis. All of the main characteristic pathological features of IgG4-RD were present: dense lymphoplasmacytic infiltration, increased numbers of IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. Conclusions: The simultaneous presence of the characteristics of both IgG4-RD and AAV makes diagnosis and treatment difficult.