bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical features of paediatric uveitis at a tertiary referral centre in São Paulo, SP, Brazil
Authors: Souto Fernanda Maria Silveira , Giampietro Bárbara Vilela , Takiuti Julia Thiemi , Campos Lucia Maria Arruda , Hirata Carlos Eduardo , Yamamoto Joyce Hisae
Published: June 2018

Aims

To analyse the clinical features, systemic associations, treatment and visual outcomes of uveitis in children from a referral centre in São Paulo, Brazil.

Methods

Clinical records of patients under 16 years old who attended the Uveitis Service, Hospital das Clinicas, Faculdadede Medicina, Universidade de São PauloFMUSP, between April and September 2017, were reviewed retrospectively. Patients with incomplete medical records, previous ocular trauma, or less than six6 months of follow-up were excluded.

Results

Thirty-nine children (25 female/14 male) were included. There was predominance of bilateral (89.7%), asymptomatic (56.4%) and recurrent/chronic cases (84.6%). The mean age at study inclusion was 10.7±3.4 years (range 3–16 years). Improvement or preservation of visual acuity (VA) was observed in 27 patients (84%); VA was not informed in 8 patients. Patients were referred early to tertiary centre (55% within 6 months of uveitis diagnosis). Anterior uveitis was the most common involvement (46%), followed by intermediate uveitis (26%). Juvenile idiopathic arthritis (JIA)-associated uveitis (41%) and immune-mediated intermediate uveitis (25.6%) were the principal non-infectious conditions; ocular toxoplasmosis (7.7%) and toxocariasis (5.1%) were the most common infectious conditions. Ocular complications were observed at first visit in 46% of patients and in 90% during final evaluation. Oral prednisone, immunosuppressive therapy (IMT) and/or biologic agents were used in all non-infectious conditions (32 children, 82%); IMT and/or biologic agents were used in all patients with JIA-associated uveitis and in 50% of patients with immune-mediated intermediate uveitis.

Conclusion

Paediatric patients with uveitis are referred early to this centre and, although severe, adequate management with systemic IMT may preserve VA.
Lower vitamin D levels are associated with higher blood glucose levels in Asian Indian women with pre-diabetes: a population-based cross-sectional study in North India
Authors: Bhatt Surya Prakash , Misra Anoop , Gulati Seema , Singh Naamrata , Pandey Ravindra Mohan
Published: June 2018

Background

Asian Indian women are predisposed to develop obesity, metabolic syndrome and vitamin D deficiency. Relationship of vitamin D deficiency with blood glucose levels has not been explored in Asian Indian women with pre-diabetes.

Objective

We evaluated the associations of serum 25-hydroxy vitamin D (25(OH)D) concentrations among adult women with the pre-diabetes residing in North India (Delhi).

Methods

This cross-sectional population-based study involved 797 women with pre-diabetes aged 20–60 years. Blood pressure, body mass index (BMI), fasting blood glucose (FBG), extent of sun exposure and serum 25(OH)D levels were assessed. For purpose of analysis, serum 25(OH)D levels (nmol/L) were categorized in quintiles as follows: 0–21.5 (first quintile), 21.51–35.60 (second quintile), 35.61–46.50 (third quintile), 46.51–62.30 (fourth quintile) and >62.31 (fifth quintile).

Result

The prevalence (%) of vitamin D deficiency, insufficiency and sufficiency was 68.6, 25.9 and 5.5, respectively. Mean age (p=0.004), systolic (p=0.05) and diastolic (p=0.04) blood pressure, weight (p=0.03), BMI (p=0.04) and FBG (p=0.02) were significantly higher in subjects with vitamin D deficiency as compared with those with vitamin D insufficiency and sufficiency. Unadjusted mean values of FBG were significantly decreased in fourth (p=0.02) and fifth quintiles (p=0.030) of 25(OH)D levels as compared with second quintile. Furthermore, after adjusting for age and family income FBG levels were significantly increased in first quintile (compared with fourth (p=0.012) and fifth (p=0.018) quintiles) and second quintile (compared with fourth (p=0.003) and fifth (p=0.004) quintiles) of 25(OH)D levels, respectively.

Conclusion

Lower vitamin D levels are associated with higher blood glucose values in Asian Indian women with pre-diabetes. These findings need confirmation in case–control and prospective studies.
Improvised first aid techniques for terrorist attacks
Authors: Loftus Andrew , Pynn Harvey , Parker Paul
Published: June 2018

Terrorist acts occur every day around the world. Healthcare professionals are often present as bystander survivors in these situations, with none of the equipment or infrastructure they rely on in their day-to-day practice. Within several countries there has been a move to disseminate the actions to take in the event of such attacks: in the UK,Run, Hide, Tell, and in the USA,Fight Back. This paper outlines how a very basic medical knowledge combined with everyday high-street items can render highly effective first aid and save lives. We discuss and summarise modern improvised techniques. These include the  ABCDE approach of treating catastrophic haemorrhage before airway management, bringing together improvised techniques from the military and wilderness medicine. We explain how improvised tourniquets, wound dressings, splinting and traction devices can be fabricated using items from the high street: nappies, tampons, cling film, duct tape and tablecloths. Cervical spine immobilisation is a labour-intensive protocol that is often practised defensively. With little evidence to support the routine use of triple immobilisation, this should be replaced with a common sense dynamic approach such as the Montana neck brace. Acid or alkali attacks are also examined with simple pragmatic advice. Analgesia is discussed in the context of a prehospital setting. Pharmacy-obtained oral morphine and diclofenac suppositories can be used to treat moderate pain without relying on equipment for intravenous/intraosseous infusion in prolonged hold situations. The differentiation between concealment and cover is summarised: scene safety remains paramount.
Growth and body composition of children aged 2–4 years after exposure to community mobilisation women’s groups in Bangladesh
Authors: Fottrell Edward , Ahmed Naveed , Nahar Badrun , Shaha Sanjit Kumer , Kuddus Abdul , Grijalva-Eternod Carlos S , Nahar Tasmin , Fall Caroline , Osmond Clive , Govoni Virginia , Finer Sarah , Yajnik Chittaranjan , Khan A K Azad , Costello Anthony , Azad Kishwar , Hitman Graham A
Published: June 2018

Background

Women’s groups interventions in Bangladesh reduced neonatal deaths by 38% and improved hygienic delivery, newborn care practices and breast feeding. We explore the longer-term impact of exposure to women’s groups during pregnancy on child growth at 2–4 years.

Methods

We performed a cross-sectional survey of child anthropometric measures (analysed as z-scores) among children born to women who had participated in the women’s groups interventions while pregnant, compared with an age-matched and sex-matched sample of children born to control mothers. Results were stratified by maternal body mass index (BMI) and adjusted for possible confounding effects of maternal education, household asset ownership and, in a separate model, mother-child height difference, a proxy for improved survival of small babies in intervention groups.

Results

Data were obtained from 2587 mother-child pairs (91% response). After adjustment for asset ownership, maternal education and potential survival effects, children whose mothers were exposed to the women’s group intervention had higher head (0.16 (0.04 to 0.28)), mid-upper arm (0.11 (0.04 to 0.19)), abdominal (0.13 (0.00 to 0.26)) and chest (0.18 (0.08 to 0.29)) circumferences than their control counterparts. No significant differences in subcutaneous fat (subscapular and triceps skinfold thickness) were observed. When stratified by maternal BMI, intervention children had higher weight, BMI and circumferences, and these effects decreased with increasing maternal BMI category.

Conclusions

Women’s groups appear to have had a lasting, positive impact on child anthropometric outcomes, with most significant results clustering in children of underweight mothers. Observed differences are likely to be of public health significance in terms of the nutritional and metabolic development of children.
A mobile revolution for healthcare? Setting the agenda for bioethics
Authors: Lucivero Federica , Jongsma Karin R
Published: June 2018

Mobile health (mHealth) is rapidly being implemented and changing our ways of doing, understanding and organising healthcare. mHealth includes wearable devices as well as apps that track fitness, offer wellness programmes or provide tools to manage chronic conditions. According to industry and policy makers, these systems offer efficient and cost-effective solutions for disease prevention and self-management. While this development raises many ethically relevant questions, so far mHealth has received only little attention in medical ethics. This paper provides an overview of bioethical issues raised by mHealth and aims to draw scholarly attention to the ethical significance of its promises and challenges. We show that the overly positive promises of mHealth need to be nuanced and their desirability critically assessed. Finally, we offer suggestions to bioethicists to engage with this emerging trend in healthcare to develop mHealth to its best potential in a morally sound way.
Current evidence for anesthesia management during endovascular stroke therapy: updated systematic review and meta-analysis
Authors: Goyal Nitin , Malhotra Konark , Ishfaq Muhammad F , Tsivgoulis Georgios , Nickele Christopher , Hoit Daniel , Arthur Adam S , Alexandrov Andrei V , Elijovich Lucas
Published: June 2018

Introduction

Debate continues about the optimal anesthetic management for patients undergoing endovascular treatment (ET) of acute ischemic stroke due to emergent large vessel occlusion.

Objective

To compare, using current evidence, the clinical outcomes and procedural characteristics among patients undergoing general anesthesia (GA) and local or monitored anesthesia (non-GA).

Methods

We performed a systematic review and meta-analysis of all available studies that involved the use of stent retrievers for ET (stentriever group). Additionally, we included studies that were published in 2015 and later, and compared the clinical outcomes among the studies using stentrievers or no stentrievers (pre-stentriever group). Outcome variables included functional independence (FI; modified Rankin Scale scores of 0–2), symptomatic hemorrhage, mortality, procedure duration, and vascular and respiratory complications. We calculated pooled odds ratios and 95% CIs using random-effects models.

Results

Sixteen studies (three randomized controlled clinical trials (RCTs) and 13 non-randomized studies) were identified comprising 5836 patients. Although non-GA was associated with higher odds of 3-month FI (OR=1.57; 95% CI 1.17 to 2.10; P=0.003) and lower odds of 3-month mortality (OR=0.62; 95% CI 0.47 to 0.82; P=0.0006, substantial heterogeneity was noted across included trials. Sensitivity analyses of RCTs showed that non-GA was inversely associated with FI (OR=0.55; 95% CI 0.34 to 0.89; P=0.01; I2=15%), while no association was noted with mortality (OR=1.36; 95% CI 0.79 to 2.34; P=0.27; I2=0%).

Conclusion

Our updated meta-analysis demonstrates favorable results with non-GA, probably owing to inclusion of non-randomized studies. Recent single-center RCTs indicate that GA is associated with higher odds of FI at 3 months, while other outcomes are similar between the two groups.
Association between whey protein, regional fat mass, and strength in resistance-trained men: a cross-sectional study
Authors: Batista Ana , Monteiro Cristina P. , Borrego Rute , Matias Catarina N. , Teixeira Filipe J. , Valamatos Maria J. , Oliveira Ana C. , Reis Joana F. , Mendes Lino , Sardinha Luís B.
Published: June 2018

The purpose of this study was to evaluate the association between whey protein supplementation, body composition, and muscle strength in resistance-trained individuals. Forty-nine healthy males, aged 18 to 35 years and were engaged in resistance training for at least 1 year, were assigned into 2 groups according to whey protein intake (whey – n = 26, age: 30.7 ± 7.4 years, body mass: 75.8 ± 9.0 kg; without whey: n = 23, age: 31.0 ± 7.4 years, body mass: 77.9 ± 9.3 kg). Using a cross-sectional design, a morning assessment of body fat mass (FM) (by dual-energy X-ray absorptiometry) and strength (using 1-repetition maximum for bench press and back squat) was performed. Nutritional assessment was performed by 3-day food records. Regarding nutritional habits, differences between total energy intake (kcal) and estimated energy requirements (kcal) were observed. Results, from raw data or controlling for energy intake, estimated energy requirements, or achieved percentage of energy requirements, showed that whey protein supplementation was inversely correlated with whole-body FM (R = –0.367 (p = 0.010); R = –0.317 (p = 0.049); R = –0.380 (p = 0.011); R = –0.321 (p = 0.047), respectively), trunk FM (R = –0.396 (p = 0.005), R = –0.367 (p = 0.022), R = –0.423 (p = 0.004), R = –0.369 (p = 0.021), respectively) and android FM (R = –0.381 (p = 0.007), R = –0.332 (p = 0.039), R = –0.383 (p = 0.010), R = –0.336 (p = 0.036), respectively). No correlations were found between muscle strength outcomes and whey protein supplementation. The present data suggest that whey protein ingestion has a positive association with whole-body and regional (trunk and android) FM.
Light-induced conidiation ofTrichodermaspp. strains is accompanied by development-dependent changes in the Ca2+binding to cell walls
Authors: Kontár Szilvia , Varečka L’udovít , Híreš Michal , Kryštofová Svetlana , Šimkovič Martin
Published: June 2018

The effect of light on the binding of Ca2+to mycelia and to cell walls isolated from aerial mycelia of three strains of Trichoderma spp. was studied. Two independent methods were used to measure the total Ca2+content in mycelia and the Ca2+bound to cell walls isolated from aerial mycelia. The results of these methods showed that the light-induced formation and maturation of conidia in Trichoderma spp. is accompanied by increased Ca2+deposition in mycelia and cell walls. Moreover, the cultivation of Trichoderma atroviride F-534 in the presence of45Ca2+under circadian illumination showed that radioactivity was exclusively localized in the light-induced conidial rings of aerial mycelia. The fluorescence microscopy of chlortetracycline-stained mycelia showed that the major fraction of Ca2+was accumulated in conidia and fructification structures, or some intracellular compartments in T. atroviride F-534 grown under circadian illumination, while only a limited amount of Ca2+was associated with hyphal surfaces. In addition, the study of45Ca2+binding to cell walls revealed that T. atroviride F-534 displays both increased45Ca2+binding capacity and elevated affinity to45Ca2+binding upon illumination. The results indicate that conidia formation and (or) maturation is associated with changes in Ca2+homeostasis.
Distributed Trade-Based Edge Device Management in Multi-Gateway IoT
Authors: Samie Farzad , Tsoutsouras Vasileios , Bauer Lars , Xydis Sotirios , Soudris Dimitrios , Henkel Jörg
Published: June 2018

The Internet-of-Things (IoT) envisions an infrastructure of ubiquitous networked smart devices offering advanced monitoring and control services. The current art in IoT architectures utilizes gateways to enable application-specific connectivity to IoT devices. In typical configurations, IoT gateways are shared among several IoT edge devices. Given the limited available bandwidth and processing capabilities of an IoT gateway, the service quality (SQ) of connected IoT edge devices must be adjusted over time not only to fulfill the needs of individual IoT device users but also to tolerate the SQ needs of the other IoT edge devices sharing the same gateway. However, having multiple gateways introduces an interdependent problem, the binding, i.e., which IoT device shall connect to which gateway.

In this article, we jointly address the binding and allocation problems of IoT edge devices in a multigateway system under the constraints of available bandwidth, processing power, and battery lifetime. We propose a distributed trade-based mechanism in which after an initial setup, gateways negotiate and trade the IoT edge devices to increase the overall SQ. We evaluate the efficiency of the proposed approach with a case study and through extensive experimentation over different IoT system configurations regarding the number and type of the employed IoT edge devices. Experiments show that our solution improves the overall SQ by up to 56% compared to an unsupervised system. Our solution also achieves up to 24.6% improvement on overall SQ compared to the state-of-the-art SQ management scheme, while they both meet the battery lifetime constraints of the IoT devices.
Observation-Level and Parametric Interaction for High-Dimensional Data Analysis
Authors: Self Jessica Zeitz , Dowling Michelle , Wenskovitch John , Crandell Ian , Wang Ming , House Leanna , Leman Scotland , North Chris
Published: June 2018

Exploring high-dimensional data is challenging. Dimension reduction algorithms, such as weighted multidimensional scaling, support data exploration by projecting datasets to two dimensions for visualization. These projections can be explored through parametric interaction, tweaking underlying parameterizations, and observation-level interaction, directly interacting with the points within the projection. In this article, we present the results of a controlled usability study determining the differences, advantages, and drawbacks among parametric interaction, observation-level interaction, and their combination. The study assesses both interaction technique effects on domain-specific high-dimensional data analyses performed by non-experts of statistical algorithms. This study is performed using Andromeda, a tool that enables both parametric and observation-level interaction to provide in-depth data exploration. The results indicate that the two forms of interaction serve different, but complementary, purposes in gaining insight through steerable dimension reduction algorithms.
Toward Battery-Free Wearable Devices
Authors: Huang Qianyi , Mei Yan , Wang Wei , Zhang Qian
Published: June 2018

Recent years have witnessed the prevalence of wearable devices. Wearable devices are intelligent and multifunctional, but they rely heavily on batteries. This greatly limits their application scope, where replacement of battery or recharging is challenging or inconvenient. We note that wearable devices have the opportunity to harvest energy from human motion, as they are worn by the users as long as being functioning. In this article, we propose a battery-free sensing platform for wearable devices in the form factor of shoes. It harvests the kinetic energy from walking or running to supply devices with power for sensing, processing, and wireless communication, covering all the functionalities of commercial wearable devices. We achieve this goal by enabling the whole system running on the harvested energy from two feet. Each foot performs separate tasks and two feet are coordinated by ambient backscatter communication. We instantiate this idea by building a prototype, containing energy harvesting insoles, power management circuits, and ambient backscatter module. Evaluation results demonstrate that the system can wake up shortly after several seconds’ walk and have sufficient Bluetooth throughput for supporting many applications. We believe that our framework can stir a lot of useful applications that were infeasible previously.
CloudHeat
Authors: Chen Shutong , Zhou Zhi , Liu Fangming , Li Zongpeng , Ren Shaolei
Published: June 2018

Datacenters are major energy consumers and dissipate an enormous amount of waste heat. Simple outdoor discharging of datacenter heat is energy-consuming and environmentally unfriendly. By harvesting datacenter waste heat and selling to the district heating system (DHS), both energy cost compensation and environment protection can be achieved. To realize such benefits in practice, an efficient market mechanism is required to incentivize the participation of datacenters. This work proposes CloudHeat, an online reverse auction mechanism for the DHS to solicit heat bids from datacenters. To minimize long-term social operational cost of the DHS and the datacenters, we apply a RFHC approach for decomposing the long-term problem into a series of one-round auctions, guaranteeing a small loss in competitive ratio. The one-round optimization is still NP-hard, and we employ a randomized auction framework to simultaneously guarantee truthfulness, polynomial running time, and an approximation ratio of 2. The performance of CloudHeat is validated through theoretical analysis and trace-driven simulation studies.
Detecting Deviations from Intended Routes Using Vehicular GPS Tracks
Authors: Fujino Takumi , Hashimoto Atsushi , Kasahara Hidekazu , Mori Mikihiko , Iiyama Masaaki , Minoh Michihiko
Published: June 2018

This article proposes a method to find intersections at which cars tend to deviate from the optimal route based on global positioning system (GPS) tracking data under the assumption that such deviations indicate that car navigation systems (CNSs) and road signage are not readily available. If the intended route is known, deviations can be enumerated by comparing the intended route with the vehicle’s actual route as observed by a GPS; however, the intended route is unknown and can differ from the route suggested by a CNS. To identify intersections with high deviation rates without knowing intended routes, we exhaustively sampled subsequences from each vehicular GPS track, and detected deviations from the optimal route for the subsequences. Although the detected deviations are not always caused by driver confusion, accumulating such erroneous detection results would yield a meaningful difference in the number of accumulated deviations at each intersection. We applied the proposed method to 3,843 GPS tracks collected from visitor drivers in the city of Kyoto. Thresholding the estimated deviation rate yielded 39 intersections from 14,543 candidates. The results show a certain level of correlation between obtained deviations and rerouting locations from actual CNS data. We also found several intersections where faulty route suggestions are provided by CNSs.
Motion-Sound Mapping through Interaction
Authors: Françoise Jules , Bevilacqua Frédéric
Published: June 2018

Technologies for sensing movement are expanding toward everyday use in virtual reality, gaming, and artistic practices. In this context, there is a need for methodologies to help designers and users create meaningful movement experiences. This article discusses a user-centered approach for the design of interactive auditory feedback using interactive machine learning. We discuss Mapping through Interaction, a method for crafting sonic interactions from corporeal demonstrations of embodied associations between motion and sound. It uses an interactive machine learning approach to build the mapping from user demonstrations, emphasizing an iterative design process that integrates acted and interactive experiences of the relationships between movement and sound. We examine Gaussian Mixture Regression and Hidden Markov Regression for continuous movement recognition and real-time sound parameter generation. We illustrate and evaluate this approach through an application in which novice users can create interactive sound feedback based on coproduced gestures and vocalizations. Results indicate that Gaussian Mixture Regression and Hidden Markov Regression can efficiently learn complex motion-sound mappings from few examples.
Intel MPX Explained
Authors: Oleksenko Oleksii , Kuvaiskii Dmitrii , Bhatotia Pramod , Felber Pascal , Fetzer Christof
Published: June 2018

Memory-safety violations are the primary cause of security and reliability issues in software systems written in unsafe languages. Given the limited adoption of decades-long research in software-based memory safety approaches, as an alternative, Intel released Memory Protection Extensions (MPX)---a hardware-assisted technique to achieve memory safety. In this work, we perform an exhaustive study of Intel MPX architecture along three dimensions: (a) performance overheads, (b) security guarantees, and (c) usability issues. We present the first detailed root cause analysis of problems in the Intel MPX architecture through a cross-layer dissection of the entire system stack, involving the hardware, operating system, compilers, and applications. To put our findings into perspective, we also present an in-depth comparison of Intel MPX with three prominent types of software-based memory safety approaches. Lastly, based on our investigation, we propose directions for potential changes to the Intel MPX architecture to aid the design space exploration of future hardware extensions for memory safety.
Regression Discontinuity in Time: Considerations for Empirical Applications
Authors: Hausman Catherine , Rapson David S.
Published: June 2018

Recent empirical work in several economic fields, particularly environmental and energy economics, has adapted the regression discontinuity (RD) framework to applications where time is the running variable and treatment begins at a particular threshold in time. In this guide for practitioners, we discuss several features of this regression discontinuity in time framework that differ from the more standard cross-sectional RD framework. First, many applications (particularly in environmental economics) lack cross-sectional variation and are estimated using observations far from the temporal threshold. This common empirical practice is hard to square with the assumptions of a cross-sectional RD, which is conceptualized for an estimation bandwidth shrinking even as the sample size increases. Second, estimates may be biased if the time-series properties of the data are ignored (for instance, in the presence of an autoregressive process), or more generally if short-run and long-run effects differ. Finally, tests for sorting or bunching near the threshold are often irrelevant, making the framework closer to an event study than a regression discontinuity design. Based on these features and motivated by hypothetical examples using air quality data, we offer suggestions for the empirical researcher wishing to use the RD in time framework.
Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling
Authors: Ariyasinghe Nethika R. , Lyra-Leite Davi M. , McCain Megan L.
Published: June 2018

Many cardiovascular diseases are associated with pathological remodeling of the extracellular matrix (ECM) in the myocardium. ECM remodeling is a complex, multifactorial process that often contributes to declines in myocardial function and progression toward heart failure. However, the direct effects of the many forms of ECM remodeling on myocardial cell and tissue function remain elusive, in part because conventional model systems used to investigate these relationships lack robust experimental control over the ECM. To address these shortcomings, microphysiological systems are now being developed and implemented to establish direct relationships between distinct features in the ECM and myocardial function with unprecedented control and resolution in vitro. In this review, we will first highlight the most prominent characteristics of ECM remodeling in cardiovascular disease and describe how these features can be mimicked with synthetic and natural biomaterials that offer independent control over multiple ECM-related parameters, such as rigidity and composition. We will then detail innovative microfabrication techniques that enable precise regulation of cellular architecture in two and three dimensions. We will also describe new approaches for quantifying multiple aspects of myocardial function in vitro, such as contractility, action potential propagation, and metabolism. Together, these collective technologies implemented as cardiac microphysiological systems will continue to uncover important relationships between pathological ECM remodeling and myocardial cell and tissue function, leading to new fundamental insights into cardiovascular disease, improved human disease models, and novel therapeutic approaches.
MET-Oncogenic and JAK2-Inactivating Alterations Are Independent Factors That Affect Regulation of PD-L1 Expression in Lung Cancer
Authors: Saigi Maria , Alburquerque-Bejar Juan J. , Mc Leer-Florin Anne , Pereira Carolina , Pros Eva , Romero Octavio A. , Baixeras Nuria , Esteve-Codina Anna , Nadal Ernest , Brambilla Elisabeth , Sanchez-Cespedes Montse
Published: June 2018

Purpose: The blockade of immune checkpoints such as PD-L1 and PD-1 is being exploited therapeutically in several types of malignancies. Here, we aimed to understand the contribution of the genetics of lung cancer to the ability of tumor cells to escape immunosurveillance checkpoints.

Experimental Design: More than 150 primary non–small cell lung cancers, including pulmonary sarcomatoid carcinomas, were tested for levels of the HLA-I complex, PD-L1, tumor-infiltrating CD8+ lymphocytes, and alterations in main lung cancer genes. Correlations were validated in cancer cell lines using appropriate treatments to activate or inhibit selected pathways. We also performed RNA sequencing to assess changes in gene expression after these treatments.

Results: MET-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas STK11 mutations were correlated with negative immunostaining. In MET-altered cancer cells, MET triggered a transcriptional increase of PD-L1 that was independent of the IFNγ-mediated JAK/STAT pathway. The activation of MET also upregulated other immunosuppressive genes (PDCD1LG2 and SOCS1) and transcripts involved in angiogenesis (VEGFA and NRP1) and in cell proliferation. We also report recurrent inactivating mutations in JAK2 that co-occur with alterations in MET and STK11, which prevented the induction of immunoresponse-related genes following treatment with IFNγ.

Conclusions: We show that MET activation promotes the expression of several negative checkpoint regulators of the immunoresponse, including PD-L1. In addition, we report inactivation of JAK2 in lung cancer cells that prevented the response to IFNγ. These alterations are likely to facilitate tumor growth by enabling immune tolerance and may affect the response to immune checkpoint inhibitors. Clin Cancer Res; 24(18); 4579–87. ©2018 AACR.
Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer
Authors: Yang Yang , Mamouni Kenza , Li Xin , Chen Yanhua , Kavuri Sravan , Du Yuhong , Fu Haian , Kucuk Omer , Wu Daqing
Published: June 2018

Docetaxel resistance remains a major obstacle in the treatment of prostate cancer bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of prostate cancer in preclinical models. DRD2 is ubiquitously expressed in prostate cancer cell lines and significantly reduced in prostate cancer tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in prostate cancer cells, but effectively induces cell-cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1, and survivin and increases the expression of p53, p21, and p27. Intriguingly, bromocriptine markedly reduces androgen receptor levels, partially through Hsp90-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in prostate cancer cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in prostate cancer. Mol Cancer Ther; 17(9); 1859–70. ©2018 AACR.
YAP Is Essential for Treg-Mediated Suppression of Antitumor Immunity
Authors: Ni Xuhao , Tao Jinhui , Barbi Joseph , Chen Qian , Park Benjamin V. , Li Zhiguang , Zhang Nailing , Lebid Andriana , Ramaswamy Anjali , Wei Ping , Zheng Ying , Zhang Xuehong , Wu Xingmei , Vignali Paolo , Yang Cui-Ping , Li Huabin , Pardoll Drew , Lu Ling , Pan Duojia , Pan Fan
Published: June 2018

Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFβ/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target.

Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026–43. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899
Precision Prevention and Early Detection of Cancer: Fundamental Principles
Authors: Rebbeck Timothy R. , Burns-White Karen , Chan Andrew T. , Emmons Karen , Freedman Matthew , Hunter David J. , Kraft Peter , Laden Francine , Mucci Lorelei , Parmigiani Giovanni , Schrag Deborah , Syngal Sapna , Tamimi Rulla M. , Viswanath Kasisomayajula , Yurgelun Matthew B. , Garber Judy E.
Published: June 2018

Prevention and early detection is critical for reducing the population cancer burden. Two approaches have been used: Population approaches change social norms (e.g., smoking bans) or impose incentives (e.g., cigarette taxes); high-risk strategies intervene upon individuals with elevated cancer risk (e.g., smoking cessation). Knowledge about carcinogenesis mechanisms, extreme exposures, and inherited susceptibility provides opportunities to develop precision prevention and early-detection (PPED) strategies. PPED aims to understand the basis of risk, identify groups that optimally benefit from interventions, characterize heterogeneity in intervention responses, optimize intervention timing, and minimize toxicities. We propose a framework around which PPED strategies can be developed. Currently available cancer prevention and early-detection approaches have the potential to reduce a large proportion of the cancer burden in the population. However, even if fully implemented, existing methods cannot fully eliminate the cancer burden. New PPED approaches that exploit the growing knowledge of molecular and biological cancer mechanisms should be developed and implemented. Cancer Discov; 8(7); 803–11. ©2018 AACR.
Exosomes Shuttle TREX1-Sensitive IFN-Stimulatory dsDNA from Irradiated Cancer Cells to DCs
Authors: Diamond Julie M. , Vanpouille-Box Claire , Spada Sheila , Rudqvist Nils-Petter , Chapman Jessica R. , Ueberheide Beatrix M. , Pilones Karsten A. , Sarfraz Yasmeen , Formenti Silvia C. , Demaria Sandra
Published: June 2018

Radiotherapy (RT) used at immunogenic doses leads to accumulation of cytosolic double-stranded DNA (dsDNA) in cancer cells, which activates type I IFN (IFN-I) via the cGAS/STING pathway. Cancer cell–derived IFN-I is required to recruit BATF3-dependent dendritic cells (DC) to poorly immunogenic tumors and trigger antitumor T-cell responses in combination with immune checkpoint blockade. We have previously demonstrated that the exonuclease TREX1 regulates radiation immunogenicity by degrading cytosolic dsDNA. Tumor-derived DNA can also activate cGAS/STING-mediated production of IFN-I by DCs infiltrating immunogenic tumors. However, how DNA from cancer cells is transferred to the cytoplasm of DCs remains unclear. Here, we showed that tumor-derived exosomes (TEX) produced by irradiated mouse breast cancer cells (RT-TEX) transfer dsDNA to DCs and stimulate DC upregulation of costimulatory molecules and STING-dependent activation of IFN-I. In vivo, RT-TEX elicited tumor-specific CD8+ T-cell responses and protected mice from tumor development significantly better than TEX from untreated cancer cells in a prophylactic vaccination experiment. We demonstrated that the IFN-stimulatory dsDNA cargo of RT-TEX is regulated by TREX1 expression in the parent cells. Overall, these results identify RT-TEX as a mechanism whereby IFN-stimulatory dsDNA is transferred from irradiated cancer cells to DCs. We have previously shown that the expression of TREX1 is dependent on the RT dose size. Thus, these data have important implications for the use of RT with immunotherapy. Cancer Immunol Res; 6(8); 910–20. ©2018 AACR.
Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect
Authors: Gretarsdottir Helga M. , Bjornsdottir Elin , Bjornsson Einar S.
Published: June 2018

We describe a case of acute liver injury and migratory arthralgia in a patient receiving bicalutamide treatment for prostate cancer. A 67-year-old male with metastatic prostate cancer presented with a 6-day history of migratory arthralgia. He had been undergoing treatment with bicalutamide for 4 months; 3 weeks prior to symptom appearance the bicalutamide dose had been increased. He had no other symptoms. Liver tests and inflammatory markers were markedly elevated. Serology for hepatitis viruses A, B, and C, CMV, and EBV and autoimmune causes were all negative, and an ultrasound of the upper abdomen was normal. There was no history of blood transfusion, intravenous drug abuse, or alcohol abuse. Due to the suspicion of a drug-induced symptomatology, bicalutamide was discontinued and the patient started on 30 mg prednisolone daily. Three weeks later he was symptom free and after 6 weeks his liver tests were almost normal. The Roussel Uclaf Causality Assessment Method (RUCAM) suggested a high probability of liver injury. Bicalutamide has very rarely been reported as a causative agent for liver injury and to our knowledge never for migratory polyarthralgia. The migratory polyarthralgia was attributed to bicalutamide due to the absence of other etiological factors and the disappearance of symptoms after discontinuation of the drug. To our knowledge, this is the first published case report of migratory arthralgia and concomitant liver injury attributed to bicalutamide.
Acute Macular Neuroretinopathy following Oral Intake of Adrenergic Flu Treatments
Authors: Stanescu-Segall Dinu , Yap Chong , Burton Ben J.L.
Published: June 2018

Purpose: The purpose of this study was to report a case series of patients with acute macular neureretinopathy in which patients concomitantly used ephedrine or pseudo-ephedrine. Methods: This is a retrospective case review. Results: Two patients with retinal findings consistent with acute macular neuroretinopathy are presented. Conclusion: Acute macular neuroretinopathy should be considered in any young patient with unexplained loss of vision and exposed to direct or indirect adrenergic stimulation.
Metabolic Syndrome and the Iodine-Dose/Creatinine Clearance Ratio as Determinants of Contrast-Induced Acute Kidney Injury
Authors: Amiri Ali , Ghanavati Reza , Riahi Beni Hassan , Sezavar Seyyed Hashem , Sheykhvatan Mehrdad , Arab Mahsa
Published: June 2018

Background: Finding patients at risk of developing contrast-induced acute kidney injury (CI-AKI) is important because of its associated complications. In the present study, the contribution of different variables, such as the presence of metabolic syndrome (MetS), the volume creatinine clearance (V/CrCl) ratio, the iodine-dose (I-dose)/CrCl ratio, or hypertension, to CI-AKI was evaluated. Methods: A total of 255 patients undergoing elective coronary angiography with or without intervention were enrolled and divided into a MetS and a control group. All patients were assessed for the development of CI-AKI after the procedures. Results: CI-AKI occurred in 39.23% (51 of 130) of the MetS patients and 14.4% (18 of 125) of the control group (p < 0.001). The multivariable regression model showed that male sex and the use of statins decreased the risk of CI-AKI, and high triglyceride levels, I-dose/CrCl > 0.52, MetS, CrCl ≤60 mL/min, and age ≥70 years increased the risk of CI-AKI, independent of confounding factors. The difference in the mean V/CrCl ratio was statistically significant between patients who developed CI-AKI and those who did not show renal impairment (2.36 ± 1.35 vs. 1.43 ± 0.89, respectively; p < 0.001). The ROC curve analysis of I-dose/CrCl determined the best cutoff value for patients with and those without MetS as 0.51 and 0.63, with a sensitivity value of 68 and 72% and a specificity value of 73 and 74%, respectively. Conclusions: We showed that MetS is a strong risk factor for CI-AKI in nondiabetic patients undergoing elective coronary interventions; and the I-dose/CrCl ratio is a strong predictor of CI-AKI in these patients. We suggest that clinicians identify MetS patients and calculate their I-dose/CrCl ratio before coronary interventions.
Neopterin as a Biomarker in Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension
Authors: Smukowska-Gorynia Anna , Marcinkowska Justyna , Chmara Ewa , Malaczynska-Rajpold Katarzyna , Slawek-Szmyt Sylwia , Cieslewicz Artur , Janus Magdalena , Araszkiewicz Aleksander , Jankiewicz Stanislaw , Komosa Anna , Olasinska-Wisniewska Anna , Tomaszewska Iga , Mularek-Kubzdela Tatiana
Published: June 2018

Background: Upregulation of the immune system is regarded to play an important role in the etiopathobiology of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). To the best of our knowledge, neopterin (NP) has never been investigated in patients with PAH and CTEPH. Objectives: The aim of the study was to evaluate the concentration of NP in blood in order to examine its impact on outcome and relationship with disease severity in that population. Methods: Serum concentration of NP was analysed prospectively in 50 patients (36 with PAH and 14 with CTEPH vs. 31 healthy controls) and assessed in relation to clinical parameters and outcome. Results: NP concentration in the PAH and CTEPH groups combined was significantly higher than in the control group (8.68, 6.39–15.03 vs. 5.14, 4.16–5.98 nmol/L, p < 0.0000001). During 9 months of follow-up, clinical deterioration occurred in 18 patients (including 8 deaths), and NP concentration in this group was higher when compared to stable patients (15.6, 8.52–25.13 vs. 7.87, 6.18–9.89, p = 0.002). The cutoff value of NP derived from ROC curve analysis was 15.3 nmol/L (p = 0.002, AUC 0.77, p = 0.0004, HR = 4.35, 95% CI 1.43–13.18, log-rank test). On Cox regression analysis, NP predicted clinical deterioration (p = 0.009, 95% CI 1.01–1.06). NP correlated positively with NT-proBNP (p < 0.001), red blood cell distribution width (p < 0.001), and right atrium area (p = 0.002) and inversely with 6-min walking test (p = 0.002) and peak oxygen consumption (p = 0.001). Conclusions: NP concentration is increased in patients with PAH and inoperable CTEPH. Elevated NP concentration is associated with adverse clinical outcomes and correlates with clinical parameters.
Increased Expression of Programmed Death-Ligand 1 in Infiltrating Immune Cells in Hepatocellular Carcinoma Tissues after Sorafenib Treatment
Authors: Lu Li-Chun , Lee Yi-Hsuan , Chang Chun-Jung , Shun Chia-Tung , Fang Chih-Yeu , Shao Yu-Yun , Liu Tsung-Hao , Cheng Ann-Lii , Hsu Chih-Hung
Published: June 2018

Objective: Programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment (TME) has been reported to be related to prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC is unclear. Patients and Methods: Patients with HCC who received sorafenib for advanced disease at National Taiwan University Hospital, Taipei, Taiwan, and who had paired HCC tissues obtained before and after sorafenib treatment were included in the study group. HCC patients not treated with sorafenib who had paired primary and recurrent or metastatic tissues were identified as the reference group. The membrane PD-L1 staining, detected by immunohistochemistry (IHC) using SP142 antibody, was semiquantitatively scored in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). Additional IHC assays were employed to characterize the PD-L1-expressing ICs. Results: Twenty-three advanced HCC patients with pre- and post-sorafenib paired HCC tissues were included in the study group. The median duration of sorafenib treatment was 4.3 months (range: 1.3–18.7). PD-L1 expression in ICs was significantly higher in post-sorafenib HCC tissues than in pre-sorafenib HCC tissues (pre-sorafenib vs. post-sorafenib IHC 0/1/2/3: 11/5/5/2 vs. 5/5/2/11, p = 0.016). However, PD-L1 expression in TCs was not significantly different between pre- and post-sorafenib tissues (IHC 0/1/2/3: 19/2/0/2 vs. 14/5/0/4, p = 0.094). In the reference group of 44 patients not treated with sorafenib, PD-L1 expression in ICs and TCs was not significantly different between the paired primary and metastatic HCC tissues. By performing IHC double staining with PD-L1 and CD68, we found the PD-L1-expressing ICs were mainly CD68-positive macrophages. PD-L1 expression levels of pre- and post-sorafenib tissues were not associated with patients’ overall survival or duration of sorafenib treatment. Conclusions: PD-L1 expression in ICs was significantly increased in post-sorafenib HCC tissues. The mechanisms and clinical significance of this observation warrants further investigation.