bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual placement and support (IPS) for patients with offending histories: the IPSOH feasibility cluster randomised trial protocol
Authors: Khalifa N , Talbot E , Schneider J , Walker D M , Bates P , Bird Y , Davies D , Brookes C , Hall J , Völlm B
Published: July 2016

Introduction

People with involvement in forensic psychiatric services face many obstacles to employment, arising from their offending, as well as their mental health problems. This study aims to assess the feasibility of conducting a randomised controlled trial (RCT) to evaluate the effectiveness of individual placement and support (IPS), in improving employment rates and associated psychosocial outcomes in forensic psychiatric populations. IPS has been found consistently to achieve employment rates above 50% in psychiatric patients without a history of involvement in criminal justice services.

Methods/design

This is a single-centre feasibility cluster RCT. Clusters will be defined according to clinical services in the community forensic services of Nottinghamshire Healthcare NHS Foundation Trust (NHCT). IPS will be implemented into 2 of the randomly assigned intervention clusters in the community forensic services of NHCT. A feasibility cluster RCT will estimate the parameters required to design a full RCT. The primary outcome is the proportion of people in open employment at 12-month follow-up. Secondary outcome measures will include employment, educational activities, psychosocial and economic outcomes, as well as reoffending rates. Outcome measures will be recorded at baseline, 6 months and 12 months. In accordance with the UK Medical Research Council guidelines on the evaluation of complex interventions, a process evaluation will be carried out; qualitative interviews with patients and staff will explore general views of IPS as well as barriers and facilitators to implementation. Fidelity reviews will assess the extent to which the services follow the principles of IPS prior, during and at the end of the trial.

Ethics and dissemination

Ethical approval was obtained from the East Midlands Research Ethics Committee-Nottingham 1 (REC reference number 15/EM/0253). Final and interim reports will be prepared for project funders, the study sponsor and clinical research network. Findings will be disseminated through peer-reviewed journals, conferences and event presentations.

Trial registration number

NCT02442193; Pre-results.
Does examining the whole lymph node improve detection of lymph node metastases in colorectal carcinomas?
Authors: Lynch Nicola , Williamson Sophia L H
Published: July 2016

There is uncertainty on the best approach to histological examination of macroscopically negative lymph nodes obtained from resections for colorectal carcinomas. In this study we reviewed the lymph nodes from all 54 colorectal resections for colorectal carcinoma with positive lymph nodes obtained in 1 year. Macroscopically negative nodes had been sliced and all the tissue embedded. There were 20 lymph nodes that had a metastasis seen in only one section of the sliced node, from 13 resections; 6 patients could have had their staging changed if the nodes had been sampled rather than all embedded and examined. The median size of the smallest metastasis for each patient was 2 mm. We suggest that all tissue from macroscopically negative lymph nodes should be examined.
Natural language processing in pathology: a scoping review
Authors: Burger Gerard , Abu-Hanna Ameen , de Keizer Nicolette , Cornet Ronald
Published: July 2016

Background

Encoded pathology data are key for medical registries and analyses, but pathology information is often expressed as free text.

Objective

We reviewed and assessed the use of NLP (natural language processing) for encoding pathology documents.

Materials and methods

Papers addressing NLP in pathology were retrieved from PubMed, Association for Computing Machinery (ACM) Digital Library and Association for Computational Linguistics (ACL) Anthology. We reviewed and summarised the study objectives; NLP methods used and their validation; software implementations; the performance on the dataset used and any reported use in practice.

Results

The main objectives of the 38 included papers were encoding and extraction of clinically relevant information from pathology reports. Common approaches were word/phrase matching, probabilistic machine learning and rule-based systems. Five papers (13%) compared different methods on the same dataset. Four papers did not specify the method(s) used. 18 of the 26 studies that reported F-measure, recall or precision reported values of over 0.9. Proprietary software was the most frequently mentioned category (14 studies); General Architecture for Text Engineering (GATE) was the most applied architecture overall. Practical system use was reported in four papers. Most papers used expert annotation validation.

Conclusions

Different methods are used in NLP research in pathology, and good performances, that is, high precision and recall, high retrieval/removal rates, are reported for all of these. Lack of validation and of shared datasets precludes performance comparison. More comparative analysis and validation are needed to provide better insight into the performance and merits of these methods.
Mechanical thrombectomy for pediatric acute ischemic stroke: review of the literature
Authors: Satti Sudhakar , Chen Jennifer , Sivapatham Thinesh , Jayaraman Mahesh , Orbach Darren
Published: July 2016

Objective

Given recent strongly positive randomized controlled adult mechanical thrombectomy trials, we sought to perform a comprehensive review of available literature on IA pediatric stroke intervention, with a focus on modern mechanical devices.

Methods

PubMed search for pediatric patients undergoing IA treatment of acute ischemic stroke (AIS) using modern devices between 2008 and 2015. 29 patients were included in this analysis.

Results

Average age was 10.3 years, 74.1% male, middle cerebral and basilar arteries represented 89.6% of 36 occluded vessels, and average pediatric stroke scale score of 18.1. Average time from symptom onset to intervention was 8.8 hours and 13.8% of patients received IV tissue plasminogen activator prior to mechanical thrombectomy. Stent retrievers were used in 58.6% of cases, the Penumbra system in 34.5%, and the Merci device in 27.6%. Modified Thrombolysis In Cerebral Infarction 2b/3 recanalization was achieved in 75.9% of cases. There were no major adverse events related to the intervention, although one procedure was associated with device malfunction without a definite change in long-term outcome. The average modified Rankin Scale (mRS) score was <1 (0.86) at the longest available follow-up period, based on clinical description or provided mRS score.

Conclusions

This study suggests that mechanical thrombectomy in pediatric patients presenting with high pediatric NIH Stroke Scale scores and proximal large vessel occlusion is associated with high recanalization rates and excellent clinical outcome, although this is a retrospective review and the sample size is too small to make any definitive conclusions. This study provides class IVC evidence that endovascular treatment of pediatric AIS increases the chance of a good clinical outcome.
Barriers and facilitators for goals of care discussions between residents and hospitalised patients
Authors: Shah Kalpa , Swinton Marilyn , You John J
Published: July 2016

Purpose

To observe how residents are engaging in goals of care discussions with patients and identify thematic patterns that inhibited (barriers) and promoted discussion (facilitators) about goals of care.

Design

Admission encounters between residents and patients admitted to a tertiary care academic hospital were recorded and analysed using a qualitative descriptive method. Patients included in the study were individuals over the age of 65 being admitted to the internal medicine service. Residents were eligible if they were trainees in family medicine, emergency medicine, general surgery or internal medicine who were on call for the inpatient medicine rotation.

Results

A total of 15 resident–patient encounters were recorded and analysed, of which 12 encounters included a goals of care discussion. Barriers to goals of care discussions were due to missed opportunities to clarify patient’s preferences for life-sustaining treatment and missed opportunities to engage the patient in further discussion. Facilitators to goals of care discussions were use of simple language and exploration of patient’s previous experiences with life-sustaining treatment.

Conclusions

Asking about patients’ previous experiences with life support can be an effective strategy to gauge the patient’s understanding and goals of care preferences. This knowledge can improve residents’ skill in communicating with their patients about goals of care and inform future education initiatives.
Numerical investigation on the femtosecond pulse propagation and free carriers’ evolution in silicon-on-insulator waveguides
Authors: Wen Jin , Ma Chengju , Fan Wei , Fu Haiwei , Jia Zhenan
Published: July 2016

The femtosecond pulse propagation and free carriers’ evolution in the silicon-on-insulator (SOI) waveguides have been numerically investigated considering the carrier’s lifetime and the pulse width of the input pulse at 1.5 [Formula: see text]m regime. Numerical results show that the free carriers’ density profile becomes gentle between the leading edge and trailing edge of the pulse in time domain due to the decreasing of the pulse intensity caused by the nonlinear absorption, which becomes more remarkable when the pulse width expands. It can be found that lifetime ranging from 5 ns to 100 ns does not affect the free carriers’ evolution clearly in femtosecond regime. In addition, the refractive index modulation can be appeared in the process of pulse propagation and free carriers evolution with lower peak power of 200 W. This research can supply some contribution to the insight of free carriers evolution in SOI waveguides.
Gauge dependence and self-force from Galilean to Einsteinian free fall, compact stars falling into black holes, Hawking radiation and the Pisa tower at the general relativity centennial
Authors: Spallicci Alessandro D. A. M. , van Putten Maurice H. P. M.
Published: July 2016

Obviously, in Galilean physics, the universality of free fall implies an inertial frame, which in turns implies that the mass [Formula: see text] of the falling body is omitted (because it is a test mass; put otherwise, the center of mass of the system coincides with the center of the main, and fixed, mass [Formula: see text]; or else, we consider only a homogeneous gravitational field). Conversely, an additional (in the opposite or same direction) acceleration proportional to [Formula: see text] would rise either for an observer at the center of mass of the system, or for an observer at a fixed distance from the center of mass of [Formula: see text]. These elementary, but overlooked, considerations fully respect the equivalence principle (EP) and the (local) identity of an inertial or a gravitational pull for an observer in the Einstein cabin. They value as fore-runners of the self-force and gauge dependency in general relativity. Because of its importance in teaching and in the history of physics, coupled to the introductory role to Einstein’s EP, the approximate nature of Galilei’s law of free fall is explored herein. When stepping into general relativity, we report how the geodesic free fall into a black hole was the subject of an intense debate again centered on coordinate choice. Later, we describe how the infalling mass and the emitted gravitational radiation affect the free fall motion of a body. The general relativistic self-force might be dealt with to perfectly fit into a geodesic conception of motion. Then, embracing quantum mechanics, real black holes are not classical static objects any longer. Free fall has to handle the Hawking radiation, and leads us to new perspectives on the varying mass of the evaporating black hole and on the varying energy of the falling mass. Along the paper, we also estimate our findings for ordinary masses being dropped from a Galilean or Einsteinian Pisa-like tower with respect to the current state of the art drawn from precise measurements in ground and space laboratories, and to the constraints posed by quantum measurements. Appendix A describes how education physics and high impact factor journals discuss the free fall. Finally, case studies conducted on undergraduate students and teachers are reviewed.
One-step hydrothermal synthesis of NiS/MoS2-rGO composites and their application as catalysts for hydrogen evolution reaction
Authors: Wu Huaping , Qiu Ye , Zhang Junma , Chai Guozhong , Lu Congda , Liu Aiping
Published: July 2016

The composites of sulphide and reduced graphene oxide (NiS/MoS2-rGO) were synthesized through a facile solvent-assisted hydrothermal method. The introduction of NiS was paramount not only in enhancing the conductivity of whole catalysts but also in modulating the layer structures of MoS2 with additional active sites. Moreover, the NiS and rGO functioned together in controlling the morphology of as-prepared composites, resulting in uniformly distributed NiS/MoS2 nanosheets perpendicular to rGO scaffold. This further contributed to the excellent hydrogen evolution performance of the composites with a small onset overpotential of 80[Formula: see text]mV and Tafel slope as low as 65[Formula: see text]mV/decade.
New perspectives on the origin of olivine-rich troctolites and associated harrisites from the Ligurian ophiolites (Italy)
Authors: Renna Maria Rosaria , Tribuzio Riccardo , Ottolini Luisa
Published: July 2016

The mid-ocean ridge (MOR)-type gabbroic sequences from the Internal Ligurian ophiolites include olivine-rich troctolite lenses up to tens of metres thick. For one of these lenses, a portion of metre-scale thickness characterized by skeletal to dendritic olivines (harrisites) was observed near the contact with host gabbros. Spinels from the olivine-rich troctolites locally include Ti-pargasite to kaersutite frequently associated with phlogopite to Na-phlogopite. Spinel-hosted amphibole displays rare earth element (REE) patterns characterized by a negative Eu anomaly, thereby recording a magmatic process associated with plagioclase segregation. The amphiboles show variable depletion of light REE (LREE) relative to middle REE (MREE), and heavy REE (HREE) that are weakly enriched to depleted with respect to MREE. Crystallization of the inclusion-bearing spinels is attributed to cooling of hybrid melts that originated by interaction between primitive melts and gabbro-related melts relatively rich in SiO
2
and incompatible elements. Clinopyroxene and amphibole from the harrisites show extensive variability for trace element compositions, albeit characterized by subparallel incompatible element patterns. This chemical variability was most probably acquired in response to rapid crystal growth related to undercooling of the harrisite parental melt. We propose that the melt undercooling was related to interaction of a primitive melt batch with a gabbroic crystal mush.

Supplementary material
: Details of the analytical technique are available at
http://doi.org/10.6084/m9.figshare.c.3284312
End of the Kiaman Superchron in the Permian of SW England: magnetostratigraphy of the Aylesbeare Mudstone and Exeter groups
Authors: Hounslow Mark W. , McIntosh Gregg , Edwards Richard A. , Laming Deryck J. C. , Karloukovski Vassil
Published: July 2016

The chronology of Permian strata in SW England is fragmentary and largely based on radiometric dating of associated volcanic units. Magnetostratigraphy from the
c.
2 km of sediments in the Exeter and Aylesbeare Mudstone groups was undertaken to define a detailed chronology, using the end of the Kiaman Superchron and the overlying reverse and normal polarity in the Middle and Upper Permian as age constraints. The palaeomagnetic directions are consistent with other European Permian palaeopoles, with data passing fold and reversal tests. The end of the Kiaman Superchron (in the Wordian) occurs in the uppermost part of the Exeter Group. The overlying Aylesbeare Mudstone Group is early Capitanian to latest Wuchiapingian in age. The Changhsingian and most of the Lower Triassic sequence is absent. Magnetostratigraphic comparison with the Southern Permian Basin shows that the Exeter and Aylesbeare Mudstone groups are closely comparable in age with the Havel and Elbe Subgroups of the Rotliegend II succession. The Altmark unconformities in these successions appear similar in age to the sequence boundaries in SW England, indicating that both may be climate controlled. Clasts in the Exeter Group, from unroofing of the Dartmoor Granite, first occurred at a minimum of
c.
8 myr after formation of the granite.

Supplementary material:
Additional sampling, magnetic fabric and palaeomagnetic data are available at
http://doi.org/10.6084/m9.figshare.c.3283400
Zircon U–Pb ages, δ
18
O and whole-rock Nd isotopic compositions of the Dire Dawa Precambrian basement, eastern Ethiopia: implications for the assembly of Gondwana
Authors: Yeshanew Fitsum Girum , Pease Victoria , Abdelsalam Mohamed G. , Whitehouse Martin J.
Published: July 2016

New high spatial resolution secondary ion mass spectrometry (SIMS) zircon dating from the Dire Dawa Precambrian basement yields crystallization ages at
c
. 790 Ma and 600 – 560 Ma. Two of the youngest samples are pervasively deformed, indicating that orogenesis continued until
c
. 560 Ma. SIMS δ
18
O
zrn
shows bimodality, with the oldest sample (
c
. 790 Ma) and inherited zircons of that age in the younger samples having values of 7.8 – 9.6‰, whereas the Ediacaran samples have δ
18
O
zrn
values of 4.9 – 7.2‰. These δ
18
O
zrn
ratios are higher than mantle values and indicate a supracrustal input to the source of the Dire Dawa granitoids. All samples have unradiogenic ε
Nd
(
t
) values of −10.3 to −5.8 and Nd model ages of 1.72 – 1.42 Ga. These attributes suggest that the Dire Dawa granitoids were mostly derived from reworking of long-lived crustal sources. The occurrence of
c
. 580 – 550 Ma orogenesis in both the Dire Dawa basement and the juvenile Western Ethiopian Shield and the confinement of
c
. 630 Ma metamorphism to only the latter indicate that these two lithospheric blocks of contrasting isotopic compositions amalgamated at
c
. 580 – 550 Ma. This suggests that the Mozambique Ocean, which separated these two lithospheric blocks, was completely consumed during the late Ediacaran to early Cambrian.
Basin-scale architecture of deeply emplaced sill complexes: Jameson Land, East Greenland
Authors: Eide Christian Haug , Schofield Nick , Jerram Dougal A. , Howell John A.
Published: July 2016

Igneous sills are common components in rifted sedimentary basins globally. Much work has focused on intrusions emplaced at relatively shallow palaeodepths (0 – 1.5 km). However, owing to constraints of seismic reflection imaging and limited field exposures, intrusions emplaced at deeper palaeodepths (>1.5 km) within sedimentary basins are not as well understood in regard to their emplacement mechanisms and host-rock interactions. Results from a world-class, seismic-scale outcrop of intruded Jurassic sedimentary rocks in East Greenland are presented here. Igneous intrusions and their host rocks have been studied in the field and utilizing a 22 km long ‘virtual outcrop’ acquired using helicopter-mounted lidar. The results suggest that the geometries of the deeply emplaced sills (
c.
3 km) are dominantly controlled by host-rock lithology, sedimentology and cementation state. Sills favour mudstones and even exploit centimetre-scale mudstone-draped dune-foresets in otherwise homogeneous sandstones. Sills in poorly cemented intervals show clear ductile structures, in contrast to sills in cemented units, which show only brittle emplacement structures. The studied host rock is remarkably undeformed despite intrusion. Volumetric expansion caused by the intrusions is almost exclusively accommodated by vertical jack-up of the overburden, on a 1:1 ratio, implying that intrusions may play a significant role in uplift of a basin if emplaced at deep basinal levels.

Supplementary materials:
Uninterpreted versions of Figures 7, 8 and 11 are available at
http://doi.org/10.6084/m9.figshare.c.3281882
Historians of geology in the field: a half-century of INHIGEO excursions
Authors: Johnston Mike R. , Taylor Kenneth L.
Published: July 2016

When INHIGEO was born at Yerevan in 1967, it was agreed that field excursions would be an integral part of its activities. Although the bylaw that was adopted to this effect has since lapsed, the practice of combining meetings and excursions has continued. Meeting venues and the excursions associated with them are suggested by members in the host country and their organization is very much a local responsibility. Although the meetings commonly have a theme specific to them, the excursions may be more general depending on what can be achieved in the general vicinity of the venue and the interests and specializations of those running them. While it is accepted practice to visit geologically important sites, there is also a recognition that participants often appreciate the inclusion of localities or monuments of historical and cultural interest. This reflects the professional breadth of INHIGEO's membership (whose main disciplines span the geosciences as well as the history of science, in addition to some other fields) and also acknowledges the general understanding that geology, like every science, develops within the cultural milieus where it is practised. Excursions organized with specifically historical objectives respond to a variety of ideas about the goals of historical understanding, ranging along a scientific–historical spectrum. Excursions may be short, lasting from a few hours to a half or even a full day (these are frequently held during the course of the meeting); longer excursions may last up to a week or even more and are almost always scheduled either prior to or after the close of the meeting sessions. Whatever their duration, INHIGEO excursions have always proved to be educational and enlightening and are often among the most memorable of a meeting's experiences.
The stratigraphy and structure of the Faroese continental margin
Authors: Ólavsdóttir Jana , Eidesgaard Óluva R. , Stoker Martyn S.
Published: July 2016

This paper presents a summary of the stratigraphy and structure of the Faroese region. As the Faroese area is mostly covered by volcanic material, the nature of the pre-volcanic geology remains largely unproven. Seismic refraction data provide some indications of the distribution of crystalline basement, which probably comprises Archaean rocks, with the overlying cover composed predominantly of Upper Mesozoic (Cretaceous?) and Cenozoic strata. The Cenozoic succession is dominated by the syn-break-up Faroe Islands Basalt Group, which crops out on the Faroe Islands (where it is up to 6.6 km thick) and shelf areas; post-break-up sediments are preserved in the adjacent deep-water basins, including the Faroe–Shetland Basin. Seismic interpretation of the post-volcanic strata shows that almost every sub-basin in the Faroe–Shetland Basin has been affected by structural inversion, particularly during the Miocene. These effects are also observed on the Faroe Platform, the Munkagrunnur Ridge and the Fugloy Ridge, where interpretation of low-gravity anomalies suggests a large-scale fold pattern. The structure of the Iceland–Faroe Ridge, which borders the NW part of the Faroe area, remains ambiguous. The generally thick crust, together with the absence of well-defined seawards-dipping reflectors, may indicate that much of it is underlain by continental material.
Nitric oxide production contributes toBacillus anthracisedema toxin-associated arterial hypotension and lethality: ex vivo and in vivo studies in the rat
Authors: Li Yan , Cui Xizhong , Xu Wanying , Ohanjanian Lernik , Sampath-Kumar Hanish , Suffredini Dante , Moayeri Mahtab , Leppla Stephen , Fitz Yvonne , Eichacker Peter Q.
Published: July 2016

We showed previously that Bacillus anthracis edema toxin (ET), comprised of protective antigen (PA) and edema factor (EF), inhibits phenylephrine (PE)-induced contraction in rat aortic rings and these effects are diminished in endothelial-denuded rings. Therefore, employing rat aortic ring and in vivo models, we tested the hypothesis that nitric oxide (NO) contributes to ET's arterial effects. Compared with rings challenged with PA alone, ET (PA + EF) reduced PE-stimulated maximal contractile force (MCF) and increased the PE concentration producing 50% MCF (EC50) ( P < 0.0001). Compared with placebo, l-nitro-arginine methyl-ester (l-NAME), an NO synthase (NOS) inhibitor, reduced ET's effects on MCF and EC50in patterns that approached or were significant ( P = 0.06 and 0.03, respectively). In animals challenged with 24-h ET infusions, l-NAME (0.5 or 1.0 mg·kg−1·h−1) coadministration increased survival to 17 of 28 animals (60.7%) compared with 4 of 27 (14.8%) given placebo ( P = 0.01). Animals receiving l-NAME but no ET all survived. Compared with PBS challenge, ET increased NO levels at 24 h and l-NAME decreased these increases ( P < 0.0001). ET infusion decreased mean arterial blood pressure (MAP) in placebo and l-NAME-treated animals ( P < 0.0001) but l-NAME reduced decreases in MAP with ET from 9 to 24 h ( P = 0.03 for the time interaction). S-methyl-l-thiocitrulline, a selective neuronal NOS inhibitor, had effects in rings and, at a high dose in vivo models, comparable to l-NAME, whereas N′-[3-(aminomethyl)benzyl]-acetimidamide, a selective inducible NOS inhibitor, did not. NO production contributes to ET's arterial relaxant, hypotensive, and lethal effects in the rat.
Right ventricular metabolic adaptations to high-intensity interval and moderate-intensity continuous training in healthy middle-aged men
Authors: Heiskanen Marja A. , Leskinen Tuija , Heinonen Ilkka H. A. , Löyttyniemi Eliisa , Eskelinen Jari-Joonas , Virtanen Kirsi , Hannukainen Jarna C. , Kalliokoski Kari K.
Published: July 2016

Despite the recent studies on structural and functional adaptations of the right ventricle (RV) to exercise training, adaptations of its metabolism remain unknown. We investigated the effects of short-term, high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on RV glucose and fat metabolism. Twenty-eight untrained, healthy 40–55 yr-old-men were randomized into HIIT ( n = 14) and MICT ( n = 14) groups. Subjects performed six supervised cycle ergometer training sessions within 2 wk (HIIT session: 4–6 × 30 s all-out cycling/4-min recovery; MICT session: 40–60 min at 60% peak O2 uptake). Primary outcomes were insulin-stimulated RV glucose uptake (RVGU) and fasted state RV free fatty acid uptake (RVFFAU) measured by positron emission tomography. Secondary outcomes were changes in RV structure and function, determined by cardiac magnetic resonance. RVGU decreased after training (−22% HIIT, −12% MICT, P = 0.002 for training effect), but RVFFAU was not affected by the training ( P = 0.74). RV end-diastolic and end-systolic volumes, respectively, increased +5 and +7% for HIIT and +4 and +8% for MICT ( P = 0.002 and 0.005 for training effects, respectively), but ejection fraction mildly decreased (−2% HIIT, −4% MICT, P = 0.034 for training effect). RV mass and stroke volume remained unaltered. None of the observed changes differed between the training groups ( P > 0.12 for group × training interaction). Only 2 wk of physical training in previously sedentary subjects induce changes in RV glucose metabolism, volumes, and ejection fraction, which precede exercise-induced hypertrophy of RV.

Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/right-ventricular-metabolic-adaptations-to-exercise-training/ .
Dendritic cells induce Tc1 cell differentiation via the CD40/CD40L pathway in mice after exposure to cigarette smoke
Authors: Kuang Liang-Jian , Deng Ting-Ting , Wang Qin , Qiu Shi-Lin , Liang Yi , He Zhi-Yi , Zhang Jian-Quan , Bai Jing , Li Mei-Hua , Deng Jing-Min , Liu Guang-Nan , Liu Ji-Feng , Zhong Xiao-Ning
Published: July 2016

Dendritic cells and CD8+T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40−/−mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40−/−dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40−/−) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40−/−mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40−/−cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke.
Loss of CCR2 signaling alters leukocyte recruitment and exacerbates γ-herpesvirus-induced pneumonitis and fibrosis following bone marrow transplantation
Authors: Gurczynski Stephen J. , Procario Megan C. , O'Dwyer David N. , Wilke Carol A. , Moore Bethany B.
Published: July 2016

CCR2-expressing leukocytes are required for the progression of fibrosis in models of induced lung injury as well as models of bone marrow transplant (BMT)-related idiopathic pneumonia syndrome. Infection with murid γ-herpesvirus-68 (γHV-68) results in severe pneumonitis and pulmonary fibrosis following syngeneic BMT; however, the roles that various proinflammatory leukocyte populations play in this process remain unclear. Deletion of CCR2 in both non-BMT and BMT mice increased early lytic viral replication and resulted in a reduction in the numbers of lung-infiltrating GR1+,F4/80+ and CXCR1+ cells, while maintaining robust neutrophil infiltration. Similarly, in γHV-68-infected CCR2−/−BMT mice, recruitment of monocytes and lymphocytes were reduced whereas neutrophil recruitment was increased compared with wild-type (WT) BMT mice. Interestingly, levels of profibrotic IL-17 were increased in infected CCR2 BMT mice compared with WT BMT. Furthermore, an increase in lung-associated collagen was detected even though there was an overall decrease in the number of profibrotic CCR2+ fibrocytes detected in the lungs of CCR2−/−BMT mice. These data indicate that, contrary to most models of fibrosis, deletion of CCR2 offers no protection from γ-herpesvirus-induced pneumonitis and fibrosis, and, indeed, CCR2+ cells play a suppressive role during the development of pulmonary fibrosis following γ-herpesvirus infection post-BMT by limiting IL-7 and collagen production.
Stability of a Quartic Functional Equation in Restricted Domains
Authors: Chung Jaeyoung , Ju Yu-Min
Published: July 2016

LetXbe a real normed space andYa Banach space andf:X→Y. We prove the Ulam-Hyers stability theorem for the quartic functional equationf(2x+y)+f(2x-y)-4f(x+y)-4f(x-y)-24f(x)+6f(y)=0in restricted domains. As a consequence we consider a measure zero stability problem of the above inequality whenf:R→Y.
Estimate of Impact on the Oral Health-Related Quality of Life of Older Thai People by the Provision of Dentures through the Royal Project
Authors: Srisilapanan Patcharawan , Korwanich Narumanas , Jienmaneechotchai Sutha , Dalodom Supranee , Veerachai Nontalee , Vejvitee Warangkana , Roseman Jeffrey
Published: July 2016

Purpose.To estimate the impact of the provision of dentures to Thai older people by the Royal Project on their oral health-related quality of life.Methods.A purposive cross-sectional study of a sample of 812 subjects was conducted. The Oral Impacts on Daily Performances (OIDP) measure was used to assess the oral health-related quality of life.Results.Four groups of older people with different tooth types were studied. 216 (26.6%) had natural teeth (NT). 189 (23.3%) had natural and replaced teeth (NRT). 167 (20.6%) had below the minimum number of teeth but had no dentures (Edent) and 240 were edentate with complete dentures provided by the Royal Project (ECD) (29.6%). Overall, 36.5% had at least one oral impact. Eating was the most affected oral impact. When compared to the group with natural teeth (NT), the Edent group was significantly more likely to report having impacts on eating OR = 6.5 (3.9–10.9), speaking clearly OR = 43.7 (12.7–15.07), emotional stability OR = 16.5 (6.0–45.6), and social contacts OR = 4.6 (2.2–9.5) (p<0.001).Conclusion.Those who are edentulous are much more likely to have an oral impact on their daily performances than those provided dentures. Provision of dentures may lead to improvement of considerable oral impacts.
Analysis of the Intermediate-State Contributions to Neutrinoless Doubleβ−Decays
Authors: Hyvärinen Juhani , Suhonen Jouni
Published: July 2016

A comprehensive analysis of the structure of the nuclear matrix elements (NMEs) of neutrinoless double beta-minus (0νβ-β-) decays to the0+ground and first excited states is performed in terms of the contributing multipole states in the intermediate nuclei of0νβ-β-transitions. We concentrate on the transitions mediated by the light (l-NMEs) Majorana neutrinos. As nuclear model we use the proton-neutron quasiparticle random-phase approximation (pnQRPA) with a realistic two-nucleon interaction based on the Bonn one-boson-exchangeGmatrix. In the computations we include the appropriate short-range correlations, nucleon form factors, and higher-order nucleonic weak currents and restore the isospin symmetry by the isoscalar-isovector decomposition of the particle-particle proton-neutron interaction parametergpp.
A Similarity Classifier with Bonferroni Mean Operators
Authors: Kurama Onesfole , Luukka Pasi , Collan Mikael
Published: July 2016

A similarity classifier based on Bonferroni mean based operators is introduced. The new Bonferroni mean based variant of the similarity classifier is also extended to cover a new Bonferroni-OWA variant. The new Bonferroni-OWA based similarity classifier raises the question of how to accomplish the weighting needed and for this reason we also examine a number of linguistic quantifiers for weight generation. The new proposed similarity classifier variants are tested on four real world medical research related data sets. The results are compared with results from two previously presented similarity classifiers, one based on the generalized mean and another based on an arithmetic mean operator. The results show that comparatively better classification accuracy can be reached with the proposed new similarity classifier variants.
Relationship between Branched-Chain Amino Acids, Metabolic Syndrome, and Cardiovascular Risk Profile in a Chinese Population: A Cross-Sectional Study
Authors: Hu Wen , Sun Luning , Gong Yingyun , Zhou Ying , Yang Panpan , Ye Zhengqin , Fu Jinxiang , Huang Aijie , Fu Zhenzhen , Yu Weinan , Zhao Yang , Yang Tao , Zhou Hongwen
Published: July 2016

Objective.This study aimed to evaluate the relationship between branched-chain amino acids (BCAAs), metabolic syndrome (MS), and other cardiovascular (CV) risk factors in middle-aged and elderly Chinese population at high risk for the development of cardiovascular disease (CVD).Methods.1302 subjects were enrolled from the Huai’an Diabetes Prevention Program.Results.BCAAs levels were positively correlated with MS, its components, and CV risk profile. The odds ratio (OR) for MS among subjects in the fourth quartile of BCAAs levels showed a 2.17-fold increase compared with those in the first quartile. BCAAs were independently associated with high Framingham risk score even after adjusting for MS and its components (P<0.0001). Additionally, the OR for high CV risk was 3.20-fold (P<0.0001) in participants in the fourth BCAAs quartile with MS compared with participants in the first BCAAs quartile without MS.Conclusions.Increased BCAAs levels are independent risk factors of MS and CVD in addition to the traditional factors in middle-aged and elderly Chinese population. The development of CVD in MS patients with high level BCAAs is accelerated. Intervention studies are needed to investigate whether the strategy of BCAAs reduction has impacts on endpoints in patients with higher CV risk. This study is registered withChiCTR-TRC-14005029.
Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer
Authors: Ma Ming-zhe , Zhang Yan , Weng Ming-zhe , Wang Shou-hua , Hu Ye , Hou Zhao-yuan , Qin Yi-yu , Gong Wei , Zhang Yong-Jie , Kong Xiang , Wang Jian-dong , Quan Zhi-wei
Published: July 2016

Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361–71. ©2016 AACR.
JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2–Targeted Therapies
Authors: Manole Simin , Richards Edward J. , Meyer Aaron S.
Published: July 2016

Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling–based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients. Cancer Res; 76(18); 5219–28. ©2016 AACR.
αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor
Authors: Lu Huimin , Wang Tao , Li Jing , Fedele Carmine , Liu Qin , Zhang Jianzhong , Jiang Zhong , Jain Dhanpat , Iozzo Renato V. , Violette Shelia M. , Weinreb Paul H. , Davis Roger J. , Gioeli Daniel , FitzGerald Thomas J. , Altieri Dario C. , Languino Lucia R.
Published: July 2016

Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Ptenpc−/−, carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, because it is not regulated by a different αv-containing integrin, αvβ3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of αvβ6-expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor–increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy. Cancer Res; 76(17); 5163–74. ©2016 AACR.
Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer
Authors: Leung Felix , Bernardini Marcus Q. , Brown Marshall D. , Zheng Yingye , Molina Rafael , Bast Robert C. , Davis Gerard , Serra Stefano , Diamandis Eleftherios P. , Kulasingam Vathany
Published: July 2016

Background: Ovarian cancer is the most lethal gynecological malignancy. Our integrated -omics approach to ovarian cancer biomarker discovery has identified kallikrein 6 (KLK6) and folate-receptor 1 (FOLR1) as promising candidates but these markers require further validation.

Methods: KLK6, FOLR1, CA125, and HE4 were investigated in three independent serum cohorts with a total of 20 healthy controls, 150 benign controls, and 216 ovarian cancer patients. The serum biomarker levels were determined by ELISA or automated immunoassay.

Results: All biomarkers demonstrated elevations in the sera of ovarian cancer patients compared with controls (P < 0.01). Overall, CA125 and HE4 displayed the strongest ability (AUC 0.80 and 0.82, respectively) to identify ovarian cancer patients and the addition of HE4 to CA125 improved the sensitivity from 36% to 67% at a set specificity of 95%. In addition, the combination of HE4 and FOLR1 was a strong predictor of ovarian cancer diagnosis, displaying comparable sensitivity (65%) to the best-performing CA125-based models (67%) at a set specificity of 95%.

Conclusions: The markers identified through our integrated -omics approach performed similarly to the clinically approved markers CA125 and HE4. Furthermore, HE4 represents a powerful diagnostic marker for ovarian cancer and should be used more routinely in a clinical setting.

Impact: The implications of our study are 2-fold: (i) we have demonstrated the strengths of HE4 alone and in combination with CA125, lending credence to increasing its usage in the clinic; and (ii) we have demonstrated the clinical utility of our integrated -omics approach to identifying novel serum markers with comparable performance to clinical markers. Cancer Epidemiol Biomarkers Prev; 25(9); 1333–40. ©2016 AACR.
The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature
Authors: Yuan Shengxian , Wang Jie , Yang Yuan , Zhang Jin , Liu Hui , Xiao Juanjuan , Xu Qingguo , Huang Xinhui , Xiang Bangde , Zhu Shaoliang , Li Lequn , Liu Jingfeng , Liu Lei , Zhou Weiping
Published: July 2016

Purpose: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.

Experimental Design: Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.

Results: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%–99%] and 74% (95% CI, 58%–86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98–16.6, P < 0.05).

Conclusions: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289–97. ©2016 AACR.