bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening residents for infant lumbar puncture readiness with just-in-time simulation-based assessments
Authors: Kessler David O , Chang Todd P , Auerbach Marc , Fein Daniel M , Lavoie Megan E , Trainor Jennifer , Lee Moon O , Gerard James M , Grossman Devin , Whitfill Travis , Pusic Martin
Published: October 2016

Background

Determining when to entrust trainees to perform procedures is fundamental to patient safety and competency development.

Objective

To determine whether simulation-based readiness assessments of first year residents immediately prior to their first supervised infant lumbar punctures (LPs) are associated with success.

Methods

This prospective cohort study enrolled paediatric and other first year residents who perform LPs at 35 academic hospitals from 2012 to 2014. Within a standardised LP curriculum, a validated 4-point readiness assessment of first year residents was required immediately prior to their first supervised LP. A score ≥3 was required for residents to perform the LP. The proportion of successful LPs (<1000 red blood cells on first attempt) was determined. Process measures included success on any attempt, number of attempts, analgesia usage and use of the early stylet removal technique.

Results

We analysed 726 LPs reported from 1722 residents (42%). Of the 432 who underwent readiness assessments, 174 (40%, 95% CI 36% to 45%) successfully performed their first LP. Those who were not assessed succeeded in 103/294 (35%, 95% CI 30% to 41%) LPs. Assessed participants reported more frequent direct attending supervision of the LP (diff 16%; 95% CI 8% to 22%), greater use of topical analgesia (diff 6%; 95% CI 1% to 12%) and greater use of the early stylet removal technique (diff 11%; 95% CI 4% to 19%) but no difference in number of attempts or overall procedural success.

Conclusions

Simulation-based readiness assessments performed in a point-of-care fashion were associated with several desirable behaviours but were not associated with greater clinical success with LP.
Using digital story telling to assess health students’ knowledge of interprofessional roles in the care of the older adult
Authors: Frost Jane , Isbel Stephen , Kellett Jane , Lawlis Tanya
Published: October 2016

Background

Digital story telling (DST) is an innovative way to allow students to assess the care needs of an older adult and creates an opportunity for interdisciplinary involvement. Traditionally, a single healthcare discipline approach is used by higher education institutions for preclinical training in the care of the older adult. Interprofessional learning (IPL) is generally not integrated well into the health professional curricula of Australian Universities.

Aim

To explore the use of Mask-Ed as a way of eliciting students understanding of their roles in patient care and to determine readiness for IPL in a cohort of health students prior to clinical placement.

Method

An online survey of students prior to their first clinical placement was undertaken. The survey incorporated a digital story of a Mask-Ed character and the readiness for IPL scale.

Results

Students recognised the importance of IPL. However, only 25% of students had an advanced understanding of their own roles and no student showed an advanced understanding of the other disciplines roles in the care of the older adult.

Conclusions

In this study, DST using Mask-Ed assisted with students' understanding of interprofessional roles in the care of the older adult. Our findings demonstrated that IPL is important, and this was further enhanced by the use of Mask-Ed simulation.
Can emergency medicine research benefit from adaptive design clinical trials?
Authors: Flight Laura , Julious Steven A , Goodacre Steve
Published: October 2016

Background

Adaptive design clinical trials use preplanned interim analyses to determine whether studies should be stopped or modified before recruitment is complete. Emergency medicine trials are well suited to these designs as many have a short time to primary outcome relative to the length of recruitment. We hypothesised that the majority of published emergency medicine trials have the potential to use a simple adaptive trial design.

Methods

We reviewed clinical trials published in three emergency medicine journals between January 2003 and December 2013. We determined the proportion that used an adaptive design as well as the proportion that could have used a simple adaptive design based on the time to primary outcome and length of recruitment.

Results

Only 19 of 188 trials included in the review were considered to have used an adaptive trial design. A total of 154/165 trials that were fixed in design had the potential to use an adaptive design.

Conclusions

Currently, there seems to be limited uptake in the use of adaptive trial designs in emergency medicine despite their potential benefits to save time and resources. Failing to take advantage of adaptive designs could be costly to patients and research. It is recommended that where practical and logistical considerations allow, adaptive designs should be used for all emergency medicine clinical trials.
Examining the Validity of the Acs-Nsqip Risk Calculator in Plastic Surgery: Lack of Input Specificity, Outcome Variability and Imprecise Risk Calculations
Authors: Johnson Cassandra , Campwala Insiyah , Gupta Subhas
Published: October 2016

American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) created the Surgical Risk Calculator, to allow physicians to offer patients a risk-adjusted 30-day surgical outcome prediction. This tool has not yet been validated in plastic surgery. A retrospective analysis of all plastic surgery-specific complications from a quality assurance database from September 2013 through July 2015 was performed. Patient preoperative risk factors were entered into the ACS Surgical Risk Calculator, and predicted outcomes were compared with actual morbidities. The difference in average predicted complication rate versus the actual rate of complication within this population was examined. Within the study population of patients with complications (n=104), the calculator accurately predicted an above average risk for 20.90% of serious complications. For surgical site infections, the average predicted risk for the study population was 3.30%; this prediction was proven only 24.39% accurate. The actual incidence of any complication within the 4924 patients treated in our plastic surgery practice from September 2013 through June 2015 was 1.89%. The most common plastic surgery complications include seroma, hematoma, dehiscence and flap-related complications. The ACS Risk Calculator does not present rates for these risks. While most frequent outcomes fall into general risk calculator categories, the difference in predicted versus actual complication rates indicates that this tool does not accurately predict outcomes in plastic surgery. The ACS Surgical Risk Calculator is not a valid tool for the field of plastic surgery without further research to develop accurate risk stratification tools.
Nanosims Imaging: An Approach for Visualizing and Quantifying Lipids in Cells and Tissues
Authors: He Cuiwen , Fong Loren G , Young Stephen G , Jiang Haibo
Published: October 2016

Over the past few decades, several approaches have been used to image lipids in cells and tissues, but most have limited spatial resolution and sensitivity. Here, we discuss a relatively new approach, nanoscale secondary ion mass spectrometry imaging, that makes it possible to visualize lipids in cells and tissues in a quantitative fashion and with high spatial resolution and high sensitivity.
Structural and optical properties of TiO2–Ge nanoparticles prepared through laser ablation in liquid medium
Authors: Shahzada Shaista , Fatima Anbarin , Nazir Asma , Mehmood Arshad , Mehmood Mazhar , Nadeem Ali
Published: November 2016

Quantum dot (QD) composite nanoparticles of titania germanium (TiO2–Ge) were fabricated by pulsed laser ablation of composite targets of TiO2–Ge immersed in deionized water. The single phase crystallanity, lattice parameters, and the evaluation of crystallite size of nanoparticles was investigated by X-ray diffraction (XRD). The morphology of the samples was analyzed through scanning electron microscopic studies. The average particle size calculated through XRD and measured through scanning electron microscope is in the range from 18 to 29 nm and are in agreement with each other. Compositional study was carried out through electron dispersive X-ray analysis showing that the ablation rate of Ge is smaller than TiO2. Optical properties were measured by UV–visible transmission spectra and Raman spectroscopy. The band gap of composite particles varies from the UV to the visible range by varying concentration of Ge QDs. This work shows that pulsed laser ablation in liquid media is an easy approach to synthesize ultrafine, contamination-free nanosized material, which is difficult to produce by other conventional methods.
Via-Aware Dogleg Routing Using Boolean Satisfiability
Authors: Mukherjee Shyamapada , Roy Suchismita
Published: November 2016

Boolean Satisfiability (SAT)-based channel routing with via-aware pin doglegging is presented in this paper. The effect of the pin dogleg layout of connecting wires has been tested separately for input–output pins and output pins only with controlled use of vias for dogleg during detailed routing. Dogleg may reduce the channel width required for laying down all nets and hence decrease the total chip area. However, invalid selection of dogleg may increase the channel width or may identify a routable circuit as unroutable. Unwanted dogleg may also increase the use of vias (switches) required for changing the track from one to another and may create a congested area with vias. Congested via may introduce lithographic printing problem during manufacturing and power leakage problem. The proposed technique considers all these constraints to provide an optimal result and gives a compact layout for a circuit with controlled via for doglegging. The results obtained show that pin dogleg layout produces a more compact layout for connecting wires with supervised via when compared to dogleg-free routing or doglegged routing with unsupervised via for some standard benchmark circuits. It yields optimal results with reduced number of tracks in a channel and smaller chip size.
Quantum group signature scheme based on controlled quantum teleportation
Authors: Chen F. L. , Han Z. F.
Published: November 2016

Group signature scheme is a method of allowing a member of a group to sign a message anonymously on behalf of the group. The group administrator is in charge of adding group members and has the ability to reveal the original signer in the event of disputes. Based on controlled quantum teleportation with three-particle entangled W states, we propose a new quantum group signature scheme with designated receiver. Security analysis proves that the proposed scheme possesses the characteristics of group signature and resists the usual attacks. Compared with previous proposed schemes, this scheme follows security definition of group signature fully and meets its basic requirements.
Responsive filtration membranes by polymer self-assembly
Authors: Kaner Papatya , Bengani-Lutz Prity , Sadeghi Ilin , Asatekin Ayse
Published: November 2016

Membrane technologies are essential for water treatment, bioprocessing and chemical manufacturing. Stimuli-responsive membranes respond to changes in feed conditions (e.g., temperature, pH) or external stimuli (e.g., magnetic field, light) with a change in performance parameters (permeability, selectivity). This enables new functionalities such as tunable performance, self-cleaning and smart-valve behavior. Polymer self-assembly is a crucial tool for manufacturing such membranes using scalable methods, enabling easier commercialization. This review surveys approaches to impart stimuli responsive behavior to membrane filters using polymer self-assembly.
Valuing a Logging Externality: Loss of the Water Purification Service of Temperate Coastal Rainforests
Authors: Knowler Duncan , Page Ashley , Cooper Andrew , Araujo H. Andres
Published: November 2016

In many biodiversity rich watersheds, there is a lack of understanding concerning the trade-offs between timber harvesting and maintaining the watershed’s other ecosystem services, where losses of these services can occur as an externality from timber harvesting. As a result, the potential benefit from an appropriate mix of activities in multiple-use watersheds frequently remains unrealized. Our study provides insight into such trade-offs by estimating the value of a loss in a forest’s water purification/filtration service due to sedimentation caused by logging (the externality). More specifically, we develop a model to quantify the economic impact of increased sedimentation from forest roads on the quality of raw water withdrawn by a municipal water utility. Our approach is novel in several ways. First, we recognize the complex response of the water treatment plant to elevated sedimentation (turbidity) by considering a stochastic environmental influence on water system performance; to accommodate this complexity, we estimate the number of times turbidity exceeds an acceptable threshold by using a count data estimation procedure. Second, we generate alternative time series for turbidity that vary according to assumptions about forest management (logging versus no logging), traffic volume (road use intensity) and aggregate road length. We find that reductions in the economic value of the water purification/filtration service is more sensitive to traffic volume than other considerations but only when the road use is High, as the welfare effect in other cases is modest. Our analysis will be helpful to forest planners who must consider the trade-offs in forest management when timber harvesting can have harmful impacts on important ecosystem services, such as water purification/filtration.
The AND-OR Game
Authors: Hassidim Avinatan , Kaplan Haim , Mansour Yishay , Nisan Noam
Published: November 2016

We consider a simple simultaneous first price auction for two identical items in a complete information setting. Our goal is to analyze this setting for a simple, yet highly interesting, AND-OR game, where one agent is single minded and the other is unit demand. We find a mixed equilibrium of this game and show that every other equilibrium admits the same expected allocation and payments. In addition, we study the equilibrium, highlighting the change in revenue and social welfare as a function of the players’ valuations.
Index Problems for Game Automata
Authors: Facchini Alessandro , Murlak Filip , Skrzypczak Michał
Published: November 2016

For a given regular language of infinite trees, one can ask about the minimal number of priorities needed to recognize this language with a nondeterministic, alternating, or weak alternating parity automaton. These questions are known as, respectively, the nondeterministic, alternating, and weak Rabin-Mostowski index problems. Whether they can be answered effectively is a long-standing open problem, solved so far only for languages recognizable by deterministic automata (the alternating variant trivializes).

We investigate a wider class of regular languages, recognizable by so-called game automata, which can be seen as the closure of deterministic ones under complementation and composition. Game automata are known to recognize languages arbitrarily high in the alternating Rabin-Mostowski index hierarchy; that is, the alternating index problem does not trivialize anymore.

Our main contribution is that all three index problems are decidable for languages recognizable by game automata. Additionally, we show that it is decidable whether a given regular language can be recognized by a game automaton.
Tighter buffer dimensioning in AFDX networks
Authors: Benammar Nassima , Bauer Henri , Ridouard Frédéric , Richard Pascal
Published: November 2016

The AFDX (Avionics Full DupleX Switched Ethernet) is the backbone network of most recent avionic communication systems. These systems require deterministic buffer dimensioning for certification reasons. As in such systems, static design is often preferred over dynamic allocation, a dimensioning in terms of frames rather than in terms of bits can be required.

A common approach consists in deriving the worst-case buffer size in terms of frames from the worst-case in bits. However, we show that this can lead to an overestimation of the buffer size. Thus, we propose a dedicated approach for a tighter dimensioning. Eventually, the two approaches are compared on a sample AFDX configuration.
SIGCSE 2017 Chairs Roundtable
Authors: Maher Mary Lou
Published: November 2016

What are the challenges that Department Chairs face? How would you design the ideal Department Chair? What are the features of a great Department Chair? What are the issues in having a poor Department Chair? The summary at the end of this article demonstrates the challenges that face anyone that takes on this critical role.
Sparse polynomials in FLINT
Authors: Groves A. Whitman , Roche Daniel S.
Published: November 2016

We have implemented a high-performance C library for sparse polynomials, which is provided as an add-on module to the open-source computation library FLINT [7]. Our implementation incorporates a number of recent theoretical advances in supersparse polynomial arithmetic, most notably recent algorithms for sparse interpolation and multiplication. We provide a summary of the provided functionality, a selection of key implementation decisions, and some preliminary timing data.
An interview with Judith Redi
Authors: Redi Judith , Riegler Michael Alexander
Published: November 2016

Judith Redi was interviewed by Michael Riegler.
Deciphering Genetic Intratumor Heterogeneity and Its Impact on Cancer Evolution
Authors: Rosenthal Rachel , McGranahan Nicholas , Herrero Javier , Swanton Charles
Published: November 2016

Cancer is a disease reliant on the generation of mutations and the subsequent selection of those subpopulations endowed with the greatest fitness advantage. Beginning with a heterogeneous landscape of somatic alterations, various selective pressures acting on a tumor can shape the way it evolves. In this review, we first discuss the current bioinformatics tools available to tease apart the heterogeneous nature of a tumor and second consider the impact that evolutionary forces have on sculpting a tumor. Neighboring subclones may alter the microenvironment cultivating either cooperation or competition between clonal populations. Additionally, the harsh environment brought about by therapy and the immune system may force adaptation. Finally, we examine recent analyses focused on precancerous samples, which help to reveal clonal selection occurring during the earliest stages of tumor development, as well as work that has identified patterns of somatic evolution observed in normal tissues.
Impacts of Insect Herbivores on Plant Populations
Authors: Myers Judith H. , Sarfraz Rana M.
Published: November 2016

Apparent feeding damage by insects on plants is often slight. Thus, the influences of insect herbivores on plant populations are likely minor. The role of insects on host-plant populations can be elucidated via several methods: stage-structured life tables of plant populations manipulated by herbivore exclusion and seed-addition experiments, tests of the enemy release hypothesis, studies of the effects of accidentally and intentionally introduced insect herbivores, and observations of the impacts of insect species that show outbreak population dynamics. These approaches demonstrate that some, but not all, insect herbivores influence plant population densities. At times, insect-feeding damage kills plants, but more often, it reduces plant size, growth, and seed production. Plant populations for which seed germination is site limited will not respond at the population level to reduced seed production. Insect herbivores can influence rare plant species and need to be considered in conservation programs. Alterations due to climate change in the distributions of insect herbivores indicate the possibility of new influences on host plants. Long-term studies are required to show if density-related insect behavior stabilizes plant populations or if environmental variation drives most temporal fluctuations in plant densities. Finally, insects can influence plant populations and communities through changing the diversity of nonhost species, modifying nutrient fluxes, and rejuvenating over mature forests.
Myocardial interstitial levels of serotonin and its major metabolite 5-hydroxyindole acetic acid during ischemia-reperfusion
Authors: Du Cheng-Kun , Zhan Dong-Yun , Akiyama Tsuyoshi , Inagaki Tadakatsu , Shishido Toshiaki , Shirai Mikiyasu , Pearson James T.
Published: October 2016

The aim of this study was to examine the accumulation of serotonin (5-HT) and degradation of 5-HT taken up into cells in the ischemic region during myocardial ischemia-reperfusion. Using microdialysis technique in anesthetized rats, we monitored myocardial interstitial levels of 5-HT and its metabolite produced by monoamine oxidase (MAO), 5-hydroxyindole acetic acid (5-HIAA), during 30-min coronary occlusion followed by 45-min reperfusion, and investigated the effects of local administration of the MAO inhibitor pargyline and the 5-HT uptake inhibitor fluoxetine. In the vehicle group, the dialysate 5-HT concentration increased from 1.3 ± 0.2 nM at baseline to 29.6 ± 2.8 nM at 22.5–30 min of occlusion, but the dialysate 5-HIAA concentration did not change from baseline (9.9 ± 1.1 nM). Upon reperfusion, the dialysate 5-HT concentration increased further to a peak (34.2 ± 4.2 nM) at 0–7.5 min and then declined. The dialysate 5-HIAA concentration increased to 31.9 ± 5.2 nM at 7.5–15 min of reperfusion and maintained this high level until 45 min. Pargyline markedly suppressed the increase in dialysate 5-HIAA concentration after reperfusion and increased the averaged dialysate 5-HT concentration during the reperfusion period. Fluoxetine suppressed the increase in dialysate 5-HT concentration during occlusion but did not change dialysate 5-HT or 5-HIAA concentration after reperfusion. During ischemia, 5-HT secreted from ischemic tissues accumulates but 5-HT degradation by MAO is suppressed. After reperfusion, degradation of 5-HT taken up into cells is enhanced and contributes to the clearance of accumulated 5-HT. This degradation following cellular uptake is dependent on MAO activity but not the fluoxetine-sensitive uptake transporter.

NEW & NOTEWORTHY By monitoring myocardial interstitial levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid, we investigated 5-HT kinetics during myocardial ischemia-reperfusion. 5-HT accumulates but 5-HT degradation is suppressed during ischemia. After reperfusion, 5-HT degradation is enhanced and this degradation is dependent on monoamine oxidase activity but not fluoxetine-sensitive uptake transporter.
Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging
Authors: Toth Peter , Tarantini Stefano , Csiszar Anna , Ungvari Zoltan
Published: October 2016

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer’s disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined.
BRD4 mediates NF-κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation
Authors: Tian Bing , Zhao Yingxin , Sun Hong , Zhang Yueqing , Yang Jun , Brasier Allan R.
Published: October 2016

Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-κB/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-β challenge in a mouse model. These data provide a detailed mechanism for how activated NF-κB and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.
A sequence upstream of canonical PDZ-binding motif within CFTR COOH-terminus enhances NHERF1 interaction
Authors: Sharma Neeraj , LaRusch Jessica , Sosnay Patrick R. , Gottschalk Laura B. , Lopez Andrea P. , Pellicore Matthew J. , Evans Taylor , Davis Emily , Atalar Melis , Na Chan-Hyun , Rosson Gedge D. , Belchis Deborah , Milewski Michal , Pandey Akhilesh , Cutting Garry R.
Published: October 2016

The development of cystic fibrosis transmembrane conductance regulator (CFTR) targeted therapy for cystic fibrosis has generated interest in maximizing membrane residence of mutant forms of CFTR by manipulating interactions with scaffold proteins, such as sodium/hydrogen exchange regulatory factor-1 (NHERF1). In this study, we explored whether COOH-terminal sequences in CFTR beyond the PDZ-binding motif influence its interaction with NHERF1. NHERF1 displayed minimal self-association in blot overlays (NHERF1, Kd= 1,382 ± 61.1 nM) at concentrations well above physiological levels, estimated at 240 nM from RNA-sequencing and 260 nM by liquid chromatography tandem mass spectrometry in sweat gland, a key site of CFTR function in vivo. However, NHERF1 oligomerized at considerably lower concentrations (10 nM) in the presence of the last 111 amino acids of CFTR (20 nM) in blot overlays and cross-linking assays and in coimmunoprecipitations using differently tagged versions of NHERF1. Deletion and alanine mutagenesis revealed that a six-amino acid sequence1417EENKVR1422and the terminal1478TRL1480(PDZ-binding motif) in the COOH-terminus were essential for the enhanced oligomerization of NHERF1. Full-length CFTR stably expressed in Madin-Darby canine kidney epithelial cells fostered NHERF1 oligomerization that was substantially reduced (∼5-fold) on alanine substitution of EEN, KVR, or EENKVR residues or deletion of the TRL motif. Confocal fluorescent microscopy revealed that the EENKVR and TRL sequences contribute to preferential localization of CFTR to the apical membrane. Together, these results indicate that COOH-terminal sequences mediate enhanced NHERF1 interaction and facilitate the localization of CFTR, a property that could be manipulated to stabilize mutant forms of CFTR at the apical surface to maximize the effect of CFTR-targeted therapeutics.
The Beta Subunit of Hemoglobin (HBB2/HBB) Suppresses Neuroblastoma Growth and Metastasis
Authors: Maman Shelly , Sagi-Assif Orit , Yuan Weirong , Ginat Ravit , Meshel Tsipi , Zubrilov Inna , Keisari Yona , Lu Weiyue , Lu Wuyuan , Witz Isaac P.
Published: October 2016

Soluble pulmonary factors have been reported to be capable of inhibiting the viability of cancer cells that metastasize to the lung, but the molecular identity was obscure. Here we report the isolation and characterization of the beta subunit of hemoglobin as a lung-derived antimetastatic factor. Peptide mapping in the beta subunit of human hemoglobin (HBB) defined a short C-terminal region (termed Metox) as responsible for activity. In tissue culture, both HBB and murine HBB2 mediated growth arrest and apoptosis of lung-metastasizing neuroblastoma cells, along with a variety of other human cancer cell lines. Metox acted similarly and its administration in human tumor xenograft models limited the development of adrenal neuroblastoma tumors as well as spontaneous lung and bone marrow metastases. Expression studies in mice indicated that HBB2 is produced by alveolar epithelial and endothelial cells and is upregulated in mice bearing undetectable metastasis. Our work suggested a novel function for HBB as a theranostic molecule: an innate antimetastasis factor with potential utility as an anticancer drug and a biomarker signaling the presence of clinically undetectable metastasis. Cancer Res; 77(1); 14–26. ©2016 AACR.
Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF
Authors: Han Su Yeon , Ko Aram , Kitano Haruhisa , Choi Chel Hun , Lee Min-Sik , Seo Jinho , Fukuoka Junya , Kim Soo-Youl , Hewitt Stephen M. , Chung Joon-Yong , Song Jaewhan
Published: October 2016

The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non–small cell lung cancer cells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90. Cancer Res; 77(2); 343–54. ©2016 AACR.
HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone
Authors: Day Kathleen C. , Hiles Guadalupe Lorenzatti , Kozminsky Molly , Dawsey Scott J. , Paul Alyssa , Broses Luke J. , Shah Rajal , Kunja Lakshmi P. , Hall Christopher , Palanisamy Nallasivam , Daignault-Newton Stephanie , El-Sawy Layla , Wilson Steven James , Chou Andrew , Ignatoski Kathleen Woods , Keller Evan , Thomas Dafydd , Nagrath Sunitha , Morgan Todd , Day Mark L.
Published: October 2016

Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites. Cancer Res; 77(1); 74–85. ©2016 AACR.
Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis
Authors: Verma Nandini , Müller Anna-Katharina , Kothari Charu , Panayotopoulou Effrosini , Kedan Amir , Selitrennik Michael , Mills Gordon B. , Nguyen Lan K. , Shin Sungyoung , Karn Thomas , Holtrich Uwe , Lev Sima
Published: October 2016

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4–HER3 binding, suggesting that the PYK2–NDRG1–NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy. Cancer Res; 77(1); 86–99. ©2016 AACR.
KRAS/NF-κB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis
Authors: Yuan Peng , He Xiao-Hong , Rong Ye-Fei , Cao Jing , Li Yong , Hu Yun-Ping , Liu Yingbin , Li Dangsheng , Lou Wenhui , Liu Mo-Fang
Published: October 2016

KRAS activation occurring in more than 90% of pancreatic ductal adenocarcinomas (PDAC) drives progression and metastasis, but the underlying mechanisms involved in these processes are still poorly understood. Here, we show how KRAS acts through inflammatory NF-κB signaling to activate the transcription factor YY1, which represses expression of the tumor suppressor gene miR-489. In PDAC cells, repression of miR-489 by KRAS signaling inhibited migration and metastasis by targeting the extracellular matrix factors ADAM9 and MMP7. miR-489 downregulation elevated levels of ADAM9 and MMP7, thereby enhancing the migration and metastasis of PDAC cells. Together, our results establish a pivotal mechanism of PDAC metastasis and suggest miR-489 as a candidate therapeutic target for their attack. Cancer Res; 77(1); 100–11. ©2016 AACR.
Adherence to the WCRF/AICR Dietary Recommendations for Cancer Prevention and Risk of Cancer in Elderly from Europe and the United States: A Meta-Analysis within the CHANCES Project
Authors: Jankovic Nicole , Geelen Anouk , Winkels Renate M. , Mwungura Blaise , Fedirko Veronika , Jenab Mazda , Illner Anne K. , Brenner Hermann , Ordóñez-Mena José M. , Kiefte de Jong Jessica C. , Franco Oscar H. , Orfanos Philippos , Trichopoulou Antonia , Boffetta Paolo , Agudo Antonio , Peeters Petra H. , Tjønneland Anne , Hallmans Göran , Bueno-de-Mesquita H. Bas , Park Yikyung , Feskens Edith J. , de Groot Lisette C. , Kampman Ellen
Published: October 2016

Background: It is unknown whether dietary recommendations for cancer prevention are applicable to the elderly. We analyzed WCRF/AICR recommendations in cohorts of European and U.S. adults ages 60 years and above.

Methods: Individual participant data meta-analysis included 362,114 participants (43% women), from seven prospective cohort studies, free from cancer at enrollment. The WCRF/AICR diet score was based on: (i) energy-dense foods and sugary drinks, (ii) plant foods, (iii) red and processed meat, and (iv) alcoholic drinks. Cox proportional hazards regression was used to examine the association between the diet score and cancer risks. Adjusted, cohort-specific HRs were pooled using random-effects meta-analysis. Risk advancement periods (RAP) were calculated to quantify the time period by which the risk of cancer was postponed among those adhering to the recommendations.

Results: After a median follow-up of 11 to 15 years across cohorts, 70,877 cancer cases were identified. Each one-point increase in the WCRF/AICR diet score [range, 0 (no) to 4 (complete adherence)] was significantly associated with a lower risk of total cancer [HR, 0.94; 95% confidence interval (CI), 0.92–0.97], cancers of the colorectum (HR, 0.84; 95% CI, 0.80–0.89) and prostate (HR, 0.94; 95% CI, 0.92–0.97), but not breast or lung. Adherence to an additional component of the WCRF/AICR diet score significantly postponed the incidence of cancer at any site by 1.6 years (RAP, −1.6; 95% CI, −4.09 to −2.16).

Conclusions: Adherence to WCRF/AICR dietary recommendations is associated with lower risk of cancer among older adults.

Impact: Dietary recommendations for cancer prevention are applicable to the elderly. Cancer Epidemiol Biomarkers Prev; 26(1); 136–44. ©2016 AACR.
U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma
Authors: Singh Harpreet , Brave Michael , Beaver Julia A. , Cheng Joyce , Tang Shenghui , Zahalka Eias , Palmby Todd R. , Venugopal Rajesh , Song Pengfei , Liu Qi , Liu Chao , Yu Jingyu , Chen Xiao Hong , Wang Xing , Wang Yaning , Kluetz Paul G. , Daniels Selena R. , Papadopoulos Elektra J. , Sridhara Rajeshwari , McKee Amy E. , Ibrahim Amna , Kim Geoffrey , Pazdur Richard
Published: October 2016

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.
Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer
Authors: Liu Chengfei , Armstrong Cameron M. , Lou Wei , Lombard Alan , Evans Christopher P. , Gao Allen C.
Published: October 2016

Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 resensitizes resistant cells to abiraterone treatment. In abiraterone-resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone-resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer. Mol Cancer Ther; 16(1); 35–44. ©2016 AACR.
Cytology at the Time of HPV: Some Things to Think about when Discussing HPV
Authors: Valentine Kristi , Vanden Broeck Davy , Benoy Ina , Truyens Marie , Bogers Johannes
Published: November 2016

‘In the current 28 Member States of the European Union (EU), approximately 34,000 new cases of cervical cancer and 13,000 deaths occur' [Ferlay et al.: Eur J Cancer 2014;49:1374-1403]. ‘The current 10-fold gradient in the mortality rates of cervical cancer among the EU Member States largely reflects the persistent absence, or inadequate implementation of cervical cancer screening programmes more than 10 years after organized, population-based screening programmes following European quality assurance guidelines were unanimously recommended by the Health Ministers of the EU' [Council of the European Union: Off J Eur Union 2003;327:34-38]. This article will compare the strengths, weaknesses and risks of the following 4 cervical health screening strategies: HPV as a triage of cytology, cytology as a triage of HPV, cotesting (parallel) or cytology at the time of HPV (HPV-informed guided screening). ‘The optimal screening strategy should identify those cervical cancer precursors likely to progress to invasive cancers (maximizing the benefits of screening) and avoid the detection and unnecessary treatment of transient HPV infection and its associated benign lesions that are not destined to become cancerous (minimizing the potential harms of screening)' [Saslow et al.: Am J Clin Pathol 2012;137:516-542].
Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation
Authors: Fender Erin A. , Widmer R. Jay , Hodge David O. , Cooper George M. , Monahan Kristi H. , Peterson Laurie A. , Holmes David R. , Packer Douglas L.
Published: October 2016

Background:

The frequency of pulmonary vein stenosis (PVS) after ablation for atrial fibrillation has decreased, but it remains a highly morbid condition. Although treatment strategies including pulmonary vein dilation and stenting have been described, the long-term impacts of these interventions are unknown. We evaluated the presentation of severe PVS, and examined the risk for restenosis after intervention using either balloon angioplasty (BA) alone or BA with stenting.

Methods:

This was a prospective, observational study of 124 patients with severe PVS evaluated between 2000 and 2014.

Results:

All 124 patients were identified as having severe PVS by computed tomography in 219 veins. One hundred two patients (82%) were symptomatic at diagnosis. The most common symptoms were dyspnea (67%), cough (45%), fatigue (45%), and decreased exercise tolerance (45%). Twenty-seven percent of patients experienced hemoptysis. Ninety-two veins were treated with BA, 86 were treated with stenting, and 41 veins were not treated. A 94% acute procedural success rate was observed and did not differ by initial management. Major procedural complications occurred in 4 of the 113 patients (3.5%) who underwent invasive assessment, and minor complications occurred in 15 patients (13.3%). Overall, 42% of veins developed restenosis including 27% of veins (n=23) treated with stenting and 57% of veins (n=52) treated with BA. The 3-year overall rate of restenosis was 37%, with 49% of BA-treated veins and 25% of stented veins developing restenosis (hazard ratio, 2.77; 95% confidence interval, 1.72–4.45;
P
<0.001). After adjustment for age, CHA2DS2-VASc score, hypertension, and the time period of the study, there was still a significant difference in the risk of restenosis for BA versus stenting (hazard ratio, 2.46; 95% confidence interval, 1.47–4.12;
P
<0.001).

Conclusions:

The diagnosis of PVS is challenging because of nonspecific symptoms and the need for dedicated pulmonary vein imaging. There is no difference in acute success by type of initial intervention; however, stenting significantly reduces the risk of subsequent pulmonary vein restenosis in comparison with BA.