bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma
Authors: Liu Hao , Naxerova Kamila , Pinter Matthias , Incio Joao , Lee Hang , Shigeta Kohei , Ho William W. , Crain Jonathan A. , Jacobson Alex , Michelakos Theodoros , Dias-Santos Daniella , Zanconato Andrea , Hong Theodore S. , Clark Jeffrey W. , Murphy Janet E. , Ryan David P. , Deshpande Vikram , Lillemoe Keith D. , Fernandez-del Castillo Carlos , Downes Michael , Evans Ronald M. , Michaelson James , Ferrone Cristina R. , Boucher Yves , Jain Rakesh K. 
Published: June 2017

Abstract
Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.
Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.
Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339–0.750; P = 0.001] analyses. Propensity score–adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts.
Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959–69. ©2017 AACR.
Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay
Authors: Wang Lisha , Harms Paul W. , Palanisamy Nallasivam , Carskadon Shannon , Cao Xuhong , Siddiqui Javed , Patel Rajiv M. , Zelenka-Wang Sylvia , Durham Alison B. , Fullen Douglas R. , Harms Kelly L. , Su Fengyun , Shukla Sudhanshu , Mehra Rohit , Chinnaiyan Arul M. 
Published: June 2017

Abstract
Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.
Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients.
Results: RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (&lt;73 years) had a significantly higher virus positivity than those from elderly patients (≥73 years; 64.9% vs. 34.2%, P = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient R2 = 0.932, P &lt; 0.0001).
Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. Clin Cancer Res; 23(18); 5622–30. ©2017 AACR.
Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer
Authors: Prieur Alexandre , Cappellini Monica , Habif Guillaume , Lefranc Marie-Paule , Mazard Thibault , Morency Eric , Pascussi Jean-Marc , Flacelière Maud , Cahuzac Nathalie , Vire Bérengère , Dubuc Benjamin , Durochat Amandine , Liaud Pierre , Ollier Jérémy , Pfeiffer Caroline , Poupeau Sophie , Saywell Véronique , Planque Chris , Assenat Eric , Bibeau Frédéric , Bourgaux Jean-François , Pujol Pascal , Sézeur Alain , Ychou Marc , Joubert Dominique 
Published: June 2017

Abstract
Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.
Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.
Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.
Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS–mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267–80. ©2017 AACR.
Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells
Authors: Mohamed Ahmed A. , Tan Shyh-Han , Xavier Charles P. , Katta Shilpa , Huang Wei , Ravindranath Lakshmi , Jamal Muhammad , Li Hua , Srivastava Meera , Srivatsan Eri S. , Sreenath Taduru L. , McLeod David G. , Srinivasan Alagarsamy , Petrovics Gyorgy , Dobi Albert , Srivastava Shiv 
Published: June 2017

Abstract
The oncogenic activation of the ETS-related gene (ERG) due to gene fusions is present in over half of prostate cancers in Western countries. Because of its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for prostate cancer. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified, confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG–positive VCaP cells led to decreased levels of NOTCH1 and 2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH1 and 2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative prostate cancer) and RWPE-1 (benign prostate–derived immortalized) cells. Furthermore, inhibition of NOTCH by the small-molecule γ-secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (bicalutamide and enzalutamide) or the androgen biosynthesis inhibitor (abiraterone) in VCaP cells. Combined treatment with bicalutamide and GSI-1 showed strongest inhibition of AR, ERG, NOTCH1, NOTCH2, and PSA protein levels along with decreased cell growth, cell survival, and enhanced apoptosis. Intriguingly, this effect was not observed in ERG-negative prostate cancer cells or immortalized benign/normal prostate epithelial cells. These data underscore the synergy of AR and NOTCH inhibitors in reducing the growth of ERG-positive prostate cancer cells.
Implications: Combinational targeting of NOTCH and AR signaling has therapeutic potential in advanced ERG-driven prostate cancers. Mol Cancer Res; 15(10); 1308–17. ©2017 AACR.
Multicenter Experience Evaluating Transcatheter Pulmonary Valve Replacement in Bovine Jugular Vein (Contegra) Right Ventricle to Pulmonary Artery Conduits
Authors: Morray Brian H. , McElhinney Doff B. , Boudjemline Younes , Gewillig Marc , Kim Dennis W. , Grant Elena K. , Bocks Martin L. , Martin Mary H. , Armstrong Aimee K. , Berman Darren , Danon Saar , Hoyer Mark , Delaney Jeffrey W. , Justino Henri , Qureshi Athar M. , Meadows Jeffery J. , Jones Thomas K. 
Published: June 2017

Background—
Follow-up of transcatheter pulmonary valve replacement (TPVR) with the Melody valve has demonstrated good short-term and long-term outcomes, but there are no published studies focused on valve performance in the Contegra bovine jugular vein conduit.

Methods and Results—

This is a retrospective, multicenter study of the short- and intermediate-term outcomes of Melody TPVR within the Contegra conduit in the right ventricle to pulmonary artery position. Data from 13 centers were included in the analysis. During the study period, 136 patients underwent 139 catheterizations for attempted Melody TPVR with a median follow-up of 3 years (1 day to 9.1 years). Of the 136 patients, 117 underwent successful Melody TPVR. Two patients underwent a second Melody TPVR. The majority of patients underwent placement of ≥1 stents before transcatheter pulmonary valve implantation. There was a significant reduction in peak conduit pressure gradient acutely after transcatheter pulmonary valve implantation (39 versus 10 mm Hg;
P
<0.001). At most recent follow-up, the maximum pulmonary valve gradient by echocardiogram remained significantly reduced relative to prevalve implant measurements (65.9 versus 27.3 mm Hg;
P
<0.001). The incidence of Melody transcatheter pulmonary valve stent fracture (3.4%) and infectious endocarditis (4.3%) were both low. Serious adverse events occurred in 3 patients.

Conclusions—
Melody TPVR in Contegra conduits is safe and effective and can be performed in a wide range of conduit sizes with preserved valve function and low incidence of stent fracture and endocarditis.
Association Between Modifiable Risk Factors and Pharmaceutical Expenditures Among Adults With Atherosclerotic Cardiovascular Disease in the United States: 2012–2013 Medical Expenditures Panel Survey
Authors: Salami Joseph A. , Valero‐Elizondo Javier , Ogunmoroti Oluseye , Spatz Erica S. , Rana Jamal S. , Virani Salim S. , Blankstein Ron , Younus Adnan , Arrieta Alejandro , Blaha Michael J. , Veledar Emir , Nasir Khurram 
Published: June 2017

Background

Atherosclerotic cardiovascular disease (
ASCVD
) causes most deaths in the United States and accounts for the highest healthcare spending. The association between the modifiable risk factors (
MRF
s) of
ASCVD
and pharmaceutical expenditures are largely unknown.

Methods and Results

We examined the association between
MRF
s and pharmaceutical expenditures among adults with
ASCVD
using the 2012 and 2013 Medical Expenditure Panel Survey. A 2‐part model was used while accounting for the survey's complex design to obtain nationally representative results. All costs were adjusted to 2013 US dollars using the gross domestic product deflator. The annual total pharmaceutical expenditure among those with
ASCVD
was $71.6 billion, 33% of which was for medications for cardiovascular disease and 14% medications for diabetes mellitus. The adjusted relationship between
MRF
s and pharmaceutical expenditures showed significant marginal increase in average annual pharmaceutical expenditure associated with inadequate physical activity ($519 [95% confidence interval (
CI
), $12–918;
P
=0.011]), dyslipidemia ($631 [95%
CI
, $168–1094;
P
=0.008]), hypertension: ($1078 [95%
CI
, $697–1460;
P
<0.001)], and diabetes mellitus ($2006 [95%
CI
, $1470–2542]). Compared with those with optimal
MRFs
(0–1), those with average
MRFs
(2–3) spent an average of $1184 (95%
CI
, $805–1564;
P
<0.001) more on medications, and those with poor
MRFs
(≥4) spent $2823 (95%
CI
, $2338–3307;
P
<0.001) more.

Conclusions

Worsening
MRFs
were proportionally associated with higher annual pharmaceutical expenditures among patients with established
ASCVD
regardless of non‐
ASCVD
comorbidity. In‐depth studies of the roles played by other factors in this association can help reduce medication‐related expenditures among
ASCVD
patients.
Metastatic Renal Cell Carcinoma Masquerading as Jugular Foramen Paraganglioma: A Role for Novel Magnetic Resonance Imaging
Authors: Thomas Andrew J. , Wiggins Richard H. , Gurgel Richard K. 
Published: June 2017

Objectives: To describe a case of metastatic renal cell carcinoma (RCC) masquerading as a jugular foramen paraganglioma (JP). To compare imaging findings between skull base metastatic RCC and histologically proven paraganglioma. Methods: A case of unexpected metastatic skull base RCC is reviewed. Computed tomography (CT) and magnetic resonance imaging (MRI) were compared between 3 confirmed cases of JP and our case of metastatic RCC. Diffusion-weighted MRI (DW-MRI) sequences and computed apparent diffusion coefficient (ADC) values were compared between these entities. Results: A 55-year-old man presents with what appears clinically and radiographically to be JP. The tumor was resected, then discovered on postoperative pathology to be metastatic RCC. Imaging was retrospectively compared between 3 histologically confirmed cases of JP and our case of skull base RCC. The RCC metastasis was indistinguishable from JP on CT and traditional MRI but distinct by ADC values calculated from DW-MRI. Conclusions: Metastatic RCC at the skull base may mimic the clinical presentation and radiographic appearance of JP. The MRI finding of flow voids is seen in both paraganglioma and metastatic RCC. Diffusion-weighted MRI is able to distinguish these entities, highlighting its potential utility in distinguishing skull base lesions.
Aesthetics in Thyroid Surgery: The Patient Perspective
Authors: Chaung Katrina , Duke William S. , Oh Sun Jung , Behr Amanda , Waller Jennifer L. , Daniel Jeannie , Terris David J. 
Published: June 2017

ObjectivesTo define characteristics that influence patient perceptions of thyroidectomy scar cosmesis.Study DesignProspective cohort study.SettingTertiary endocrine surgery practice in an academic medical center.Subjects and MethodsInstitutional review board–approved trial in which 136 subjects were recruited from a population of patients being seen for either thyroid or sinus surgery and evaluated standardized photographs, superimposed with computer‐generated thyroidectomy scars of varying lengths (2, 4, and 6 cm) and widths (1 and 2 mm), and graded their perception of the scars using the observer scar assessment scale (OSAS) domains of the patient and observer scar assessment scale.ResultsThere were 69 subjects in the thyroid group and 67 in the nonthyroid group. Controlling for width, longer scars were perceived as worse than shorter scars; controlling for length, thicker scars were perceived as worse than thinner scars (P <. 01). Beyond 2 cm, thick scars were judged to be worse than thin scars, even when they were shorter. There was no difference in the mean overall OSAS scores between surgery, sex, or age groups. Nonwhites tended to judge scars as being worse than whites did (P <. 01).ConclusionAs expected, patients of all demographics prefer shorter scars compared with longer scars and thinner scars over thick scars. Ethnic differences in scar perception were identified and deserve additional study. Surgeons should endeavor to perform thyroid surgery through the smallest incision that allows the operation to be performed safely to minimize the cosmetic impact of the operation.
Validation of Patient-Reported Outcomes Measurement Information System Computerized Adaptive Tests Against the Foot and Ankle Outcome Score for 6 Common Foot and Ankle Pathologies
Authors: Koltsov Jayme C. B. , Greenfield Stephen T. , Soukup Dylan , Do Huong T. , Ellis Scott J. 
Published: June 2017

Background: The field of foot and ankle surgery lacks a widely accepted gold-standard patient-reported outcome instrument. With the changing infrastructure of the medical profession, more efficient patient-reported outcome tools are needed to reduce respondent burden and increase participation while providing consistent and reliable measurement across multiple pathologies and disciplines. The primary purpose of the present study was to validate 3 Patient-Reported Outcomes Measurement Information System computer adaptive tests (CATs) most relevant to the foot and ankle discipline against the Foot and Ankle Outcome Score (FAOS) and the Short Form 12 general health status survey in patients with 6 common foot and ankle pathologies. Methods: Patients (n = 240) indicated for operative treatment for 1 of 6 common foot and ankle pathologies completed the CATs, FAOS, and Short Form 12 at their preoperative surgical visits, 1 week subsequently (before surgery), and at 6 months postoperatively. The psychometric properties of the instruments were assessed and compared. Results: The Patient-Reported Outcomes Measurement Information System CATs each took less than 1 minute to complete, whereas the FAOS took 6.5 minutes, and the Short Form 12 took 3 minutes. CAT scores were more normally distributed and had fewer floor and ceiling effects than those on the FAOS, which reached as high as 24%. The CATs were more precise than the FAOS and had similar responsiveness and test-retest reliability. The physical function and mobility CATs correlated strongly with the activities subscale of the FAOS, and the pain interference CAT correlated strongly with the pain subscale of the FAOS. The CATs and FAOS were responsive to changes with operative treatment for 6 common foot and ankle pathologies. Conclusions: The CATs performed as well as or better than the FAOS in all aspects of psychometric validity. The Patient-Reported Outcomes Measurement Information System CATs show tremendous potential for improving the study of patient outcomes in foot and ankle research through improved precision and reduced respondent burden. Level of Evidence: Level II, prospective comparative study.
Uniform neural tissue models produced on synthetic hydrogels using standard culture techniques
Authors: Barry Christopher , Schmitz Matthew T , Propson Nicholas E , Hou Zhonggang , Zhang Jue , Nguyen Bao K , Bolin Jennifer M , Jiang Peng , McIntosh Brian E , Probasco Mitchell D , Swanson Scott , Stewart Ron , Thomson James A , Schwartz Michael P , Murphy William L 
Published: June 2017

The aim of the present study was to test sample reproducibility for model neural tissues formed on synthetic hydrogels. Human embryonic stem (ES) cell-derived precursor cells were cultured on synthetic poly(ethylene glycol) (PEG) hydrogels to promote differentiation and self-organization into model neural tissue constructs. Neural progenitor, vascular, and microglial precursor cells were combined on PEG hydrogels to mimic developmental timing, which produced multicomponent neural constructs with 3D neuronal and glial organization, organized vascular networks, and microglia with ramified morphologies. Spearman’s rank correlation analysis of global gene expression profiles and a comparison of coefficient of variation for expressed genes demonstrated that replicate neural constructs were highly uniform to at least day 21 for samples from independent experiments. We also demonstrate that model neural tissues formed on PEG hydrogels using a simplified neural differentiation protocol correlated more strongly to in vivo brain development than samples cultured on tissue culture polystyrene surfaces alone. These results provide a proof-of-concept demonstration that 3D cellular models that mimic aspects of human brain development can be produced from human pluripotent stem cells with high sample uniformity between experiments by using standard culture techniques, cryopreserved cell stocks, and a synthetic extracellular matrix. Impact statement Pluripotent stem (PS) cells have been characterized by an inherent ability to self-organize into 3D “organoids” resembling stomach, intestine, liver, kidney, and brain tissues, offering a potentially powerful tool for modeling human development and disease. However, organoid formation must be quantitatively reproducible for applications such as drug and toxicity screening. Here, we report a strategy to produce uniform neural tissue constructs with reproducible global gene expression profiles for replicate samples from multiple experiments.
Role of Employment in 11-Year Changes of Clinical Oral Health: A Multilevel Longitudinal Analysis
Authors: Al-Sudani F.Y.H. , Vehkalahti M.M. , Bernabé E. , Knuuttila M. , Suominen A.L. 
Published: June 2017

The objective was to investigate the role of employment in the 11-y changes of clinically determined oral health. We used data from the longitudinal Health 2011 Survey, including reinvited subjects from the Health 2000 Survey. Data were gathered by clinical oral examinations, interviews, and questionnaires of those aged 30 to 63 y ( n = 1,031) in 2000. Exposures were change in employment from baseline to follow-up and length of unemployment. Outcomes measures were the numbers of missing teeth, sound teeth, filled teeth, decayed teeth, and teeth with periodontal pockets (≥4 mm and ≥6 mm). Separate mixed-effects and conventional negative binomial regression models were fitted for each oral health outcome. Demographic, socioeconomic, and oral health–related behaviors were added as covariates to the analyses. The findings showed that unemployment was inconsistently associated with poorer clinically determined oral health over 11 y. These effects were attributed to income and education and, to a lesser extent, to oral health–related behaviors. The length of unemployment was also inconsistently associated with oral health. The study concluded that one socioeconomic factor, unemployment, had a partial impact on oral health. Knowledge Transfer Statement: The findings of this study can help clinicians and oral health policy makers to reorient oral health services toward those who are unemployed as a risk group for poor oral health. The research highlights the role of employment in the longitudinal changes of clinically determined oral health, taking into consideration other socioeconomic factors. The study concluded that unemployment seemed to have a role in social inequalities of oral health.