bluuebunny/crossref_metadata_2025 huggingface dataset:
The NH2 terminus regulates voltage-dependent gating of CALHM ion channels
Authors: Tanis Jessica E. , Ma Zhongming , Foskett J. Kevin
Published: May 2017

Calcium homeostasis modulator protein-1 (CALHM1) and its Caenorhabditis elegans (ce) homolog, CLHM-1, belong to a new family of physiologically important ion channels that are regulated by voltage and extracellular Ca2+ (Ca2+o) but lack a canonical voltage-sensing domain. Consequently, the intrinsic voltage-dependent gating mechanisms for CALHM channels are unknown. Here, we performed voltage-clamp experiments on ceCLHM-1 chimeric, deletion, insertion, and point mutants to assess the role of the NH2 terminus (NT) in CALHM channel gating. Analyses of chimeric channels in which the ceCLHM-1 and human (h)CALHM1 NH2 termini were interchanged showed that the hCALHM1 NT destabilized channel-closed states, whereas the ceCLHM-1 NT had a stabilizing effect. In the absence of Ca2+o, deletion of up to eight amino acids from the ceCLHM-1 NT caused a hyperpolarizing shift in the conductance-voltage relationship with little effect on voltage-dependent slope. However, deletion of nine or more amino acids decreased voltage dependence and induced a residual conductance at hyperpolarized voltages. Insertion of amino acids into the NH2-terminal helix also decreased voltage dependence but did not prevent channel closure. Mutation of ceCLHM-1 valine 9 and glutamine 13 altered half-maximal activation and voltage dependence, respectively, in 0 Ca2+. In 2 mM Ca2+o, ceCLHM-1 NH2-terminal deletion and point mutant channels closed completely at hyperpolarized voltages with apparent affinity for Ca2+o indistinguishable from wild-type ceCLHM-1, although the ceCLHM-1 valine 9 mutant exhibited an altered conductance-voltage relationship and kinetics. We conclude that the NT plays critical roles modulating voltage dependence and stabilizing the closed states of CALHM channels.
Pulmonary toxicity of e-cigarettes
Authors: Chun Lauren F. , Moazed Farzad , Calfee Carolyn S. , Matthay Michael A. , Gotts Jeffrey E.
Published: May 2017

Electronic cigarettes (e-cigarettes or e-cigs) are designed to heat and aerosolize mixtures of vegetable glycerin, propylene glycol, nicotine, and flavoring additives, thus delivering nicotine by inhalation in the absence of combustion. These devices were originally developed to facilitate smoking cessation and have been available in the United States for over a decade. Since 2010, e-cig use has expanded rapidly, especially among adolescents, despite a paucity of short- and long-term safety data. Patterns of use have shifted to include never smokers and many dual users of e-cigs and combustible tobacco products. Over the last several years, research into the potential toxicities of e-cig aerosols has grown exponentially. In the interim, regulatory policymakers across the world have struggled with how to regulate an increasingly diverse array of suppliers and products, against a backdrop of strong advocacy from users, manufacturers, and tobacco control experts. Herein we provide an updated review of the pulmonary toxicity profile of these devices, summarizing evidence from cell culture, animal models, and human subjects. We highlight the major gaps in our current understanding, emphasize the challenges confronting the scientific and regulatory communities, and identify areas that require more research in this important and rapidly evolving field.
Peroxisome proliferator-activated receptor-γ enhances human pulmonary artery smooth muscle cell apoptosis through microRNA-21 and programmed cell death 4
Authors: Green David E. , Murphy Tamara C. , Kang Bum-Yong , Bedi Brahmchetna , Yuan Zhihong , Sadikot Ruxana T. , Hart C. Michael
Published: May 2017

Pulmonary hypertension (PH) is a progressive disorder whose cellular pathogenesis involves enhanced smooth muscle cell (SMC) proliferation and resistance to apoptosis signals. Existing evidence demonstrates that the tumor suppressor programmed cell death 4 (PDCD4) affects patterns of cell growth and repair responses in the systemic vasculature following experimental injury. In the current study, the regulation PDCD4 and its functional effects on growth and apoptosis susceptibility in pulmonary artery smooth muscle cells were explored. We previously demonstrated that pharmacological activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) attenuated hypoxia-induced proliferation of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting the expression and mitogenic functions of microRNA-21 (miR-21). In the current study, we hypothesize that PPARγ stimulates PDCD4 expression and HPASMC apoptosis by inhibiting miR-21. Our findings demonstrate that PDCD4 is reduced in the mouse lung upon exposure to chronic hypoxia (10% O2 for 3 wk) and in hypoxia-exposed HPASMCs (1% O2). HPASMC apoptosis was reduced by hypoxia, by miR-21 overexpression, or by siRNA-mediated PPARγ and PDCD4 depletion. Activation of PPARγ inhibited miR-21 expression and resultant proliferation, while restoring PDCD4 levels and apoptosis to baseline. Additionally, pharmacological activation of PPARγ with rosiglitazone enhanced PDCD4 protein expression and apoptosis in a dose-dependent manner as demonstrated by increased annexin V detection by flow cytometry. Collectively, these findings demonstrate that PPARγ confers growth-inhibitory signals in hypoxia-exposed HPASMCs through suppression of miR-21 and the accompanying derepression of PDCD4 that augments HPASMC susceptibility to undergo apoptosis.
Role for reactive oxygen species in flow-stimulated inner medullary collecting duct endothelin-1 production
Authors: Wheatley Will , Kohan Donald E.
Published: May 2017

Inner medullary collecting duct (IMCD)-derived endothelin-1 (ET-1) is stimulated by volume expansion, in part through augmented luminal flow, whereupon it can elicit natriuresis and diuresis. Since flow can alter nitric oxide (NO) and reactive oxygen species (ROS), both of which can affect collecting duct salt transport, we asked whether NO and/or ROS mediate flow-stimulated IMCD ET-1. Mouse IMCD3 cells were exposed to flow, and ET-1/GAPDH mRNA was assessed. A shear stress of 10 dyn/cm2for 1 h increased ET-1 mRNA by fourfold compared with no flow (ET-1 flow response). Global NO synthase (NOS) inhibition [ NG-nitro-l-arginine methyl ester (l-NAME)] reduced the ET-1 flow response; however, pharmacological inhibition of NOS1 or NOS2, inhibition of NOS3 siRNA, inhibition of arginase inhibition, removal of media l-Arg, or inhibition of NO-dependent signaling pathways (PKG, guanylyl cyclase, or NF-κB) did not affect the ET-1 flow response. Tempol reduced the ET-1 flow response; no further inhibition occurred with l-NAME. Superoxide dismutase, but not catalase, reduced the ET-1 flow response. Inhibition of NAPDH oxidase (NOX) (apocynin), pharmacological inhibition of NOX1/4, or NOX4 siRNA reduced the ET-1 flow response. Finally, flow increased IMCD3 ROS production and this was inhibited by apocynin, NOX1/4 inhibition, and, to a small extent, by l-NAME. Taken together, these data suggest that NOX4-derived ROS in general, and possibly superoxide in particular, are involved in flow-stimulated IMCD ET-1 production. To our knowledge, this is the first report of flow-stimulated ROS production by the CD, as well as the first report of such flow-stimulated CD ROS exerting a biological effect.
Increased left ventricular extracellular volume and enhanced twist function in type 1 diabetic individuals
Authors: Vasanji Zainisha , Sigal Ronald J. , Eves Neil D. , Isaac Debra L. , Friedrich Matthias G. , Chow Kelvin , Thompson Richard B.
Published: May 2017

Individuals with type 1 diabetes (T1D) characteristically have high glycemic levels that over time can result in reactive fibrosis and abnormalities in myocardial function. T1 mapping with magnetic resonance imaging (MRI) can estimate the extent of reactive fibrosis by measurement of the extracellular volume fraction (ECV). The extent of alterations in the ECV and associated changes in left ventricular (LV) function and morphology in individuals with T1D is unknown. Fourteen individuals with long-term T1D and 14 sex-, age-, and body mass index-matched controls without diabetes underwent MRI measurement of myocardial T1 and ECV values as well as LV function and morphology. Ventricular mass, volumes, and global function (LVEF and circumferential/longitudinal/radial strain) were similar in those with T1D and controls. However, those with T1D had larger myocardial ECV (22.1 ± 1.8 vs. 20.1 ± 2.1, P = 0.008) and increased native (noncontrast) myocardial T1 values (1,211 ± 44 vs. 1,172 ± 43 ms, P < 0.001) as compared with controls. Both the ECV and native T1 values significantly correlated with several components of torsion and circumferential-longitudinal shear strain ( Ecl, the shear strain component associated with twist). Individuals with T1D had increased systolic torsion ( P = 0.035), systolic torsion rate ( P = 0.032), peak Ecl ( P = 0.001), and rates of change of systolic ( P = 0.007) and diastolic ( P = 0.007) Ecl. Individuals with T1D, with normal structure, LVEF, and strain, have increased extracellular volume and increased native T1 values with associated augmented torsion and Ecl. These measures may be useful in detecting the early stages of diabetic cardiomyopathy and warrant larger prospective studies.

NEW & NOTEWORTHY Individuals with type 1 diabetes, with normal left ventricular structure and function (ejection fraction and strain), have signs of interstitial fibrosis, measured with MRI as increased extracellular volume fraction and increased native myocardial T1, which significantly correlated with a number of measures of augmented left ventricular twist function. These measures may be useful in detecting the early stages of diabetic cardiomyopathy.
Obesity-induced discrepancy between contractile and metabolic phenotypes in slow- and fast-twitch skeletal muscles of female obese Zucker rats
Authors: Acevedo Luz M. , Raya Ana I. , Ríos Rafael , Aguilera-Tejero Escolástico , Rivero José-Luis L.
Published: May 2017

A clear picture of skeletal muscle adaptations to obesity and related comorbidities remains elusive. This study describes fiber-type characteristics (size, proportions, and oxidative enzyme activity) in two typical hindlimb muscles with opposite structure and function in an animal model of genetic obesity. Lesser fiber diameter, fiber-type composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of muscle fiber types were assessed in slow (soleus)- and fast (tibialis cranialis)-twitch muscles of obese Zucker rats and compared with age (16 wk)- and sex (females)-matched lean Zucker rats ( n = 16/group). Muscle mass and lesser fiber diameter were lower in both muscle types of obese compared with lean animals even though body weights were increased in the obese cohort. A faster fiber-type phenotype also occurred in slow- and fast-twitch muscles of obese rats compared with lean rats. These adaptations were accompanied by a significant increment in histochemical succinic dehydrogenase activity of slow-twitch fibers in the soleus muscle and fast-twitch fiber types in the tibialis cranialis muscle. Obesity significantly increased plasma levels of proinflammatory cytokines but did not significantly affect protein levels of peroxisome proliferator-activated receptors PPARγ or PGC1α in either muscle. These data demonstrate that, in female Zucker rats, obesity induces a reduction of muscle mass in which skeletal muscles show a diminished fiber size and a faster and more oxidative phenotype. It was noteworthy that this discrepancy in muscle's contractile and metabolic features was of comparable nature and extent in muscles with different fiber-type composition and antagonist functions.

NEW & NOTEWORTHY This study demonstrates a discrepancy between morphological (reduced muscle mass), contractile (shift toward a faster phenotype), and metabolic (increased mitochondrial oxidative enzyme activity) characteristics in skeletal muscles of female Zucker fatty rats. It is noteworthy that this inconsistency was comparable (in nature and extent) in muscles with different structure and function.
Individual hemoglobin mass response to normobaric and hypobaric “live high–train low”: A one-year crossover study
Authors: Hauser Anna , Troesch Severin , Saugy Jonas J. , Schmitt Laurent , Cejuela-Anta Roberto , Faiss Raphael , Steiner Thomas , Robinson Neil , Millet Grégoire P. , Wehrlin Jon P.
Published: May 2017

The purpose of this research was to compare individual hemoglobin mass (Hbmass) changes following a live high-train low (LHTL) altitude training camp under either normobaric hypoxia (NH) or hypobaric hypoxia (HH) conditions in endurance athletes. In a crossover design with a one-year washout, 15 male triathletes randomly performed two 18-day LHTL training camps in either HH or NH. All athletes slept at 2,250 meters and trained at altitudes <1,200 meters. Hbmass was measured in duplicate with the optimized carbon monoxide rebreathing method before (pre) and immediately after (post) each 18-day training camp. Hbmass increased similarly in HH (916–957 g, 4.5 ± 2.2%, P < 0.001) and in NH (918–953 g, 3.8 ± 2.6%, P < 0.001). Hbmass changes did not differ between HH and NH ( P = 0.42). There was substantial interindividual variability among subjects to both interventions (i.e., individual responsiveness or the individual variation in the response to an intervention free of technical noise): 0.9% in HH and 1.7% in NH. However, a correlation between intraindividual ΔHbmass changes (%) in HH and in NH ( r = 0.52, P = 0.048) was observed. HH and NH evoked similar mean Hbmass increases following LHTL. Among the mean Hbmass changes, there was a notable variation in individual Hbmass response that tended to be reproducible.

NEW & NOTEWORTHY This is the first study to compare individual hemoglobin mass (Hbmass) response to normobaric and hypobaric live high-train low using a same-subject crossover design. The main findings indicate that hypobaric and normobaric hypoxia evoked a similar mean increase in Hbmass following 18 days of live high-train low. Notable variability and reproducibility in individual Hbmass responses between athletes was observed, indicating the importance of evaluating individual Hbmass response to altitude training.
The Combination of the Tumor Markers Suggests the Histological Diagnosis of Lung Cancer
Authors: Liu Linjie , Teng Jinlong , Zhang Lijun , Cong Peishan , Yao Yuan , Sun Guirong , Liu Zhijun , Yu Teng , Liu Mingjun
Published: May 2017

Tumor markers are beneficial for the diagnosis and therapy monitoring of lung cancer. However, the value of tumor markers in lung cancer histological diagnosis is unknown. In this study, we analyzed the serum levels of six tumor markers (CEA, CYFRA21-1, SCC, NSE, ProGRP, and CA125) in 2097 suspected patients with lung cancer and determined whether the combination of the tumor markers was useful for histological diagnosis of lung cancer. We found that CYFRA21-1 was the most sensitive marker in NSCLC. ProGRP showed a better clinical performance than that of NSE in discriminating between SCLC and NSCLC. The serum level of CYFRA21-1 or SCC was significantly higher in squamous carcinoma (p<0.05), and the levels of ProGRP and NSE were significantly higher in SCLC (p<0.05). According to the criteria established, SCLC and NSCLC were discriminated with sensitivity of 87.12 and 62.63% and specificity of 64.61 and 99.5%, respectively. The sensitivity and specificity in the differentiation of adenocarcinoma and squamous carcinoma were 68.1 and 81.63% and 70.73 and 65.93%, with NPV of 46.03 and 68.97% and PPV of 85.82 and 79.47%, respectively. Our results suggested the combination of six tumor markers could discriminate the histological types of lung cancer.
The Electric Current Effect on Electrochemical Deconsolidation of Spherical Fuel Elements
Authors: Chen Xiaotong , Lu Zhenming , Zhao Hongsheng , Liu Bing , Zhu Junguo , Tang Chunhe
Published: May 2017

For High-Temperature Gas-Cooled Reactor in China, fuel particles are bonded into spherical fuel elements by a carbonaceous matrix. For the study of fuel failure mechanism from individual fuel particles, an electrochemical deconsolidation apparatus was developed in this study to separate the particles from the carbonaceous matrix by disintegrating the matrix into fine graphite powder. The deconsolidated graphite powder and free particles were characterized by elemental analysis, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), and ceramography. The results showed that the morphology, size distribution, and element content of deconsolidated graphite matrix and free particles were notably affected by electric current intensity. The electrochemical deconsolidation mechanism of spherical fuel element was also discussed.
Major Polymorphisms of Genes Involved in Homocysteine Metabolism in Malaria Patients in Ouagadougou, Burkina Faso
Authors: Yameogo Noé , Télesphore Bazie Bapio Valérie Elvira Jean , Ouattara Abdoul Karim , Yameogo Pouiré , Compaore Tegwinde Rebeca , Obiri-Yeboah Dorcas , Djigma Florencia Wenkuuni , Karou Simplice Damintoti , Simpore Jacques
Published: May 2017

This study analyzed the four main polymorphisms of the genes in homocysteine metabolism in malaria patients. Forty-two randomly selected subjects, diagnosed positive for Plasmodium falciparum, were included. The four genotypes were detected by real-time PCR using the MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, and MTRR 66A>G detection kit (Sacace Biotechnologies REF: T01002-96-S). The results revealed frequencies of 90% 677CC, 10% 677CT, and 00% 677TT for MTHFR C677T; 78.6% 1298AA, 19% 1298AC, and 2.4% 1298CC for MTHFR A1298C; 61.9% 2756AA, 33.3% 2756AG, and 4.8% 2756GG for MTR A2756G; and 50% of 66AA, 45% of 66AG, and 5% of 66GG for MTRR A66G. Correlations were found between A2756G MTR genotypes and parasitaemia (P=0.02), MTRR A66G and hemoglobin genotypes (P=0.009), and MTHFR A1298C and sex (P=0.01). This study demonstrated for the first time an association between the A2756G MTR alleles and Plasmodium falciparum malaria in Burkina Faso and gave an overview of the genotypic distribution of the major SNPs influencing the metabolism of homocysteine.
Surrogate Safety Analysis of Pedestrian-Vehicle Conflict at Intersections Using Unmanned Aerial Vehicle Videos
Authors: Chen Peng , Zeng Weiliang , Yu Guizhen , Wang Yunpeng
Published: May 2017

Conflict analysis using surrogate safety measures (SSMs) has become an efficient approach to investigate safety issues. The state-of-the-art studies largely resort to video images taken from high buildings. However, it suffers from heavy labor work, high cost of maintenance, and even security restrictions. Data collection and processing remains a common challenge to traffic conflict analysis. Unmanned Aerial Systems (UASs) or Unmanned Aerial Vehicles (UAVs), known for easy maneuvering, outstanding flexibility, and low costs, are considered to be a novel aerial sensor. By taking full advantage of the bird’s eye view offered by UAV, this study, as a pioneer work, applied UAV videos for surrogate safety analysis of pedestrian-vehicle conflicts at one urban intersection in Beijing, China. Aerial video sequences for a period of one hour were analyzed. The detection and tracking systems for vehicle and pedestrian trajectory data extraction were developed, respectively. Two SSMs, that is, Postencroachment Time (PET) and Relative Time to Collision (RTTC), were employed to represent how spatially and temporally close the pedestrian-vehicle conflict is to a collision. The results of analysis showed a high exposure of pedestrians to traffic conflict both inside and outside the crosswalk and relatively risking behavior of right-turn vehicles around the corner. The findings demonstrate that UAV can support intersection safety analysis in an accurate and cost-effective way.
The Patch-Levy-Based Bees Algorithm Applied to Dynamic Optimization Problems
Authors: Hussein Wasim A. , Abdullah Siti Norul Huda Sheikh , Sahran Shahnorbanun
Published: May 2017

Many real-world optimization problems are actually of dynamic nature. These problems change over time in terms of the objective function, decision variables, constraints, and so forth. Therefore, it is very important to study the performance of a metaheuristic algorithm in dynamic environments to assess the robustness of the algorithm to deal with real-word problems. In addition, it is important to adapt the existing metaheuristic algorithms to perform well in dynamic environments. This paper investigates a recently proposed version of Bees Algorithm, which is called Patch-Levy-based Bees Algorithm (PLBA), on solving dynamic problems, and adapts it to deal with such problems. The performance of the PLBA is compared with other BA versions and other state-of-the-art algorithms on a set of dynamic multimodal benchmark problems of different degrees of difficulties. The results of the experiments show that PLBA achieves better results than the other BA variants. The obtained results also indicate that PLBA significantly outperforms some of the other state-of-the-art algorithms and is competitive with others.
The CFS-PML for 2D Auxiliary Differential Equation FDTD Method Using Associated Hermite Orthogonal Functions
Authors: Jiang Feng , Miao Xiao-Ping , Lu Feng , Su Li-Yuan , Ma Yao
Published: May 2017

The complex frequency shifted (CFS) perfectly matched layer (PML) is proposed for the two-dimensional auxiliary differential equation (ADE) finite-difference time-domain (FDTD) method combined with Associated Hermite (AH) orthogonal functions. According to the property of constitutive parameters of CFS-PML (CPML) absorbing boundary conditions (ABCs), the auxiliary differential variables are introduced. And one relationship between field components and auxiliary differential variables is derived. Substituting auxiliary differential variables into CPML ABCs, the other relationship between field components and auxiliary differential variables is derived. Then the matrix equations are obtained, which can be unified with Berenger’s PML (BPML) and free space. The electric field expansion coefficients can thus be obtained, respectively. In order to validate the efficiency of the proposed method, one example of wave propagation in two-dimensional free space is calculated using BPML, UPML, and CPML. Moreover, the absorbing effectiveness of the BPML, UPML, and CPML is discussed in a two-dimensional (2D) case, and the numerical simulations verify the accuracy and efficiency of the proposed method.
Spatholobus suberectus Exhibits Antidiabetic Activity In Vitro and In Vivo through Activation of AKT‐AMPK Pathway
Authors: Zhao Peijun , Alam Md Badrul , Lee Seok-hyun , Kim Young-Jun , Lee Seul , An Hongyan , Choi Hee-Jeong , Son Hyeong-U , Park Chul-Hong , Kim Hyo-Hyun , Lee Sang-Han
Published: May 2017

Glucose deposition in peripheral tissue is an important parameter for the treatment of type 2 diabetes mellitus. The aim of this study was to investigate the effects of Spatholobus suberectus (Ss) on glucose disposal in skeletal muscle cells and additionally explore its in vivo antidiabetic potential. Treatment of ethanolic extract of S. suberectus (EeSs) significantly enhanced the glucose uptake, mediated through the enhanced expression of GLUT4 in skeletal muscle via the stimulation of AKT and AMPK pathways in C2C12 cells. Moreover, EeSs have potential inhibitory action on α‐glucosidase activity and significantly lowered the postprandial blood glucose levels in STZ‐induced diabetic mice, associated with increased expression of GLUT4 and AKT and/or AMPK‐mediated signaling cascade in skeletal muscle. Furthermore, administration of EeSs significantly boosted up the antioxidant enzyme expression and also mitigated the gluconeogenesis enzyme such as PEPCK and G‐6‐Pase enzyme expression in liver tissue of STZ‐induced diabetic mice model. Collectively, these findings suggest that EeSs have a high potentiality to mitigate diabetic symptoms through stimulating glucose uptake in peripheral tissue via the activation of AKT and AMPK signaling cascade and augmenting antioxidant potentiality as well as blocking the gluconeogenesis process in diabetic mice.
Hyper IgE Syndrome and Renal Cell Carcinoma
Authors: Patel Neel H. , Ferretti Mark , Phillips John L.
Published: May 2017

Hyper IgE Syndrome (HIES) is an immunodeficiency disorder characterized by increased serum levels of IgE, eczema, and recurrent cutaneous and pulmonary infections. In this report, we present, to our knowledge, the first documented case of renal cell carcinoma (RCC) found in a patient with HIES. The patient received infectious disease clearance prior to obtaining a partial nephrectomy which revealed clear cell histology. Both HIES and RCC have an immunological basis for their pathophysiology and may involve common pathways. Further studies may provide insight into any possible link and clinicians should be mindful of immunocompromised patients who present with risk factors for genitourinary malignancy.
Automatic Image Annotation Based on Particle Swarm Optimization and Support Vector Clustering
Authors: Hao Zhangang , Ge Hongwei , Gu Tianpeng
Published: May 2017

With the progress of network technology, there are more and more digital images of the internet. But most images are not semantically marked, which makes it difficult to retrieve and use. In this paper, a new algorithm is proposed to automatically annotate images based on particle swarm optimization (PSO) and support vector clustering (SVC). The algorithm includes two stages: firstly, PSO algorithm is used to optimize SVC; secondly, the trained SVC algorithm is used to annotate the image automatically. In the experiment, three datasets are used to evaluate the algorithm, and the results show the effectiveness of the algorithm.
Obesity and Prognostic Variables in Colombian Breast Cancer Patients: A Cross-Sectional Study
Authors: Cuello-López Javier , Fidalgo-Zapata Ana , Vásquez-Trespalacios Elsa
Published: May 2017

Introduction. Obesity is an established risk factor for cancer and cancer-related deaths, including that of the breast. While the prevalence of female obesity has accelerated over the past decade in many developing countries, such as Colombia, the prevalence of overweight and obesity specifically in breast cancer populations has not been fully described. Methods. A cross-sectional study including 849 women diagnosed with breast cancer between 2009 and 2014. Based on body mass index, prevalence of overweight (BMI ≥ 25 < 30) and obesity (BMI ≥ 30) and associations of BMI with clinical and tumor histopathological features were analyzed. Results. Colombian breast cancer patients had a prevalence of overweight of 34.28% and obesity of 28.15%. Mean BMI was comparable between premenopausal and postmenopausal women (27.2 versus 27.7, resp.). Among premenopausal women, higher BMI was significantly positively associated with hormone receptor negative tumors, as well as with greater lymphovascular invasion. Conclusions. Colombian breast cancer patients exhibit a significant prevalence of overweight and obesity. Associations of high BMI and poor prognosis variables in the premenopausal population suggest risk of aggressive disease in this population. Future studies to further validate our observations are warranted in order to implement multidisciplinary clinical guidelines.
Myopic versus Far-Sighted Behaviors in Dynamic Supply Chain Coordination through Advertising with Reference Price Effect
Authors: Zu Yafei , Chen Lianghua
Published: May 2017

To better understand the different effects of the myopic and far-sighted behaviors on the advertising coordination in dynamic supply chain, this paper takes the reference price effect into consideration and formulates four differential game models for the two-level supply chain composed of a manufacturer and a retailer in the situation of Stackelberg game. In our models, the market demand is assumed to be affected by the goodwill, reference price, and the advertising investment, in which the advertising investment can promote the construction of goodwill and such goodwill can further enhance the reference price. The results show that the participating members in the supply chain should invest more in advertisement to improve the goodwill and the relative reference price reflected in the minds of consumers. A far-sighted manufacturer will invest more in the advertisement and charge a higher wholesale price regardless of the behavior choice of the retailer. However, such kind of ignorance leads to different results on the retail pricing strategies of the retailer. The numerical analyses are given in the end to verify the effectiveness of the conclusions which provide the theoretical support to the dynamic supply chain coordination in practice.
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
Authors: Tech Katherine , Tikunov Andrey P. , Farooq Hamza , Morrissy A. Sorana , Meidinger Jessica , Fish Taylor , Green Sarah C. , Liu Hedi , Li Yisu , Mungall Andrew J. , Moore Richard A. , Ma Yussanne , Jones Steven J.M. , Marra Marco A. , Vander Heiden Matthew G. , Taylor Michael D. , Macdonald Jeffrey M. , Gershon Timothy R.
Published: May 2017

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.
A Comparison of the Natural History of HPV Infection and Cervical Abnormalities among HIV-Positive and HIV-Negative Women in Senegal, Africa
Authors: Whitham Hilary K. , Hawes Stephen E. , Chu Haitao , Oakes J. Michael , Lifson Alan R. , Kiviat Nancy B. , Sow Papa Salif , Gottlieb Geoffrey S. , Ba Selly , Sy Marie P. , Kulasingam Shalini L.
Published: May 2017

Background: There is evidence of an interaction between HIV and human papillomavirus (HPV) resulting in increased HPV-associated morbidity and cancer mortality among HIV-positive women. This study aims to determine how the natural history of cervical HPV infection differs by HIV status.

Methods: A total of 1,320 women (47% were positive for HIV-1 and/or HIV-2) were followed for an average of two years in Senegal, West Africa between 1994 and 2010. Cytology (with a sub-sample of histology) and HPV DNA testing were performed at approximately 4-month intervals yielding data from over 7,900 clinic visits. Competing risk modeling was used to estimate rates for transitioning between three clinically relevant natural history stages: Normal, HPV, and HSIL (high-grade squamous intraepithelial lesions). Among HIV-positive women, exploratory univariate analyses were conducted examining the impact of HPV type, infection with multiple HPV types, HIV type, CD4+ count, and age.

Results: HIV-positive women had higher rates of progression and lower rates of regression compared with HIV-negative women (i.e., adverse transitions). HIV-positive women had a 2.55 [95% confidence interval (CI), 1.69–3.86; P < 0.0001] times higher rate of progression from HPV to HSIL than HIV-negative women (with 24-month absolute risks of 0.18 and 0.07, respectively). Among HIV-positive women, HPV-16/18 infection and CD4+ count <200/mm3 were associated with adverse transitions.

Conclusions: Adverse HIV effects persist throughout HPV natural history stages.

Impact: In the limited-resource setting of sub-Saharan Africa where cervical cancer screening is not widely available, the high-risk population of HIV-positive women may be ideal for targeted screening. Cancer Epidemiol Biomarkers Prev; 26(6); 886–94. ©2017 AACR.
Do Men and Women Need to Be Screened Differently with Fecal Immunochemical Testing? A Cost-Effectiveness Analysis
Authors: Meulen Miriam P. van der , Kapidzic Atija , Leerdam Monique E. van , van der Steen Alex , Kuipers Ernst J. , Spaander Manon C.W. , de Koning Harry J. , Hol Lieke , Lansdorp-Vogelaar Iris
Published: May 2017

Background: Several studies suggest that test characteristics for the fecal immunochemical test (FIT) differ by gender, triggering a debate on whether men and women should be screened differently. We used the microsimulation model MISCAN-Colon to evaluate whether screening stratified by gender is cost-effective.

Methods: We estimated gender-specific FIT characteristics based on first-round positivity and detection rates observed in a FIT screening pilot (CORERO-1). Subsequently, we used the model to estimate harms, benefits, and costs of 480 gender-specific FIT screening strategies and compared them with uniform screening.

Results: Biennial FIT screening from ages 50 to 75 was less effective in women than men [35.7 vs. 49.0 quality-adjusted life years (QALY) gained, respectively] at higher costs (€42,161 vs. −€5,471, respectively). However, the incremental QALYs gained and costs of annual screening compared with biennial screening were more similar for both genders (8.7 QALYs gained and €26,394 for women vs. 6.7 QALYs gained and €20,863 for men). Considering all evaluated screening strategies, optimal gender-based screening yielded at most 7% more QALYs gained than optimal uniform screening and even resulted in equal costs and QALYs gained from a willingness-to-pay threshold of €1,300.

Conclusions: FIT screening is less effective in women, but the incremental cost-effectiveness is similar in men and women. Consequently, screening stratified by gender is not more cost-effective than uniform FIT screening.

Impact: Our conclusions support the current policy of uniform FIT screening. Cancer Epidemiol Biomarkers Prev; 26(8); 1328–36. ©2017 AACR.
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations
Authors: Huang Franklin W. , Mosquera Juan Miguel , Garofalo Andrea , Oh Coyin , Baco Maria , Amin-Mansour Ali , Rabasha Bokang , Bahl Samira , Mullane Stephanie A. , Robinson Brian D. , Aldubayan Saud , Khani Francesca , Karir Beerinder , Kim Eejung , Chimene-Weiss Jeremy , Hofree Matan , Romanel Alessandro , Osborne Joseph R. , Kim Jong Wook , Azabdaftari Gissou , Woloszynska-Read Anna , Sfanos Karen , De Marzo Angelo M. , Demichelis Francesca , Gabriel Stacey , Van Allen Eliezer M. , Mesirov Jill , Tamayo Pablo , Rubin Mark A. , Powell Isaac J. , Garraway Levi A.
Published: May 2017

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n = 102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.

Significance: Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. Cancer Discov; 7(9); 973–83. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 920
The Influence of the Manner of Performing the Thyroid Ultrasound Examination on the Reliability of the Assessment of the Thyroid Size in School-Aged Children
Authors: Zygmunt Arkadiusz , Adamczewski Zbigniew , Zygmunt Agnieszka , Karbownik-Lewinska Malgorzata , Lewinski Andrzej
Published: May 2017

Background/Aims: Goitre incidence in school-aged children evaluated using ultrasonography is one of the essential indicators of iodine intake in a given area. The aim of the study was to examine what the difference is between the volume of the thyroid gland measured in the supine and sitting position and to determine the intra-observer, inter-observer, and inter-position variations. Methods: The survey was conducted among 87 children (56 girls and 31 boys aged 7–13 years, mean age 10.44 ± 1.72 years). Results: The thyroid volume measured in a sitting position was significantly lower than that measured in the supine position. The intra-observer variations for the total thyroid volume equalled 9.56–9.65%. The inter-observer variations were significantly higher and amounted to 34.5–35.7%. Conclusions: The way in which ultrasound evaluation is performed is important for the analysis of the results. It is crucial to aim for the smallest inter-observer variation, which can be achieved by strictly defining the methods of the thyroid measurement and comparing one’s measuring techniques with the reference method. The use of standards in ultrasound evaluation performed in the supine position, as well as the use of standards without a strict determination of the study method, can lead to erro­neous conclusions.
Amrubicin Monotherapy for Patients with Platinum-Pretreated Non-Gastrointestinal Non-Pancreatic Extrapulmonary Neuroendocrine Carcinoma
Authors: Ebata Takahiro , Shimoi Tatsunori , Ishiwata Tsukasa , Iwasawa Shunichiro , Bun Seiko , Yunokawa Mayu , Yonemori Kan , Takiguchi Yuichi , Tamura Kenji
Published: May 2017

Objective: The aim of this study was to investigate the clinical usefulness of amrubicin therapy for patients with non-gastrointestinal (GI) non-pancreatic extrapulmonary neuroendocrine carcinoma (EP-NEC). Methods: The medical records of patients from the 2 participating institutions were retrospectively reviewed. The eligibility criteria were: patients with non-GI non-pancreatic EP-NEC who received amrubicin monotherapy after platinum-based chemotherapy. Patients in whom the platinum-free interval (interval between the last day of platinum administration and the first subsequent documentation of disease progression) was 90 days or longer were classified into the platinum-sensitive group. Results: The study was conducted in a total of 13 patients identified as eligible. The response rate was 45.4% (5/11). The median progression-free survival and overall survival were 6.0 and 10.6 months, respectively. A platinum-free interval of ≥90 days was identified as a significant predictor of a longer progression-free survival time. Grade 3 or 4 neutropenia was observed in 61.5% (8/13) of the patients. One patient died of treatment-related febrile neutropenia. Conclusions: Amrubicin monotherapy as second-line chemotherapy after failure of first-line platinum-based chemotherapy showed good efficacy in patients with non-GI non-pancreatic EP-NEC. Neutropenia was encountered as the most serious adverse event.
The Role of Radiotherapy in the Definitive and Postoperative Treatment of Advanced Head and Neck Cancer
Authors: Semrau Robert
Published: May 2017

Radiotherapy plays an important role in the treatment of head and neck cancer. It represents the main curative option in advanced tumors. Due to technical progress of treatment appliances, the translation of radiobiological research into clinical praxis (altered fractionation), and the concurrent application of chemotherapy (radiochemotherapy), the efficacy of radiotherapy has markedly improved. Current developments focus on the integration of functional imaging into the treatment planning process to allow individualized dose prescription. Different systemic agents have shown to improve prognosis when applied concurrently with radiotherapy, whereas induction chemotherapy has not proven to be of further benefit. Treatment of human papillomavirus-related oropharyngeal carcinomas is challenging. Reduced treatment intensity for this entity is being investigated but cannot be recommended for clinical routine at this point. Adjuvant radiotherapy and radiochemotherapy improve the prognosis in high-risk head and neck cancer after surgical treatment. Further reductions in the treated neck volume in adjuvant radiotherapy need clinical investigation.
Effect of Digoxin Use Among Medicaid Enrollees With Atrial Fibrillation
Authors: Adedinsewo Demilade , Xu Junjun , Agasthi Pradyumna , Oderinde Adesoji , Adekeye Oluwatoyosi , Sachdeva Rajesh , Rust George , Onwuanyi Anekwe
Published: May 2017

Background—

Recently published analysis of contemporary atrial fibrillation (AF) cohorts showed an association between digoxin and increased mortality and hospitalizations; however, other studies have demonstrated conflicting results. Many AF cohort studies did not or were unable to examine racial differences. Our goal was to examine risk factors for hospitalizations and mortality with digoxin use in a diverse real-world AF patient population and evaluate racial differences.

Methods and Results—

We performed a retrospective cohort analysis of claims data for Medicaid beneficiaries, aged 18 to 64 years, with incident diagnosis of AF in 2008 with follow-up until December 31, 2009. We created Kaplan–Meier curves and constructed multivariable Cox proportional hazard models for mortality and hospitalization. We identified 11 297 patients with an incident diagnosis of AF in 2008, of those, 1401 (12.4%) were on digoxin. Kaplan–Meier analysis demonstrated an increased risk of hospitalization with digoxin use overall and within race and heart failure groups. In adjusted models, digoxin was associated with an increased risk of hospitalization (adjusted hazard ratio, 1.54; 95% confidence interval, 1.39–1.70) and mortality (adjusted hazard ratio, 1.50; 95% confidence interval, 1.05–2.13). Overall, blacks had a higher risk of hospitalization but similar mortality when compared with whites regardless of digoxin use. We found no significant interaction between race and digoxin use for mortality (
P
=0.4437) and hospitalization (
P
=0.7122).

Conclusions—

Our study demonstrates an overall increased risk of hospitalizations and mortality with digoxin use but no racial/ethnic differences in outcomes were observed. Further studies including minority populations are needed to critically evaluate these associations.
Acute and Long-Term Effects of Full-Power Electroporation Ablation Directly on the Porcine Esophagus
Authors: Neven Kars , van Es René , van Driel Vincent , van Wessel Harry , Fidder Herma , Vink Aryan , Doevendans Pieter , Wittkampf Fred
Published: May 2017

Background—

Esophageal ulceration and fistula are complications of pulmonary vein isolation using thermal energy sources. Irreversible electroporation is a novel, nonthermal ablation modality for pulmonary vein isolation. A single 200 J application can create deep myocardial lesions. Acute and chronic effects of this new energy source on the esophagus are unknown.

Methods and Results—

In 8 pigs (±70 kg), the suprasternal esophagus was surgically exposed. A linear suction device with a single 35-mm long and 6-mm wide protruding linear electrode inside a plastic suction cup was used for ablation. Single, nonarcing, nonbarotraumatic, cathodal 100 and 200 J applications were delivered at 2 different sites on the anterior esophageal adventitia. No proton-pump inhibitors were administered during follow-up. Esophagoscopy was performed at days 2 and 7. After euthanasia at day 60, the esophagus was evaluated visually and histologically. All ablations were uneventful. Esophagoscopy at day 2 showed small white densities in the ablated areas, which appeared to be small intraepithelial vesicles. No epithelial erythema, erosions, or ulcerations were seen. At day 7, all densities had disappeared, and all esophaguses appeared completely normalized. After euthanasia, there were no macroscopically visible lesions on the adventitia or epithelium. Histologically, a small scar was observed at the outer part of the muscular layer, whereas the mucosa and submucosa were normal.

Conclusions—

Esophageal architecture remains unaffected 2 months after irreversible electroporation, purposely targeting the adventitia. Irreversible electroporation seems to be a safe modality for catheter ablation near the esophagus.
Spatial Resolution Requirements for Accurate Identification of Drivers of Atrial Fibrillation
Authors: Roney Caroline H. , Cantwell Chris D. , Bayer Jason D. , Qureshi Norman A. , Lim Phang Boon , Tweedy Jennifer H. , Kanagaratnam Prapa , Peters Nicholas S. , Vigmond Edward J. , Ng Fu Siong
Published: May 2017

Background—

Recent studies have demonstrated conflicting mechanisms underlying atrial fibrillation (AF), with the spatial resolution of data often cited as a potential reason for the disagreement. The purpose of this study was to investigate whether the variation in spatial resolution of mapping may lead to misinterpretation of the underlying mechanism in persistent AF.

Methods and Results—

Simulations of rotors and focal sources were performed to estimate the minimum number of recording points required to correctly identify the underlying AF mechanism. The effects of different data types (action potentials and unipolar or bipolar electrograms) and rotor stability on resolution requirements were investigated. We also determined the ability of clinically used endocardial catheters to identify AF mechanisms using clinically recorded and simulated data. The spatial resolution required for correct identification of rotors and focal sources is a linear function of spatial wavelength (the distance between wavefronts) of the arrhythmia. Rotor localization errors are larger for electrogram data than for action potential data. Stationary rotors are more reliably identified compared with meandering trajectories, for any given spatial resolution. All clinical high-resolution multipolar catheters are of sufficient resolution to accurately detect and track rotors when placed over the rotor core although the low-resolution basket catheter is prone to false detections and may incorrectly identify rotors that are not present.

Conclusions—

The spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism. Therefore, the interpretation of human AF data must be taken in the context of the spatial resolution of the recordings.