bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal Strategies for Manufacturers with the Reference Effect under Carbon Emissions-Sensitive Random Demand
Authors: Zhang Baojun , Qu Shaojian , Li Panpan , Huang Ripeng
Published: October 2018

In this paper, we study the optimal strategies for a newsvendor system with joint reference effect, carbon emissions-sensitive random demand, and strategic customers’ behavior. The newsvendor’s decisions are to determine the selling price, production quantity, and carbon emissions under exogenous and endogenous price cases, respectively. We also explore how the loss aversions affect the newsvendor’s decisions. It is shown that the newsvendor has a uniquely optimal policy. The influence of the reference effect makes the final decisions deviate from the optimal solutions of the classical model. Furthermore, the sensitivity analysis indicates that the loss aversions have a great impact on the newsvendor’s decisions. Finally, more managerial implications are derived by numerical simulations.
Carbon Dioxide Absorption Modeling for Off-Gas Treatment in the Nuclear Fuel Cycle
Authors: Gabitto Jorge , Tsouris Costas
Published: October 2018

The absorption of carbon dioxide is an important process in many practical applications such as reduction of greenhouse gases, separation and purification processes in the chemical and petroleum industries, and capture of radioactive isotopes in the nuclear fuel cycle The goal of this research is to develop a dynamic model to simulate CO2 absorption by using different alkanolamines as absorption solvents. The model is based upon transient mass and energy balances for the chemical species commonly present in CO2 gas-liquid absorption. A computer code has been written to implement the proposed model. Simulation results are discussed. The reported model simulates well the response to dynamic changes in input conditions. The proposed model can be used to optimize and control the separation of carbon-14 in the form of CO2 in the nuclear industry.
Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis
Authors: Geng Rong-Xin , Li Ning , Xu Yang , Liu Jun-hui , Yuan Fan-en , Sun Qian , Liu Bao-Hui , Chen Qian-Xue
Published: October 2018

Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.
Targeted Molecular Magnetic Resonance Imaging Detects Brown Adipose Tissue with Ultrasmall Superparamagnetic Iron Oxide
Authors: Hu Qingqiao , Chen Xiangxun , Liu Juan , Di Wenjuan , Lv Shan , Tang Lijun , Ding Guoxian
Published: October 2018

The peptide (CKGGRAKDC-NH2) specifically targets the brown adipose tissue (BAT). Here we applied this peptide coupled with polyethylene glycol (PEG)-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to detect BAT in vivo by magnetic resonance imaging (MRI). The peptide was conjugated with PEG-coated USPIO nanoparticles to obtain targeted USPIO nanoprobes. Then the nanoprobes for BAT were evaluated in mice. T2⁎-weighted images were performed, precontrast and postcontrast USPIO nanoparticles. Finally, histological analyses proved the specific targeting. The specificity of targeted USPIO nanoprobes was observed in mice. The T2⁎ relaxation time of BAT in the targeted group decreased obviously compared to the controls (P<0.001). Prussian blue staining and transmission electron microscope confirmed the specific presence of iron oxide. This study demonstrated that peptide (CKGGRAKDC-NH2) coupled with PEG-coated USPIO nanoparticles could identify BAT noninvasively in vivo with MRI.
Annual Variation in Soil Enzyme Activity in a Paddy Field: Soil Temperature and Nutrient Availability Are Important for Controlling Enzyme Activities
Authors: Kunito Takashi , Shiroma Takashi , Moro Hitoshi , Sumi Hirotaka
Published: October 2018

Annual variations in enzyme activities involved in carbon (C), nitrogen (N), phosphorus (P), and sulfur (S) cycling and soil physicochemical properties were examined in a Japanese paddy field. All the enzyme activities determined at the field soil temperature (range, 2.2°C–28.3°C) increased exponentially with soil temperature (p<0.001). Significant negative correlations were found between Bray-2P concentration and the ratio of acid phosphatase to β-D-glucosidase activity (Spearman r = −0.631, p = 0.005) and between total N and the ratio of L-asparaginase to β-D-glucosidase activity (r = −0.612, p=0.007), suggesting that in accordance with the resource allocation model, acid phosphatase and L-asparaginase were synthesized by microorganisms depending on the temporal changes in soil P and N availability. These results suggest the significance of soil temperature in controlling in situ enzyme activities in paddy soil and also that the stoichiometry of enzyme activities associated with C, N, and P acquisition reflects the soil nutrient availability.
Necrotizing Enterocolitis in Moderate Preterm Infants
Authors: Nair Jayasree , Longendyke Rachel , Lakshminrusimha Satyan
Published: October 2018

Necrotizing enterocolitis (NEC) is a devastating morbidity usually seen in preterm infants, with extremely preterm neonates (EPT ≤28 weeks) considered at highest risk. Moderately preterm infants (MPT 28–34 weeks) constitute a large percentage of NICU admissions. In our retrospective data analysis of NEC in a single regional perinatal center, NEC was observed in 10% of extremely EPT and 7% of MPT, but only 0.7% of late-preterm/term admissions. There was an inverse relationship between postnatal age at onset of NEC and gestational age at birth. Among MPT infants with NEC, maternal hypertensive disorders (29%) and small for gestational age (SGA-15%) were more common than in EPT infants (11.6 and 4.6%, resp.). Congenital gastrointestinal anomalies were common among late preterm/term infants with NEC. SGA MPT infants born to mothers with hypertensive disorders are particularly at risk and should be closely monitored for signs of NEC. Identifying risk factors specific to each gestational age may help clinicians to tailor interventions to prevent NEC.
Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells
Authors: Gener Petra , Seras-Franzoso Joaquin , Callejo Patricia González , Andrade Fernanda , Rafael Diana , Martínez Francesc , Montero Sara , Arango Diego , Sayós Joan , Abasolo Ibane , Schwartz Simó
Published: October 2018

There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non-CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT.
Utilization of Electroplating Sludge as Subgrade Backfill Materials: Mechanical and Environmental Risk Evaluation
Authors: Zhang Yu , Shi Peixin , Chen Lijuan , Tang Qiang
Published: October 2018

The electroplating sludge may pose serious threat to human health and surrounding environment without safe treatment. This paper investigated the feasibility of using electroplating sludge as subgrade backfill materials, by evaluating the mechanical properties and environmental risk of the cement‐coal fly ash solidified sludge. In this study, Portland cement and coal fly ash are used to solidify/stabilize the sludge. After curing for 7, 14, and 28 days, the stabilization/solidification sludge specimens were subject to a series of mechanical, leaching, and microcosmic tests. It was found that the compressive strength increased with the increase of cement content, curing time, and the cement replacement by coal fly ash besides water content. Among these factors, the impact of water content on the compressive strength is most noticeable. It was observed that the compressive strength declined by 87.1% when the water content increased from 0% to 10%. Besides, leaching tests showed that the amount of leaching heavy metals were under the standard limit. These results demonstrated utilization of electroplating sludge in subgrade backfill material may provide an alternative for the treatment of electroplating sludge.
A Hiccup in Hiccup Management: Cardiac Arrest from Previously Undiagnosed Congenital Long QT Syndrome
Authors: Hughes Robert , Sheele Johnathan M.
Published: October 2018

We report the case of a person who went into cardiac arrest after being given chlorpromazine for hiccups and was subsequently diagnosed with congenital Long QT Syndrome. Long QT Syndrome is an uncommon, congenital condition that carries a high risk of sudden cardiac death. Clinicians need to recognize the risk that chlorpromazine may prolong the QTc and prepare to manage potential complications.
α‐Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions
Authors: Tao Mengqing , Jiang Jia , Wang Lin , Li Yan , Mao Qingcheng , Dong Jiyang , Zuo Jian
Published: October 2018

α‐Mangostin (MAN) is a bioactive xanthone isolated from mangosteen. This study was designed to investigate its therapeutic effects on acute lung injury (ALI) and explore the underlying mechanisms of action. Rats from treatment groups were subject to oral administration of MAN for 3 consecutive days beforehand, and then ALI was induced in all the rats except for normal controls via an intraperitoneal injection with lipopolysaccharide. The severity of disease was evaluated by histological examination and hematological analysis. Protein expressions in tissues and cells were examined with immunohistochemical and immunoblotting methods, respectively. The levels of cytokines and nicotinamide adenine dinucleotide (NAD) were determined using ELISA and colorimetric kits, respectively. It was found that MAN treatment significantly improved histological conditions, reduced leucocytes counts, relieved oxidative stress, and declined TNF‐α levels in ALI rats. Meanwhile, MAN treatment decreased expressions of nicotinamide phosphoribosyltransferase (NAMPT) and Sirt1 both in vivo and in vitro, which was accompanied with a synchronized decline of NAD and TNF‐α. Immunoblotting assay further showed that MAN downregulated HMGB1, TLR4, and p‐p65 in RAW 264.7 cells. MAN induced declines of both HMGB1/TLR4/p‐p65 and TNF‐α were substantially reversed by cotreatment with nicotinamide mononucleotide or NAD. These results suggest that downregulation of NAMPT/NAD by MAN treatments contributes to the alleviation of TLR4/NF‐κB‐mediated inflammations in macrophage, which is essential for amelioration of ALI in rats.
Isolation and Characterization of Pectic Polysaccharide Fraction fromIn VitroSuspension Culture ofFumaria officinalisL.
Authors: Ognyanov Manol , Georgiev Yordan , Petkova Nadezhda , Ivanov Ivan , Vasileva Ivelina , Kratchanova Maria
Published: October 2018

In the current study, an acidic polysaccharide from thein vitrosuspension culture ofFumaria officinalisL. was obtained by extraction with 0.8% (w/v) aqueous ammonium oxalate. The polysaccharide fraction mainly consisted of galacturonic acid (41.0%), followed by galactose (7.3%) and arabinose (5.6%). This suggests the presence of arabinogalactan side chains in the rhamnogalacturonan-I segment of the studied pectin, which was mainly built up by homogalacturonan segments. The pectin was evaluated as low-methyl-esterified (45.0%) with degree of acetylation 3.4%. The polymer fraction was consisted of different molecular weight populations in the range of 6–600 kDa. The high amount of 4-L-hydroxyproline (11.7% of total protein) and the specific positive reaction to Yariv’s phenylglycoside reagent indicated the presence of an arabinogalactan protein in the cell walls. The functional properties of the polysaccharide fraction were evaluated, as it possessed better water-holding capacity than oil-holding capacity. The studied pectin demonstrated significant foaming ability and promising emulsifying properties in a concentration 1%. Therefore, the isolated polysaccharide fraction could be successfully used as emulsifier and foaming agent in food products and pharmaceutical supplements.
Study on the Characteristics of Safety Distribution Changing with Buried Depth for Metro Station in Upper‐Soft and Lower‐Hard Stratum
Authors: Sun Keguo , Xu Weiping , Qiu Wenge , Li Haobo , Xian Qingyu , Li Tao
Published: October 2018

The reasonable buried depth of metro station should be investigated for Qingdao with the upper‐soft and lower‐hard stratum. Strength reduction method has been utilized to study FOS of metro station under different buried depths. As the buried depth increases, the curve of FOS can be divided into three parts as the slowly changed part, the rapidly‐increased part, and the gradually‐decreased part. Taking FOS = 1 as limitation, the formula of least rock cover thickness has been derived. Based upon the formula, the characteristics of safety distribution changing with buried depth for metro station which behaves as three zones (DI, E, DII) have been discovered. Two typical metro stations have been used to verify the research results.
Influence of Carbon Addition to Fe‐Mn‐Si Type Alloy on the Structure and Shape Memory Effect
Authors: Prendota Witold , Goc Kamil , Miyazawa Shunsuke , Takasaki Akito , Rybicki Damian , Kapusta Czeslaw
Published: October 2018

The study presented is focused on the influence of carbon addition on properties of the Fe‐Mn‐Si type intelligent materials with basic composition of Fe64Mn30Si6 (wt. %). Three alloys were prepared, starting from elemental powders, with 0, 0.1, and 0.3 wt. % of carbon, at corresponding silicon content reduction. For the synthesis, the mechanical alloying, sintering, and annealing were applied. Further process involved deformation and subsequent heating in a furnace. High temperature X‐ray diffraction patterns, obtained at room temperature and up to 600°C, showed evolution of α′, γ, and ε phase peaks. The study revealed that a small carbon addition (of 0.1 wt. %), could increase shape recovery stress, even up to 1.8% after one cycle of training. The higher carbon content leads to a deterioration of the property. Also, relative density differences are observed between the sintered Fe64Mn30Si6 (wt. %) alloys with before/after annealing with/without mechanical alloying involvement.
The Role of Wearable Devices in Multiple Sclerosis
Authors: Sparaco Maddalena , Lavorgna Luigi , Conforti Renata , Tedeschi Gioacchino , Bonavita Simona
Published: October 2018

Multiple sclerosis (MS) is the most common neurological disorder in young adults. The prevalence of walking impairment in people with MS (pwMS) is estimated between 41% and 75%. To evaluate the walking capacity in pwMS, the patient reported outcomes (PROs) and performance-based tests (i.e., the 2-minute walk test, the 6-minute walk test, the Timed 25-Foot Walk Test, the Timed Up and Go Test, and the Six Spot Step Test) could be used. However, some studies point out that the results of both performance-based tests and objective measures (i.e., by accelerometer) could not reflect patient reports of walking performance and impact of MS on daily life. This review analyses different motion sensors embedded in smartphones and motion wearable device (MWD) that can be useful to measure free-living walking behavior, to evaluate falls, fatigue, sedentary lifestyle, exercise, and quality of sleep in everyday life of pwMS. Caveats and limitations of MWD such as variable accuracy, user adherence, power consumption and recharging, noise susceptibility, and data management are discussed as well.
Driving Risk Detection Model of Deceleration Zone in Expressway Based on Generalized Regression Neural Network
Authors: Qi Weiwei , Wang Zhexuan , Tang Ruru , Wang Linhong
Published: October 2018

Drivers’ mistakes may cause some traffic accidents, and such accidents can be avoided if prompt advice could be given to drivers. So, how to detect driving risk is the key factor. Firstly, the selected parameters of vehicle movement are reaction time, acceleration, initial speed, final speed, and velocity difference. The ANOVA results show that the velocity difference is not significant in different driving states, and the other four parameters can be used as input variables of neural network models in deceleration zone of expressway, which have fifteen different combinations. Then, the detection model results indicate that the prediction accuracy rate of testing set is up to 86.4%. An interesting finding is that the number of input variables is positively correlated with the prediction accuracy rate. By applying the method, the dangerous state of vehicles could be released through mobile internet as well as drivers' start of risky behaviors, such as fatigue driving, drunk driving, speeding driving, and distracted driving. Numerical analyses have been conducted to determine the conditions required for implementing this detection method. Furthermore, the empirical results of the present study have important implications for the reduction of crashes.
Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
Authors: Sato-Kaneko Fumi , Wang Xiaodong , Yao Shiyin , Hosoya Tadashi , Lao Fitzgerald S. , Messer Karen , Pu Minya , Shukla Nikunj M. , Cottam Howard B. , Chan Michael , Carson Dennis A. , Corr Maripat , Hayashi Tomoko
Published: October 2018

For an activating immunotherapy such as adjuvants, a compound that can prolong immune stimulation may enhance efficacy. We leveraged data from two prior high throughput screens with NF-κB and interferon reporter cell lines to identify 4H-chromene-3-carbonitriles as a class of compounds that prolonged activation in both screens. We repurchased 23 of the most promising candidates. Out of these compounds we found#1to be the most effective agent in stimulating the release of cytokines and chemokines from immune cells, including murine primary bone marrow derived dendritic cells. Mechanistically,#1inhibited tubulin polymerization, and its effect on immune cell activation was abolished in cells mutated in the beta-tubulin gene (TUBB) encoding the site where colchicine binds. Treatment with#1resulted in mitochondrial depolarization followed by mitogen-activated protein kinase activation. Because tubulin polymerization modulating agents have been used for chemotherapy to treat malignancy and#1activated cytokine responses, we hypothesized that#1could be effective for cancer immunotherapy. Intratumoral injection of#1delayed tumor growth in a murine syngeneic model of head and neck cancer. When combined with PD-1 blockade, tumor growth slowed in the injected tumor nodule and there was an abscopal effect in an uninjected nodule on the contralateral flank, suggesting central antitumor immune activation. Thus, we identified a new class of tubulin depolymerizing agent that acts as both an innate and an adaptive immune activating agent and that limits solid tumor growth when used concurrently with a checkpoint inhibitor.
First Paleogenetic Evidence of Probable Syphilis and Treponematoses Cases in the Brazilian Colonial Period
Authors: Guedes Lucélia , Dias Ondemar , Neto Jandira , Ribeiro da Silva Laura da Piedade , Mendonça de Souza Sheila M. F. , Iñiguez Alena Mayo
Published: October 2018

Despite interest in the origins of syphilis, paleopathological analysis has not provided answers, and paleogenetic diagnosis remains a challenge. Even venereal syphilis has low infectivity which means there are few circulating bacteria for most of the individual’s life. Human remains recovered from the Nossa Senhora do Carmo Church (17th to 19th centuries) and the Praça XV Cemetery (18th to 19th centuries), Rio de Janeiro, Brazil, were subjected toTreponemapaleogenetic analysis. Historical data point to endemic treponemal infections in the city, including venereal syphilis. Based on the physiopathology ofTreponema palliduminfection, 25 samples, mostly from skull remains of young adults, with no visible paleopathological evidence of treponematoses, were analyzed. PCR with three molecular targets,tpp47,polA, andtpp15, were applied. Ancient DNAtpp15 sequences were recovered from two young adults from each archaeological site and revealed the polymorphism that characterizesT. p.subsp.pallidumin a female up to 18 years old, suggesting a probable case of syphilis infection. The results indicated that the epidemiological context and the physiopathology of the disease should be considered in syphilis paleogenetic detection. The findings ofTreponemasp. aDNA are consistent with historical documents that describe venereal syphilis and yaws as endemic diseases in Rio de Janeiro. Data on the epidemiological characteristics of the disease and its pathophysiology offer new perspectives in paleopathology.
Endovascular Management of a Refractory Pseudoaneurysm of the Sternocleidomastoid Artery Caused by Attempted Internal Jugular Central Line Placement with Long-Term Follow-Up: A Case Report and Review
Authors: Abdel-Aty Yassmeen , Bellew Michael P.
Published: October 2018

Introduction. This case report shows successful treatment of a refractory sternocleidomastoid branch of the superior thyroid artery (SBSTA) pseudoaneurysm using endovascular glue embolization in a patient who refused surgery. Case Presentation. A 63-year-old female with multiple comorbidities presented with a firm 7 cm tender mass located in the right neck. Ultrasound showed pseudoaneurysm and a 7 × 3.3 × 4 cm multilobular hematoma in the location of the previous central line. CTA showed a corresponding heterogeneous mass. Serial imaging demonstrated enlargement over 2 weeks. Angiogram showed contrast blush off of the SBSTA. Management and Outcome. SBSTA was embolized using glue. Repeat angiogram showed embolization and no contrast blush. One month later, the mass was no longer pulsatile but present on physical exam. CTA showed decreased size. 8 months later, her neck was soft without mass. Discussion. Pseudoaneurysms of the external carotid artery are rare and usually due to trauma. Pseudoaneurysms after central line placement are documented, but most are complications of femoral central lines. A handful of cases of superior thyroid artery pseudoaneurysms due to several etiologies are reported, but none involving the SBSTA. Therapeutic options include surveillance, compression, thrombin injection, embolization, and surgery. Endovascular management offers an alternative for patients unwilling or unable to undergo open surgery.
Leachate Recirculation for Enhancing Methane Generation within Field Site in China
Authors: Liu Lei , Xiong Huan , Ma Jun , Ge Sai , Yu Xiao , Zeng Gang
Published: October 2018

Leachate recirculation is a critical element in the evaluation of the availability of methane production enhancement in bioreactor landfills. Field experiments in leachate injection were conducted in horizontal wells at a landfill in Hubei Province in China. The experiments included the long-term test of methane concentration and production in three cells; the test was operated with nonrecirculation (NR), continued recirculation (CR), and descending recirculation (DR). The average methane concentration in CR is 54.8%, which is higher than that in the NR and DR sites. The average biogas flow rate in the CR site was 2.2 times that in the NR site. The recirculation loading should be determined with the specific conditions, to effectively improve the methane production in field site. The position of the gas collection well was also very important, coordinating with the distribution of the leachate injection well and influence area of the liquid injection. The long-term monitoring of injection volume and gas production is essential to determine the reliability of recirculation for methane reuse.
A Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics
Authors: Quist Jelmar , Mirza Hasan , Cheang Maggie C.U. , Telli Melinda L. , O'Shaughnessy Joyce A. , Lord Christopher J. , Tutt Andrew N.J. , Grigoriadis Anita
Published: October 2018

The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1, and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors (∼50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.
EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC
Authors: Krishnamoorthy Gnana P. , Davidson Natalie R. , Leach Steven D. , Zhao Zhen , Lowe Scott W. , Lee Gina , Landa Iňigo , Nagarajah James , Saqcena Mahesh , Singh Kamini , Wendel Hans-Guido , Dogan Snjezana , Tamarapu Prasanna P. , Blenis John , Ghossein Ronald A. , Knauf Jeffrey A. , Rätsch Gunnar , Fagin James A.
Published: October 2018

Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors.

Significance:

Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors.

This article is highlighted in the In This Issue feature, p. 151
Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats
Authors: Lee Hyung Gon , Song Ji A , Han Dong Soo , Woo Kyeong Wan , Yoon Myung Ha
Published: October 2018

This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and α2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective α2-adrenoceptor (yohimbine), α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (‡ p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (‡ p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and α2A, α2B, and α2C-adrenoceptors contributed to the antiallodynic effects of areca nut.
Extension of the Clinical Significance of the “Cog”
Authors: Wang Kaishi , Jiang Yi , Zhang Zhifei , Lu Yongtian , Ni Yusu
Published: October 2018

Objective: To study the clinical anatomy of the epitympanum, the attic, and its medial wall, to try to discover a new clinical operation-related anatomical landmark, and to investigate the adjacent anatomical relationship with this landmark. Materials and Methods: Eight donor temporal bone specimens were dissected endoscopically. For 29 healthy persons (17 males and 12 females), CT images of the temporal bone (57 ears) were taken, 3-dimensional (3-D) reconstruction and multidimensional plane reconstruction were performed, and identification and assessment of 3-D spatial relationships between any 2 of these complex structures were done. Results: 3-D images of the temporal bone structures including the facial nerve, the cochlea, the semicircular canal, and the brain plate were reconstructed and shown in detail. We discovered a new clinical surgery-related anatomical landmark (the “cog” tangent and the trailing edge of the cog). Based on the tangent and the trailing edge of the cog, we quantified the anatomical relationship between it and its neighboring important structures. Conclusion: Based on endoscopic anatomy and the temporal bone spiral CT 3-D structure reconstruction of the epitympanum, the attic, and the adjacent structures, we found an extension of the clinical significance the cog. Quantification of the adjacent anatomical relationship of this landmark is very important for otology microsurgical operation.
Changes of Early Sepsis Biomarker Presepsin Level during Hemodialysis: Influence of β2-Microglobulin Clearance of Dialysis Membrane: A Preliminary Study
Authors: Shiota Jun
Published: October 2018

Background: Although presepsin (P-SEP) is an early sepsis biomarker, sepsis is often suspected after starting hemodialysis (HD). To enhance the utility of P-SEP, we investigated whether pre-HD P-SEP levels could be predicted using the P-SEP levels from blood samples collected after starting HD. Methods: We observed P-SEP level changes due to HD and dialyzer passage in HD patients using a dialysis membrane with a β2-microglobulin (β2-MG) clearance of either ≥50 mL/min (high-flux) or < 30 mL/min (intermediate-flux). We calculated the removal ratios for the elimination of P-SEP or the predicted pre-HD P-SEP levels based on the correction of hemoconcentration. Results: The P-SEP levels significantly decreased at 4 h after starting HD (n = 8) using membranes with a β2-MG clearance ≥50 mL/min; the removal ratios at 2 and 4 h were 42.8 ± 7.9% and 58.8 ± 18.4%, respectively. In contrast, the P-SEP levels did not decrease during the passage of dialyzer in 2 patients with a β2-MG clearance < 30 mL/min, and the P-SEP levels increased during HD in all patients (n = 10, including the abovementioned 2 patients) with a β2-MG clearance < 30 mL/min. The predicted pre-HD P-SEP levels (y) were strongly correlated with the actually measured pre-HD P-SEP levels (x) (R2 = 0.9562) using the regression equation: y = 1.0987x. Conclusion: The levels of P-SEP with a molecular weight near that of β2-MG decreased similarly to those of β2-MG during HD using membranes with a β2-MG clearance ≥50 mL/min. On the contrary, the levels of P-SEP rather increased during HD with a β2-MG clearance < 30 mL/min, suggesting that P-SEP appeared not to be eliminated. Furthermore, the pre-HD P-SEP levels might be predictable by the correction of hemoconcentration using even blood samples collected after starting HD with a β2-MG clearance < 30 mL/min.
Challenging Diagnosis of a Solitary Retroperitoneal Mass: A Case Report of Castleman’s Disease and Review of the Literature
Authors: Carrion Diego M. , Alvarez-Maestro Mario , Gómez Rivas Juan , Brygadyr Yaroslav , García-Fernandez Eugenia , Martínez-Piñeiro Luis
Published: October 2018

Castleman’s disease (CD) is an uncommon type of lymphoproliferative disorder. Its etiology and prevalence are unclear. The retroperitoneum is a very rare site for presentation of the unicentric variant, where it mimics malignant tumors. A 59-year-old man is referred to the urology outpatient clinic for the study of microhematuria found in a routine analysis. CT scan of the abdomen identified a solid, circumscribed mass, measuring 28 × 30 × 31 mm in the left para-aortic zone, with homogeneous contrast enhancement. Excisional surgery and regional lymphadenectomy were performed via laparoscopy. Postoperative course concurred without incidences. Histological diagnosis confirmed unicentric CD, hyaline-vascular type. CD is a rare entity, and the unicentric type presents as an asymptomatic mass. Retroperitoneum is a rare localization, where initial imaging diagnosis is unclear and surgical resection is the preferred treatment.
A Case of a Cavitary Iris Melanoma with Aqueous Cytological Modulation
Authors: McGrath Lindsay A. , Bacon James F. , Rundle Paul , Rennie Ian G. , Mudhar Hardeep Singh
Published: October 2018

Malignant melanoma is the most common primary malignant tumour of the iris, but represents a small proportion of all uveal melanomas. The authors describe a 34-year-old male with a pigmented lesion of the iris. The lesion remained stable for 7 years, but the patient re-presented after this time with sudden enlargement of the mass and hyphaema. Excisional biopsy confirmed cavitary melanoma of the iris. This is the first reported case of cavitation in a primary iris melanoma. The patient has not had any further adjuvant treatment and remains metastasis free at 5 years of follow-up.
Effect of Baseline Impedance on Ablation Lesion Dimensions
Authors: Barkagan Michael , Rottmann Markus , Leshem Eran , Shen Changyu , Buxton Alfred E. , Anter Elad
Published: October 2018

Background:

Radiofrequency ablation using irrigated catheters is performed using a power-controlled mode. However, lesion size is dependent on current delivery at a particular impedance, such that a power value alone may not reflect actual energy delivery, resulting in lesion size variability at similar power settings. We hypothesized that modulating baseline impedance at fixed power settings affects ablation lesion dimensions.

Methods:

In 20 ex vivo swine hearts, radiofrequency ablation was performed using an irrigated catheter at a fixed power setting of 30 W per 20 seconds and a multistepped impedance load (100–210Ω). In 4 in vivo thigh muscle preparations and right atria, ablation was performed using similar power settings at 3 baseline impedances: low (90–130Ω), intermediate (131–180Ω), and high (181–224Ω). The relationship between baseline impedance, current, and lesion dimensions was examined.

Results:

Baseline impedance had a strong negative correlation with current squared (
I
2
) for all experimental models: ex vivo (R=−0.94;
P
<0.0001), thigh muscle (R=−0.93;
P
<0.0001), and right atria (R=−0.94;
P
<0.0001). Lesion dimensions at similar power settings were highly variable and directly related to
I
2
(width [R=0.853], depth [R=0.814]). In the thigh muscle, lesion depth was 8.2±0.7, 6.5±0.8, and 4.2±0.5 mm for low, intermediate, and high impedance, respectively (
P
<0.0001). In right atria lines, low baseline impedance resulted in wider lines (7.2±1.4 mm) relative to intermediate (5.8±1.8 mm) and high impedance (4.7±1.7 mm;
P
<0.0001).

Conclusions:

Radiofrequency ablation in a power control mode results in variable lesion dimensions that are partially related to differences in baseline impedance and current output. Ablation at a lower baseline impedance results in increased current output and lesion dimensions.
Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys
Authors: Takenaka Tsuneo , Inoue Tsutomu , Miyazaki Takashi , Kobori Hiroyuki , Nishiyama Akira , Ishii Naohito , Hayashi Matsuhiko , Suzuki Hiromichi
Published: October 2018

Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type-1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II–induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp-SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.
Body Silhouette Trajectories Across the Lifespan and Vascular Aging
Authors: van Sloten Thomas T. , Boutouyrie Pierre , Lisan Quentin , Tafflet Muriel , Thomas Frédérique , Guibout Catherine , Climie Rachel E. , Pannier Bruno , Sharman James E. , Laurent Stéphane , Jouven Xavier , Empana Jean-Philippe
Published: October 2018

Vascular aging is a major contributor to cardiovascular disease and can be quantified by higher carotid stiffness, intima-media thickness and diameter, and hypertension. Weight gain across the lifetime may be an important, modifiable determinant of vascular aging. We therefore aimed to assess lifetime body silhouette trajectories (a marker of weight change across the lifespan) in relation to vascular aging in late adulthood. We used cross-sectional data from a community-based cohort study (n=8243; age, 59.4; 38.7% women). A linear mixed model was used to assess trajectories of recalled body silhouettes from age 8 to 45 years. We assessed carotid artery properties (ultrasonography), resting hypertension (blood pressure ≥140/90 mm Hg or use of antihypertensives), and exaggerated exercise blood pressure, a marker of masked hypertension (systolic blood pressure ≥150 mm Hg during submaximal exercise) at study recruitment when the participants were 50 to 75 years of age. We identified 5 distinct body silhouette trajectories: lean stable (32.0%), lean increase (11.1%), moderate stable (32.5%), lean-marked increase (16.3%), and heavy stable (8.1%). Compared with individuals in the lean-stable trajectory, those in the moderate-stable, lean-marked increase, and heavy-stable trajectories had higher carotid stiffness, intima-media thickness and diameter (odds ratios between 1.23 and 2.10 for highest quartile versus lowest quartile of manifestations of vascular aging;
P
<0.05) and were more likely to have resting hypertension and exaggerated exercise blood pressure, after adjustment for potential confounders (odds ratios between 1.31 and 1.60;
P
<0.05). Vascular aging was most prominent among individuals who were lean in early life but markedly gained weight during young adulthood and among those who were heavy in early life and maintained weight.
Pulse Wave Velocity Is Associated With Greater Risk of Dementia in Mild Cognitive Impairment Patients
Authors: Rouch Laure , Cestac Philippe , Sallerin Brigitte , Andrieu Sandrine , Bailly Henri , Beunardeau Maëlle , Cohen Adrien , Dubail Delphine , Hernandorena Intza , Seux Marie-Laure , Vidal Jean-Sébastien , Hanon Olivier
Published: October 2018

To investigate the association between pulse wave velocity, intima-media thickness, carotid artery diameter, carotid plaques, and conversion from mild cognitive impairment to dementia. Three hundred and seventy-five elderly ambulatory subjects with mild cognitive impairment were followed yearly to examine potential conversion to dementia. Vascular function was assessed by carotid-femoral pulse wave velocity. Vascular structure was evaluated by intima-media thickness, carotid artery diameter, and carotid plaques using an ultrasonographic assessment of carotid arteries. One hundred and five patients (28%) converted to dementia during a mean follow-up period of 4.5 years. Higher pulse wave velocity was associated with greater risk of conversion to dementia (1-SD increase of pulse wave velocity: hazard ratio, 1.33; 95% CI, 1.04–1.71;
P
=0.02) independently of age, sex, educational level, systolic blood pressure, cardiovascular diseases, body mass index, calcium channel blockers intake, Mini–Mental State Examination at baseline, and apoE ε4 status. Intima-media thickness, carotid plaques, and carotid artery diameter did not predict conversion to dementia (1-SD increase of intima-media thickness: hazard ratio, 0.93; 95% CI, 0.73–1.18;
P
=0.55; presence of carotid plaques: hazard ratio, 1.08; 95% CI, 0.62–1.87;
P
=0.79; 1-SD increase of carotid artery diameter: hazard ratio, 1.08; 95% CI, 0.89–1.31;
P
=0.44). Pulse wave velocity was associated with conversion to dementia, whereas intima-media thickness, carotid plaques, or carotid artery diameter were not after controlling for age and other confounding factors. Arterial stiffness could identify mild cognitive impairment patients at higher risk of dementia and may be a therapeutic target to delay or prevent the onset of dementia.
Sex Differences in Renal Inflammation and Injury in High-Fat Diet–Fed Dahl Salt-Sensitive Rats
Authors: Fernandes Roxanne , Garver Hannah , Harkema Jack R. , Galligan James J. , Fink Gregory D. , Xu Hui
Published: October 2018

We examined the impact of sex on high-fat diet (HFD)–induced renal alterations in Dahl salt-sensitive and Sprague Dawley rats. In Dahl rats, HFD (60% kcal from fat for 24–26 weeks starting at weaning) significantly and equally increased blood pressure in males and females when compared with rats fed a control diet (10% kcal from fat). Male Dahl rats on HFD exhibited progressive renal histological injury and moderately increased renal macrophage infiltration at 10 and 24 weeks of feeding when compared with males on control diet. Female Dahl rats had lower grade renal injury and less macrophage infiltration (except at 17 weeks) than males regardless of diet. Male Dahl rats on both diets showed progressively increasing numbers of renal T-cells, a pattern not observed in females. HFD per se did not significantly affect renal T-cell number. Male Dahl rats had lower renal regulatory T-cells cell ratio than females at 24 weeks. Renal macrophage and T-cell infiltrations were highly correlated to final mean arterial pressure levels in males but not in females. Sprague Dawley rats fed HFD were normotensive without significant renal injury/inflammation after 24 weeks of feeding. In summary, HFD feeding fails to increase arterial blood pressure in Sprague Dawley rats but strongly promotes hypertension in both male and female Dahl salt-sensitive rats. Only Dahl males, however, exhibited blood pressure-associated renal inflammation and injury. Maintenance of regulatory T-cells ratio may protect against hypertension-associated renal injury/inflammation but not HFD-induced hypertension.