bluuebunny/crossref_metadata_2025 huggingface dataset:
Displaying radiation exposure and cost information at order entry for outpatient diagnostic imaging: a strategy to inform clinician ordering
Authors: Kruger Jenna F , Chen Alice Hm , Rybkin Alex , Leeds Kiren , Guzman David , Vittinghoff Eric , Goldman L Elizabeth
Published: January 2016

Background

Displaying radiation exposure and cost information at electronic order entry may encourage clinicians to consider the value of diagnostic imaging.

Methods

An urban safety-net health system displayed radiation exposure information for CT and cost information for CT, MRI and ultrasound on an electronic referral system for outpatient ordering. We assessed whether there were differences in numbers of outpatient CT scans and MRIs per month relative to ultrasounds before and after the intervention, and evaluated primary care clinicians’ responses to the intervention.

Results

There were 23 171 outpatient CTs, 15 052 MRIs and 43 266 ultrasounds from 2011 to 2014. The ratio of CTs to ultrasounds decreased by 15% (95% CI 9% to 21%), from 58.2 to 49.6 CTs per 100 ultrasounds; the ratio of MRIs to ultrasounds declined by 13% (95% CI 7% to 19%), from 37.5 to 32.5 per 100. Of 300 invited, 190 (63%) completed the web-based survey in 17 clinics. 154 (81%) noticed the radiation exposure information and 158 (83.2%) noticed the cost information. Clinicians believed radiation exposure information was more influential than cost information: when unsure clinically about ordering a test (radiation=69.7%; cost=46.4%), when a patient wanted a test not clinically indicated (radiation=77.5%; cost=54.8%), when they had a choice between imaging modalities (radiation=77.9%; cost=66.6%), in patient care discussions (radiation=71.9%; cost=43.2%) and in trainee discussions (radiation=56.5%; cost=53.7%). Resident physicians and nurse practitioners were more likely to report that the cost information influenced them (p<0.05).

Conclusions

Displaying radiation exposure and cost information at order entry may improve clinician awareness about diagnostic imaging safety risks and costs. More clinicians reported the radiation information influenced their clinical practice.
The Healthcare Complaints Analysis Tool: development and reliability testing of a method for service monitoring and organisational learning
Authors: Gillespie Alex , Reader Tom W
Published: January 2016

Background

Letters of complaint written by patients and their advocates reporting poor healthcare experiences represent an under-used data source. The lack of a method for extracting reliable data from these heterogeneous letters hinders their use for monitoring and learning. To address this gap, we report on the development and reliability testing of the Healthcare Complaints Analysis Tool (HCAT).

Methods

HCAT was developed from a taxonomy of healthcare complaints reported in a previously published systematic review. It introduces the novel idea that complaints should be analysed in terms of severity. Recruiting three groups of educated lay participants (n=58, n=58, n=55), we refined the taxonomy through three iterations of discriminant content validity testing. We then supplemented this refined taxonomy with explicit coding procedures for seven problem categories (each with four levels of severity), stage of care and harm. These combined elements were further refined through iterative coding of a UK national sample of healthcare complaints (n= 25, n=80, n=137, n=839). To assess reliability and accuracy for the resultant tool, 14 educated lay participants coded a referent sample of 125 healthcare complaints.

Results

The seven HCAT problem categories (quality, safety, environment, institutional processes, listening, communication, and respect and patient rights) were found to be conceptually distinct. On average, raters identified 1.94 problems (SD=0.26) per complaint letter. Coders exhibited substantial reliability in identifying problems at four levels of severity; moderate and substantial reliability in identifying stages of care (except for ‘discharge/transfer’ that was only fairly reliable) and substantial reliability in identifying overall harm.

Conclusions

HCAT is not only the first reliable tool for coding complaints, it is the first tool to measure the severity of complaints. It facilitates service monitoring and organisational learning and it enables future research examining whether healthcare complaints are a leading indicator of poor service outcomes.HCATis freely available to download and use.
The Medicines Advice Service Evaluation (MASE): a randomised controlled trial of a pharmacist-led telephone based intervention designed to improve medication adherence
Authors: Lyons Imogen , Barber Nicholas , Raynor David K , Wei Li
Published: January 2016

Aim

To test the effectiveness of a tailored, pharmacist-led centralised advice service to improve adherence to patients on established medications.

Methods

A parallel group randomised controlled trial was conducted. Patients prescribed at least one oral medication for type 2 diabetes and/or lipid regulation were eligible to participate. 677 patients of a mail-order pharmacy were recruited and randomised (340 intervention, 337 control). The intervention comprised two tailored telephone consultations with a pharmacist, 4–6 weeks apart, plus a written summary of the discussion and a medicines reminder chart. The primary outcome was self-reported adherence to medication at 6-month follow-up, collected via a postal questionnaire, analysed using generalised estimating equations. Secondary outcomes included prescription refill adherence, lipid and glycaemic control and patient satisfaction.

Results

In intention-to-treat analysis 36/340 (10.6%) of the intervention group were non-adherent (<90% of medication taken in the past 7 days) at 6 months compared with 66/337 (19.6%) in the control group, yielding an unadjusted OR of 1.54 (95% CI 1.11 to 2.15, p=0.01). Analyses of dispensing data also showed that the odds of being classified as adherent (≥90%) were 60% greater for the intervention group compared with the control group (OR 1.60, 95% CI 1.14 to 2.24, p<0.01). In a subsample of patients who provided blood samples, glycaemic and lipid control did not differ significantly between groups (p=0.06 and p=0.24, respectively) but positive trends were observed. Ninety-two per cent of intervention group patients reported that they were satisfied with the service overall.

Conclusions

A telephone intervention, led by a pharmacist and tailored to the individuals’ needs, can significantly improve medication adherence in patients with long-term conditions, using a mail-order pharmacy. Further work is needed to confirm a trend towards improved clinical outcome.

Trial registration number

NCT01864239.
Rationale for and design of the Idiopathic Pulmonary Fibrosis–PRospective Outcomes (IPF-PRO) registry
Authors: O'Brien Emily C , Durheim Michael T , Gamerman Victoria , Garfinkel Sandy , Anstrom Kevin J , Palmer Scott M , Conoscenti Craig S
Published: January 2016

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterised by progressive loss of lung function. Its clinical course is variable but ultimately fatal. There is a need for a multicentre patient registry incorporating longitudinal clinical data and biological samples to improve understanding of the natural history of IPF and contemporary practice patterns.

Methods/design

The Idiopathic Pulmonary Fibrosis–PRospective Outcomes (IPF-PRO) registry is a national IPF registry in the USA. This registry will enrol approximately 300 patients with newly diagnosed IPF over 2 years at approximately 14 tertiary pulmonary care sites. Participants will be followed for 3–5 years and will receive usual care, as defined by their physician. Clinical data from the year prior to diagnosis will be collected from medical record review on enrolment. Subsequently, data on diagnostic evaluations, pulmonary function tests, physical examinations, laboratory data and clinical events will be collected at routine clinical visits and via a call centre. Participants will complete patient-reported outcome questionnaires at enrolment and then at approximately 6-month intervals. Blood samples for cellular, genetic and transcriptomic analyses will be collected at the same intervals.

Results

The first results from the IPF-PRO registry will be presented in 2015.

Conclusions

The IPF-PRO registry will improve understanding of the natural history of IPF, its impact on patients and current practice in the diagnosis and care of patients with IPF. The registry will establish a repository of biological samples from a well-characterised patient population for future research.

Clinical trial number

NCT01915511.
Complex shoulder girdle injuries following mountain bike accidents and a review of the literature
Authors: Lea Matthew Alexander , Makaram Navnit , Srinivasan Makaram S
Published: January 2016

Background

Mountain and road bike accidents are particularly common with the increased popularity of the sport. We reviewed the attendances in our emergency department over a 4-year period looking at cycling injuries to detect the level and grade of these injuries and their outcomes.

Method

Royal Blackburn Hospital caters for a population of 550 000. A search through the Hospital information system revealed 104 patients with fractures following mountain bike injuries. These were looked at in more detail. We present a series of 5 severe shoulder girdle injuries following mountain bike accidents in this cohort, to highlight the serious level of injury sustained in this sport. We searched MEDLINE and EMBASE databases over the past 10 years using the keywords, mountain, biking and fracture. This yielded 7 papers. We compared our series with the literature.

Results

104 fractures following mountain bike accidents between 2008 and 2011. Fractures of the upper limb were the most common (88.5%) with the clavicle being the most commonly fractured bone (28.8%).

Conclusions

Major scapular injuries with destruction or disruption of the four bar linkage of the shoulder girdle are very common following mountain accidents. Clavicular fractures are the commonest upper limb injury. It is easy to miss a disruption to the four-bar linkage associated with a clavicular injury. This paper highlights the severity of the injuries sustained in mountain bike accidents of the upper limb and requirement of adequate protection in this exhilarating sport.
Assessment of intracranial aneurysm rupture based on morphology parameters and anatomical locations
Authors: Zheng Yongtao , Xu Feng , Ren Jinma , Xu Qiang , Liu Yingjun , Tian Yanlong , Leng Bing
Published: January 2016

Objectives

The aim of the present study was to identify image-based morphological parameters and anatomical locations associated with intracranial aneurysm (IA) rupture.

Methods

Nine morphological parameters and aneurysm location were evaluated in 150 patients with saccular IAs (82 unruptured, 68 ruptured) using three-dimensional geometry. Aneurysm location and morphological parameters including size, aspect ratio, size ratio, height–width ratio, flow angle, aneurysm inclination angle, parent artery angle, vessel angle, and aneurysm shape were explored to identify a correlation with aneurysm rupture. These factors were analyzed using a two-tailed independent Student t test or the χ test for significance. Significant factors were further examined using logistic regression analysis. Additionally, receiver operating characteristic (ROC) analysis was performed to evaluate each parameter.

Results

Statistically significant differences were observed in ruptured and unruptured groups for aspect ratio, size ratio, height–width ratio, flow angle, aneurysm inclination angle, vessel angle, aneurysm shape, and aneurysm location. Logistic regression analysis further revealed that size ratio (OR 1.66; 95% CI 1.05 to 2.64), height–width ratio (OR 14.22; 95% CI 2.67 to 75.88), aneurysm inclination angle (OR 1.04; 95% CI 1.01 to 1.07), aneurysm shape (OR 4.68; 95% CI 2.44 to 8.98), and aneurysm location (OR 1.60; 95% CI 1.15 to 2.23) had the strongest independent correlation with ruptured IA. The ROC analysis showed that the size ratio and flow angle had the highest area under the curve, with values of 0.735 and 0.730, respectively.

Conclusions

Size ratio, height–width ratio, aneurysm inclination angle, aneurysm shape, and aneurysm location might be important for discriminating between ruptured and unruptured aneurysms. Further investigation will determine whether these morphological parameters and anatomical locations will be reliable predictors of aneurysm rupture.
From particle counting to Gaussian tomography
Authors: Parthasarathy K. R. , Sengupta Ritabrata
Published: January 2016

The momentum and position observables in an [Formula: see text]-mode boson Fock space [Formula: see text] have the whole real line [Formula: see text] as their spectrum. But the total number operator [Formula: see text] has a discrete spectrum [Formula: see text]. An [Formula: see text]-mode Gaussian state in [Formula: see text] is completely determined by the mean values of momentum and position observables and their covariance matrix which together constitute a family of [Formula: see text] real parameters. Starting with [Formula: see text] and its unitary conjugates by the Weyl displacement operators and operators from a representation of the symplectic group [Formula: see text] in [Formula: see text], we construct [Formula: see text] observables with spectrum [Formula: see text] but whose expectation values in a Gaussian state determine all its mean and covariance parameters. Thus measurements of discrete-valued observables enable the tomography of the underlying Gaussian state and it can be done by using five one-mode and four two-mode Gaussian symplectic gates in single and pair mode wires of [Formula: see text]. Thus the tomography protocol admits a simple description in a language similar to circuits in quantum computation theory. Such a Gaussian tomography applied to outputs of a Gaussian channel with coherent input states permit a tomography of the channel parameters. However, in our procedure the number of counting measurements exceeds the number of channel parameters slightly. Presently, it is not clear whether a more efficient method exists for reducing this tomographic complexity.

As a byproduct of our approach an elementary derivation of the probability generating function of [Formula: see text] in a Gaussian state is given. In many cases the distribution turns out to be infinitely divisible and its underlying Lévy measure can be obtained. However, we are unable to derive the exact distribution in all cases. Whether this property of infinite divisibility holds in general is left as an open problem.
Compact and On-the-Fly Secure Dynamic Reconfiguration for Volatile FPGAs
Authors: Kashyap Hirak , Chaves Ricardo
Published: January 2016

The dynamic partial reconfiguration functionality of FPGAs can be attacked, particularly when the FPGA is remotely located or the configuration bitstreams are sent through insecure networks. The existing FPGA technologies provide some built-in security mechanisms; however, these are often inadequate. The existing solutions still impose a significant impact on the reconfiguration process and on the available resources.

This article proposes a solution to improve the security of dynamic partial reconfiguration of FPGAs, without significantly affecting the reconfiguration performance. The proposed solution changes the encryption key of the remotely received bitstream by a randomly generated key, unique for each configuration, when storing them in the external unsecured memory. The native frame-wise error detection mechanism combined with an additional CBC-MAC authentication mechanism, allows for an improved countermeasure against replay attack and wrongful bitstream usage. The proposed solution introduces an overhead of 1% of the available resources on the target FPGA and provides the lowest impact on the reconfiguration process when compared to the state of the art, achieving a reconfiguration throughput of 2.5Gbps. Regarding the built-in security mechanism provided by the Xilinx FPGAs, the solution herein proposed provides better security and improves the reconfiguration performance by more than 3 times.
Machine learning meets visualization for extracting insights from text data
Authors: Soto Axel J. , Kiros Ryan , Keselj Vlado , Milios Evangelos
Published: January 2016

Historically, text mining methods have been enriched substantially by both statistical learning and symbolic AI. Different approaches have been extensively applied over the last 30 years to extract "knowledge" from text. However, in scenarios where the path from data to decisions is unclear, or where different users may be interested in different solutions, the involvement of the user or analyst in the text mining process becomes crucial. Visual Text Analytics aims at addressing these problems by incorporating concepts from Visual Analytics to text mining and natural language processing (Keim et. al, 2010).
Message from the editor
Authors: Chow Chi-Yin
Published: January 2016

In the first section, we have a special issue of some topic of interest to the SIGSPATIAL community. The topic of this issue is "Mobile Data Analytics" which is edited by our associate editor Dr. Chi-Yin Chow (Ted). Dr. Chow is currently an Assistant Professor in the Department of Computer Science, City University of Hong Kong.
Mobile data analytics
Authors: Chow Chi-Yin
Published: January 2016

With the rapid advancement of mobile devices and location acquisition technologies, more and more large-scale location-based data have been available for data analytics and realizing new location-aware services. Various large-scale location-based data including user-generated data in location-based social networks (LBSNs) and GPS data reported from vehicles or sensors have led to research challenges and opportunists in location-based services, intelligent transportation systems, geographic information systems, urban computing, and smart cities. Different computer science techniques, e.g., data mining, machine learning, artificial intelligence, and spatial and spatio-temporal databases, can be used or combined to address such challenges.
Brillouin Optical Time Domain Analysis Sensor for Active Vibration Control of a Cantilever Beam
Authors: Minardo Aldo , Coscetta Agnese , Pirozzi Salvatore , Zeni Luigi
Published: January 2016

The paper reports the use of a distributed optical fiber sensor based on stimulated Brillouin scattering, for structural vibration control. A cantilevered flexible aluminum beam was used as test-bed for vibration control. The proposed approach allows acquiring simultaneously the dynamic strain at several locations. The dynamic strain measured at one (or more) fiber location can be used to implement any vibration control algorithm. Experimental results are reported in which a voice coil, positioned near the fixed end of the cantilever beam, was employed as actuator for the reduction of the vibrations related to the first bending mode of the beam.
The Correlation of Serums CCL11, CCL17, CCL26, and CCL27 and Disease Severity in Patients with Urticaria
Authors: Lu Tao , Jiao Xiaoyang , Si Mengya , He Ping , Zou Jinbo , Zhang Shuping , Zeng Kang
Published: January 2016

Background.Chemokines may be involved in the pathogenesis of urticaria, but their correlation with disease severity as well as eruption type is unclear.Objectives.The aim of this study was to explore the expression of chemokines in patients with urticaria. The association between disease severity and levels of chemokines was analysed.Materials and Methods.Serums CCL11, CCL17, CCL26, and CCL27, D-dimer, C-reactive protein, and total IgE were measured in 51 patients with urticaria and in 25 healthy control subjects.Results.Serums CCL11, CCL17, CCL26, and CCL27 were significantly higher in patients with urticaria than in the healthy controls (P<0.05). Serum CCL27 strongly correlated with urticarial disease severity. Serums CCL17, CCL26, and CCL27 significantly correlated with D-dimer, while innercorrelations were noted among the chemokines.Conclusion.Our findings reveal that chemokines participate in the pathogenesis of urticaria. Further study in larger cohort is needed to testify whether they could be the biomarkers for predicting the severity of urticaria.
Depth-Sensitive Raman Investigation of Metal-Oxide-Semiconductor Structures: Absorption as a Tool for Variation of Exciting Light Penetration Depth
Authors: Borowicz Paweł
Published: January 2016

Presented work focuses the attention on two regions of MOS structure placed in the vicinity of the semiconductor/dielectric interface, in particular: on part of dielectric layer and thin layer of the substrate. In the presented work the application of absorption as a tool that can vary the absorption depth of excitation light into the semiconductor substrate is discussed. The changes of the absorption depth of visible light allows to obtain Raman signal from places in the substrate placed at different distances from the dielectric/semiconductor interface. The series of Raman spectra obtained from visible excitation in the case of varying absorption depth allowed to analyze the structure of the substrate as a function of distance from the interface. Deep ultraviolet Raman study regarding part of silicon dioxide layer placed directly at the interface is not discussed so far which makes the analysis of the structure of this part of dielectric layer possible. Comparison of reported in this work Raman data with structure of silicon/silicon dioxide interface obtained from other experimental techniques proves the applicability of proposed methodology.
Incremental Density-Based Link Clustering Algorithm for Community Detection in Dynamic Networks
Authors: Meng Fanrong , Zhang Feng , Zhu Mu , Xing Yan , Wang Zhixiao , Shi Jihong
Published: January 2016

Community detection in complex networks has become a research hotspot in recent years. However, most of the existing community detection algorithms are designed for the static networks; namely, the connections between the nodes are invariable. In this paper, we propose an incremental density-based link clustering algorithm for community detection in dynamic networks, iDBLINK. This algorithm is an extended version of DBLINK which is proposed in our previous work. It can update the local link community structure in the current moment through the change of similarity between the edges at the adjacent moments, which includes the creation, growth, merging, deletion, contraction, and division of link communities. Extensive experimental results demonstrate that iDBLINK not only has a great time efficiency, but also maintains a high quality community detection performance when the network topology is changing.
Applications of Fuss-Catalan Numbers to Success Runs of Bernoulli Trials
Authors: Dilworth S. J. , Mane S. R.
Published: January 2016

In a recent paper, the authors derived the exact solution for the probability mass function of the geometric distribution of orderk, expressing the roots of the associated auxiliary equation in terms of generating functions for Fuss-Catalan numbers. This paper applies the above formalism for the Fuss-Catalan numbers to treat additional problems pertaining to occurrences of success runs. New exact analytical expressions for the probability mass function and probability generating function and so forth are derived. First, we treat sequences of Bernoulli trials withr≥1occurrences of success runs of lengthkwithl-overlapping. The casel<0, where there must be a gap of at leastltrials between success runs, is also studied. Next we treat the distribution of the waiting time for therthnonoverlapping appearance of a pair of successes separated by at mostk-2failures (k≥2).
Time Delay Effect on Regenerative Chatter in Tandem Rolling Mills
Authors: Liu Xiaochan , Zang Yong , Gao Zhiying , Zeng Lingqiang
Published: January 2016

The interstand tension coupling effect and strip gauge variation passed on to next stand with time delay are the main causes for regenerative chatter in tandem rolling mills. To study the effect of different factors on the stability of tandem rolling mills, different models considering different interstand factors were built. Through stability analysis of these models by employing the Lyapunov indirect method and integral criterion, more detailed and quantitative explanation is put forward to regenerative chatter mechanism in rolling. To study the time delay effect as a single factor on the stability of tandem rolling mills, stability charts of the chatter model including the time delay effect and model neglecting the delay time were compared. The results show that the time delay effect reduces the critical velocity of multistand mills slightly in the big picture. But it alters the relationship between two adjacent stands by worsening the downstream stand stability. To get preferable rolling process parameter configuration for the tandem rolling mills, the time delay effect in rolling must be involved.
A Unified Spectro-Geometric-Ritz Method for Vibration Analysis of Open and Closed Shells with Arbitrary Boundary Conditions
Authors: Shi Dongyan , Zhao Yunke , Wang Qingshan , Teng Xiaoyan , Pang Fuzhen
Published: January 2016

This paper presents free vibration analysis of open and closed shells with arbitrary boundary conditions using a spectro-geometric-Ritz method. In this method, regardless of the boundary conditions, each of the displacement components of open and closed shells is represented simultaneously as a standard Fourier cosine series and several auxiliary functions. The auxiliary functions are introduced to accelerate the convergence of the series expansion and eliminate all the relevant discontinuities with the displacement and its derivatives at the boundaries. The boundary conditions are modeled using the spring stiffness technique. All the expansion coefficients are treated equally and independently as the generalized coordinates and determined using Rayleigh-Ritz method. By using this method, a unified vibration analysis model for the open and closed shells with arbitrary boundary conditions can be established without the need of changing either the equations of motion or the expression of the displacement components. The reliability and accuracy of the proposed method are validated with the FEM results and those from the literature.
Design, Analysis, and Experimental Evaluation of a Double Coil Magnetorheological Fluid Damper
Authors: Hu Guoliang , Liu Fengshuo , Xie Zheng , Xu Ming
Published: January 2016

A magnetorheological (MR) damper is one of the most advanced devices used in a semiactive control system to mitigate unwanted vibration because the damping force can be controlled by changing the viscosity of the internal magnetorheological (MR) fluids. This study proposes a typical double coil MR damper where the damping force and dynamic range were derived from a quasistatic model based on the Bingham model of MR fluid. A finite element model was built to study the performance of this double coil MR damper by investigating seven different piston configurations, including the numbers and shapes of their chamfered ends. The objective function of an optimization problem was proposed and then an optimization procedure was constructed using the ANSYS parametric design language (APDL) to obtain the optimal damping performance of a double coil MR damper. Furthermore, experimental tests were also carried out, and the effects of the same direction and reverse direction of the currents on the damping forces were also analyzed. The relevant results of this analysis can easily be extended to the design of other types of MR dampers.
Left Atrial Myxoma Hypervascularized from the Right Coronary Artery: An Interesting Cath Lab Finding
Authors: Oliveira Marcos Danillo Peixoto , Tamazato Adriano Ossuna , de Fazzio Fernando Roberto , Kajita Luiz J. , Ribeiro Expedito E. , Lemos Pedro Alves
Published: January 2016

Primary cardiac tumors are rare and approximately half of them are atrial myxomas. They rarely remain asymptomatic, especially if large. The imaging of a myxoma by contrast dye during coronary angiography is an infrequent sign, which clarifies the vascular supply of the tumor. We report herein an interesting and rare case of a left atrial myxoma hypervascularized from the right coronary artery.
Modulating the Substrate Stiffness to Manipulate Differentiation of Resident Liver Stem Cells and to Improve the Differentiation State of Hepatocytes
Authors: Cozzolino Angela Maria , Noce Valeria , Battistelli Cecilia , Marchetti Alessandra , Grassi Germana , Cicchini Carla , Tripodi Marco , Amicone Laura
Published: January 2016

In many cell types, several cellular processes, such as differentiation of stem/precursor cells, maintenance of differentiated phenotype, motility, adhesion, growth, and survival, strictly depend on the stiffness of extracellular matrix that, in vivo, characterizes their correspondent organ and tissue. In the liver, the stromal rigidity is essential to obtain the correct organ physiology whereas any alteration causes liver cell dysfunctions. The rigidity of the substrate is an element no longer negligible for the cultivation of several cell types, so that many data so far obtained, where cells have been cultured on plastic, could be revised. Regarding liver cells, standard culture conditions lead to the dedifferentiation of primary hepatocytes, transdifferentiation of stellate cells into myofibroblasts, and loss of fenestration of sinusoidal endothelium. Furthermore, standard cultivation of liver stem/precursor cells impedes an efficient execution of the epithelial/hepatocyte differentiation program, leading to the expansion of a cell population expressing only partially liver functions and products. Overcoming these limitations is mandatory for any approach of liver tissue engineering. Here we propose cell lines as in vitro models of liver stem cells and hepatocytes and an innovative culture method that takes into account the substrate stiffness to obtain, respectively, a rapid and efficient differentiation process and the maintenance of the fully differentiated phenotype.
Stromal Derived Factor‐1/CXCR4 Axis Involved in Bone Marrow Mesenchymal Stem Cells Recruitment to Injured Liver
Authors: Xiao Ling Kuai , Peng Li , Jian Feng Zhang , Wei Cao , Wei Yan Yuan , Nan Shao , Cheng Qi Guan , Zhi Wei Wang
Published: January 2016

The molecular mechanism of bone marrow mesenchymal stromal stem cells (BMSCs) mobilization and migration to the liver was poorly understood. Stromal cell‐derived factor‐1 (SDF‐1) participates in BMSCs homing and migration into injury organs. We try to investigate the role of SDF‐1 signaling in BMSCs migration towards injured liver. The expression of CXCR4 in BMSCs at mRNA level and protein level was confirmed by RT‐PCR, flow cytometry, and immunocytochemistry. The SDF‐1 or liver lysates induced BMSCs migration was detected by transwell inserts. CXCR4 antagonist, AMD3100, and anti‐CXCR4 antibody were used to inhibit the migration. The Sprague‐Dawley rat liver injury model was established by intraperitoneal injection of thioacetamide. The concentration of SDF‐1 increased as modeling time extended, which was determined by ELISA method. The Dir‐labeled BMSCs were injected into the liver of the rats through portal vein. The cell migration in the liver was tracked by in vivo imaging system and the fluorescent intensity was measured. In vivo, BMSCs migrated into injured liver which was partially blocked by AMD3100 or anti‐CXCR4 antibody. Taken together, the results demonstrated that the migration of BMSCs was regulated by SDF‐1/CXCR4 signaling which involved in BMSCs recruitment to injured liver.
An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers
Authors: Prueitt Robyn L. , Wallace Tiffany A. , Glynn Sharon A. , Yi Ming , Tang Wei , Luo Jun , Dorsey Tiffany H. , Stagliano Katherine E. , Gillespie John W. , Hudson Robert S. , Terunuma Atsushi , Shoe Jennifer L. , Haines Diana C. , Yfantis Harris G. , Han Misop , Martin Damali N. , Jordan Symone V. , Borin James F. , Naslund Michael J. , Alexander Richard B. , Stephens Robert M. , Loffredo Christopher A. , Lee Dong H. , Putluri Nagireddy , Sreekumar Arun , Hurwitz Arthur A. , Ambs Stefan
Published: January 2016

Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer–prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055–65. ©2015 AACR.
Macrophage Infiltration and Alternative Activation during Wound Healing Promote MEK1-Induced Skin Carcinogenesis
Authors: Weber Christine , Telerman Stephanie B. , Reimer Andreas S. , Sequeira Ines , Liakath-Ali Kifayathullah , Arwert Esther N. , Watt Fiona M.
Published: January 2016

Macrophages are essential for the progression and maintenance of many cancers, but their role during the earliest stages of tumor formation is unclear. To test this, we used a previously described transgenic mouse model of wound-induced skin tumorigenesis, in which expression of constitutively active MEK1 in differentiating epidermal cells results in chronic inflammation (InvEE mice). Upon wounding, the number of epidermal and dermal monocytes and macrophages increased in wild-type and InvEE skin, but the increase was greater, more rapid, and more sustained in InvEE skin. Macrophage ablation reduced tumor incidence. Furthermore, bioluminescent imaging in live mice to monitor macrophage flux at wound sites revealed that macrophage accumulation was predictive of tumor formation; wounds with the greatest number of macrophages at day 5 went on to develop tumors. Gene expression profiling of flow-sorted monocytes, macrophages, and T cells from InvEE and wild-type skin showed that as wound healing progressed, InvEE macrophages altered their phenotype. Throughout wound healing and after wound closure, InvEE macrophages demonstrated sustained upregulation of several markers implicated in alternative macrophage activation including arginase-1 (ARG1) and mannose receptor (CD206). Notably, inhibition of ARG1 activity significantly reduced tumor formation and epidermal proliferation in vivo, whereas addition of L-arginase to cultured keratinocytes stimulated proliferation. We conclude that macrophages play a key role in early, inflammation-mediated skin tumorigenesis, with mechanistic evidence suggesting that ARG1 secretion drives tumor development by stimulating epidermal cell proliferation. These findings highlight the importance of cancer immunotherapies aiming to polarize tumor-associated macrophages toward an antitumor phenotype. Cancer Res; 76(4); 805–17. ©2016 AACR.
Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells
Authors: Vineretsky Karin A. , Karagas Margaret R. , Christensen Brock C. , Kuriger-Laber Jacquelyn K. , Perry Ann E. , Storm Craig A. , Nelson Heather H.
Published: January 2016

Natural killer (NK)–cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10–5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors. Cancer Res; 76(2); 370–6. ©2016 AACR.
Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
Authors: Chartier Cecile , Raval Janak , Axelrod Fumiko , Bond Chris , Cain Jennifer , Dee-Hoskins Cristina , Ma Shirley , Fischer Marcus M. , Shah Jalpa , Wei Jie , Ji May , Lam Andrew , Stroud Michelle , Yen Wan-Ching , Yeung Pete , Cancilla Belinda , O'Young Gilbert , Wang Min , Kapoun Ann M. , Lewicki John , Hoey Timothy , Gurney Austin
Published: January 2016

Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713–23. ©2015 AACR.
EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer
Authors: Amato Katherine R. , Wang Shan , Tan Li , Hastings Andrew K. , Song Wenqiang , Lovly Christine M. , Meador Catherine B. , Ye Fei , Lu Pengcheng , Balko Justin M. , Colvin Daniel C. , Cates Justin M. , Pao William , Gray Nathanael S. , Chen Jin
Published: January 2016

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFRT790M mutations in vitro and inhibited tumor growth and progression in an inducible EGFRL858R+T790M-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. Cancer Res; 76(2); 305–18. ©2016 AACR.
JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis
Authors: Li Na , Dhar Shilpa S. , Chen Tsai-Yu , Kan Pu-Yeh , Wei Yongkun , Kim Jae-Hwan , Chan Chia-Hsin , Lin Hui-Kuan , Hung Mien-Chie , Lee Min Gyu
Published: January 2016

Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared with normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer. Cancer Res; 76(4); 831–43. ©2016 AACR.
Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression
Authors: Picon-Ruiz Manuel , Pan Chendong , Drews-Elger Katherine , Jang Kibeom , Besser Alexandra H. , Zhao Dekuang , Morata-Tarifa Cynthia , Kim Minsoon , Ince Tan A. , Azzam Diana J. , Wander Seth A. , Wang Bin , Ergonul Burcu , Datar Ram H. , Cote Richard J. , Howard Guy A. , El-Ashry Dorraya , Torné-Poyatos Pablo , Marchal Juan A. , Slingerland Joyce M.
Published: January 2016

Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell–like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491–504. ©2016 AACR.
Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen
Authors: Ning Chengcheng , Xie Bingying , Zhang Lin , Li Chunsheng , Shan Weiwei , Yang Bingyi , Luo Xuezhen , Gu Chao , He Qizhi , Jin Hongyan , Chen Xiaojun , Zhang Zhenbo , Feng Youji
Published: January 2016

Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68+CD163+ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68+CD163+ macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. Cancer Res; 76(6); 1354–66. ©2016 AACR.