bluuebunny/crossref_metadata_2025 huggingface dataset:
Citizenship status and engagement in HIV care: an observational cohort study to assess the association between reporting a national ID number and retention in public-sector HIV care in Johannesburg, South Africa
Authors: Shearer Kate , Clouse Kate , Meyer-Rath Gesine , MacLeod William , Maskew Mhairi , Sanne Ian , Long Lawrence , Fox Matthew P
Published: January 2017

Objective

In many resource-limited settings, people from rural areas migrate to urban hubs in search of work. Thus, urban public-sector HIV clinics in South Africa (SA) often cater to both local residents and patients from other provinces and/or countries. The objective of this analysis was to compare programmatic treatment outcomes by citizenship status in an urban clinic in SA.

Setting

An urban public-sector HIV treatment facility in Johannesburg, SA.

Participants

We included all antiretroviral therapy (ART)-naïve, non-pregnant patients who initiated standard first-line treatment from January 2008 to December 2013. 12 219 patients were included and 59.5% were women.

Primary outcome measure

Patients were followed from ART initiation until death, transfer, loss to follow-up (LTF), or data set closure. We describe attrition (mortality and LTF) stratified by SA citizenship status (confirmed SA citizens (with national ID number), unconfirmed SA citizens (no ID), and foreign nationals) and model the risk of attrition using Cox proportional hazards regression.

Results

70% of included patients were confirmed SA citizens, 19% were unconfirmed SA citizens, and 11% were foreign nationals. Unconfirmed SA citizens were far more likely to die or become LTF than other patients. A similar proportion of foreign nationals (18.2%) and confirmed SA citizens (17.7%) had left care at 1 year compared with 47.0% of unconfirmed SA citizens (adjusted hazard ratio (aHR) unconfirmed SA vs confirmed SA: 2.68; 95% CI 2.42 to 2.97). By the end of follow-up, 75.5% of unconfirmed SA citizens had left care, approximately twice that of any other group.

Conclusions

Unconfirmed SA citizens were more likely to drop out of care after ART initiation than other patients. Further research is needed to determine whether this observed attrition is representative of migration and/or self-transfer to another HIV clinic as such high rates of attrition pose challenges for the success of the national ART programme.
MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study
Authors: Honkoop Persijn J , Simpson Andrew , Bonini Matteo , Snoeck-Stroband Jiska B , Meah Sally , Fan Chung Kian , Usmani Omar S , Fowler Stephen , Sont Jacob K
Published: January 2017

Introduction

Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations.

Methods and analysis

In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations.

Ethics

This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK.

Trial registration number

NCT02774772.
Quantifying Queensland patients with cancer health service usage and costs: study protocol
Authors: Callander Emily , Topp Stephanie M , Larkins Sarah , Sabesan Sabe , Bates Nicole
Published: January 2017

Introduction

The overall mortality rate for cancer has declined in Australia. However, socioeconomic inequalities exist and the out-of-pocket costs incurred by patients in Australia are high compared with some European countries. There is currently no readily available data set to provide a systematic means of measuring the out-of-pocket costs incurred by patients with cancer within Australia. The primary aim of the project is to quantify the direct out-of-pocket healthcare expenditure of individuals in the state of Queensland, who are diagnosed with cancer.

Methods and analysis

This project will build Australia's first model (called CancerCostMod) of out-of-pocket healthcare expenditure of patients with cancer using administrative data from Queensland Cancer Registry, for all individuals diagnosed with any cancer in Queensland between 1 July 2011 and 30 June 2012, linked to their Admitted Patient Data Collection, Emergency Department Information System, Medicare Benefits Schedule and Pharmaceutical Benefits Scheme records from 1 July 2011 to 30 June 2015. No identifiable information will be provided to the authors. The project will use a combination of linear and logistic regression modelling, Cox proportional hazards modelling and machine learning to identify differences in survival, total health system expenditure, total out-of-pocket expenditure and high out-of-pocket cost patients, adjusting for demographic and clinical confounders, and income group, Indigenous status and geographic location. Results will be analysed separately for different types of cancer.

Ethics and dissemination

Human Research Ethics approval has been obtained from the Townsville Hospital and Health Service Human Research Ethics Committee (HREC/16/QTHS/110) and James Cook University Human Research Ethics Committee (H6678). Permission to waive consent has been sought from Queensland Health under the Public Health Act 2005.
Job strain and the incidence of coronary heart diseases: does the association differ among occupational classes? A contribution from a pooled analysis of Northern Italian cohorts
Authors: Ferrario Marco M , Veronesi Giovanni , Bertù Lorenza , Grassi Guido , Cesana Giancarlo
Published: January 2017

Objectives

To assess the association between job strain (JS) and the incidence of coronary heart disease (CHD) in North Italian employed men, adopting a stratified analysis by occupational class (OC).

Methods

The study was conducted on 4103 working men, CHD-free at baseline, enrolled in population-based and factory-based cohorts. Risk factor measurements and follow-up procedures were carried out adopting the WHO MONICA standardised procedures. OCs were derived from the Erikson-Goldthorpe-Portocarero classification. JS categories were defined based on overall sample medians of psychological job demand (PJD) and decision latitude (DL) derived from items of the Job Content Questionnaire, satisfying construct validity criteria. Age-adjusted and risk factors-adjusted CHD HRs were estimated from Cox models, contrasting high-strain (high PJD and low DL) versus non-high-strain categories.

Results

In a median follow-up of 14.6 years, 172 CHD events occurred, corresponding to a CHD incidence rate of 2.78/1000 person-years. In the overall sample, high-strain compared with non-high-strain workers evidenced a 39% excess CHD risk, not statistically significant. No association was found among managers and proprietors. Conversely, the HR of high strain versus non-high strain was 1.78 (95% CI 1.20 to 2.66) among non-manual and manual workers, with no substantial differences between them. The exclusion of the events occurring in the first 3 years of follow-up did not change the results. Adopting the quadrant-term JS groupings, among manual and non-manual workers, high-strain and active (high PJD and high DL) categories in comparison to the low strain one (low PJD and high DL) showed HRs of 2.92 and 2.47, respectively.

Conclusions

Our findings support the association of JS and CHD incidence among manual and non-manual workers. The non-high strain may not be the best reference category, when assessing the contribution of JS in determining CHD incidence.
Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study
Authors: Bouhnik Yoram , Carbonnel Franck , Laharie David , Stefanescu Carmen , Hébuterne Xavier , Abitbol Vered , Nachury Maria , Brixi Hedia , Bourreille Arnaud , Picon Laurence , Bourrier Anne , Allez Matthieu , Peyrin-Biroulet Laurent , Moreau Jacques , Savoye Guillaume , Fumery Mathurin , Nancey Stephane , Roblin Xavier , Altwegg Romain , Bouguen Guillaume , Bommelaer Gilles , Danese Silvio , Louis Edouard , Zappa Magaly , Mary Jean-Yves
Published: January 2017

Objective

The efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohn's disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success.

Design

We performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort.

Results

From January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion.

Conclusions

A successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation.

Clinical Trial registration number

NCT01183403; Results.
Timing of vessel imaging for suspected large vessel occlusions does not affect groin puncture time in transfer patients with stroke
Authors: Liang John W , Stein Laura , Wilson Natalie , Fifi Johanna T , Tuhrim Stanley , Dhamoon Mandip S
Published: January 2017

Background

Access to endovascular therapy (ET) in cases of acute ischemic stroke may be limited, and rapid transfer of eligible patients to hospitals with endovascular capability is needed.

Objective

To determine the optimal timing of diagnostic CT angiography to confirm large vessel occlusion (LVO).

Methods

Of 57 emergency department transfers to Mount Sinai Hospital (MSH) for possible ET from January 2015 through March 2016, 39 (68%) underwent ET, among whom 22 (56%) had CT angiography before transfer and 17 (44%) had CT angiography on arrival. We compared mean outside hospital arrival to groin puncture (OTG) time between the two groups using t-tests and Wilcoxon rank sum tests. OTG was defined as the difference between groin puncture and outside hospital arrival time minus ambulance travel time.

Results

Average age was 73±13 years and average National Institute of Health Stroke Scale score was 19±5. There was no difference in average OTG time between the two groups (191 min for CT angiography at outside hospital vs 190 min for CT angiography at MSH (p=0.99 for t-test and 0.69 for rank sum test)). Among the 18 patients who were transferred but did not receive ET, 10 had no LVO, 5 had large established infarcts on arrival and 3 had post-tissue plasminogen activator hemorrhage. In 9/10 patients without LVO, CT angiography was not performed before transfer.

Conclusions

CT angiography timing in the transfer process does not affect OTG time, but 90% of patients without LVO had not had CT angiography before transfer. Hence, it might be beneficial to obtain a CT angiogram at the outside hospital, if it can be acquired and read rapidly, to avoid the cost and potential clinical deterioration associated with unnecessary transfers.
Using genetic pedigree reconstruction to estimate effective spawner abundance from redd surveys: an example involving Pacific lamprey (Entosphenus tridentatus)
Authors: Whitlock S.L. , Schultz L.D. , Schreck C.B. , Hess J.E.
Published: January 2017

Redd surveys are a commonly used technique for indexing the abundance of sexually mature fish in streams; however, substantial effort is often required to link redd counts to actual spawner abundance. In this study, we describe how genetic pedigree reconstruction can be used to estimate effective spawner abundance in a stream reach, using Pacific lamprey (Entosphenus tridentatus) as an example. Lamprey embryos were sampled from redds within a 2.5 km reach of the Luckiamute River, Oregon, USA. Embryos were found in only 20 of the 48 redds sampled (suggesting 58% false redds); however, multiple sets of parents were detected in 44% of the true redds. Estimates from pedigree reconstruction suggested that there were 0.48 (95% CI: 0.29–0.88) effective spawners per redd and revealed that individual lamprey contributed gametes to a minimum of between one and six redds, and in one case, spawned in patches that were separated by over 800 m. Our findings demonstrate the utility of pedigree reconstruction techniques for both inferring spawning-ground behaviors and providing useful information for refining lamprey redd survey methodologies.
Population and individual identification of coho salmon in British Columbia through parentage-based tagging and genetic stock identification: an alternative to coded-wire tags
Authors: Beacham Terry D. , Wallace Colin , MacConnachie Cathy , Jonsen Kim , McIntosh Brenda , Candy John R. , Devlin Robert H. , Withler Ruth E.
Published: January 2017

Parentage-based tagging (PBT) and genetic stock identification (GSI) were used to identify individual coho salmon (Oncorhynchus kisutch) to specific populations and brood years. In total, 20 242 individuals from 117 populations were genotyped at 304 single nucleotide polymorphisms (SNPs) via direct sequencing of amplicons. Coho salmon from 15 populations were assigned via parentage analysis that required the genotypes of both parents. The overall accuracy of assignment for 1939 coho salmon to the correct population was 100%, and to correct brood year within population was also 100%. Inclusion of individuals requiring only a single parental genotype for identification resulted in assignments of 2101 individuals, with an accuracy of 99.95% (2000–2001) to population and 100.0% to age. With 23 regions defined by the coded-wire tag (CWT) program, and individuals displaying an assignment probability <0.85 excluded from the analysis, mean regional assignment accuracy of individuals via GSI was 98.4% over all 23 regions. A PBT–GSI or PBT system of identification will provide an alternate method of identification in the assessment and management of Canadian-origin coho salmon relative to the existing CWT program.
Emergent Yang–Mills theories from universal extra dimensions
Authors: Chkareuli J. L. , Kepuladze Z.
Published: January 2017

We study emergent Yang–Mills theories which could origin from universal extra dimensions. Particularly, some vector field potential terms or polynomial vector field constraints introduced into five-dimensional (5D) non-Abelian gauge theory is shown to lead to spontaneous violation of an underlying spacetime symmetry and generate vector pseudo-Goldstone modes as conventional four-dimensional (4D) gauge boson candidates. As a special signature, apart from conventional gauge couplings, there appear an infinite number of the properly suppressed direct multi-boson (multi-photon in particular) interaction couplings in emergent Yang–Mills theories whose observation could shed light on their high-dimensional nature. Moreover, in these theories, an internal symmetry also appeared spontaneously broken to its diagonal subgroups. This breaking originates from the extra vector field components playing the role of some adjoint scalar field multiplet in the 4D spacetime. So, one naturally has the Higgs effect without a specially introduced scalar field multiplet. Remarkably, when applied to Grand Unified Theories (GUTs), this results in an automatic breakdown of emergent GUTs down to the Standard Model (SM) just at the 5D Lorentz violation scale M.
Baryons and chiral symmetry
Authors: Liu Keh-Fei
Published: January 2017

The relevance of chiral symmetry in baryons is highlighted in three examples in the nucleon spectroscopy and structure. The first one is the importance of chiral dynamics in understanding the Roper resonance. The second one is the role of chiral symmetry in the lattice calculation of [Formula: see text] term and strangeness. The third one is the role of chiral [Formula: see text] anomaly in the anomalous Ward identity in evaluating the quark spin and the quark orbital angular momentum. Finally, the chiral effective theory for baryons is discussed.
SIMILARITIES/DISSIMILARITIES ANALYSIS OF PROTEIN SEQUENCES BASED ON PCA-FFT
Authors: PING PENGYAO , ZHU XIANYOU , WANG LEI
Published: January 2017

In this paper, a novel method to analyze the similarity/dissimilarity of protein sequences based on Principal Component Analysis-Fast Fourier Transformation (PCA-FFT) is proposed, in which, the PCA is utilized to transform protein sequences into time series and the FFT is utilized to analyze the time series while considering them as signals. To test the effectiveness of our newly proposed method, it is applied to analyze the similarity/dissimilarity of 16 different ND5 protein sequences and 29 different spike protein sequences, respectively. Furthermore, the correlation analysis is presented for comparing with others methods, and the simulation results show that it has better performances in the aspects of computation complexity and recognition degree than some existing methods.
Consistent Multilevel RDT-ERA for Output-Only Ambient Modal Identification of Structures
Authors: Feng Zhouquan , Shen Wenai , Chen Zhengqing
Published: January 2017

This paper presents an improved method called the consistent multilevel random decrement technique in conjunction with eigensystem realization algorithm (RDT-ERA) for modal parameter identification of linear dynamic systems using the ambient vibration data. The conventional RDT-ERA is briefly revisited first and the problem of triggering level selection in the RDT is thoroughly studied. Due to the use of a single triggering level by the conventional RDT-ERA, an inappropriate triggering level may produce poor random decrement (RD) functions, thereby yielding a poor estimate of modal parameters. In the proposed consistent multilevel RDT-ERA, multiple triggering levels are used and a consistency analysis is proposed to sift out the RD functions that deviate largely from the majority of the RD functions. Then the ERA is applied to the retained RD functions for modal parameter identification. Subsequently, a similar consistency analysis is conducted on the identified modal parameters to sift out the outliers. Finally, the final estimates of the modal parameters are calculated using weighted averaging with the weights set proportional to the number of RD segments extracted from the corresponding triggering levels. The proposed method is featured by the fact that the information from the signal is fully utilized using multiple triggering levels and the outliers are sifted out using consistency analysis, thus making the identified result more accurate and reliable. The effectiveness and accuracy of the method have been demonstrated in the examples using the simulated data and experimental data.
Adverse metabolic phenotype of female offspring exposed to preeclampsia in utero: a characterization of the BPH/5 mouse in postnatal life
Authors: Sutton Elizabeth F. , Lob Heinrich E. , Song Jiunn , Xia YunWei , Butler Scott , Liu Chin-Chi , Redman Leanne M. , Sones Jenny L.
Published: January 2017

Preeclampsia (PE) is a devastating disorder of pregnancy that classically presents with maternal hypertension and proteinuria after 20 wk of gestation. In addition to being a leading cause of maternal and fetal morbidity/mortality, epidemiological and prospective studies have revealed long-term consequences for both the mother and baby of preeclamptic pregnancies, including chronic hypertension as well as other cardiovascular diseases and metabolic derangements. To better understand the effect of in utero exposure of PE on offspring, we utilized the BPH/5 mouse, a spontaneous model of the maternal and fetal PE syndrome. We hypothesized that young BPH/5 offspring would have altered metabolic and cardiovascular phenotypes. Indeed, BPH/5 growth-restricted offspring showed excess catch-up growth by early adulthood due to hyperphagia and increased white adipose tissue (WAT) accumulation, with inflammation markers isolated to the reproductive WAT depot only. Both excessive WAT accumulation and the inflammatory WAT phenotype were corrected by pair-feeding young BPH/5 female mice. We also found that young BPH/5 female mice showed evidence of leptin resistance. Indeed, chronic hyperleptinemia has been shown to characterize other rodent models of PE; however, the maternal metabolic profile before pregnancy has not been fully understood. Furthermore, we found that these mice show signs of cardiovascular anomalies (hypertension and cardiomegaly) and altered signaling within the reproductive axis in early life. Future studies will involve challenging the physiological metabolic state of BPH/5 mice through pair-feeding to reduce WAT before pregnancy and determining its causal role in adverse pregnancy outcomes.
Conjoint representation of texture ensemble and location in the parahippocampal place area
Authors: Park Jeongho , Park Soojin
Published: January 2017

Texture provides crucial information about the category or identity of a scene. Nonetheless, not much is known about how the texture information in a scene is represented in the brain. Previous studies have shown that the parahippocampal place area (PPA), a scene-selective part of visual cortex, responds to simple patches of texture ensemble. However, in natural scenes textures exist in spatial context within a scene. Here we tested two hypotheses that make different predictions on how textures within a scene context are represented in the PPA. The Texture-Only hypothesis suggests that the PPA represents texture ensemble (i.e., the kind of texture) as is, irrespective of its location in the scene. On the other hand, the Texture and Location hypothesis suggests that the PPA represents texture and its location within a scene (e.g., ceiling or wall) conjointly. We tested these two hypotheses across two experiments, using different but complementary methods. In experiment 1, by using multivoxel pattern analysis (MVPA) and representational similarity analysis, we found that the representational similarity of the PPA activation patterns was significantly explained by the Texture-Only hypothesis but not by the Texture and Location hypothesis. In experiment 2, using a repetition suppression paradigm, we found no repetition suppression for scenes that had the same texture ensemble but differed in location (supporting the Texture and Location hypothesis). On the basis of these results, we propose a framework that reconciles contrasting results from MVPA and repetition suppression and draw conclusions about how texture is represented in the PPA.

NEW & NOTEWORTHY This study investigates how the parahippocampal place area (PPA) represents texture information within a scene context. We claim that texture is represented in the PPA at multiple levels: the texture ensemble information at the across-voxel level and the conjoint information of texture and its location at the within-voxel level. The study proposes a working hypothesis that reconciles contrasting results from multivoxel pattern analysis and repetition suppression, suggesting that the methods are complementary to each other but not necessarily interchangeable.
Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles
Authors: Carrasco Dario I. , Vincent Jacob A. , Cope Timothy C.
Published: January 2017

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6 and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles.

NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons.
Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing
Authors: Watkins Roger H. , Wessberg Johan , Backlund Wasling Helena , Dunham James P. , Olausson Håkan , Johnson Richard D. , Ackerley Rochelle
Published: January 2017

C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological “signatures” (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information.

NEW & NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch.
HMGA2–FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer
Authors: Dong Jiaqiang , Wang Rui , Ren Gui , Li Xiaowei , Wang Jingbo , Sun Yi , Liang Jie , Nie Yongzhan , Wu Kaichun , Feng Bin , Shang Yulong , Fan Daiming
Published: January 2017

Purpose: Chemoresistance is the main cause of treatment failure in cancer and is associated with distant metastases and epithelial-to-mesenchymal transition (EMT). This study was aimed to explore the mechanism of metastases and EMT in chemoresistant gastric cancer.

Experimental Design: A key molecular pathway was identified via gene profiling and a bioinformatic analysis in a chemoresistant gastric cancer model. The roles of FOXL2, HMGA2, and ITGA2 were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic gastric cancer animal model. The regulation of FOXL2 by HMGA2 was explored via immunoprecipitation and luciferase reporter assays. The expression of these proteins in gastric cancer tissues was examined by IHC.

Results: HMGA2 and FOXL2 directly regulated the metastasis and EMT of chemoresistant gastric cancer. The interaction between HMGA2 and pRb facilitated the transactivation of FOXL2 by E2F1, and ITGA2 was the downstream effector of the HMGA2–FOXL2 pathway. HMGA2, FOXL2, and ITGA2 were associated with the TNM classification and staging of gastric cancer and were increased in metastatic lymph nodes and distant metastases. Increased HMGA2, FOXL2, and ITGA2 levels were associated with reduced overall survival periods of patients with gastric cancer.

Conclusions: This study demonstrated that the transactivation of FOXL2 driven by interactions between HMGA2 and pRb might exert critical effects on the metastases and EMT of chemoresistant gastric cancer. Blocking the HMGA2–FOXL2–ITGA2 pathway could serve as a new strategy for gastric cancer treatment. Clin Cancer Res; 23(13); 3461–73. ©2017 AACR.
Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL
Authors: Jones Luke , Richmond Jennifer , Evans Kathryn , Carol Hernan , Jing Duohui , Kurmasheva Raushan T. , Billups Catherine A. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B.
Published: January 2017

Purpose: Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing promising therapies for clinical assessment in high-risk patients. Patient-derived xenograft (PDX) models of ALL provide a clinically relevant platform for assessing novel drugs, with efficacy generally assessed by enumerating circulating human lymphoblasts in mouse peripheral blood (PB) as an indicator of disease burden. While allowing indirect measurement of disease burden in real time, this technique cannot assess treatment effects on internal reservoirs of disease. We explore benefits of bioluminescence imaging (BLI) to evaluate drug responses in ALL PDXs, compared with PB monitoring. BLI-based thresholds of drug response are also explored.

Experimental Design: ALL PDXs were lentivirally transduced to stably express luciferase and green fluorescent protein. In vivo PDX responses to an induction-type regimen of vincristine, dexamethasone, and L-asparaginase were assessed by BLI and PB. Residual disease at day 28 after treatment initiation was assessed by flow cytometric analysis of major organs. BLI and PB were subsequently used to evaluate efficacy of the Bcl-2 inhibitor venetoclax.

Results: BLI considerably accelerated and enhanced detection of leukemia burden compared with PB and identified sites of residual disease during treatment in a quantitative manner, highlighting limitations in current PB-based scoring criteria. Using BLI alongside enumeration of human lymphoblasts in PB and bone marrow, we were able to redefine response criteria analogous to the clinical setting.

Conclusions: BLI substantially improves the stringency of preclinical drug testing in pediatric ALL PDXs, which will likely be important in prioritizing effective agents for clinical assessment. Clin Cancer Res; 23(14); 3744–55. ©2017 AACR.
Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4
Authors: Sowalsky Adam G. , Kissick Haydn T. , Gerrin Sean J. , Schaefer Rachel J. , Xia Zheng , Russo Joshua W. , Arredouani M. Simo , Bubley Glenn J. , Sanda Martin G. , Li Wei , Ye Huihui , Balk Steven P.
Published: January 2017

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established.

Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities.

Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci.

Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823–33. ©2017 AACR.
PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers
Authors: Packer Leisl M. , Geng Xinyan , Bonazzi Vanessa F. , Ju Robert J. , Mahon Clare E. , Cummings Margaret C. , Stephenson Sally-Anne , Pollock Pamela M.
Published: January 2017

Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1. The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637–48. ©2017 AACR.
Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies
Authors: Makena Monish R. , Koneru Balakrishna , Nguyen Thinh H. , Kang Min H. , Reynolds C. Patrick
Published: January 2017

T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)–dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. Mol Cancer Ther; 16(4); 649–61. ©2017 AACR.
Sensitive Skin: Assessment of the Skin Barrier Using Confocal Raman Microspectroscopy
Authors: Richters Renée J.H. , Falcone Denise , Uzunbajakava Natallia E. , Varghese Babu , Caspers Peter J. , Puppels Gerwin J. , van Erp Piet E.J. , van de Kerkhof Peter C.M.
Published: January 2017

Background/Aims: Sensitive skin (SS), a frequently reported condition in the Western world, has been suggested to be underlined by an impaired skin barrier. The aim of this study was to investigate the skin barrier molecular composition in SS subjects using confocal Raman microspectroscopy (CRS), and to compare it with that of non-SS (NSS) individuals as well as atopic dermatitis (AD) and allergic rhinoconjunctivitis (AR) subjects, who frequently report SS. Methods: Subjects with SS (n = 29), NSS (n = 30), AD (n = 11), and AR (n = 27) were included. Stratum corneum (SC) thickness, water, ceramides/fatty acids, and natural moisturizing factor (NMF) were measured by CRS along with transepidermal water loss and capacitance on the ventral forearm, thenar, and cheek. Sebum levels were additionally measured on the forearm and cheek. Results: No differences between SS and NSS subjects were found regarding SC thickness, water, and NMF content, yet a trend towards lower ceramides/fatty acids was observed in the cheek. Compared to AD subjects, the SS group showed higher ceramides/fatty acid content in the forearm, whereas no differences emerged with AR. The correlation of macroscopic biophysical techniques and CRS was weak, yet CRS confirmed the well-known lower content of NMF and water, and thinner SC in subjects with filaggrin mutations. Conclusion: The skin barrier in SS is not impaired in terms of SC thickness, water, NMF, and ceramides/fatty acid content. The failure of biophysical techniques to follow alterations in the molecular composition of the skin barrier revealed by CRS emphasizes a strong need in sensitive and specific tools for in vivo skin barrier analysis.
Uveal Melanoma Cell Seeding after Transretinal Tumor Biopsy
Authors: Koch Konrad R. , Hishmi Ahmed M. , Ortmann Monika , Heindl Ludwig M.
Published: January 2017

Background/Aims: To report a case and the histopathology of uveal melanoma cell seeding following transretinal tumor biopsy for a suspected uveal lesion. Methods: Interventional case report. Results: A 66-year-old male presented with a pigmented perilimbal episcleral lesion overlying an intraocular mass at the pars plana, 3.5 years after transretinal biopsy and ruthenium plaque brachytherapy for a choroidal melanoma at the posterior pole. The patient underwent enucleation of the eye. Histopathology confirmed a recurrence of uveal melanoma with intra- and extrascleral tumor portions. Serial sections revealed the posterior border of this newfound pars plana melanoma separated from the radiation scar by a viable and tumor-free choroidal area, thus failing to establish a continuity between secondary and primary tumor. Conclusion: Transretinal tumor biopsy is of high diagnostic and prognostic value in the management of uveal lesions, but also bears the potential risk for tumor cell seeding.
Cariogenic Potential of Sucrose Associated with Maltodextrin on Dental Enamel
Authors: Rezende Gabriela , Arthur Rodrigo A. , Grando Debora , Hashizume Lina N.
Published: January 2017

Maltodextrin is a hydrolysate of cornstarch and has been widely used in the food industry associated with sucrose. The addition of starch can increase the cariogenic potential of sucrose; however, there are sparse data regarding the cariogenicity of sucrose associated with maltodextrin. Therefore, the aim of this study was to test in situ if maltodextrin could increase the cariogenic potential of sucrose. This was an in situ, randomized, crossover, split-mouth, and double-blind study. Volunteers wore palatal appliances containing bovine enamel blocks for 2 periods of 14 days. They dripped the following solutions on the enamel blocks 8 times per day: deionized distilled water (DDW), maltodextrin (M), sucrose + maltodextrin (S+M), or sucrose (S). At the end of each experimental period, biofilms were collected and analyzed for microbiological (mutans streptococci, lactobacilli, and total microorganisms counts) and biochemical (calcium, inorganic phosphate, fluoride, and insoluble extracellular polysaccharides concentrations) compositions. The enamel demineralization was assessed by microhardness. Treatments S and S+M resulted in a lower inorganic composition and higher concentration of insoluble extracellular polysaccharides in the biofilms, and higher enamel mineral loss compared to DDW and M. It can be concluded that the cariogenic potential of sucrose is not changed when this carbohydrate is associated with maltodextrin (dextrose equivalent 13-17).
The mTORC1 Complex Is Significantly Overactivated in SDHX-Mutated Paragangliomas
Authors: Oudijk Lindsey , Papathomas Thomas , de Krijger Ronald , Korpershoek Esther , Gimenez-Roqueplo Anne-Paule , Favier Judith , Canu Letizia , Mannelli Massimo , Rapa Ida , Currás-Freixes Maria , Robledo Mercedes , Smid Marcel , Papotti Mauro , Volante Marco
Published: January 2017

Aim: We aimed at exploring the activation pattern of the mTOR pathway in sporadic and hereditary pheochromocytomas (PCCs) and paragangliomas (PGLs). Methods: A total of 178 PCCs and 44 PGLs, already characterized for the presence of germline mutations in VHL, RET, NF1, MAX, SDHA, SDHB, SDHC, and SDHD as well as somatic mutations in VHL, RET, H-RAS, and MAX, were included in 5 tissue microarrays and tested using immunohistochemistry for mTOR and Rictor as well as the phosphorylated forms of mTOR, p70S6K, AMPK, AKT, 4EBP1, S6, and Raptor. Results: The positive correlation among most of the molecules investigated proved the functional activation of the mTOR pathway in PCCs/PGLs. Total mTOR, p-S6K and p-S6, and mTORC1-associated molecules p-Raptor and p-AMPK were all significantly overexpressed in PGLs rather than in PCCs, and in the head and neck rather than in abdominal locations. None of the markers, except for the low expression of p-mTOR, was associated with malignancy. Cluster 1 PCCs/PGLs had higher total mTOR, p-Raptor, and p-S6 expression than cluster 2 PCCs/PGLs. In contrast, p-mTOR and mTORC2-associated molecule Rictor were significantly overexpressed in cluster 2 tumors. Within cluster 1, molecules active in the mTORC1 complex were significantly overexpressed in SDHX- as compared to VHL-mutated tumors. Conclusion: In summary, the mTOR pathway is activated in a high proportion of PCCs/PGLs, with a preferential overactivation of the mTORC1 complex in PGLs of the head and neck and/or harboring SDHX mutations.