bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary healthcare usage and morbidity among immigrant children compared with non-immigrant children: a population-based study in Norway
Authors: Fadnes Lars T , Møen Kathy Ainul , Diaz Esperanza
Published: October 2016

Objectives

Health status, disease spectrum and use of healthcare have been reported to vary across groups of migrants and according to the different phases of migration. However, most studies are conducted among adults. This study assesses usage of primary healthcare (PHC) by children with immigrant background compared with non-immigrant children in Norway and describes their relative morbidity burden.

Design

Population-based retrospective cohort study.

Setting

This study used 3 linked population-based registers in Norway for children under 18 years of age in 2008.

Main exposure and outcome measures

Immigrants were defined as children with both parents born abroad, and further classified into first and second generation, and according to the World Bank income categories of their parents' country of origin. Usage and morbidity were assessed with negative binomial regression and logistic regression analyses, respectively. Further, population-attributable fraction analyses on PHC visits were conducted to estimate the impact on the primary health system.

Participants

1 168 365 children including 119 251 with immigrant background.

Results

The mean number of visits to PHC for non-immigrant children was 1.40 compared with 1.19 for immigrants from high-income countries (HIC) and 1.76 for immigrants from low-income countries (LIC). Compared with non-immigrants, first generation immigrants used PHC significantly less after adjusting for age and sex (incidence risk ratio (IRR) 0.70 (HIC) to 0.93 (LIC)) while second generation immigrant children generally used PHC more (IRR 1.03 (HIC) to 1.43 (LIC)); however, the median number of visits were similar between all groups. The morbidity spectrum also varied between the groups.

Conclusions

Compared with non-immigrants, the excess number of consultations attributable to immigrant groups corresponds to around 1.3% of PHC visits among children.
Experiences of violence across life course and its effects on mobility among participants in the International Mobility in Aging Study
Authors: Guedes Dimitri Taurino , Vafaei Afshin , Alvarado Beatriz Eugenia , Curcio Carmen Lucia , Guralnik Jack M , Zunzunegui María Victoria , Guerra Ricardo Oliveira
Published: October 2016

Background

Life course exposure to violence may lead to disability in old age. We examine associations and pathways between life course violence and mobility disability in older participants of the International Mobility in Aging Study (IMIAS).

Methods

A cross-sectional study using IMIAS 2012 baseline. Men and women aged 65–74 years were recruited at 5 cities (n=1995): Kingston and Saint-Hyacinthe (Canada), Tirana (Albania), Manizales (Colombia) and Natal (Brazil). Mobility was assessed by the Short Physical Performance Battery (SPPB) and by 2 questions on difficulty in walking and climbing stairs. Childhood physical abuse history and the HITS instrument were used to gather information on childhood exposure to violence and violence by intimate partners or family members. Multivariate logistic regression and mediation analysis models were constructed to explore the significance of direct and indirect effects of violence on mobility. Interaction effects of gender on violence and on each of the mediators were tested.

Results

Experiences of physical violence at any point of life were associated with mobility disability (defined as SPPB<8 or limitation in walking/climbing stairs) while psychological violence was not. Chronic conditions, C reactive protein, physical activity and depression mediated the effect of childhood exposure to violence on both mobility outcomes. Chronic conditions and depression were pathways between family and partner violence and both mobility outcomes. Physical activity was a significant pathway linking family violence to mobility. Gender interactions were not significant.

Conclusions

Our results provide evidence for the detrimental effects of life course exposure to violence on mobility in later life.
Runout analysis and mobility observations for large open pit slope failures
Authors: Whittall John , Eberhardt Erik , McDougall Scott
Published: October 2016

Objectively forecasting the runout of a potential open pit slope failure, in addition to identifying the failure itself, is a critical component of a mine’s risk management plan. Recent losses arising from large open pit slope failures demonstrate shortcomings in current practice. A dataset of 105 pit slope failures was compiled to compare open pit runout trends against established empirical runout relationships for natural landslides. Fahrböschung angle versus volume and Fahrböschung angle versus slope angle relationships provide reasonable runout estimates. Open pit slopes have the advantage of removing the influence of morphological features, vegetation, and liquefiable substrates while controlling the travel path angle and roughness. In such a controlled environment, landslide mobility has a strong sensitivity to slope angle, material properties, and fall height, and is only modestly sensitive to volume. A grouping of highly mobile open pit slope cases involving weathered, saturated, collapsible rock mass materials exceed expected runout distances when compared with established runout trends. This suggests mobility for these weaker rock masses is controlled by pore pressures mediating basal friction. The result is that two different runout exceedance trends are observed based on whether the unstable rock mass involves fresh, strong rocks or weathered weak rocks.
Genetic diversity and population structure of castor (Ricinus communis L.) germplasm within the US collection assessed with EST-SSR markers
Authors: Wang M.L. , Dzievit M. , Chen Z. , Morris J.B. , Norris J.E. , Barkley N.A. , Tonnis B. , Pederson G.A. , Yu J.
Published: October 2016

Castor is an important oilseed crop and although its oil is inedible, it has multiple industrial and pharmaceutical applications. The entire US castor germplasm collection was previously screened for oil content and fatty acid composition, but its genetic diversity and population structure has not been determined. Based on the screening results of oil content, fatty acid composition, and country origins, 574 accessions were selected and genotyped with 22 polymorphic EST-SSR markers. The results from cluster analysis, population structure, and principal component analysis were consistent, and partitioned accessions into four subpopulations. Although there were certain levels of admixtures among groups, these clusters and subpopulations aligned with geographic origins. Both divergent and redundant accessions were identified in this study. The US castor germplasm collection encompasses a moderately high level of genetic diversity (pairwise dissimilarity coefficient = 0.53). The results obtained here will be useful for choosing accessions as parents to make crosses in breeding programs and prioritizing accessions for regeneration to improve germplasm management. A subset of 230 accessions was selected and will be planted in the field for establishing a core collection of the US castor germplasm. Further evaluation of the US castor germplasm collection is also discussed.
Associated symmetric pair and multiplicities of admissible restriction of discrete series
Authors: Vargas Jorge A.
Published: October 2016

Let [Formula: see text] be a symmetric pair for a real semisimple Lie group [Formula: see text] and [Formula: see text] its associated pair. For each irreducible square integrable representation [Formula: see text] of [Formula: see text] so that its restriction to [Formula: see text] is admissible, we find an irreducible square integrable representation [Formula: see text] of [Formula: see text] which allows us to compute the Harish-Chandra parameter of each irreducible [Formula: see text]-subrepresentation of [Formula: see text] as well as its multiplicity. The computation is based on the spectral analysis of the restriction of [Formula: see text] to a maximal compact subgroup of [Formula: see text]
A short proof of backward uniqueness for some geometric evolution equations
Authors: Kotschwar Brett
Published: October 2016

We present a simple, direct proof of the backward uniqueness of solutions to a class of second-order geometric evolution equations which includes the Ricci and cross-curvature flows. The proof, based on a classical argument of Agmon–Nirenberg, uses the logarithmic convexity of a certain energy quantity in the place of Carleman inequalities. We further demonstrate the applicability of the technique to the [Formula: see text]-curvature flow and other higher-order equations.
Leakage Reduction of SRAM-Based Look-Up Table Using Dynamic Power Gating
Authors: Nag Abhishek , Nath Debanjali , Pradhan Sambhu Nath
Published: October 2016

Leakage power reduction of an SRAM-based look-up table (LUT) in field-programmable gate array (FPGA) has been achieved in this work by implementing an efficient and dynamic power gating technique. The logic of gating is based on the theory of automatically shutting down the power supply to the inactive blocks of LUT during runtime, contrary to all previous works which involved manual intervention for the implementation of power gating. Two techniques of power gating are introduced in this work, PG1 and PG2. PG1 results in more power savings than PG2, however, PG2 has an advantage of low area overhead. Simulation has been carried out for all possible input combinations of LUT, designed in Cadence Virtuoso tool at 45[Formula: see text]nm technology. The results indicate a leakage power reduction of up to 50% in PG1 technique, with an average area overhead of 14.15%. The power savings in PG2 is up to 38%, with a minimal increase in area of 1.76%. The power bounce noise is also analyzed for the proposed techniques and reported.
The graph structure of graph groups that are subgroups of Thompson’s group V
Authors: Corwin Nathan , Haymaker Kathryn
Published: October 2016

We determine exactly which graph products, also known as Right Angled Artin Groups, embed into Richard Thompson’s group [Formula: see text]. It was shown by Bleak and Salazar-Díaz that [Formula: see text] was an obstruction. We show that this is the only obstruction. This is shown by proving a graph theory result giving an alternate description of simple graphs without an appropriate induced subgraph.
Rasmussen s-invariants of satellites do not detect slice knots
Authors: Cha Jae Choon , Kim Min Hoon
Published: October 2016

We present a large family of knots for which the Rasmussen [Formula: see text]-invariants of arbitrary satellites do not detect sliceness. This answers a question of Hedden. The proof hinges on work of Kronheimer–Mrowka and Cochran–Harvey–Horn.
The four-genus of a link, Levine–Tristram signatures and satellites
Authors: Powell Mark
Published: October 2016

We give a new proof that the Levine–Tristram signatures of a link give lower bounds for the minimal sum of the genera of a collection of oriented, locally flat, disjointly embedded surfaces that the link can bound in the 4-ball. We call this minimal sum the 4-genus of the link. We also extend a theorem of Cochran, Friedl and Teichner to show that the 4-genus of a link does not increase under infection by a string link, which is a generalized satellite construction, provided that certain homotopy triviality conditions hold on the axis curves, and that enough Milnor's [Formula: see text]-invariants of the closure of the infection string link vanish. We construct knots for which the combination of the two results determines the 4-genus.
On the traceless SU(2) character variety of the 6-punctured 2-sphere
Authors: Kirk Paul
Published: October 2016

We exhibit the traceless SU(2) character variety of a 6-punctured 2-sphere as a 2-fold branched cover of [Formula: see text], branched over the singular Kummer surface, with the branch locus in [Formula: see text] corresponding to the binary dihedral representations. This follows from an analysis of the map induced on SU(2) character varieties by the 2-fold branched cover [Formula: see text] branched over [Formula: see text] points, combined with the theorem of Narasimhan–Ramanan which identifies [Formula: see text] with [Formula: see text]. The singular points of [Formula: see text] correspond to abelian representations, and we prove that each has a neighborhood in [Formula: see text] homeomorphic to a cone on [Formula: see text].
Intrinsic 3-linkedness is not preserved by Y∇ moves
Authors: O'Donnol Danielle
Published: October 2016

This paper introduces a number of new intrinsically 3-linked graphs through five new constructions. We prove that intrinsic 3-linkedness is not preserved by [Formula: see text] moves. We will see that the graph [Formula: see text], which is obtained through a [Formula: see text] move on [Formula: see text], is not intrinsically 3-linked.
A survey on Heegaard Floer homology and concordance
Authors: Hom Jennifer
Published: October 2016

In this survey paper, we discuss several different knot concordance invariants coming from the Heegaard Floer homology package of Ozsváth and Szabó. Along the way, we prove that if two knots are concordant, then their knot Floer complexes satisfy a certain type of stable equivalence.
A small infinitely-ended 2-knot group
Authors: Budney R. , Hillman J. A.
Published: October 2016

We show that a 2-knot group discovered in the course of a census of 4-manifolds with small triangulations is an HNN extension with finite base and proper associated subgroups, and has the smallest base among such knot groups.
Logarithmic corrections to the entropy of scalar field in BTZ black hole spacetime
Authors: Singh Dharm Veer , Sachan Shobhit
Published: October 2016

The entanglement entropy correlates two quantum subsystems which are part of a larger system. A logarithmic divergence term present in the entanglement entropy is universal in nature and directly proportional to the conformal anomaly. We study this logarithmic divergence term of entropy for massive scalar field in [Formula: see text] dimensions by applying numerical techniques to entanglement entropy approach. This (2+1)-dimensional massive theory can be obtained from the (3+1)-dimensional massless scalar field via dimensional reduction. We also calculated mass corrections to entanglement entropy for scalar field. Finally, we observe that the area law contribution to the entanglement entropy is not affected by this mass term and the universal quantities depend upon the basic properties of the system.
Test Environment-Dependent Discrete Binomial-Type Software Reliability Models
Authors: Inoue Shinji , Yamada Shigeru
Published: October 2016

We have no doubt that the software reliability growth process in the testing phase depends on the test environment factors, such as the attained testing coverage, the number of test-runs and the debugging skills, which affect the software failure occurrence or fault detection phenomenon in the testing phase. In this paper, we propose software reliability models that consider the effects of the testing environment factors. Our models are developed by a program size-dependent discrete binomial-type software reliability modeling approach. This modeling approach is also consistent with software reliability data collection and enables us to consider the effect of the program size. Finally, we compare the accuracy of our models in terms of mean square errors (MSE) and Akaike’s information criterion (AIC) with the existing corresponding model by using actual data.
Diseases transmission in a z-ary tree
Authors: Debs P. , Haberkorn T.
Published: October 2016

Consider a Galton–Watson tree [Formula: see text] of height [Formula: see text], each leaf is either infected by one of [Formula: see text] diseases or not infected at all. In other words, [Formula: see text] at generation [Formula: see text] is infected by the [Formula: see text]th infection with probability [Formula: see text] and sane with probability [Formula: see text]. Moreover, the infections are independently distributed for each leaf.

Infections spread along the tree based on deterministic specific rules. We study the limit distribution of the disease of the root of [Formula: see text] as [Formula: see text] goes to infinity.

We also study the specific case of a [Formula: see text]-ary tree, and we prove convergence of the distribution of the root node for [Formula: see text].
New p-dimensional lattices from cyclic extensions
Authors: Nunes José Valter Lopes , Interlando J. Carmelo , Neto Trajano Pires da Nóbrega , Lopes José Othon Dantas
Published: October 2016

In this work, [Formula: see text]-dimensional point-lattices are constructed from a number field [Formula: see text], where [Formula: see text] is a cyclic extension of degree [Formula: see text], an odd unramified prime in [Formula: see text]. Families of lattices whose packing densities asymptotically approach those of [Formula: see text], [Formula: see text], are explicitly exhibited.
Synthesis of Nanosilver Particles in the Texture of Bank Notes to Produce Antibacterial Effect
Authors: Lari Mohammad Hossein Asadi , Esmaili Vahid , Naghavi Seyed Mohammad Ebrahim , Kimiaghalam Amir Hossein , Sharifaskari Emadaldin
Published: October 2016

Silver particles show antibacterial and antiseptic properties at the nanoscale. Such properties result from an alteration in the binding capacity of silver atoms in bits of less than 6.5[Formula: see text]nm which enables them to kill harmful organisms. Silver nanoparticles are now the most broadly used agents in the area of nanotechnology after carbon nanotubes. Given that currency bills are one of the major sources of bacterial disseminations and their contamination has recently been nominated as a critical factor in gastrointestinal infections and possibly colon cancers, here we propose a new method for producing antibacterial bank notes by using silver nanoparticles. Older bank notes are sprayed with acetone to clean the surface. The bank note is put into a petri-dish containing a solution of silver nitrate and ammonia so that it is impregnated. The bank notes are then reduced with the formaldehyde gas, which penetrates its texture and produces silver nanoparticles in the cellulose matrix. The side products of the reactions are quickly dried off and the procedure ends with the drying of the bank note. The transmission electron microscope (TEM) images confirmed the nanoscale size range for the formed particles while spectroscopy methods, such as XRD, provided proof for the metallic nature of the particles. Bacterial challenge tests then showed that no colonies of the three tested bacterium (Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa survived on the sample after a 72[Formula: see text]h incubation period. This study has provided a method for synthesizing silver NPs directly into the texture of fabrics and textiles (like that of bank notes) which can result in lower production costs, making the use of silver NPs economically beneficial. The method, specifically works on the fabric of bank notes, suggesting a method to tackle the transmission of bacteria through bank notes. Moreover, this study is a testament to the strong antibacterial nature of even low concentrations of silver NPs.
Numerical investigation of the growth kinetics for macromolecular microsphere composite hydrogel based on the TDGL equation
Authors: Wu Dating , Zhang Hui
Published: October 2016

We present results of a detailed numerical investigation of the phase separation kinetic process of the macromolecular microsphere composite (MMC) hydrogel. Based on the Flory-Huggins-de Gennes-like reticular free energy, we use the time-dependent Ginzburg–Landau (TDGL) mesoscopic model (called MMC-TDGL model) to simulate the phase separation process. Domain growth is investigated through the pair correlation function. Then we obtain the time-dependent characteristic domain size, which reflects the growth kinetics of the MMC hydrogel. The results indicate that the growth law based on the MMC-TDGL equation is consistent with the modified Lifshitz–Slyozov theory.
Identification of residues of the archaeal RNA-binding Nip7 proteins specific to environmental conditions
Authors: Medvedev Kirill E. , Kolchanov Nikolay A. , Afonnikov Dmitry A.
Published: October 2016

The understanding of biological and molecular mechanisms providing survival of cells under extreme temperatures and pressures will help to answer fundamental questions related to the origin of life and to design of biotechnologically important enzymes with new properties. Here, we analyze amino acid sequences of the Nip7 proteins from 35 archaeal species to identify positions containing mutations specific to the hydrostatic pressure and temperature of organism’s habitat. The number of such positions related to pressure change is much lower than related to temperature change. The results suggest that adaptation to temperature changes of the Nip7 protein cause more pronounced modifications in sequence and structure, than to the pressure changes. Structural analysis of residues at these positions demonstrated their involvement in salt-bridge formation, which may reflect the importance of protein structure stabilization by salt-bridges at extreme environmental conditions.
Revival of Bell nonlocality across a quantum spin chain
Authors: Batle J. , Abutalib M. , Abdalla S. , Farouk Ahmed
Published: October 2016

The transmission of pure and mixed states along a quantum spin chain is investigated. Nonlocality between two qubits will evolve as it is transmitted through the quantum channel in a way that may violate or not the Clauser–Horne–Shimony–Holt (CHSH) Bell inequality at different times. This violation of local realism is analogue to the so-called sudden death and sudden birth features of entanglement. In the quantum channel, which will turn to be a damping one, some (mixed) states will be preferred according to the nature of the quantum correlations that are preserved during the evolution along the spin chain.
A Novel Superoxide Anion Radical Nonenzymatic Electrochemical Sensor Based on PtRuCu Ternary Alloy Nanoparticles/Graphene Composite Modified Electrode
Authors: Ren Jujie , Zhai Miao , Cui Min , Li Liujia , Yu Congcong , Yu Xudong , Ji Xueping
Published: October 2016

A superoxide anion radical (O[Formula: see text] nonenzymatic electrochemical sensor based on PtRuCu ternary alloy nanoparticles/electrochemically reduced graphene oxide (ERGO) composite modified glassy carbon electrode (PtRuCu/ERGO/GCE) was developed. ERGO and PtRuCu/ERGO composites were characterized by scanning electron microscopy. The prepared PtRuCu/ERGO/GCE showed remarkable performance toward the electrocatalytic reduction of (O[Formula: see text]. The sensor possessed a high sensitivity of 1725[Formula: see text]A[Formula: see text][Formula: see text][Formula: see text]mM[Formula: see text][Formula: see text]cm[Formula: see text], a wide linear range of 7.5–330[Formula: see text][Formula: see text]M ([Formula: see text]0.993) and a low detection limit of 0.7[Formula: see text][Formula: see text]M ([Formula: see text]/[Formula: see text]), as well as excellent selectivity, reproducibility and stability, which can be attributed to the synergistic effect of ERGO and PtRuCu ternary alloy nanoparticles. Therefore, the prepared sensor is promising for electrochemical determination of O[Formula: see text].
The Language of Life
Authors: Palmenberg Ann C.
Published: October 2016

Science is our best current approximation of the way things work. You cannot do science unless you believe there is a discernable truth inherent to the arrangement of our tangible world. The problem is, we in our given time never know where exactly the asymptote lies or how far we are from it. My curiosity about the natural world is innate, but fate has variously gifted me with outstanding personal opportunities to indulge that curiosity through the study of viruses. To a woman of the boomer generation, professional paths were not always open-door, and to a certain extent they still aren't. Whether such points should now be viewed as obstacles or stepping stones is a matter of perspective. RNA viruses, and the multiple, seminal mentors who taught me their secrets, have defined my career. Some of their stories are told here as they dovetail with mine. If there is any unity to this, it would be a pursuit of the language of life, or sequence analysis, as taught to us by natural selection. The intent here is not a legacy but an example. Science is a beautiful fate.
Moving On Out: Transport and Packaging of Influenza Viral RNA into Virions
Authors: Lakdawala Seema S. , Fodor Ervin , Subbarao Kanta
Published: October 2016

Influenza A viruses bear an eight-segmented single-stranded negative-sense RNA genome that is replicated in the nucleus. Newly synthesized viral RNA (vRNA) segments are exported from the nucleus and transported to the plasma membrane for packaging into progeny virions. Influenza viruses exploit many host proteins during these events, and this is the portion of the viral life cycle when genetic reassortment among influenza viruses occurs. Reassortment among influenza A viruses allows viruses to expand their host range, virulence, and pandemic potential. This review covers recent studies on the export of vRNAs from the nucleus and their transport through the cytoplasm, progressive assembly, and packaging into progeny virus particles. Understanding these events and the constraints on genetic reassortment has implications for assessment of the pandemic potential of newly emerged influenza viruses, for vaccine production, for determination of viral fitness, and for identification of novel therapeutic targets.
Bugs Are Not to Be Silenced: Small RNA Pathways and Antiviral Responses in Insects
Authors: Mongelli Vanesa , Saleh Maria-Carla
Published: October 2016

Like every other organism on Earth, insects are infected with viruses, and they rely on RNA interference (RNAi) mechanisms to circumvent viral infections. A remarkable characteristic of RNAi is that it is both broadly acting, because it is triggered by double-stranded RNA molecules derived from virtually any virus, and extremely specific, because it targets only the particular viral sequence that initiated the process. Reviews covering the different facets of the RNAi antiviral immune response in insects have been published elsewhere. In this review, we build a framework to guide future investigation. We focus on the remaining questions and avenues of research that need to be addressed to move the field forward, including issues such as the activity of viral suppressors of RNAi, comparative genomics, the development of detailed maps of the subcellular localization of viral replication complexes with the RNAi machinery, and the regulation of the antiviral RNAi response.
Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment
Authors: Liu Yang , Pandeswara Srilakshmi , Dao Vinh , Padrón Álvaro , Drerup Justin M. , Lao Shunhua , Liu Aijie , Hurez Vincent , Curiel Tyler J.
Published: October 2016

mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1–8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)–mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell–dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L+ CD8+ central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520–31. ©2016 AACR.
Thyroid Cancer: Risk-Stratified Management and Individualized Therapy
Authors: Raue Friedhelm , Frank-Raue Karin
Published: October 2016

Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012–21. ©2016 AACR.

See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”
Pheochromocytoma: The First Metabolic Endocrine Cancer
Authors: Jochmanova Ivana , Pacak Karel
Published: October 2016

Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics has allowed us to take a closer look at the metabolic changes present in pheochromocytomas (PHEO) and paragangliomas (PGL). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies. Clin Cancer Res; 22(20); 5001–11. ©2016 AACR.

See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”
MicroRNA let-7, T Cells, and Patient Survival in Colorectal Cancer
Authors: Dou Ruoxu , Nishihara Reiko , Cao Yin , Hamada Tsuyoshi , Mima Kosuke , Masuda Atsuhiro , Masugi Yohei , Shi Yan , Gu Mancang , Li Wanwan , da Silva Annacarolina , Nosho Katsuhiko , Zhang Xuehong , Meyerhardt Jeffrey A. , Giovannucci Edward L. , Chan Andrew T. , Fuchs Charles S. , Qian Zhi Rong , Ogino Shuji
Published: October 2016

Experimental evidence suggests that the let-7 family of noncoding RNAs suppresses adaptive immune responses, contributing to immune evasion by the tumor. We hypothesized that the amount of let-7a and let-7b expression in colorectal carcinoma might be associated with limited T-lymphocyte infiltrates in the tumor microenvironment and worse clinical outcome. Utilizing the molecular pathological epidemiology resources of 795 rectal and colon cancers in two U.S.-nationwide prospective cohort studies, we measured tumor-associated let-7a and let-7b expression levels by quantitative reverse-transcription PCR, and CD3+, CD8+, CD45RO (PTPRC)+, and FOXP3+ cell densities by tumor tissue microarray immunohistochemistry and computer-assisted image analysis. Logistic regression analysis and Cox proportional hazards regression were used to assess associations of let-7a (and let-7b) expression (quartile predictor variables) with T-cell densities (binary outcome variables) and mortality, respectively, controlling for tumor molecular features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Compared with cases in the lowest quartile of let-7a expression, those in the highest quartile were associated with lower densities of CD3+ [multivariate odds ratio (OR), 0.40; 95% confidence interval (CI), 0.23–0.67; Ptrend = 0.003] and CD45RO+ cells (multivariate OR, 0.31; 95% CI, 0.17–0.58; Ptrend = 0.0004), and higher colorectal cancer-specific mortality (multivariate hazard ratio, 1.82; 95% CI, 1.42–3.13; Ptrend = 0.001). In contrast, let-7b expression was not significantly associated with T-cell density or colorectal cancer prognosis. Our data support the role of let-7a in suppressing antitumor immunity in colorectal cancer and suggest let-7a as a potential target of immunotherapy. Cancer Immunol Res; 4(11); 927–35. ©2016 AACR.
CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma
Authors: Chao Timothy , Furth Emma E. , Vonderheide Robert H.
Published: October 2016

Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas. Using a genetically engineered mouse model of PDA, we found that tumor and stromal cells differentially expressed CXCR2 ligands, with Cxcl5 high in tumor and Cxcl2 high in stroma. Cxcl5 expression was associated with mutant Kras expression and regulated by NF-κB activation. Host CXCR2 inhibition by genetic ablation prevented neutrophil accumulation in pancreatic tumors and led to a T cell–dependent suppression of tumor growth. In the absence of neutrophils, activated and functional T cells infiltrated pancreatic tumors otherwise devoid of effector T cells. Thus, the CXCR2–ligand axis helps establish an immunosuppressive microenvironment in PDA, highlighting the potential utility of targeting this axis as a novel therapy for this deadly disease. Cancer Immunol Res; 4(11); 968–82. ©2016 AACR.
Paroxetine, Cognitive Therapy or Their Combination in the Treatment of Social Anxiety Disorder with and without Avoidant Personality Disorder: A Randomized Clinical Trial
Authors: Nordahl Hans M. , Vogel Patrick A. , Morken Gunnar , Stiles Tore C. , Sandvik Pål , Wells Adrian
Published: October 2016

Background: The most efficacious treatments for social anxiety disorder (SAD) are the SSRIs and cognitive therapy (CT). Combined treatment is advocated for SAD but has not been evaluated in randomized trials using CT and SSRI. Our aim was to evaluate whether one treatment is more effective than the other and whether combined treatment is more effective than the single treatments. Methods: A total of 102 patients were randomly assigned to paroxetine, CT, the combination of CT and paroxetine, or pill placebo. The medication treatment lasted 26 weeks. Of the 102 patients, 54% fulfilled the criteria for an additional diagnosis of avoidant personality disorder. Outcomes were measured at posttreatment and 12-month follow-up assessments. Results: CT was superior to paroxetine alone and to pill placebo at the end of treatment, but it was not superior to the combination treatment. At the 12-month follow-up, the CT group maintained benefits and was significantly better than placebo and paroxetine alone, whereas there were no significant differences among combination treatment, paroxetine alone, and placebo. Recovery rates at 12 months were much higher in the CT group (68%) compared to 40% in the combination group, 24% in the paroxetine group, and 4% in the pill placebo group. Conclusions: CT was the most effective treatment for SAD at both posttreatment and follow-up compared to paroxetine and better than combined treatment at the 12-month follow-up on the Liebowitz Social Anxiety Scale. Combined treatment provided no advantage over single treatments; rather there was less effect of the combined treatment compared to CT alone.
A Comparison of Dual Attention, Eye Movements, and Exposure Only during Eye Movement Desensitization and Reprocessing for Posttraumatic Stress Disorder: Results from a Randomized Clinical Trial
Authors: Sack Martin , Zehl Stefanie , Otti Alexander , Lahmann Claas , Henningsen Peter , Kruse Johannes , Stingl Markus
Published: October 2016

Background: Currently, there is controversy on the possible benefits of dual-attention tasks during eye movement desensitization and reprocessing (EMDR) for patients with posttraumatic stress disorder (PTSD). Methods: A total of 139 consecutive patients (including 85 females) suffering from PTSD were allocated randomly among 3 different treatment conditions: exposure with eyes moving while fixating on the therapist's moving hand (EM), exposure with eyes fixating on the therapist's nonmoving hand (EF), and exposure without explicit visual focus of attention as control condition (EC). Except for the variation in stimulation, treatment strictly followed the standard EMDR manual. Symptom changes from pre- to posttreatment were measured with the Clinician-Administered PTSD Scale (CAPS) by an investigator blinded to treatment allocation. Results: In total, 116 patients completed the treatment, with an average of 4.6 sessions applied. Intention-to-treat analysis revealed a significant improvement in PTSD symptoms with a high overall effect size (Cohen's d = 1.96, 95% CI: 1.67-2.24) and a high remission rate of PTSD diagnosis (79.8%). In comparison to the control condition, EM and EF were associated with significantly larger pre-post symptom decrease (ΔCAPS: EM = 35.8, EF = 40.5, EC = 31.0) and significantly larger effect sizes (EM: d = 2.06, 95% CI: 1.55-2.57, EF: d = 2.58, 95% CI: 2.01-3.11, EC: d = 1.44, 95% CI: 0.97-1.91). No significant differences in symptom decrease and effect size were found between EM and EF. Conclusions: Exposure in combination with an explicit external focus of attention leads to larger PTSD symptom reduction than exposure alone. Eye movements have no advantage compared to visually fixating on a nonmoving hand.
Ginkgolide B Inhibits Human Bladder Cancer Cell Migration and Invasion Through MicroRNA-223-3p
Authors: Zhi Yi , Pan Jinhong , Shen Wenhao , He Peng , Zheng Ji , Zhou Xiaozhou , Lu Gensheng , Chen Zhiwen , Zhou Zhansong
Published: October 2016

Background/Aims: Ginkgolide B (GB) is currently used as an anticancer drug for treatment of some malignant cancers. However, whether it may have therapeutic effects on bladder cancer remains unknown. Here, we studied the effects of GB on bladder cancer cells. Methods: Bladder cells were treated with different doses of GB, and the effects on ZEB1 and microRNA-223-3p (miR-223-3p) were analyzed by RT-qPCR and/or Western blot. Prediction of a regulatory relationship between miR-93 and 3'-UTR of Beclin-1 mRNA was performed by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Results: We found that GB dose-dependently decreased ZEB1 protein, but not mRNA, in bladder cancer cells, resulting in suppression of cell invasion. Moreover, in bladder cancer cells, GB dose-dependently decreased the levels of miR-223-3p, which suppressed the protein translation of ZEB1 through binding to 3'-UTR of ZEB1 mRNA. Overexpression of miR-223-3p decreased ZEB1 protein, while depletion of miR-223-3p increased ZEB1 protein in bladder cancer cells. Conclusion: GB inhibits bladder cancer cell invasiveness through suppressing ZEB1 protein translation via upregulating miR-223-3p.
Lipid Metabolism in Vascular Smooth Muscle Cells Infuenced by HCMV Infection
Authors: Li Lingfang , Li Yifan , Dai Ziyu , Liu Meitong , Wang Bing , Liu Shuiping , Wang Lili , Chen Liyu , Tan Yurong , Wu Guojun
Published: October 2016

Background: The present study was designed to observe the infection of human cytomegalovirus (HCMV) to human vascular smooth muscle cells (VSMCs), and the effect of viral infection on lipid metabolism in VSMCs. Methods: The cytopathic effects were observed by inverted microscopy and viral infection were examined by electron microscopy and RT-PCR. The lipid metabolism related gene profiling of VSMCs after HCMV infection was assayed by cDNA assay and the abnormal expression of genes were validated by quantitative RT-PCR. The content of cholesterol in VSMCs after HCMV infection was assayed by cholesterol detection kit. Results: VSMCs showed obvious cytopathic effects after HCMV infection. Intact viral particles could be detected in VSMCs using electron microscope. By use of RT-PCR technology, IE gene of HCMV could be amplified from VSMCs. The expression of cell lipid metabolism related gene profiling showed obvious disorders. The expression levels of HMG-CoA synthase and HMG-CoA reductase after infection increased significantly. The cellular cholesterol content (µmol/106 cells) was significantly higher than that of mock infected group at 72h post infection. Conclusion: HCMV can infect VSMCs and the infection can affect cellular lipid metabolism related gene expression, which get involved in the occurrence and development of atherosclerosis (AS).
Sorafenib Inhibits Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Inhibition of Macrophage Infiltration
Authors: Ma Wenting , Tao Le , Wang Xuefei , Liu Qinyi , Zhang Wei , Li Qiuying , He Chunfeng , Xue Dongying , Zhang Jie , Liu Cheng
Published: October 2016

Aims: Sorafenib, which has been used extensively for the treatment of renal cell cancer and advanced hepatocellular carcinoma (HCC), has also been shown to have antifibrotic effects in liver fibrosis. However, the effects of sorafenib on renal fibrosis are unknown. Therefore, we investigated whether sorafenib inhibited renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and further explored the potential mechanism. Methods: Mice underwent UUO followed by vehicle or sorafenib treatment. The expression of CD68, a macrophage marker, and the pro-inflammatory cytokines, MCP1 and CXCR3, were immunohistochemically analyzed. The involvement of macrophages in the formation of renal fibrosis was studied using confocal microscopy. Results: Renal histopathology improved in the UUO-sorafenib mice. Sorafenib notably suppressed TGF-β1-mediated renal fibrogenic effects. The mRNA and protein expressions of CD68, MCP1, and CXCR3 in the obstructed kidney were significantly decreased by sorafenib. Immunohistochemistry showed that CD68 and CXCR3 had a similar distribution, whereas MCP1 was observed predominantly in the tubular epithelial cells. Double immunofluorescence demonstrated that CD68-positive macrophages could co-localize with CXCR3. It also revealed that CXCR3 interacted with CXCL11 in the UUO mouse kidneys. Widespread adhesion of macrophages to myofibroblasts was markedly inhibited in UUO-sorafenib mouse kidneys. Conclusions: Taken together, the results indicated that sorafenib had protective effects against renal fibrosis; its mechanism of action was associated with inhibition of macrophage infiltration via the CXCR3/CXCL11 pathway. These data suggest the clinical potential of sorafenib for treatment of renal fibrosis and illustrate the immunological mechanisms underlying the protective effects of sorafenib.
Pretreatment of RPE Cells with Lutein Can Mitigate Bevacizumab-Induced Increases in Angiogenin and bFGF
Authors: Vilà Natàlia , Coblentz Jacqueline , Moreira-Neto Carlos , Bravo-Filho Vasco , Zoroquiain Pablo , Burnier Jr. Miguel N.
Published: October 2016

Purpose: To determine whether pretreatment of retinal pigmented epithelial (RPE) cells with lutein can affect the response of cells to bevacizumab therapy. Methods: One human RPE cell line (ARPE-19) was used for all experiments. The cells were treated with lutein in different concentrations (0.01, 0.1, 1, 10, or 100 μg/ml). After 24 h, all plates were treated with bevacizumab (0.25 mg/ml). Media were harvested 24 h later for sandwich ELISA-based angiogenesis arrays. A Quantibody Human Angiogenesis Array was used in order to quantify the secretion of the following 10 proangiogenic cytokines: angiogenin, ANG2, EGF, bFGF, HB-EGF, PDGF-BB, leptin, PIGF, HGF and VEGF. Results: Treatment with bevacizumab alone led to a significant decrease in VEGF, as well as a significant increase in angiogenin and bFGF. Pretreatment with 0.1 and 1.0 μg/ml of lutein led to significant decreases in both bFGF and angiogenin following treatment with bevacizumab compared to bevacizumab treatment alone. Lutein alone did not modify the secretion of proangiogenic cytokines. Conclusions: Pretreatment of human RPE cells in culture with specific doses of lutein prior to bevacizumab treatment mitigated the increase in bFGF and angiogenin caused by bevacizumab monotherapy.