bluuebunny/crossref_metadata_2025 huggingface dataset:
Perinatal Outcome in Women with Hypertensive Disorders of Pregnancy: A Retrospective Cohort Study
Authors: Endeshaw Gezehagn , Berhan Yifru
Published: January 2015

Background. Hypertensive disorders of pregnancy (HDP) are multisystem diseases known to increase the risk of perinatal mortality worldwide, with a significant proportion of these deaths occurring in low income countries. However, little is known about the obstetric and treatment predictors of perinatal mortality in women with HDP. Methods. A retrospective cohort study design was used to include 1015 hypertensive pregnant women who gave birth to 1110 babies between 2008 and 2013 in three university teaching hospitals. Bivariate and multivariate regression models were used to estimate the associations between selected predictor variables and perinatal mortality taking the onset of HDP illness to death or discharge from the hospital as the time period. Results. There were 322 perinatal deaths resulting in a perinatal mortality rate (PMR) of 290/1000 total births. The proportion of stillbirths was more than 4-fold higher than early neonatal deaths (81% versus 19%). The multivariate analysis demonstrated that multiparity (OR, 1.6; 95% CI, 1.12–228), grand multiparity (OR, 2.8; 95% CI, 1.55–4.92), preterm (OR, 1.5; 95% CI, 1.02–2.35) and very preterm gestational age (OR, 7.7; 95% CI, 5.26–11.20), lack of antenatal care (OR, 2.0; 95% CI, 1.43–2.67), having eclampsia (OR, 4.1; 95% CI, 2.85–6.04), antepartum or before (OR, 6.6; 95% CI, 3.40–12.75) and intrapartum onset of HDP (OR, 4.0; 95% CI, 1.99–8.04), raised SGOT level (OR, 2.3; 95% CI, 1.30–3.91), vaginal delivery (OR, 5.3; 95% CI, 2.93–9.54), low fetal birth weight (OR, 4.3; 95% CI, 2.56–7.23), and maternal death (OR, 12.8; 95% CI, 2.99–54.49) were independent predictors of perinatal mortality. Conclusion. This study showed that the PMR of HDP was among the highest in the world. Parity, gestational age, type and onset of HDP, mode of delivery, birthweight, and maternal outcome were strong predictors of perinatal mortality.
Short-Term Power Load Point Prediction Based on the Sharp Degree and Chaotic RBF Neural Network
Authors: Niu Dongxiao , Lu Yan , Xu Xiaomin , Li Bingjie
Published: January 2015

In order to realize the predicting and positioning of short-term load inflection point, this paper made reference to related research in the field of computer image recognition. It got a load sharp degree sequence by the transformation of the original load sequence based on the algorithm of sharp degree. Then this paper designed a forecasting model based on the chaos theory and RBF neural network. It predicted the load sharp degree sequence based on the forecasting model to realize the positioning of short-term load inflection point. Finally, in the empirical example analysis, this paper predicted the daily load point of a region using the actual load data of the certain region to verify the effectiveness and applicability of this method. Prediction results showed that most of the test sample load points could be accurately predicted.
Antithrombotic Therapy in Patients with Acute Coronary Syndrome in the Intermountain Heart Collaborative Study
Authors: Knight Stacey , Klaskala Winslow , Woller Scott C. , Horne Benjamin D. , Bunch T. Jared , Le Viet T. , Mills Roger M. , Muhlestein Joseph B.
Published: January 2015

Objective. To determine factors associated with single antiplatelet (SAP) or dual antiplatelet (DAP) therapy and anticoagulants (AC) use in hospital and after discharge among patients with acute coronary syndrome (ACS).Methods. We evaluated 5,294 ACS patients in the Intermountain Heart Collaborative Study from 2004 to 2009. Multivariable logistic regressions were used to determine predictors of AC or AP use.Results. In hospital, 99% received an AC, 79% DAP, and 19% SAP; 78% had DAP + AC. Coronary stents were the strongest predictors of DAP use in hospital compared to SAP (P<0.001). After discharge, 77% received DAP, 20% SAP, and 9% AC; 5% had DAP + AC. DAP compared to SAP was less likely for patients on AC (odds ratio [OR] = 0.30,P<0.0001) after discharge. Placement of a stent increased the likelihood of DAP (bare metal: OR = 54.8,P<0.0001; drug eluting: OR = 59.4,P<0.0001). 923 had atrial fibrillation and 337 had a history of venous thromboembolism; these patients had increased use of AC (29% and 40%, resp.).Conclusion. While in-hospital use of AC was nearly universal, postdischarge AC use was rare. Concern for providing the best antithrombotic therapy, while maintaining an acceptable bleeding risk, may explain the selection decisions.
Vibration Characteristics Induced by Cavitation in a Centrifugal Pump with Slope Volute
Authors: Zhang Ning , Yang Minguan , Gao Bo , Li Zhong
Published: January 2015

Cavitation is one of the instability sources in centrifugal pump, which would cause some unexpected results. The goal of this paper was to analyze the influence of cavitation process on different frequency bands in a centrifugal pump with slope volute. And special attention was paid to low frequency signals, which were often filtered in the reported researches. Results show that at noncavitation condition, vibration level is closely related to flow structure interior pump. At partial flow rates, especially low flow rates, vibration level increases rapidly with the onset of rotating stall. At cavitation condition, it is proved that cavitation process has a significant impact on low frequency signals. With cavitation number decreasing, vibration level first rises to a local maximum, then it drops to a local minimum, and finally it rises again. At different flow rates, vibration trends in variable frequency bands differ obviously. Critical point inferred from vibration level is much larger than that from 3% head drop, which indicates that cavitation occurs much earlier than that reflected in head curve. Also, it is noted that high frequency signals almost increase simultaneously with cavitation occurring, which can be used to detect cavitation in centrifugal pump.
Risk Factors and Prognostic Significance of Retropancreatic Lymph Nodes in Gastric Adenocarcinoma
Authors: Xue Lian , Chen Xiao-Long , Zhang Wei-Han , Yang Kun , Chen Xin-Zu , Zhang Bo , Chen Zhi-Xin , Chen Jia-Ping , Zhou Zong-Guang , Hu Jian-Kun
Published: January 2015

Background. The studies on risk factors and metastatic rate of retropancreatic (number 13) lymph nodes in gastric adenocarcinoma were few and the results were still controversial. The aim of this study was to elucidate risk factors and prognostic significance of number 13 lymph nodes in gastric adenocarcinoma.Method. From January 2000 to December 2011, 114 patients who underwent gastrectomy with number 13 lymph nodes dissection were enrolled and followed up to January 2014. Patients were grouped according to whether number 13 lymph nodes were positive or negative.Results. The metastatic rate of number 13 lymph nodes was 22.8%. In multivariate analysis, pT stage (P=0.027), pN stage (P=0.005), and number 11p (P=0.015) lymph nodes were independent risk factors of positive number 13 lymph nodes. In all patients (P<0.001) and subpopulation with TNM III stage (P=0.007), positive number 13 lymph nodes had significantly worse prognosis than those of patients with negative number 13 LNs in Kaplan-Meier analysis.Conclusion. Number 13 lymph nodes had relatively high metastatic rate and led to poor prognosis. pT stage, pN stage, and number 11p lymph nodes were independent risk factors of positive number 13 lymph nodes.
Quantitative iTRAQ LC-MS/MS Proteomics Reveals the Proteome Profiles of DF-1 Cells after Infection with Subgroup J Avian Leukosis Virus
Authors: Li Xiaofei , Wang Qi , Gao Yanni , Qi Xiaole , Wang Yongqiang , Gao Honglei , Gao Yulong , Wang Xiaomei
Published: January 2015

Avian leukosis virus subgroup J (ALV-J) is an avian oncogenic retrovirus that can induce various clinical tumors and has caused severe economic losses in China. To improve our understanding of the host cellular responses to virus infection and the pathogenesis of ALV-J infection, we applied isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with multidimensional liquid chromatography-tandem mass spectrometry to detect the protein changes in DF-1 cells infected and mock-infected with ALV-J. A total of 75 cellular proteins were significantly changed, including 33 upregulated proteins and 42 downregulated proteins. The reliability of iTRAQ-LC MS/MS was confirmed via real-time PCR. Most of these proteins were related to the physiological functions of metabolic processes, biosynthetic processes, responses to stimuli, protein binding, signal transduction, cell cytoskeleton, and so forth. We also found some proteins that play important roles in apoptosis and oncogenicity. The differentially expressed proteins identified may provide valuable information to elucidate the pathogenesis of virus infection and virus-host interactions.
Food Processing and Maillard Reaction Products: Effect on Human Health and Nutrition
Authors: Tamanna Nahid , Mahmood Niaz
Published: January 2015

Maillard reaction produces flavour and aroma during cooking process; and it is used almost everywhere from the baking industry to our day to day life to make food tasty. It is often called nonenzymatic browning reaction since it takes place in the absence of enzyme. When foods are being processed or cooked at high temperature, chemical reaction between amino acids and reducing sugars leads to the formation of Maillard reaction products (MRPs). Depending on the way the food is being processed, both beneficial and toxic MRPs can be produced. Therefore, there is a need to understand the different types of MRPs and their positive or negative health effects. In this review we have summarized how food processing effects MRP formation in some of the very common foods.
The Use of a Green Fluorescent Protein Porcine Model to Evaluate Host Tissue Integration into Extracellular Matrix Derived Bionanocomposite Scaffolds
Authors: Smith S. E. , White R. A. , Grant D. A. , Grant S. A.
Published: January 2015

When using heterogeneous extracellular matrix (ECM) derived scaffolds for soft tissue repair, current methods of in vivo evaluation can fail to provide a clear distinction between host collagen and implanted scaffolds making it difficult to assess host tissue integration and remodeling. The purpose of this study is both to evaluate novel scaffolds conjugated with nanoparticles for host tissue integration and biocompatibility and to assess green fluorescent protein (GFP) expressing swine as a new animal model to evaluate soft tissue repair materials. Human-derived graft materials conjugated with nanoparticles were subcutaneously implanted into GFP expressing swine to be evaluated for biocompatibility and tissue integration through histological scoring and confocal imaging. Histological scoring indicates biocompatibility and remodeling of the scaffolds with and without nanoparticles at 1, 3, and 6 months. Confocal microscope images display host tissue integration into scaffolds although nonspecificity of GFP does not allow for quantification of integration. However, the confocal images do allow for spatial observation of host tissue migration into the scaffolds at different depths of penetration. The study concludes that the nanoparticle scaffolds are biocompatible and promote integration and that the use of GFP expressing swine can aid in visualizing the scaffold/host interface and host cell/tissue migration.
Residential Exposure to Urban Traffic Is Associated with Increased Carotid Intima-Media Thickness in Children
Authors: Armijos Rodrigo X. , Weigel M. Margaret , Myers Orrin B. , Li Wen-Whai , Racines Marcia , Berwick Marianne
Published: January 2015

Chronic exposure to urban traffic pollution is documented to promote atherosclerosis in adults but little is known about its potential effects in children. Our study examined the association of long-term exposure to traffic with carotid intima-media thickness (cIMT) in 287 healthy children. Residential proximity and distance-weighted traffic density (DWTD) were used as proximity markers for traffic-related air pollution exposure. The multivariable analyses revealed that children residing <100 meters from the nearest heavily trafficked road had cIMT mean and maximum measurements that were increased by 15% and 11% compared to those living ≥ 200 meters away (P=0.0001). Similar increases in cIMT were identified for children in the highest versus lowest DWTD tertile. Children who resided 100–199 meters from traffic or in the middle DWTD tertile also exhibited increased cIMT but these differences were not statistically significant. No statistically significant differences were identified between residential distance to traffic or DWTD and systemic inflammation indicators (CRP, IL-6). The study results suggest that exposure to urban traffic promotes arterial remodeling in children. This finding is important since even small increases in cIMT over time can potentially lead to earlier progression to atherosclerosis. It is also important because traffic-related pollution is potentially modifiable.
What Do the Hospital Pharmacists Think about the Quality of Pharmaceutical Care Services in a Pakistani Province? A Mixed Methodology Study
Authors: Murtaza Ghulam , Kousar Rozina , Azhar Saira , Khan Shujaat Ali , Mahmood Qaisar
Published: January 2015

The objective of this study was to evaluate the perception of hospital pharmacists regarding quality of pharmaceutical care services in Khyber Pakhtunkhwa (KPK) Province, Pakistan, through qualitative as well as quantitative approach. For qualitative study, snow ball sampling technique was used. In quantitative part, a cross-sectional study was conducted in 112 hospital pharmacists (out of 128 accessed ones) from both private and public hospitals in six major divisions (divisions are the third tier of government in Pakistan, between the provinces and districts) of KPK. The qualitative study yielded five major themes during thematic analysis: (a) patients reporting, (b) lack of patient counseling, (c) lack of participation in health awareness programs, (d) pharmacists reducing the prescribing errors, and (e) insufficient number of pharmacists. A great proportion (67.9%) of the pharmacists was unsatisfied with their participation in health awareness programs. Findings of both phases revealed that hospital pharmacists in Pakistan are not actively participating in the provision of pharmaceutical care services. They are facing various hurdles for their active participation in patient care; major obstacles include the unavailability of sufficient number of pharmacists, lack of appropriate time for patient counseling, and poor relationship between pharmacists and other health care providers.
Single Intravitreal Aflibercept Injection for Unilateral Acute Nonarteritic Ischemic Optic Neuropathy
Authors: Ayhan Ziya , Kocaoğlu Gamze , Yaman Aylin , Bajin Meltem Söylev , Saatci A. Osman
Published: January 2015

Acute nonarteritic ischemic optic neuropathy (ANAION) is the most common optic neuropathy in the elderly population without a well-established treatment. A 67-year-old man with a sudden painless visual loss in his left eye of one-day duration was diagnosed to have left ANAION. Next day, 2 mg aflibercept injection was injected intravitreally in OS. Visual acuity improved to 7/10 from 1/10 a week after the injection. Mean retinal nerve fiber layer thickness (RNFLT) was reduced to 159,7 μm from 182,4 μm at the first week. Visual fields improved dramatically during the follow-up of three months. The aim of this study is to present a case having ANAION treated with a single intravitreal aflibercept injection and discuss the place of intravitreal anti-VEGF injections in the treatment of armamentarium of ANAION.
N-(1-Pyrenyl) Maleimide Induces Bak Oligomerization and Mitochondrial Dysfunction in Jurkat Cells
Authors: Huang Pei-Rong , Hung Shu-Chen , Pao Chia-Chu , Wang Tzu-Chien V.
Published: January 2015

N-(1-pyrenyl) maleimide (NPM) is a fluorescent reagent that is frequently used as a derivatization agent for the detection of thio-containing compounds. NPM has been shown to display a great differential cytotoxicity against hematopoietic cancer cells. In this study, the molecular mechanism by which NPM induces apoptosis was examined. Here, we show that treatment of Jurkat cells with NPM leads to Bak oligomerization, loss of mitochondrial membrane potential (Δψm), and release of cytochrome C from mitochondria to cytosol. Induction of Bak oligomerization appears to play a critical role in NPM-induced apoptosis, as downregulation of Bak by shRNA significantly prevented NPM-induced apoptosis. Inhibition of caspase 8 by Z-IETD-FMK and/or depletion of Bid did not affect NPM-induced oligomerization of Bak. Taken together, these results suggest that NPM-induced apoptosis is mediated through a pathway that is independent of caspase-8 activation.
Phylogenetic Groups ofEscherichia coliStrains from Patients with Urinary Tract Infection in Iran Based on the New Clermont Phylotyping Method
Authors: Iranpour Darioush , Hassanpour Mojtaba , Ansari Hossein , Tajbakhsh Saeed , Khamisipour Gholamreza , Najafi Akram
Published: January 2015

Objectives.In 2013, Clermont classifiedE. colistrains into eight phylogenetic groups using a new quadruplex PCR method. The aims of this study were to identify the phylogenetic groups ofE. colibased on this method and to assess their antibiotic resistance patterns in Bushehr, Iran.Methods. In this cross-sectional study, 140E. coliisolates were subjected to phylogenetic typing by a quadruplex PCR method. Antimicrobial susceptibility testing was performed by disk diffusion method.Results. Phylogenetic group B2 was most predominant (39.3%), followed by unknown (27.1%), E (9.3%), C and clade I (each 6.4%), B1 (5%), F and D (each 2.9%), and A (0.7%). The most common antibiotic resistance was related to amoxicillin (82.1%) and the least to meropenem (0.7%). 82.14% of isolates were multiple drug resistant (MDR). Antibiotic resistance was mainly detected in group B2 (50%).Conclusions.Our findings showed the high prevalence of MDRE. coliisolates with dominance of group B2. About 25% ofE. coliisolates belong to the newly described phylogroups C, E, F, and clade I. Such studies need to be done also in other regions to provide greater understanding of the antibiotic resistance pattern and the prevalences of different phylogenetic groups.
MS Prevalence and Patients’ Characteristics in the District of Braga, Portugal
Authors: Figueiredo José , Silva Ângela , Cerqueira João J. , Fonseca Joaquim , Pereira Paulo A.
Published: January 2015

Multiple Sclerosis (MS) is a chronic autoimmune disease of the Central Nervous System causing inflammation and neurodegeneration. There are only 3 epidemiological studies in Portugal, 2 in the Centre and 1 in the North, and there is the need to further study MS epidemiology in this country. The objective of this work is to contribute to the MS epidemiological knowledge in Portugal, describing the patients’ epidemiological, demographic, and clinical characteristics in the Braga district of Portugal. This is a cross-sectional study of 345 patients followed in two hospitals of Braga district. These hospitals cover a resident population of 866,012 inhabitants. The data was collected from the clinical records, and 31/12/2009 was established as the prevalence day. For all MS patients, demographic characteristics and clinical outcomes are reported. We have found an incidence of 2.74/100,000 and a prevalence of 39.82/100,000 inhabitants. Most patients have an EDSS of 3 or lower and a mean age of 42 years. The diagnosis was done at mean age of 35, with RRMS being the disease type in more than 80% of patients. In this cohort, we found a female : male ratio of 1.79. More than 50% of patients are treated with Interferonβ-1b IM or IFNβ-1a SC 22 μg.
Potential Inhibitors for Isocitrate Lyase ofMycobacterium tuberculosisand Non-M. tuberculosis: A Summary
Authors: Lee Yie-Vern , Wahab Habibah A. , Choong Yee Siew
Published: January 2015

Isocitrate lyase (ICL) is the first enzyme involved in glyoxylate cycle. Many plants and microorganisms are relying on glyoxylate cycle enzymes to survive upon downregulation of tricarboxylic acid cycle (TCA cycle), especiallyMycobacterium tuberculosis(MTB). In fact, ICL is a potential drug target for MTB in dormancy. With the urge for new antitubercular drug to overcome tuberculosis treat such as multidrug resistant strain and HIV-coinfection, the pace of drug discovery has to be increased. There are many approaches to discovering potential inhibitor for MTB ICL and we hereby review the updated list of them. The potential inhibitors can be either a natural compound or synthetic compound. Moreover, these compounds are not necessary to be discovered only from MTB ICL, as it can also be discovered by a non-MTB ICL. Our review is categorized into four sections, namely, (a) MTB ICL with natural compounds; (b) MTB ICL with synthetic compounds; (c) non-MTB ICL with natural compounds; and (d) non-MTB ICL with synthetic compounds. Each of the approaches is capable of overcoming different challenges of inhibitor discovery. We hope that this paper will benefit the discovery of better inhibitor for ICL.
The Effect of Bicarbonate Administration via Continuous Venovenous Hemofiltration on Acid-Base Parameters in Ventilated Patients
Authors: Allegretti Andrew S. , Flythe Jennifer E. , Benda Vinod , Robinson Emily S. , Charytan David M.
Published: January 2015

Background. Acute kidney injury (AKI) and metabolic acidosis are common in the intensive care unit. The effect of bicarbonate administration on acid-base parameters is unclear in those receiving continuous venovenous hemofiltration (CVVH) and mechanical ventilatory support.Methods. Metabolic and ventilatory parameters were prospectively examined in 19 ventilated subjects for up to 96 hours following CVVH initiation for AKI at an academic tertiary care center. Mixed linear regression modeling was performed to measure changes in pH, partial pressure of carbon dioxide (pCO2), serum bicarbonate, and base excess over time.Results. During the 96-hour study period,pCO2levels remained stable overall (initialpCO242.0 ± 14.6 versus end-studypCO243.8 ± 16.1 mmHg;P=0.13for interaction with time), for those with initialpCO2≤40 mmHg (31.3 ± 5.7 versus 35.0 ± 4.8;P=0.06) and for those with initialpCO2>40 mmHg (52.7 ± 12.8 versus 53.4 ± 19.2;P=0.57).pCO2decreased during the immediate hours following CVVH initiation (42.0 ± 14.6 versus 37.3 ± 12.6 mmHg), though this change was nonsignificant (P=0.052).Conclusions. We did not detect a significant increase inpCO2in response to the administration of bicarbonate via CVVH in a ventilated population. Additional studies of larger populations are needed to confirm this finding.
Qualitative and Quantitative Analysis of Eclipta prostrata L. by LC/MS
Authors: Han Lifeng , Liu Erwei , Kojo Agyemang , Zhao Jing , Li Wei , Zhang Yi , Wang Tao , Gao Xiumei
Published: January 2015

Eclipta prostrata L. is one of the Chinese medicinal tonics which are usually used for treating loose teeth, dizziness, tinnitus, hemoptysis, hematuria, and uterine bleeding. However, quality control of this herbal medicine has been not satisfactory. This study reported its qualitative and quantitative analyses based on LC/MS method. UHPLC‐DAD‐Q‐TOF‐MS fingerprinting and MS fragmentation cleavage pathway were investigated for qualitative analysis. Furthermore, a method for simultaneous quantitative determination of nine compounds, luteolin 7‐O‐β‐D‐glucopyranoside, ecliptasaponin C, luteolin, eclalbasaponin IV, apigenin, ecliptasaponin A, echinocystic acid 28‐O‐β‐D‐glucopyranoside, echinocystic acid, and 3‐oxo‐16α‐hydroxy‐olean‐12‐en‐28‐oic acid in E. prostrata, was established. The method was validated for samples of E. prostrata from different habitats. The results showed good linear correlation, precision, accuracy, and repeatability that could be used for contents determination of the nine compounds in E. prostrata from different habitats.
Performance Comparison of Wavefront-Sensorless Adaptive Optics Systems by Using of the Focal Plane
Authors: Yang Huizhen , Zhang Zhen , Wu Jian
Published: January 2015

The correction capability and the convergence speed of the wavefront-sensorless adaptive optics (AO) system are compared based on two different system control algorithms, which both use the information of focal plane. The first algorithm is designed through the linear relationship between the second moment of the aberration gradients and the masked far-field intensity distribution and the second is stochastic parallel gradient descent (SPGD), which is the most commonly used algorithm in wavefront-sensorless AO systems. A wavefront-sensorless AO model is established with a 61-element deformable mirror (DM) and a CCD. Performance of the two control algorithms is investigated and compared through correcting different wavefront aberrations. Results show that the correction ability of AO system based on the proposed control algorithm is obviously better than that of AO system based on SPGD algorithm when the wavefront aberrations increase. The time needed by the proposed control algorithm is much less than that of SPGD when the AO system achieves similar correction results. Additionally, the convergence speed of the proposed control algorithm is independent of the turbulence strength while the number of intensity measurements needed by SPGD increases as the turbulence strength magnifies.
Broad, Hybrid Capture–Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches
Authors: Drilon Alexander , Wang Lu , Arcila Maria E. , Balasubramanian Sohail , Greenbowe Joel R. , Ross Jeffrey S. , Stephens Phil , Lipson Doron , Miller Vincent A. , Kris Mark G. , Ladanyi Marc , Rizvi Naiyer A.
Published: January 2015

Purpose: Broad, hybrid capture–based next-generation sequencing (NGS), as a clinical test, uses less tissue to identify more clinically relevant genomic alterations compared with profiling with multiple non-NGS tests. We set out to determine the frequency of such genomic alterations via this approach in tumors in which previous extensive non-NGS testing had not yielded a targetable driver alteration.

Experimental Design: We enrolled patients with lung adenocarcinoma with a ≤15 pack-year smoking history whose tumors previously tested “negative” for alterations in 11 genes (mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 and fusions involving ALK, ROS1, and RET) via multiple non-NGS methods. We performed hybridization capture of the coding exons of 287 cancer-related genes and 47 introns of 19 frequently rearranged genes and sequenced these to deep, uniform coverage.

Results: Actionable genomic alterations with a targeted agent based on NCCN guidelines were identified in 26% [8 of 31: EGFR G719A, BRAF V600E, SOCS5-ALK, HIP1-ALK, CD74-ROS1, KIF5B-RET (n = 2), CCDC6-RET]. Seven of these patients either received or are candidates for targeted therapy. Comprehensive genomic profiling using this method also identified a genomic alteration with a targeted agent available on a clinical trial in an additional 39% (12 of 31).

Conclusions: Broad, hybrid capture–based NGS identified actionable genomic alterations in 65% [95% confidence interval (CI), 48%–82%] of tumors from never or light smokers with lung cancers deemed without targetable genomic alterations by earlier extensive non-NGS testing. These findings support first-line profiling of lung adenocarcinomas using this approach as a more comprehensive and efficient strategy compared with non-NGS testing. Clin Cancer Res; 21(16); 3631–9. ©2015 AACR.

See related commentary by McCutcheon and Giaccone, p. 3584
CD44 Regulates Pancreatic Cancer Invasion through MT1-MMP
Authors: Jiang Wei , Zhang Yaqing , Kane Kevin T. , Collins Meredith A. , Simeone Diane M. , di Magliano Marina Pasca , Nguyen Kevin Tri
Published: January 2015

Pancreatic cancer is one of the deadliest human malignancies due to its early metastatic spread and resistance to therapy. The mechanisms regulating pancreatic cancer metastasis are so far poorly understood. Here, using both in vitro and in vivo approaches, it is demonstrated that CD44, a transmembrane glycoprotein expressed on a subset of pancreatic cancer cells, is required for the induction of epithelial–mesenchymal transition (EMT) and the activation of an invasive program in pancreatic cancer. Mechanistically, the transcription factor Snail1 (SNAI1), a regulator of the EMT program, is a downstream target of CD44 in primary pancreatic cancer cells and regulates membrane bound metalloproteinase (MMP14/MT1-MMP) expression. In turn, MT1-MMP expression is required for pancreatic cancer invasion. Thus, these data establish the CD44–Snail–MMP axis as a key regulator of the EMT program and of invasion in pancreatic cancer.

Implications: This study sets the stage for CD44 and MT1-MMP as therapeutic targets in pancreatic cancer, for which small molecule or biologic inhibitors are available.

Visual Overview: http://mcr.aacrjournals.org/content/early/2014/09/10/1541-7786.MCR-14-0076/F1.large.jpg.

Mol Cancer Res; 13(1); 9–15. ©2014 AACR.
The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain
Authors: Parker Jillian A. , Mattos Carla
Published: January 2015

The small GTPase Ras is mutated in about 20% of human cancers, primarily at active site amino acid residues G12, G13, and Q61. Thus, structural biology research has focused on the active site, impairment of GTP hydrolysis by oncogenic mutants, and characterization of protein–protein interactions in the effector lobe half of the protein. The C-terminal hypervariable region has increasingly gained attention due to its importance in H-Ras, N-Ras, and K-Ras differences in membrane association. A high-resolution molecular view of the Ras–membrane interaction involving the allosteric lobe of the catalytic domain has lagged behind, although evidence suggests that it contributes to isoform specificity. The allosteric lobe has recently gained interest for harboring potential sites for more selective targeting of this elusive “undruggable” protein. The present review reveals critical insight that isoform-specific differences appear prominently at these potentially targetable sites and integrates these differences with knowledge of Ras plasma membrane localization, with the intent to better understand the structure–function relationships needed to design isoform-specific Ras inhibitors. Mol Cancer Res; 13(4); 595–603. ©2015 AACR.
Tumors: Wounds That Do Not Heal—Redux
Authors: Dvorak Harold F.
Published: January 2015

Similarities between tumors and the inflammatory response associated with wound healing have been recognized for more than 150 years and continue to intrigue. Some years ago, based on our then recent discovery of vascular permeability factor (VPF)/VEGF, I suggested that tumors behaved as wounds that do not heal. More particularly, I proposed that tumors co-opted the wound-healing response to induce the stroma they required for maintenance and growth. Work over the past few decades has supported this hypothesis and has put it on a firmer molecular basis. In outline, VPF/VEGF initiates a sequence of events in both tumors and wounds that includes the following: increased vascular permeability; extravasation of plasma, fibrinogen and other plasma proteins; activation of the clotting system outside the vascular system; deposition of an extravascular fibrin gel that serves as a provisional stroma and a favorable matrix for cell migration; induction of angiogenesis and arterio-venogenesis; subsequent degradation of fibrin and its replacement by “granulation tissue” (highly vascular connective tissue); and, finally, vascular resorption and collagen synthesis, resulting in the formation of dense fibrous connective tissue (called “scar tissue” in wounds and “desmoplasia” in cancer). A similar sequence of events also takes place in a variety of important inflammatory diseases that involve cellular immunity. Cancer Immunol Res; 3(1); 1–11. ©2015 AACR.
Evaluation of Pulmonary and Extrapulmonary Tuberculosis in Immunocompetent Adults: A Retrospective Case Series Analysis
Authors: Ates Guler Selma , Bozkus Fulsen , Inci Mehmet Fatih , Kokoglu Omer Faruk , Ucmak Hasan , Ozden Sevinc , Yuksel Murvet
Published: January 2015

Objective: It was the aim of this study to evaluate the demographic factors and clinical features of extrapulmonary tuberculosis (EPTB) compared to those of pulmonary tuberculosis (PTB) among adult immunocompetent patients. Subjects and Methods: A total of 427 patients with clinically, radiologically and histopathologically confirmed TB were enrolled in the study, in our clinic at a tertiary care hospital in Turkey, during a 5-year period (2007-2012). Patient data were obtained retrospectively. Among the 427 patients, 55 patients with both PTB and EPTB and who were using steroids or had taken immunosuppressive drugs were excluded from the study. Results: Of the 372 patients, 227 (61%) were males and 168 (45.2%) had EPTB; 204 (54.8%) patients had PTB. The most frequent sites of EPTB were the lymph nodes (n = 45, 12.1%), pleura (n = 40, 10.7%) and brain (n = 7, 1.8%). The most common symptoms were cough (n = 174, 46.7%), night sweats (n = 127, 34.1%) and fever (n = 123, 33%). Compared to EPTB patients, PTB patients were less likely to have received Bacillus Calmette-Guérin vaccination (odds ratio 0.41, 95% confidence interval 0.2-0.63; p < 0.001). Eighty-one (48.2%) of the EPTB and 146 (71.6%) of the PTB patients were males. Pulmonary involvement was more common among men (n = 146, 71.6%) than among women (n = 58, 28.2%; p = 0.000). Conclusion: There was a high incidence of EPTB in our study. Early diagnosis of EPTB is crucial for treatment, and atypical presentations of TB should be kept in mind for immunocompetent patients living in endemic areas. Females especially should be investigated for EPTB.
The Relationship between Coronary Collateral Circulation and Neutrophil/Lymphocyte Ratio in Patients with Coronary Chronic Total Occlusion
Authors: Nacar Alper Bugra , Erayman Ali , Kurt Mustafa , Buyukkaya Eyup , Karakaş Mehmet Fatih , Akcay Adnan Burak , Buyukkaya Sule , Sen Nihat
Published: January 2015

Objectives: To investigate the relationship between neutrophil/lymphocyte ratio (NLR) and coronary collateral circulation (CCC) in patients with coronary chronic total occlusion. Subjects and Methods: Our study population consisted of 275 consecutive patients with chronic total occlusion. One hundred and thirty-eight patients with chronic total occlusion were included in the study. They were classified into 2 groups as follows: impaired CCC (group 1: Rentrop grades 0-1) and good CCC (group 2: Rentrop grades 2-3). The NLR was calculated from the complete blood count. Results: The NLR values of the patients with impaired CCC (4.5 ± 0.7) were significantly higher than of those with good CCC (2.7 ± 0.6, p < 0.001). In the multivariate logistic regression test, NLR (OR 33.36, 95% CI 8.189-135.7, p < 0.001), high-sensitivity C-reactive protein (hs-CRP; OR 2.152, 95% CI 1.226-3.777, p = 0.008), estimated glomerular filtration rate (OR 1.167, 95% CI 1.049-1.298, p = 0.004) and systolic blood pressure (OR 1.068, 95% CI 1.009-1.1310, p = 0.025) were independent predictors of impaired CCC. The NLR value >3.55 yielded an area under the curve value of 0.957 (95% CI 0.921-0.992, p < 0.001) and demonstrated a sensitivity of 95% and a specificity of 90% for the prediction of CCC. A moderate correlation between NLR and hs-CRP was observed (r = 0.443; p < 0.001). Conclusion: Our findings reveal that NLR correlates with the impaired development of coronary collaterals.
Genome-Wide Association Studies in Africans and African Americans: Expanding the Framework of the Genomics of Human Traits and Disease
Authors: Peprah Emmanuel , Xu Huichun , Tekola-Ayele Fasil , Royal Charmaine D.
Published: January 2015

Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions.
Affected Twins in the Familial Intracranial Aneurysm Study
Authors: Mackey Jason , Brown Robert D. , Sauerbeck Laura , Hornung Richard , Moomaw Charles J. , Koller Daniel L. , Foroud Tatiana , Deka Ranjan , Woo Daniel , Kleindorfer Dawn , Flaherty Matthew L. , Meissner Irene , Anderson Craig , Rouleau Guy , Connolly E. Sander , Huston John , Broderick Joseph P. ,   for the FIA Investigators
Published: January 2015

Background and Purpose: Very few cases of intracranial aneurysms (IAs) in twins have been reported. Previous work has suggested that vulnerability to IA formation is heritable. Twin studies provide an opportunity to evaluate the impact of genetics on IA characteristics, including IA location. We therefore sought to examine IA location concordance, multiplicity, and rupture status within affected twin-pairs. Methods: The Familial Intracranial Aneurysm study was a multicenter study whose goal was to identify genetic and other risk factors for formation and rupture of IAs. The study required at least three affected family members or an affected sibling pair for inclusion. Subjects with fusiform aneurysms, an IA associated with an AVM, or a family history of conditions known to predispose to IA formation, such as polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, or moyamoya syndrome were excluded. Twin-pairs were identified by birth date and were classified as monozygotic (MZ) or dizygotic (DZ) through DNA marker genotypes. In addition to zygosity, we evaluated twin-pairs by smoking status, major arterial territory of IAs, and rupture status. Location concordance was defined as the presence of an IA in the same arterial distribution (ICA, MCA, ACA, and vertebrobasilar), irrespective of laterality, in both members of a twin-pair. The Fisher exact test was used for comparisons between MZ and DZ twin-pairs. Results: A total of 16 affected twin-pairs were identified. Location concordance was observed in 8 of 11 MZ twin-pairs but in only 1 of 5 DZ twin-pairs (p = 0.08). Three MZ subjects had unknown IA locations and comprised the three instances of MZ discordance. Six of the 11 MZ twin-pairs and none of the 5 DZ twin-pairs had IAs in the ICA distribution (p = 0.03). Multiple IAs were observed in 11 of 22 MZ and 5 of 10 DZ twin-pairs. Thirteen (13) of the 32 subjects had an IA rupture, including 10 of 22 MZ twins. Conclusions: We found that arterial location concordance was greater in MZ than DZ twins, which suggests a genetic influence upon aneurysm location. The 16 twin-pairs in the present study are nearly the total of affected twin-pairs that have been reported in the literature to date. Further studies are needed to determine the impact of genetics in the formation and rupture of IAs.
Do Elderly Patients Call 911 When Presented with Clinical Scenarios Suggestive of Acute Stroke? A Cross-Sectional Study
Authors: Caruso Diego , Perez Akly Manuel , Costantini Pablo Daniel , Fridman Sebastian , Esnaola Maria Martha
Published: January 2015

Background and Purpose: Among patients with acute stroke symptoms, delay in hospital admission is the main obstacle for the use of thrombolytic therapy and other interventions associated with decreased mortality and disability. The primary aim of this study was to assess whether an elderly clinical population correctly endorsed the response to call for emergency services when presented with signs and symptoms of stroke using a standardized questionnaire. Methods: We performed a cross-sectional study among elderly out-patients (≥60 years) in Buenos Aires, Argentina randomly recruited from a government funded health clinic. The correct endorsement of intention to call 911 was assessed with the Stroke Action Test and the cut-off point was set at ≥75%. Knowledge of stroke and clinical and socio-demographic indicators were also collected and evaluated as predictors of correct endorsement using logistic regression. Results: Among 367 elderly adults, 14% correctly endorsed intention to call 911. Presented with the most typical signs and symptoms, only 65% reported that they would call an ambulance. Amaurosis Fugax was the symptom for which was called the least (15%). On average, the correct response was chosen only 37% of the time. Compared to lower levels of education, higher levels were associated to correctly endorsed intention to call 911 (secondary School adjusted OR 3.53, 95% CI 1.59-7.86 and Tertiary/University adjusted OR 3.04, 95% CI 1.12-8.21). Conclusions: These results suggest the need to provide interventions that are specifically designed to increase awareness of potential stroke signs and symptoms and appropriate subsequent clinical actions.
Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis
Authors: Marbury Thomas , Matsushima Nobuko , Chen Shuquan , Wickremasingha Prachi K. , He Ling , Dishy Victor , Brown Karen S. , Parasrampuria Dolly A.
Published: January 2015

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oraldose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng⋅h/ml) as compared with that observed in subjects off-dialysis (691.7 ng⋅h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.
Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab
Authors: Honickel Markus , Treutler Stefanie , Ryn Joanne van , Tillmann Sabine , Rossaint Rolf , Grottke Oliver
Published: January 2015

Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both threeand four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.

Note: This study was performed at the RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Screening for Rheumatic Heart Disease
Authors: Mirabel Mariana , Bacquelin Raoul , Tafflet Muriel , Robillard Corinne , Huon Bertrand , Corsenac Philippe , de Frémicourt Isabelle , Narayanan Kumar , Meunier Jean-Michel , Noël Baptiste , Hagège Albert Alain , Rouchon Bernard , Jouven Xavier , Marijon Eloi
Published: January 2015

Background—

Rheumatic heart disease (RHD) remains a major public health problem worldwide. Although early diagnosis by echocardiography may potentially play a key role in developing active surveillance, systematic evaluation of simple approaches in resource poor settings are needed.

Methods and Results—

We prospectively compared focused cardiac ultrasound (FCU) to a reference approach for RHD screening in a school children population. FCU included (1) the use of a pocket-sized echocardiography machine, (2) nonexpert staff (2 nurses with specific training), and (3) a simplified set of echocardiographic criteria. The reference approach used standardized echocardiographic examination, reviewed by an expert cardiologist, according to 2012 World Heart Federation criteria. Among the 6 different echocardiographic criteria, first tested in a preliminary phase, mitral regurgitation jet length ≥2 cm or any aortic regurgitation was considered best suited to be FCU criteria. Of the 1217 subjects enrolled (mean, 9.6±1 years; 49.6% male), 49 (4%) were diagnosed with RHD by the reference approach. The sensitivity of FCU for the detection of RHD was 83.7% (95% confidence interval, 73.3–94.0) for nurse A and 77.6% (95% confidence interval, 65.9–89.2) for nurse B. FCU yielded a specificity of 90.9% (95% confidence interval, 89.3–92.6) and 92.0% (95% confidence interval, 90.4–93.5) according to users. Percentage of agreement among nurses was 91.4%.

Conclusions—

FCU by nonexperts using pocket devices seems feasible and yields acceptable sensitivity and specificity for RHD detection when compared with the state-of-the-art approach, thereby opening new perspectives for mass screening for RHD in low-resource settings.