bluuebunny/crossref_metadata_2025 huggingface dataset:
Rationale and design of a cohort study on primary ovarian insufficiency in female survivors of Hodgkin’s lymphoma: influence on long-term adverse effects (SOPHIA)
Authors: Krul Inge M , Opstal-van Winden Annemieke W J , Zijlstra Josée M , Appelman Yolande , Schagen Sanne B , Meijboom Lilian J , Serné Erik , Lambalk Cornelis B , Lips Paul , van Dulmen-den Broeder Eline , Hauptmann Michael , Daniëls Laurien A , Aleman Berthe M P , van Leeuwen Flora E
Published: September 2018

Introduction

Hodgkin’s lymphoma (HL) has become the prototype of a curable disease. However, many young survivors suffer from late adverse effects of treatment. Both chemotherapy (CT) and radiotherapy (RT) may induce primary ovarian insufficiency (POI), which has been associated with reduced bone mineral density (BMD), neurocognitive dysfunction and possibly cardiovascular disease (CVD). While the general assumption is that POI increases CVD risk, other hypotheses postulate reverse causality, suggesting that cardiovascular risk factors determine menopausal age or that biological ageing underlies both POI and CVD risk. None of these hypotheses are supported by convincing evidence. Furthermore, most studies on POI-associated conditions have been conducted in women with early natural or surgery-induced menopause with short follow-up times. In this study, we will examine the long-term effects of CT-induced and/or RT-induced POI on BMD, cardiovascular status, neurocognitive function and quality of life in female HL survivors.

Methods and analysis

This study will be performed within an existing Dutch cohort of HL survivors. Eligible women were treated for HL at ages 15–39 years in three large hospitals since 1965 and survived for ≥8 years after their diagnosis. Women visiting a survivorship care outpatient clinic will be invited for a neurocognitive, cardiovascular and BMD assessment, and asked to complete several questionnaires and to provide a blood sample. Using multivariable regression analyses, we will compare the outcomes of HL survivors who developed POI with those who did not. Cardiovascular status will also be compared with women with natural POI.

Ethics and dissemination

This study has been approved by the Institutional Review Board of the Netherlands Cancer Institute and has been registered at ‘Toetsingonline’ from the Dutch Central Committee on Research involving Human Subjects (file no. NL44714.031.13). Results will be disseminated through peer-reviewed publications and will be incorporated in follow-up guidelines for HL survivors.
Violence experience by perpetrator and associations with HIV/STI risk and infection: a cross-sectional study among female sex workers in Karnataka, south India
Authors: Beksinska Alicja , Prakash Ravi , Isac Shajy , Mohan H L , Platt Lucy , Blanchard James , Moses Stephen , Beattie Tara S
Published: September 2018

Objectives

Female sex workers (FSWs) experience violence from a range of perpetrators, but little is known about how violence experience across multiple settings (workplace, community, domestic) impacts on HIV/sexually transmitted infection (STI) risk. We examined whether HIV/STI risk differs by the perpetrator of violence.

Methods

An Integrated Biological and Behavioural Assessment survey was conducted among random samples of FSWs in two districts (Bangalore and Shimoga) in Karnataka state, south India, in 2011. Physical and sexual violence in the past six months, by workplace (client, police, coworker, pimp) or community (stranger, rowdy, neighbour, auto-driver) perpetrators was assessed, as was physical and sexual intimate partner violence in the past 12 months. Weighted, bivariate and multivariate analyses were used to examine associations between violence by perpetrator and HIV/STI risk.

Results

1111 FSWs were included (Bangalore=718, Shimoga=393). Overall, 34.9% reported recent physical and/or sexual violence. Violence was experienced from domestic (27.1%), workplace (11.1%) and community (4.2%) perpetrators, with 6.2% of participants reporting recent violence from both domestic and non-domestic (workplace/community) perpetrators. Adjusted analysis suggests that experience of violence by workplace/community perpetrators is more important in increasing HIV/STI risk during sex work (lower condom use with clients; client or FSW under the influence of alcohol at last sex) than domestic violence. However, women who reported recent violence by domestic and workplace/community perpetrators had the highest odds of high-titre syphilis infection, recent STI symptoms and condom breakage at last sex, and the lowest odds of condom use at last sex with regular clients compared with women who reported violence by domestic or workplace/community perpetrators only.

Conclusion

HIV/STI risk differs by the perpetrator of violence and is highest among FSWs experiencing violence in the workplace/community and at home. Effective HIV/STI prevention programmes with FSWs need to include violence interventions that address violence across both their personal and working lives.
Are noise and air pollution related to the incidence of dementia? A cohort study in London, England
Authors: Carey Iain M , Anderson H Ross , Atkinson Richard W , Beevers Sean D , Cook Derek G , Strachan David P , Dajnak David , Gulliver John , Kelly Frank J
Published: September 2018

Objective

To investigate whether the incidence of dementia is related to residential levels of air and noise pollution in London.

Design

Retrospective cohort study using primary care data.

Setting

75 Greater London practices.

Participants

130 978 adults aged 50–79 years registered with their general practices on 1 January 2005, with no recorded history of dementia or care home residence.

Primary and secondary outcome measures

A first recorded diagnosis of dementia and, where specified, subgroups of Alzheimer’s disease and vascular dementia during 2005–2013. The average annual concentrations during 2004 of nitrogen dioxide (NO2), particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5) and ozone (O3) were estimated at 20×20 m resolution from dispersion models. Traffic intensity, distance from major road and night-time noise levels (Lnight) were estimated at the postcode level. All exposure measures were linked anonymously to clinical data via residential postcode. HRs from Cox models were adjusted for age, sex, ethnicity, smoking and body mass index, with further adjustments explored for area deprivation and comorbidity.

Results

2181 subjects (1.7%) received an incident diagnosis of dementia (39% mentioning Alzheimer’s disease, 29% vascular dementia). There was a positive exposure response relationship between dementia and all measures of air pollution except O3, which was not readily explained by further adjustment. Adults living in areas with the highest fifth of NO2concentration (>41.5 µg/m3) versus the lowest fifth (<31.9 µg/m3) were at a higher risk of dementia (HR=1.40, 95% CI 1.12 to 1.74). Increases in dementia risk were also observed with PM2.5, PM2.5specifically from primary traffic sources only and Lnight, but only NO2and PM2.5remained statistically significant in multipollutant models. Associations were more consistent for Alzheimer’s disease than vascular dementia.

Conclusions

We have found evidence of a positive association between residential levels of air pollution across London and being diagnosed with dementia, which is unexplained by known confounding factors.
Prevalence of respiratory bacterial infections in people with lower respiratory tract infections in Africa: the BARIAFRICA systematic review and meta-analysis protocol
Authors: Tchatchouang Serges , Bigna Jean Joel , Nzouankeu Ariane , Fonkoua Marie-Christine , Nansseu Jobert Richie , Ndangang Marie S , Kenmoe Sebastien , Penlap Véronique B , Njouom Richard
Published: September 2018

Introduction

The burden of lower respiratory tract infections (LRTIs) is a substantial public health concern. However, the epidemiology of LRTI and its bacterial aetiologies are poorly characterised, particularly in the African continent. Providing accurate data can help design cost-effective interventions to curb the burden of respiratory infections in Africa. Therefore, the aim of this systematic review and meta-analysis will be to determine the prevalence of respiratory Bacterial Aetiologies in people with low Respiratory tract Infections in Africa (BARIAFRICA) and associated factors.

Methods and analysis

We will search PubMed, EMBASE, Web of Science, African Journals Online, Cumulative Index to Nursing and Allied Health Literature, and Global Index Medicus to identify studies that reported the prevalence (of enough data to compute this estimate) of respiratory bacterial infections in people with LRTIs in Africa from 1 January 2000 to 31 March 2018, without any linguistic restrictions. Study selection, data extraction and risk of bias assessment will be conducted independently by two investigators. Heterogeneity will be evaluated using the χ² test on Cochran’s Q statistic and quantified with H and I² statistics. Prevalence will be pooled using a random-effect meta-analysis model. Subgroup and meta-regression analyses will be used to identify sources of heterogeneity of prevalence estimates. This study will be reported according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Ethics and dissemination

Since this study will be based on published data, it does not require ethical approval. This systematic review and meta-analysis is intended to serve as a basis for determining the burden of LRTIs, for identifying data gaps and for guiding future investigations in Africa. The final report will be published in peer-reviewed journals, presented in conferences and submitted to relevant health policy makers.

PROSPERO registration number

CRD42018092359.
Vascular endothelial function is impaired by aerosol from a single IQOS HeatStick to the same extent as by cigarette smoke
Authors: Nabavizadeh Pooneh , Liu Jiangtao , Havel Christopher M , Ibrahim Sharina , Derakhshandeh Ronak , Jacob III Peyton , Springer Matthew L
Published: September 2018

Background

Heated tobacco products (also called ‘heat-not-burn’ products) heat tobacco at temperatures below that of combustion, causing nicotine and other compounds to aerosolise. One such product, IQOS from Philip Morris International, is being marketed internationally with claims of harm reduction. We sought to determine whether exposure to IQOS aerosol impairs arterial flow-mediated dilation (FMD), a measure of vascular endothelial function that is impaired by tobacco smoke.

Methods

We exposed anaesthetised rats (n=8/group) via nose cone to IQOS aerosol from single HeatSticks, mainstream smoke from single Marlboro Red cigarettes or clean air for a series of consecutive 30 s cycles over 1.5–5 min. Each cycle consisted of 15 or 5 s of exposure followed by removal from the nose cone. We measured pre-exposure and postexposure FMD, and postexposure serum nicotine and cotinine.

Results

FMD was impaired comparably by ten 15 s exposures and ten 5 s exposures to IQOS aerosol and to cigarette smoke, but not by clean air. Serum nicotine levels were similar to plasma levels after humans have smoked one cigarette, confirming that exposure conditions had real-world relevance. Postexposure nicotine levels were ~4.5-fold higher in rats exposed to IQOS than to cigarettes, despite nicotine being measured in the IQOS aerosol at ~63% the amount measured in smoke. When IQOS exposure was briefer, leading to comparable serum nicotine levels to the cigarette group, FMD was still comparably impaired.

Conclusions

Acute exposures to IQOS aerosol impairs FMD in rats. IQOS use does not necessarily avoid the adverse cardiovascular effects of smoking cigarettes.
Anaemia in a llama (Lama glama): treatment, regeneration and differential diagnoses
Authors: Wagener Matthias Gerhard , Grimm Lucie Marie , Ganter Martin
Published: September 2018

Anaemia is a common finding in South American camelids presented to the veterinary clinic. This report describes the case of a llama presented with general weakness and pale conjunctives, displaying severe anaemia with a Packed Cell Volume (PCV) of 6 per cent and suffering from haemonchosis. The animal was presented in lateral recumbency before being treated with whole blood transfusion. After administering a total volume of 850-ml blood, the clinical condition improved remarkably. Regeneration of the haematological parameters required several weeks, PCV increased from 6 per cent on day 0 to 23 per cent on day 28.
Density-independent use of shallow riverine areas in juvenile Atlantic salmon
Authors: Puffer Michael , Berg Ole Kristian , Hamnes Frøydis Bolme , Bentsen Vidar , Koch Wouter , Ugedal Ola , Forseth Torbjørn , Arnekleiv Jo Vegar , Einum Sigurd
Published: September 2018

Habitat use of aquatic organisms is essential to evaluate effects of many environmental challenges like effects of hydropower regulation, where stranding may occur under hydropeaking (rapid dewatering of shallow river areas). Experimental studies as well as observations from nature with juvenile Atlantic salmon (Salmo salar) show that the proportion of the population that uses shallow depth was both independent of population density and decreases with fish size. Experiments were conducted both in the presence and in absence of older fish, during day and night, and during all four seasons. Juvenile salmon from deep areas may therefore distribute into the shallow areas even when fish density becomes reduced. Thus, low density does not lead to reduced stranding risk, and shallow areas may therefore function as a sink in a within-generation source–sink dynamic under a repeated hydropeaking scenario. The sink effect of rapid dewatering in shallow areas may be mitigated by seasonal and diurnal regulation of hydropeaking activity, but dewatering may still result in extinction of weak populations.
Control of glyphosate-resistant waterhemp with preemergence herbicides in glyphosate- and dicamba-resistant soybean
Authors: Hedges Brittany K. , Soltani Nader , Hooker David C. , Robinson Darren E. , Sikkema Peter H.
Published: September 2018

Glyphosate-resistant (GR) waterhemp was first discovered in Ontario, Canada, in 2014. In Ontario, GR waterhemp interference in previous studies reduced soybean yield up to 73%. Tank-mixes of herbicides with multiple modes-of-action are important for delaying the evolution of herbicide resistance. The objective of this study was to evaluate the efficacy of pyroxasulfone (150 g a.i. ha−1), S-metolachlor/metribuzin (1943 g a.i. ha−1), pyroxasulfone/sulfentrazone (300 g a.i. ha−1), and pyroxasulfone/flumioxazin (240 g a.i. ha−1) applied preemergence (PRE) with and without the addition of glyphosate/dicamba (1800 g a.e. ha−1) for the control of GR waterhemp in soybean. At 8 wk after treatment application (WAA), glyphosate/dicamba applied PRE controlled GR waterhemp 45%. Pyroxasulfone, S-metolachlor/metribuzin, pyroxasulfone/sulfentrazone, and pyroxasulfone/flumioxazin applied PRE controlled GR waterhemp 79%, 87%, 91%, and 95%, respectively. At 2, 4, 8, and 12 WAA, the addition of glyphosate/dicamba to the aforementioned PRE herbicides did not improve GR waterhemp control. There was no increase in GR waterhemp control with the addition glyphosate/dicamba; however, multiple herbicide modes-of-action should be utilized to reduce the selection intensity for herbicide-resistant weeds.
The Improved Light Field Depth Image and 3D Reconstruction
Authors: Fang Kui , He Xiao , Yu Hexiang
Published: September 2018

A depth map and a full focus image can be obtained by using the image sequence and the image evaluation function. The depth map obtained by gradient operator as the evaluation function has good resolution but is also affected by the deviation value. This kind of noise is different from common salt-and-pepper noise and Gaussian noise, so the median filter or mean filter cannot play a very good role. In order to improve the effect of 3D modeling, it is necessary to eliminate the deviation and retain and highlight the depth information. In this paper, an adaptive image enhancement method based on mode cooperative filtering is proposed. This method uses the general level of mode data to express the data, and uses the method of cooperative filtering to form the centralized balance and isolated deviation around the mode. Compared with other filters, the results show that it can achieve better results.
Recognition of Colored Face, Based on an Improved Color Local Binary Pattern
Authors: Li Zhi-Ming , Huang Zheng-Hai , Li Wen-Juan
Published: September 2018

In this paper, a novel feature extraction method based on an improved color local binary pattern (LBP) is proposed for color face recognition. Firstly, in a given neighborhood of every pixel, we choose some sampling points from three color channels simultaneously and the numbers of the sampling points from every channel may be different. Secondly, we use a new rule to select the threshold which does not always locate in the geometrical center of the given neighborhood. Thirdly, in order to excavate the potential of the proposed sampling method, we use the [Formula: see text]-uniform LBP to obtain the binary code of each pixel. In addition, we embed the Hamming distance into our method for improving the recognition rate of the proposed method. For evaluating the performance of our method, we implement the proposed method and several related methods on five public face databases: FERET, CMU-PIE, Georgia, FEI and Asian databases. Experimental results show that our method possesses higher recognition rates and lower computational cost than other related color face recognition methods.
Campus Data Analysis Based on Positive and Negative Sequential Patterns
Authors: Jiang Xiaoqi , Xu Tiantian , Dong Xiangjun
Published: September 2018

Campus data analysis is becoming increasingly important in mining students’ behavior. The consumption data of college students is an important part of the campus data, which can reflect the students’ behavior to a great degree. A few methods have been used to analyze students’ consumption data, such as classification, association rules, clustering, decision trees, time series, etc. However, they do not use the method of sequential patterns mining, which results in some important information missing. Moreover, they only consider the occurring (positive) events but do not consider the nonoccurring (negative) events, which may lead to some important information missing. So this paper uses a positive and negative sequential patterns mining algorithm, called NegI-NSP, to analyze the consumption data of students. Moreover, we associate students’ consumption data with their academic grades by adding the students’ academic grades into sequences to analyze the relationship between the students’ academic grades and their consumptions. The experimental results show that the students’ academic performance has significant correlation with the habits of having breakfast regularly.
Quantum gravity and BH-NS binaries
Authors: Kavic Michael J. , Minic Djordje , Simonetti John
Published: September 2018

We argue that the Black Hole-Neutron Star (BH-NS) binaries are the natural astrophysical probes of quantum gravity in the context of the new era of multi-messenger astronomy. In particular, we discuss the observable effect of enhanced BH mass loss in a BH-NS binary, due to the presence of an additional length scale tied to the intrinsic noncommutativity of quantum spacetime in quantum gravity.
Tests of gravity with galaxy clusters
Authors: Cataneo Matteo , Rapetti David
Published: September 2018

Changes in the law of gravity have far-reaching implications for the formation and evolution of galaxy clusters, and appear as peculiar signatures in their mass-observable relations, structural properties, internal dynamics, and abundance. We review the outstanding progress made in recent years towards constraining deviations from General Relativity with galaxy clusters, and give an overview of the yet untapped information becoming accessible with forthcoming surveys that will map large portions of the sky in great detail and unprecedented depth.
Pricing in Information Orchestrators and Maximizing Stable Networks
Authors: Lustosa Bernardo C. , Albertin Alberto L. , Moreira Fernando
Published: September 2018

In innovation networks based on information exchange, an orchestrating actor, or hub, captures information from peripheral actors, promotes innovation and then distributes it to the network in the form of added value. This paper identifies the pricing options proposed by the orchestrating hub that would result in the network’s stability and efficiency. Since all the companies in this ecosystem can be seen as rational agents, game theory is an appropriate framework for studying pricing as a mechanism to promote network stability. We analyze the equilibrium conditions in this context and conclude that the Nash equilibrium entails the network’s stability. Our findings indicate that, in order to maximize the innovation power of the network, the agents should be charged a price proportional to the financial benefit obtained by the net innovation. This study fills relevant gaps in the literature on monopolistic orchestrated innovation and the pricing structures of network connections.
Generalized conformal derivations of Lie conformal algebras
Authors: Fan Guangzhe , Hong Yanyong , Su Yucai
Published: September 2018

Let [Formula: see text] be a finite Lie conformal algebra. The purpose of this paper is to investigate the conformal derivation algebra [Formula: see text], the conformal quasiderivation algebra [Formula: see text] and the generalized conformal derivation algebra [Formula: see text]. The generalized conformal derivation algebra is a natural generalization of the conformal derivation algebra. Obviously, we have the following tower [Formula: see text], where [Formula: see text] is the general Lie conformal algebra. Furthermore, we mainly research the connection of these generalized conformal derivations. Finally, the conformal [Formula: see text]-derivations of Lie conformal algebras are studied. Moreover, we obtain some connections between several specific generalized conformal derivations and the conformal [Formula: see text]-derivations. In addition, all conformal [Formula: see text]-derivations of finite simple Lie conformal algebras are characterized.
Mixed multiplicities and the multiplicity of Rees modules of reductions
Authors: Thanh Truong Thi Hong , Viet Duong Quoc
Published: September 2018

This paper shows that mixed multiplicities and the multiplicity of Rees modules of good filtrations and that of their reductions are the same. As an application of this result, we obtain interesting results on mixed multiplicities and the multiplicity of Rees modules.
On the Jacobson radical of skew inverse Laurent series ring
Authors: Hashemi E. , Hamidizadeh M. , Alhevaz A.
Published: September 2018

In this paper, we study the Jacobson radical of the skew inverse Laurent series ring [Formula: see text], where [Formula: see text] is an associative unitary ring, equipped with an automorphism [Formula: see text] and an [Formula: see text]-derivation [Formula: see text]. For this aim, we introduce the condition [Formula: see text] in order to obtain the relation between [Formula: see text] and [Formula: see text]. In the following, some examples of the rings which satisfy the condition [Formula: see text] are mentioned.
Preparation and Characterization of Sulfated TiO2/Zeolite Composite Catalysts with Enhanced Photocatalytic Activity
Authors: Zhao Yuan , Li JingXiu , Wang Ling , Hao Yanan , Yang Lin , He Pingting , Xue JianJun
Published: September 2018

Sulfated TiO2nanoparticles were successfully immobilized on zeolite through improving hydrolysis-deposition method. Microstructure, crystallization, surface state and surface area of composite catalysts were characterized by SEM, XRD, FTIR spectra, XPS and BET and the photocatalytic activity was evaluated by degradation of methyl orange under UV irradiation. We optimized these factors (SO[Formula: see text] ions, calcination temperature and loading amount of sulfated TiO[Formula: see text] on photocatalytic activity and crystallization of composite photocatalysts. The results indicated that the SO[Formula: see text] ions are successfully immobilized on the surface of TiO2, and sulfated TiO2/zeolite show the highest photocatalytic activity for methyl orange at the [SO[Formula: see text]]/[Ti[Formula: see text]] molar rate of 1:1, calcination temperature of 600[Formula: see text]C for 2[Formula: see text]h, and sulfated TiO2loading amount of 40%, respectively.
Diagnostic methods and risk analysis based on fuzzy soft information
Authors: Habib Shaista , Akram Muhammad
Published: September 2018

In our daily life problem we face uncertainties in making right decisions. In this study, we propose two different decision-making problems in medical field. The first problem is fever diagnosing and second problem is mouth cancer risk analysis. In the first problem, we use fuzzy soft similarity measures and fuzzy soft matrix operations to diagnose the type of fever. We consider a hypothetical case study and manipulate similarity measures on it. Our work diagnoses different patients having similar symptoms. We also develop a small application using JAVA. In the second problem, we perform risk analysis of mouth cancer. The proposed fuzzy soft expert system takes two biochemical parameters as inputs that is, serum total malondialdehyde (MDA), and serum proton donors capacity (donors_protons) and determines the risk of mouth cancer. Our study facilitates doctors by diagnosing mouth cancer at its earlier stages. There are four main components of our fuzzy soft expert system. The first component is named as fuzzification which converts crisp input into linguistic variables and formulates fuzzy sets. The second component transforms fuzzy sets into their respective fuzzy soft sets. The third component determines indispensable parameters and performs parameter reduction. The fourth component performs risk analysis by using algorithm. We use exemplary dataset and run all the components of fuzzy soft expert system to compute cancer risk.
The signless Laplacian spectrum of rooted product of graphs
Authors: Maghsoudi Maryam , Heydari Abbas
Published: September 2018

Let [Formula: see text] be a simple graph with [Formula: see text] vertices and [Formula: see text] be a sequence of [Formula: see text] rooted graphs [Formula: see text]. The rooted product [Formula: see text], of [Formula: see text] by [Formula: see text] is constructed by identifying the root vertex of [Formula: see text] with the [Formula: see text]th vertex of [Formula: see text] for [Formula: see text]. In this paper, we introduce a method for computation of the characteristic polynomial of the signless Laplacian matrix of [Formula: see text]. Then the signless Laplacian spectrum and the signless Laplacian energy of some graphs will be computed.
The Promise of a Malaria Vaccine—Are We Closer?
Authors: Laurens Matthew B.
Published: September 2018

Malaria vaccine development has rapidly advanced in the past decade. The very first phase 3 clinical trial of the RTS,S vaccine was completed with over 15,000 African infants and children, and pilot implementation studies are underway. Next-generation candidate vaccines using novel antigens, platforms, or approaches targeting different and/or multiple stages of the Plasmodium life cycle are being tested. Many candidates, in various stages of development, promise enhanced efficacy of long duration and broad protection against genetically diverse malaria strains, with a few studies under way in target populations in endemic areas. Malaria vaccines together with other interventions promise interruption and eventual elimination of malaria in endemic areas.
Broadening the Definition of Bacterial Small RNAs: Characteristics and Mechanisms of Action
Authors: Carrier Marie-Claude , Lalaouna David , Massé Eric
Published: September 2018

The first report of trans-acting RNA-based regulation in bacterial cells dates back to 1984. Subsequent studies in diverse bacteria unraveled shared properties of trans-acting small regulatory RNAs, forming a clear definition of these molecules. These shared characteristics have been used extensively to identify new small RNAs (sRNAs) and their interactomes. Recently however, emerging technologies able to resolve RNA-RNA interactions have identified new types of regulatory RNAs. In this review, we present a broader definition of trans-acting sRNA regulators and discuss their newly discovered intrinsic characteristics.
A New Lens for RNA Localization: Liquid-Liquid Phase Separation
Authors: Langdon Erin M. , Gladfelter Amy S.
Published: September 2018

RNA localization mechanisms have been intensively studied and include localized protection of mRNA from degradation, diffusion-coupled local entrapment of mRNA, and directed transport of mRNAs along the cytoskeleton. While it is well understood how cells utilize these three mechanisms to organize mRNAs within the cytoplasm, a newly appreciated mechanism of RNA localization has emerged in recent years in which mRNAs phase-separate and form liquid-like droplets. mRNAs both contribute to condensation of proteins into liquid-like structures and are themselves regulated by being incorporated into membraneless organelles. This ability to condense into droplets is in many instances contributing to previously appreciated mRNA localization phenomena. Here we review how phase separation enables mRNAs to selectively and efficiently colocalize and be coregulated, allowing control of gene expression in time and space.
Diverse Functions of Macrophages in Different Tumor Microenvironments
Authors: Yang Ming , McKay Daniel , Pollard Jeffrey W. , Lewis Claire E.
Published: September 2018

Tumor-associated macrophages are a major constituent of malignant tumors and are known to stimulate key steps in tumor progression. In our review in this journal in 2006, we postulated that functionally distinct subsets of these cells exist in different areas within solid tumors. Here, we review the many experimental and clinical studies conducted since then to investigate the function(s), regulation, and clinical significance of macrophages in these sites. The latter include three sites of cancer cell invasion, tumor nests, the tumor stroma, and areas close to, or distant from, the tumor vasculature. A more complete understanding of macrophage diversity in tumors could lead to the development of more selective therapies to restore the formidable, anticancer functions of these cells. Cancer Res; 78(19); 5492–503. ©2018 AACR.
Methodological Challenges and Updated Findings from a Meta-analysis of the Association between Mammographic Density and Breast Cancer
Authors: Bond-Smith Daniela , Stone Jennifer
Published: September 2018

Mammographic density (MD) is an established predictor of breast cancer risk. However, there is limited information on the robustness of the risk associations for different study designs and the associated methodologic challenges. Our analysis includes 165 samples from studies published since 2006. We use a weakly informative Bayesian approach to avoid unduly optimistic estimates of uncertainty, as found in the previous literature. We find that the existing consensus from previous review studies has underestimated the strength and precision of MD as a risk marker. Moreover, although much of the published literature is based on categorical measurement of MD, there are tangible advantages in using continuous data in terms of estimate precision and relevance for different patient populations. Estimates based on the percentage of MD are more precise for lower density women, whereas absolute MD has advantages for higher density. We show that older results might not be a good proxy for current and future findings, and it would be pertinent to adjust clinical interpretations based on the older data. Using an appropriate estimation method cognizant of the importance of heterogeneity is critical to obtaining reliable and robust clinical findings that are relevant for broad patient populations.
Temporal Variability and Stability of the Fecal Microbiome: The Multiethnic Cohort Study
Authors: Fu Benjamin C. , Randolph Timothy W. , Lim Unhee , Monroe Kristine R. , Cheng Iona , Wilkens Lynne R. , Le Marchand Loïc , Lampe Johanna W. , Hullar Meredith A.J.
Published: September 2018

Background:

Measurement reliability and biological stability need to be considered when developing sampling protocols for population-based fecal microbiome studies.

Methods:

Stool samples were collected biannually over a 2-year period and sequenced for the V1–V3 region of the 16S rRNA gene in 50 participants from the Multiethnic Cohort Study. We evaluated the temporal stability of the fecal microbiome on a community level with permutational multivariate analysis of variance (PERMANOVA), as well as on taxa and diversity measures with intraclass correlation coefficients.

Results:

Interindividual differences were the predominant source of fecal microbiome variation, and variation within individual was driven more by changing abundances than by the complete loss or introduction of taxa. Phyla and diversity measures were reliable over the 2 years. Most genera were stable over time, although those with low abundances tended to be more dynamic. Reliability was lower among participants who used antibiotics, with the greatest difference seen in samples taken within 1 month of reported use.

Conclusions:

The fecal microbiome as a whole is stable over a 2-year period, although certain taxa may exhibit more temporal variability.

Impact:

When designing large epidemiologic studies, a single sample is sufficient to capture the majority of the variation in the fecal microbiome from 16S rRNA gene sequencing, while multiple samples may be needed for rare or less-abundant taxa.
Combining Vascular Normalization with an Oncolytic Virus Enhances Immunotherapy in a Preclinical Model of Advanced-Stage Ovarian Cancer
Authors: Matuszewska Kathy , Santry Lisa A. , van Vloten Jacob P. , AuYeung Amanda W.K. , Major Pierre P. , Lawler Jack , Wootton Sarah K. , Bridle Byram W. , Petrik Jim
Published: September 2018

Purpose:

Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulting in decreased tumor perfusion and elevated tumor hypoxia. We hypothesized that using 3TSR to normalize tumor vasculature prior to administration of an oncolytic Newcastle disease virus (NDV) would enhance virus delivery and trafficking of immunologic cell subsets to the tumor core, resulting in systemically enhanced immunotherapy and regression of advanced-stage epithelial ovarian cancer (EOC).

Experimental Design:

Using an orthotopic, syngeneic mouse model of advanced-stage EOC, we pretreated mice with 3TSR (4 mg/kg per day) alone or followed by combination with fusogenic NDV(F3aa) (1.0 × 108 plaque-forming units).

Results:

Treatment with 3TSR normalized tumor vasculature, enhanced blood perfusion of primary EOC tumors, and induced disease regression. Animals treated with combination therapy had the greatest reduction in primary tumor mass, ascites accumulation, and secondary lesions (50% of mice were completely devoid of peritoneal metastases). Combining 3TSR + NDV(F3aa) led to enhanced trafficking of immunologic cells into the primary tumor core.

Conclusions:

We have shown, for the first time, that NDV, like other oncolytic viruses, is a potent mediator of acute vascular shutdown and that preventing this through vascular normalization can promote regression in a preclinical model of advanced-stage ovarian cancer. This challenges the current focus on induction of intravascular thrombosis as a requisite for successful oncolytic virotherapy.

See related commentary by Bykov and Zamarin, p. 1446
Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients
Authors: Taylor Olga A. , Brown Austin L. , Brackett Julienne , Dreyer ZoAnn E. , Moore Ida Ki , Mitby Pauline , Hooke Mary C. , Hockenberry Marilyn J. , Lupo Philip J. , Scheurer Michael E.
Published: September 2018

Purpose: Methotrexate chemotherapy can be associated with neurologic complications during therapy and long-term neurologic deficits. This study evaluated demographic and clinical factors associated with incidence of methotrexate neurotoxicity and described the impact of neurotoxicity on acute lymphoblastic leukemia (ALL) therapy in pediatric patients.

Experimental Design: Patients were enrolled between 2012 and 2017 from three pediatric cancer treatment centers in the United States. Medical records for suspected cases of methotrexate neurotoxicity, defined as an acute neurologic event following methotrexate therapy, were reviewed. Cox proportional hazards models were used to estimate the association between race/ethnicity and methotrexate neurotoxicity. Multivariable linear regression models compared treatment outcomes between patients with and without methotrexate neurotoxicity.

Results: Of the 280 newly diagnosed patients enrolled, 39 patients (13.9%) experienced methotrexate neurotoxicity. Compared with non-Hispanic whites, Hispanic patients experienced the greatest risk of methotrexate neurotoxicity (adjusted HR, 2.43; 95% CI, 1.06–5.58) after accounting for sex, age at diagnosis, BMI Z-score at diagnosis, and ALL risk stratification. Patients who experienced a neurotoxic event received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 cases of neurotoxicity (15.4%) experienced relapse during the study period, compared with 13 of the 241 (2.1%) patients without neurotoxicity (P = 0.0038).

Conclusions: Hispanic ethnicity was associated with increased risk of methotrexate neurotoxicity, which was associated with treatment modifications and relapse. Understanding the mechanism and predictors of methotrexate neurotoxicity is important to improving treatment outcomes in pediatric ALL. Clin Cancer Res; 24(20); 5012–7. ©2018 AACR.
Antibody–Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non–small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade
Authors: Lo Russo Giuseppe , Moro Massimo , Sommariva Michele , Cancila Valeria , Boeri Mattia , Centonze Giovanni , Ferro Simona , Ganzinelli Monica , Gasparini Patrizia , Huber Veronica , Milione Massimo , Porcu Luca , Proto Claudia , Pruneri Giancarlo , Signorelli Diego , Sangaletti Sabina , Sfondrini Lucia , Storti Chiara , Tassi Elena , Bardelli Alberto , Marsoni Silvia , Torri Valter , Tripodo Claudio , Colombo Mario Paolo , Anichini Andrea , Rivoltini Licia , Balsari Andrea , Sozzi Gabriella , Garassino Marina Chiara
Published: September 2018

Purpose:

Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological mechanisms associated with HP have been identified.

Experimental Design:

Among 187 patients with non–small cell lung cancer (NSCLC) treated with ICI at our institute, cases with HP were identified according to clinical and radiologic criteria. Baseline histologic samples from patients treated with ICI were evaluated by IHC for myeloid and lymphoid markers. T-cell–deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDX) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC.

Results:

Among 187 patients, 152 were evaluable for clinical response. We identified four categories: 32 cases were defined as responders (21%), 42 patients with stable disease (27.7%), 39 cases were defined as progressors (25.7%), and 39 patients with HP (25.7%). Pretreatment tissue samples from all patients with HP showed tumor infiltration by M2-like CD163+CD33+PD-L1+ clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti–PD-1 but not anti–PD-1 F(ab)2 fragments.

Conclusions:

These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP.

See related commentary by Knorr and Ravetch, p. 904
Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia
Authors: Li Na , Lopez Michael A. , Linares Maria , Kumar Subodh , Oliva Stefania , Martinez-Lopez Joaquin , Xu Lian , Xu Yan , Perini Tommaso , Senapedis William , Baloglu Erkan , Shammas Masood A. , Hunter Zachary , Anderson Kenneth C. , Treon Steven P. , Munshi Nikhil C. , Fulciniti Mariateresa
Published: September 2018

Purpose:

p21-activated kinase 4 (PAK4) plays a significant biological and functional role in a number of malignancies, including multiple myeloma (MM). On the basis of our promising findings in MM, we here characterize PAK4 expression and role in WM cells, as well effect of dual PAK4-NAMPT inhibitor (KPT-9274) against WM cell growth and viability.

Experimental Design:

We have analyzed mRNA and protein expression levels of PAK4 in WM cells, and used loss-of-function approach to investigate its contribution to WM cell viability. We have further tested the in vitro and in vivo effect of KPT-9274 against WM cell growth and viability.

Results:

We report here high-level expression and functional role of PAK4 in WM, as demonstrated by shRNA-mediated knockdown; and significant impact of KPT-9274 on WM cell growth and viability. The growth inhibitory effect of KPT-9274 was associated with decreased PAK4 expression and NAMPT activity, as well as induction of apoptosis. Interestingly, in WM cell lines treated with KPT-9274, we detected a significant impact on DNA damage and repair genes. Moreover, we observed that apart from inducing DNA damage, KPT-9274 specifically decreased RAD51 and the double-strand break repair by the homologous recombination pathway. As a result, when combined with a DNA alkylating agents bendamustine and melphalan, KPT-9274 provided a synergistic inhibition of cell viability in WM cell lines and primary patient WM cells in vitro and in vivo.

Conclusions:

These results support the clinical investigation of KPT-9274 in combination with DNA-damaging agent for treatment of WM.
Sprague Dawley Rag2-Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts
Authors: Noto Fallon K. , Adjan-Steffey Valeriya , Tong Min , Ravichandran Kameswaran , Zhang Wei , Arey Angela , McClain Christopher B. , Ostertag Eric , Mazhar Sahar , Sangodkar Jaya , DiFeo Analisa , Crawford Jack , Narla Goutham , Jamling Tseten Y.
Published: September 2018

The rat is the preferred model for toxicology studies, and it offers distinctive advantages over the mouse as a preclinical research model including larger sample size collection, lower rates of drug clearance, and relative ease of surgical manipulation. An immunodeficient rat would allow for larger tumor size development, prolonged dosing and drug efficacy studies, and preliminary toxicologic testing and pharmacokinetic/pharmacodynamic studies in the same model animal. Here, we created an immunodeficient rat with a functional deletion of the Recombination Activating Gene 2 (Rag2) gene, using genetically modified spermatogonial stem cells (SSC). We targeted the Rag2 gene in rat SSCs with TALENs and transplanted these Rag2-deficient SSCs into sterile recipients. Offspring were genotyped, and a founder with a 27 bp deletion mutation was identified and bred to homozygosity to produce the Sprague-Dawley Rag2 - Rag2tm1Hera (SDR) knockout rat. We demonstrated that SDR rat lacks mature B and T cells. Furthermore, the SDR rat model was permissive to growth of human glioblastoma cell line subcutaneously resulting in successful growth of tumors. In addition, a human KRAS-mutant non–small cell lung cancer cell line (H358), a patient-derived high-grade serous ovarian cancer cell line (OV81), and a patient-derived recurrent endometrial cancer cell line (OV185) were transplanted subcutaneously to test the ability of the SDR rat to accommodate human xenografts from multiple tissue types. All human cancer cell lines showed efficient tumor uptake and growth kinetics indicating that the SDR rat is a viable host for a range of xenograft studies. Mol Cancer Ther; 17(11); 2481–9. ©2018 AACR.
SOX9/FXYD3/Src Axis Is Critical for ER+ Breast Cancer Stem Cell Function
Authors: Xue Yue , Lai Lihua , Lian Wenwen , Tu Xintao , Zhou Jiaojiao , Dong Ping , Su Dan , Wang Xiaojia , Cao Xuetao , Chen Yiding , Wang Qingqing
Published: September 2018

The presence of cancer stem cells (CSC), which possess the ability of self-renewal and cancer initiation, is correlated with poor prognosis and drug resistance of breast cancer patients. But the molecular regulatory networks for maintenance of CSC function still remain unclear. Here, we identified that an estrogen-inducible gene FXYD3, whose expression is significantly upregulated in ER+ breast CSCs, is a critical player for regulating ER+ breast CSC function. FXYD3 amplification is crucial in mediating tamoxifen resistance in ER+ breast cancer cells. Interestingly, we also find that stem cell–related transcription factor SOX9 directly promotes FXYD3 expression, and FXYD3 is indispensable for SOX9 nucleus localization, thus forming a positive regulatory feedback loop for FXYD3 amplification and function. In terms of mechanism, FXYD3 interacts with Src and ERα to form an activated complex and triggers Src to transduce nongenomic estrogen signaling for facilitating ER+ breast CSCs. Collectively, these results establish a critical role for SOX9/FXYD3/Src axis in boosting nongenomic estrogen signaling and SOX9 nucleus entry, which is required for maintenance of ER+ breast CSCs and endocrine resistance. Targeting FXYD3-mediated pathway might be a promising therapeutic strategy for hormone therapy–refractory ER+ breast cancer.

Implications:

SOX9/FXYD3/Src axis is critical for promoting CSC function and tamoxifen resistance in ER+ breast cancer.