bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAM50 Provides Prognostic Information When Applied to the Lymph Node Metastases of Advanced Breast Cancer Patients
Authors: Tobin Nicholas P. , Lundberg Arian , Lindström Linda S. , Harrell J. Chuck , Foukakis Theodoros , Carlsson Lena , Einbeigi Zakaria , Linderholm Barbro K. , Loman Niklas , Malmberg Martin , Fernö Mårten , Czene Kamila , Perou Charles M. , Bergh Jonas , Hatschek Thomas 
Published: October 2017

Abstract
Purpose: Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting.
Experimental Design: Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable loco-regional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan–Meier and/or multivariate Cox regression analyses.
Results: The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P &lt; 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan–Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer–specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance.
Conclusions: Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients. Clin Cancer Res; 23(23); 7225–31. ©2017 AACR.
NFκB-Mediated Invasiveness in CD133+ Pancreatic TICs Is Regulated by Autocrine and Paracrine Activation of IL1 Signaling
Authors: Nomura Alice , Gupta Vineet K. , Dauer Patricia , Sharma Nikita S. , Dudeja Vikas , Merchant Nipun , Saluja Ashok K. , Banerjee Sulagna 
Published: October 2017

Abstract
Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133+ cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-κB activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1β (IL1B), which activates an autocrine signaling loop that upregulates NF-κB signaling, epithelial–mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1β, the tumor-associated macrophages (TAM) also produced IL1β, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.
Implications: This study demonstrates the important role of tumor- and macrophage-derived IL1β stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1β stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs. Mol Cancer Res; 16(1); 162–72. ©2017 AACR.
Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer
Authors: Duex Jason E. , Swain Kalin E. , Dancik Garrett M. , Paucek Richard D. , Owens Charles , Churchill Mair E.A. , Theodorescu Dan 
Published: October 2017

Abstract
Urothelial carcinoma accounts for most of the bladder cancer cases. Using next-generation sequencing (NGS) technology, we found that a significant percentage (83%) of tumors had mutations in chromatin-remodeling genes. Here, we examined the functional relevance of mutations in two chromatin-remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost one-third of patients. Interestingly, almost half of missense mutations cluster in the histone-acetyltransferase (HAT) domain of EP300/CREBBP. This domain catalyzes the transfer of an acetyl group to target molecules such as histones, thereby regulating chromatin dynamics. Thus, patients with EP300 or CREBBP mutations may have alterations in the ability of the corresponding proteins to modify histone proteins and control transcriptional profiles. In fact, it was determined that many of the missense HAT mutations in EP300 (64%) and CREBBP (78%) were HAT-inactivating. These inactivating mutations also correlated with invasive disease in patients. Strikingly, the prediction software Mutation Assessor accurately predicted the functional consequences of each HAT missense mutation. Finally, a gene expression signature was developed that associated with loss of HAT activity and that this signature was associated with more aggressive cancer in four patient datasets. Further supporting the notion that this score accurately reflects HAT activity, we found it is responsive to treatment of cancer cells to mocetinostat, a histone deacetylase (HDAC) inhibitor.
Implication: This study provides a rationale for targeted sequencing of EP300 and CREBBP and use of a gene profiling signature for predicting therapeutic response in patients. Mol Cancer Res; 16(1); 69–77. ©2017 AACR.
Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell–Derived Endothelial Cells Encapsulated in a Nanomatrix Gel
Authors: Lee Shin-Jeong , Sohn Young-Doug , Andukuri Adinarayana , Kim Sangsung , Byun Jaemin , Han Ji Woong , Park In-Hyun , Jun Ho-Wook , Yoon Young-sup 
Published: October 2017

Background:
Human pluripotent stem cell (hPSC)–derived endothelial cells (ECs) have limited clinical utility because of undefined components in the differentiation system and poor cell survival in vivo. Here, we aimed to develop a fully defined and clinically compatible system to differentiate hPSCs into ECs. Furthermore, we aimed to enhance cell survival, vessel formation, and therapeutic potential by encapsulating hPSC-ECs with a peptide amphiphile (PA) nanomatrix gel.

Methods:

We induced differentiation of hPSCs into the mesodermal lineage by culturing on collagen-coated plates with a glycogen synthase kinase 3β inhibitor. Next, vascular endothelial growth factor, endothelial growth factor, and basic fibroblast growth factor were added for endothelial lineage differentiation, followed by sorting for CDH5 (VE-cadherin). We constructed an extracellular matrix–mimicking PA nanomatrix gel (PA-RGDS) by incorporating the cell adhesive ligand Arg-Gly-Asp-Ser (RGDS) and a matrix metalloproteinase-2–degradable sequence. We then evaluated whether the encapsulation of hPSC-CDH5
+
cells in PA-RGDS could enhance long-term cell survival and vascular regenerative effects in a hind-limb ischemia model with laser Doppler perfusion imaging, bioluminescence imaging, real-time reverse transcription–polymerase chain reaction, and histological analysis.

Results:

The resultant hPSC-derived CDH5
+
cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and proangiogenic activities. When injected into ischemic hind limbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared with media-, PA-RGDS–, or human umbilical vein EC–injected groups. However, the group receiving the PA-RGDS–encapsulated hPSC-ECs showed better perfusion recovery, more robust and longer cell survival (> 10 months), and higher and prolonged angiogenic and vascular incorporation capabilities than the bare hPSC-EC–injected group. Surprisingly, the engrafted hPSC-ECs demonstrated previously unknown sustained and dynamic vessel-forming behavior: initial perivascular concentration, a guiding role for new vessel formation, and progressive incorporation into the vessels over 10 months.

Conclusions:
We generated highly enriched hPSC-ECs via a clinically compatible system. Furthermore, this study demonstrated that a biocompatible PA-RGDS nanomatrix gel substantially improved long-term survival of hPSC-ECs in an ischemic environment and improved neovascularization effects of hPSC-ECs via prolonged and unique angiogenic and vessel-forming properties. This PA-RGDS–mediated transplantation of hPSC-ECs can serve as a novel platform for cell-based therapy and investigation of long-term behavior of hPSC-ECs.
Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction
Authors: Kaier Thomas E. , Twerenbold Raphael , Puelacher Christian , Marjot Jack , Imambaccus Nazia , Boeddinghaus Jasper , Nestelberger Thomas , Badertscher Patrick , Sabti Zaid , Giménez Maria Rubini , Wildi Karin , Hillinger Petra , Grimm Karin , Loeffel Sarah , Shrestha Samyut , Widmer Dayana Flores , Cupa Janosch , Kozhuharov Nikola , Miró Òscar , Martín-Sánchez F. Javier , Morawiec Beata , Rentsch Katharina , Lohrmann Jens , Kloos Wanda , Osswald Stefan , Reichlin Tobias , Weber Ekkehard , Marber Michael , Mueller Christian 
Published: October 2017

Background:
Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI.

Methods:
Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality.

Results:

Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L,
P
<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (
P
<0.0001) and 0.926 (
P
=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (
P
<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both
P
<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (
P
<0.05 for both) and similar to hs-cTnT at predicting death at 3 years.

Conclusions:
cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00470587.
Latent Rheumatic Heart Disease
Authors: Beaton Andrea , Aliku Twalib , Dewyer Alyssa , Jacobs Marni , Jiang Jiji , Longenecker Chris T. , Lubega Sulaiman , McCarter Robert , Mirabel Mariana , Mirembe Grace , Namuyonga Judith , Okello Emmy , Scheel Amy , Tenywa Emmanuel , Sable Craig , Lwabi Peter 
Published: October 2017

Background:
Screening echocardiography has emerged as a potentially powerful tool for early diagnosis of rheumatic heart disease (RHD). The utility of screening echocardiography hinges on the rate of RHD progression and the ability of penicillin prophylaxis to improve outcome. We report the longitudinal outcomes of a cohort of children with latent RHD and identify risk factors for unfavorable outcomes.

Methods:
This was a prospective natural history study conducted under the Ugandan RHD registry. Children with latent RHD and ≥1 year of follow-up were included. All echocardiograms were re-reviewed by experts (2012 World Heart Federation criteria) for inclusion and evidence of change. Bi- and multivariable logistic regression, Kaplan-Meier analysis, and Cox proportional hazards models, as well, were developed to search for risk factors for unfavorable outcome and compare progression-free survival between those treated and not treated with penicillin. Propensity and other matching methods with sensitivity analysis were implemented for the evaluation of the penicillin effect.

Results:
Blinded review confirmed 227 cases of latent RHD: 164 borderline and 63 definite (42 mild, 21 moderate/severe). Median age at diagnosis was 12 years and median follow-up was 2.3 years (interquartile range, 2.0–2.9). Penicillin prophylaxis was prescribed in 49.3% with overall adherence of 84.7%. Of children with moderate-to-severe definite RHD, 47.6% had echocardiographic progression (including 2 deaths), and 9.5% had echocardiographic regression. Children with mild definite and borderline RHD showed 26% and 9.8% echocardiographic progression and 45.2% and 46.3% echocardiographic improvement, respectively. Of those with mild definite RHD or borderline RHD, more advanced disease category, younger age, and morphological mitral valve features were risk factors for an unfavorable outcome.

Conclusions:
Latent RHD is a heterogeneous diagnosis with variable disease outcomes. Children with moderate to severe latent RHD have poor outcomes. Children with both borderline and mild definite RHD are at substantial risk of progression. Although long-term outcome remains unclear, the initial change in latent RHD may be evident during the first 1 to 2 years following diagnosis. Natural history data are inherently limited, and a randomized clinical trial is needed to definitively determine the impact of penicillin prophylaxis on the trajectory of latent RHD.
Low-Frequency Climate Modes and Antarctic Sea Ice Variations, 1982–2013
Authors: Cerrone D. , Fusco G. 
Published: October 2017

Abstract
The NCEP–NCAR composite dataset (comprising sea level pressure, 500-hPa geopotential height, 500-hPa temperature, and meridional wind stress at 10 m above the surface) is used for compiling a set of climate indices describing the most important physical modes of variability in the Southern Hemisphere (SH): the southern annular mode (SAM), semiannual oscillation (SAO), Pacific–South American (PSA), and quasi-stationary zonal wavenumber 3 (ZW3) patterns. Compelling evidence indicates that the large increase in the SH sea ice, recorded over recent years, arises from the impact of climate modes and their long-term trends. The examination of variability ranging from seasonal to interdecadal scales, and of trends within the climate patterns and total Antarctic sea ice concentration (SIC) for the 32-yr period (1982–2013), is the key focus of this paper. The results herein indicate that a progressive cooling has affected the year-to-year climate of the sub-Antarctic since the 1990s. This feature is found in association with increased positive SAM and SAO phases detected in terms of upward annual and seasonal trends (in autumn and summer) and upward decadal trends. In addition, the SIC shows upward annual, spring, and summer trends, indicating the insulation of Antarctica from the warmer flows in the midlatitudes. This picture of variations is also found to be consistent with the upward trends detected for the PSA and ZW3 patterns on the annual scale and during the last two decades. Evidence of a more frequent occurrence of the PSA–ZW3 combination could explain, in part, the significant increase of the regional and total Antarctic sea ice coverages.
Testing a Novel Method for Initializing Air Parcel Back Trajectories in Precipitating Clouds Using Reanalysis Data
Authors: Putman Annie L. , Feng Xiahong , Posmentier Eric S. , Faiia Anthony M. , Sonder Leslie J. 
Published: October 2017

AbstractLagrangian air parcel tracking is a powerful tool for estimating vapor source locations, particularly for isotope hydrology applications. Identified vapor source regions may be sensitive to the distribution of altitudes at which back trajectories are initiated. Ideally, those initial altitudes should reflect the altitudes where precipitation forms. This paper introduces a novel method for estimating these heights from reanalysis data and an air parcel lofting routine, which is referred to as the “Reanalysis” method. Using Barrow, Alaska (now known as Utqiaġvik), as a test site, the study compares the distribution of air parcel initiation heights and vapor source conditions from back trajectories initiated at 1) heights determined by the Reanalysis method and 2) heights acquired from 35-GHz vertically resolved cloud radar, termed the “Cloud Radar” method. Only 2 of the 70 events failed to produce condensation at any elevation. The distribution of air parcels generated by each method was compared on the basis of the median height and the median-adjusted overlap, and yielded excellent (n = 28), good (n = 20), fair (n = 6), and poor (n = 14) matches between the two methods. The excellent and good category events tended to produce condensation profiles with lower median heights, which translated to more similar vapor source characteristics. Poorly matched events tended to result from rain events where the Reanalysis method yielded much higher median heights than the Cloud Radar method.
Antibiotic Prophylaxis in Clean‐Contaminated Head and Neck Surgery: A Systematic Review and Meta‐analysis
Authors: Vila Peter M. , Zenga Joseph , Fowler Susan , Jackson Ryan S. 
Published: October 2017

ObjectiveTo determine the optimal duration and type of antibiotic prophylaxis in patients undergoing clean‐contaminated resection for head and neck cancer.Data SourcesSearch strategies were created by a medical librarian, implemented in multiple databases, and completed in June 2016.Review MethodsThe population of interest was adults ≥18 years undergoing clean‐contaminated head and neck surgery, intervention was postoperative antibiotic prophylaxis, comparator was duration and types of antibiotics used, outcome was the wound infection rate, and the study design was randomized controlled trials (RCTs). Studies were excluded if not randomized, did not use systemic antibiotics, did not study wound infections, or included children. After excluding duplicates, the search strategy yielded 427 abstracts. After applying inclusion and exclusion criteria, 67 studies were screened, leaving 19 RCTs for review. PRISMA guidelines were followed. A random‐effects model was used for meta‐analysis.ResultsMeta‐analysis of 340 patients in 4 RCTs showed that the pooled relative risk of wound infection was 0.98 (95% confidence interval [CI], 0.58‐1.61; P =. 718; I2 = 0.0%) in patients receiving 1 day vs 5 days of prophylaxis.ConclusionThis study provides evidence that there is no difference in the risk of wound infection with 1 day vs 5 days of systemic antibiotic prophylaxis in clean‐contaminated head and neck surgery, consistent with existing guidelines. Future large randomized trials are needed to more clearly define the appropriate choice of prophylaxis in penicillin‐allergic patients.
Accuracy of pre-interventional computed tomography angiography post-processing software and extravascularly calibrated devices to determine vessel diameters: comparison with an intravascularly located calibrated catheter
Authors: Stahlberg Erik , Planert Mathis , Anton Susanne , Panagiotopoulos Nikolaos , Horn Marco , Barkhausen Joerg , Goltz Jan Peter 
Published: October 2017

Background Accurate vessel sizing might affect treatment outcome of endovascular therapy. Purpose To compare accuracy of peripheral vessel diameter measurements using pre-interventional computed tomography angiography post processing software (CTA-PPS) and extravascularly located calibrated devices used during digital subtraction angiography (DSA) with an intravascular scaled catheter (SC). Material and Methods In 33 patients (28 men, mean age = 72 ± 11 years) a SC was used during DSA of the femoro-popliteal territory. Simultaneously, one scaled radiopaque tape (SRT) was affixed to the lateral thigh, one scaled radiopaque ruler (SRR) was positioned on the angiography table. For each patient, diameters of five anatomic landmarks were measured on DSA images after calibration using different scaled devices and CTA-PPS. Diameters were compared to SC (reference) and between groups of non-obese (NOB) and obese (OB) patients. Results In total, 660 measurements were performed. Compared to the reference, SRT overestimated the diameter by 1.2% (range = -10–12, standard deviation [SD] = 4.1%, intraclass correlation coefficient [ICC] = 0.992, 95% confidence interval [CI] = 0.989–0.992, P = 0.01), the SRR and CTA-PPS underestimated it by 21.3% (range = 1–47, SD = 9.4%, ICC = 0.864, 95% CI = 0.11–0.963, P = 0.08) and 3.2% (range = 17–38, SD = 9.7%, ICC = 0.976, 95% CI = 0.964–0.983, P = 0.01), respectively. Underestimation using the SRR was greatest in the proximal superficial-femoral artery (31%) and lowest at the P2 level of the popliteal artery (15%). In the NOB group, diameter overestimation of the SRT was 0.8% (range = 4–7, SD = 4.2%, B = 0.071, 95% CI = 0.293–0.435, P = 0.08) compared to the OB group of 1.6% (range = −7–4, SD = 2.9%, B = 0.010, 95% CI = 0.474–0.454, P = 0.96). Diameter underestimation of the SRR was 17.3% (range = 13–21, SD = 3.1%, B = 0.946, 95% CI = 0.486–1.405, P = 0.002) in the NOB group, 23.3% (range = 11–36, SD = 6.6%, B = 0.870, 95% CI = 0.268–1.472, P = 0.007) in the OB group. Conclusion For calibrated measurements SRT and CTA-PPS prove accurate compared to the reference, while SRR does not. Obesity has a significant impact on underestimation of diameter if SRR is used.