bluuebunny/crossref_metadata_2025 huggingface dataset:
Single thyroid tumour showing multiple differentiated morphological patterns and intramorphological molecular genetic heterogeneity
Authors: Schopper Heather K , Stence Aaron , Ma Deqin , Pagedar Nitin A , Robinson Robert A
Published: July 2016

Aims

A 49-year-old man presented with a single thyroid tumour that showed a combination of conventional papillary carcinoma, follicular variant of papillary carcinoma, clear cell papillary carcinoma, columnar cell carcinoma and poorly differentiated carcinoma. As all of the morphologies have been associated with papillary carcinoma in the literature, we wished to determine if they contained identical or different molecular abnormalities.

Methods

Targeted next generation sequencing (NGS) of each morphological component and metastases was performed.

Results

NGS revealed aBRAFp.K601E mutation in both the clear cell papillary carcinoma and poorly differentiated carcinoma and aKRASp.G12R mutation in the papillary carcinoma, follicular variant. Two different areas of columnar cell variant were tested, with one showing aKRASp.G12D mutation but no mutation in the other area.AKRASp.G12R mutation was seen in the metastatic clear cell variant. Two different lymph nodes had metastatic columnar cell carcinoma, one negative for mutations but the other with a compoundKRASp.G12R andKRASp.G12V mutation on different alleles. No mutations includingBRAFandKRASwere seen in the conventional papillary carcinoma.

Conclusions

Although all of the morphological patterns in this tumour have been reported as having aetiological or other association with one another, there was only partial concordance with their molecular signatures. There was significant molecular discordance, however, even with identical morphologies.
Effect of Losartan and Spironolactone on Triglyceride-Rich Lipoproteins in Diabetic Nephropathy
Authors: Srivastava Anand , Adams-Huet Beverley , Vega Gloria L , Toto Robert D
Published: July 2016

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known. We hypothesized long-term administration of either losartan 100 mg or spironolactone 25 mg once daily added onto lisinopril 80 mg once daily would improve dyslipidemia in diabetic nephropathy (DN). We measured lipid levels, very-low-density (V), intermediate-density (I), low-density (LDL), high-density (HDL) lipoprotein, LDL particle size with their respective cholesterol (C) and apolipoprotein B levels (ApoB), and urine albumin/creatinine ratio (UACR) at 12-week interval during a 48-week randomized, double-blind placebo-controlled trial in 81 patients with DN. Plasma lipids and lipoprotein C were analyzed enzymatically and Apo B was determined chemically. Data were analyzed by mixed model repeated measures. ΔUACR differed among treatment arms (placebo −24.6%, los −38.2%, spiro −51.6%, p=0.02). No correlation existed between ΔUACR and ΔTG or any of the lipid or lipoprotein measurements. Compared with placebo losartan, but not spironolactone, decreased TG (−20.9% vs +34.3%, p<0.01), V+I C(−18.8% vs +21.3%, p<0.01), and V+I-ApoB (−13.2% vs +21%, p<0.01). There were no significant changes in body weight, HbA1c or other lipoprotein variables. We conclude losartan improves dyslipidemia in patients with DN. We speculate the mechanism improved clearance of VLDL and remnant lipoproteins.

Trial registration number

NCT00381134; Results.
A comparison of acute vascular damage caused by ADAPT versus a stent retriever device after thrombectomy in acute ischemic stroke: a histological and ultrastructural study in an animal model
Authors: Peschillo S , Diana F , Berge J , Missori P
Published: July 2016

Background

It has been amply demonstrated that endovascular procedures can be successful treatment for stroke, both in terms of revascularization and clinical outcome. There is not, however, a published comparison of any histological or ultrastructural damage to the vessels that may be caused by a direct aspiration first pass technique (ADAPT) or stent retrievers (SR) used in these procedures. This study analyses and compares acute damage to the arterial wall caused by ADAPT or SR.

Material and methods

Damage to the walls of swine extracranial arteries was evaluated after ADAPT with the Penumbra system or thrombectomy with an SR (Solitaire 6×30). The procedures were performed after injecting thrombi into the selected arteries (arteries with diameters similar to those of the human internal carotid artery and first segment of the middle cerebral artery). After the procedures, the animal was euthanized and 12 arterial samples were obtained for analysis by optical and electronic microscopy.

Results

Tissue samples from the vessels treated with SR showed almost complete loss of endothelium, thickening of the internal elastic lamina, and degeneration of the elastic fibers of the bordering lamina media and adventitia. In contrast, tissue samples of the vessels treated with ADAPT had a clear integral internal elastic lamina and uninterrupted endothelial lining, although cell alignment was altered and there were surface lacerations due to manipulation of the samples.

Conclusions

Both techniques caused acute damage to the vessel walls, however, thrombectomy with SR appeared to be more harmful to all layers of the arterial wall, particularly the endothelium.
Responsiveness of a simple RAPID-3-like index compared to disease-specific BASDAI and ASDAS indices in patients with axial spondyloarthritis
Authors: Castrejón Isabel , Pincus Theodore , Wendling Daniel , Dougados Maxime
Published: July 2016

Objective

To evaluate the responsiveness of a simple routine assessment of patient index data (RAPID3)-like index that includes only 3 patient self-report measures (physical function, pain and patient global estimate) compared to that of traditional composite indices to assess change in patients with axial spondyloarthritis (Ax-SpA).

Methods

Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR) is a prospective cohort of patients with inflammatory back pain suggestive of Ax-SpA. The study included 461 patients, who met the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for Ax-SpA. A simple RAPID3-like index was compared with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the AS Disease Activity Score (ASDAS) scores for responsiveness over 6 months. Construct validity was also evaluated through Pearson correlations and discrimination of disease activity through standardised mean differences for the 3 indices.

Results

The RAPID3-like index was correlated significantly with BASDAI (r=0.84, p<0.005) and ASDAS-C-reactive protein (CRP) (r=0.74, p<0.005), similar to correlations of BASDAI with ASDAS-CRP (r=0.76, p<0.005). The percentage of patients with inactive disease ranged from 9% to 25% and with high activity from 10% to 45%, according to various measures. The capacity to discriminate between high and low disease activity was similar for the 3 indices. The strength of agreement of RAPID3 with ASDAS-CRP was moderate (0.44) and lower with BASDAI (0.37). Responsiveness over 6 months was slightly higher for ASDAS-CRP and the RAPID3-like index than that for BASDAI.

Conclusions

The RAPID3-like index provides similar information to BASDAI and ASDAS-CRP concerning responsiveness over 6 months. RAPID3 appears feasible to assess patients with Ax-SpA quantitatively over time in busy clinical settings.
Response to mass casualty events: from the battlefield to the Stop the Bleed campaign
Authors: Knudson M Margaret , Velmahos George , Cooper Zara R
Published: July 2016

In the aftermath of a number of episodes of mass casualty events, we must be reminded of how important it is to be prepared and to reflect on the knowledge accumulated over the past 15 years of war in Iraq and Afghanistan.
Aerosolized bovine lactoferrin reduces neutrophils and pro-inflammatory cytokines in mouse models of Pseudomonas aeruginosa lung infections
Authors: Valenti Piera , Frioni Alessandra , Rossi Alice , Ranucci Serena , De Fino Ida , Cutone Antimo , Rosa Luigi , Bragonzi Alessandra , Berlutti Francesca
Published: July 2016

Lactoferrin (Lf), an iron-chelating glycoprotein of innate immunity, produced by exocrine glands and neutrophils in infection/inflammation sites, is one of the most abundant defence molecules in airway secretions. Lf, a pleiotropic molecule, exhibits antibacterial and anti-inflammatory functions. These properties may play a relevant role in airway infections characterized by exaggerated inflammatory response, as in Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) subjects. To verify the Lf role in Pseudomonas aeruginosa lung infection, we evaluated the efficacy of aerosolized bovine Lf (bLf) in mouse models of P. aeruginosa acute and chronic lung infections. C57BL/6NCrl mice were challenged with 106 CFUs of P. aeruginosa PAO1 (acute infection) or MDR-RP73 strain (chronic infection) by intra-tracheal administration. In both acute and chronic infections, aerosolized bLf resulted in nonsignificant reduction of bacterial load but significant decrease of the neutrophil recruitment and pro-inflammatory cytokine levels. Moreover, in chronic infection the bLf-treated mice recovered body weight faster and to a higher extent than the control mice. These findings add new insights into the benefits of bLf as a mediator of general health and its potential therapeutic applications.
Reintroduction of fen plant communities on a degraded minerotrophic peatland
Authors: Rochefort Line , LeBlanc Marie-Claire , Bérubé Vicky , Hugron Sandrine , Boudreau Stéphanie , Pouliot Rémy
Published: July 2016

We have developed an approach to restore bogs after peat extraction, but, when sedge-peat layers are exposed, the minerotrophic remnant peat conditions require restoration towards a fen ecosystem. Three restoration techniques, all including rewetting actions, were tested to assist fen vegetation recovery. None of the restoration techniques were effective at establishing fen bryophytes. However, for vascular plants, two techniques gave promising results in terms of species composition, although the vascular plant cover remained lower than in the reference fens. Depending on the site conditions, we suggest applying two restoration techniques to restore peatlands in areas of exposed sedge peat. In areas where sparse cover of fen species may have spontaneously established, rewetting should be carried out to raise water levels and create favourable conditions for their expansion. In areas covered with undesirable species or with inadequate topography for rewetting, surface peat should be remodeled and vegetation introduced. Since mechanized diaspore transfer did not result in a satisfactory cover of fen plants, other means of introduction could be considered, alone or in combination. A complementary fertilization experiment showed that fertilization with phosphorus could be an effective solution to enhance the establishment of mechanically introduced plant diaspores.
A review of the plants of the Princeton chert (Eocene, British Columbia, Canada)
Authors: Pigg Kathleen B. , DeVore Melanie L.
Published: July 2016

The Princeton chert is one of the most completely studied permineralized floras of the Paleogene. Remains of over 30 plant taxa have been described in detail, along with a diverse assemblage of fungi that document a variety of ecological interactions with plants. As a flora of the Okanagan Highlands, the Princeton chert plants are an assemblage of higher elevation taxa of the latest early to earliest middle Eocene, with some components similar to those in the related compression floras. However, like the well-known floras of Clarno, Appian Way, the London Clay, and Messel, the Princeton chert provides an additional dimension of internal structure. In the present study, we outline the history of Princeton chert plant research, starting with Boneham and others, and extending into studies by Stockey and her students and colleagues. These studies were undertaken primarily at the University of Alberta, Edmonton. We then re-examine the individual elements of the Princeton chert flora, using the framework of the currently recognized Angiosperm Phylogeny Group (APG III) phylogeny and in light of recent fossil discoveries. We hope that this update will bring to mind new aspects of the significance of the Princeton chert flora to Paleogene paleobiology, biogeography, and plant evolution.
Generating Intelligent Summary Terms for Improving Knowledge Discovery in Software Bug Repositories
Authors: Nagwani Naresh Kumar , Verma Shrish
Published: July 2016

Software bug records are stored and managed using bug tracking tools. A software bug is characterized by a number of attributes like bug id, opened date, closed date, reported by, assigned to, summary (title), description and set of comments. Summary and description are the two important attributes of a bug. Description gives the detailed information about a bug, whereas summary (title) of a bug gives a quick glance and short information about a bug. The objective of this study is to discover the relationship between description and summary attributes of a bug and to find whether summary of a bug is really the compact and intelligent information of description of a bug. This finding helps in providing a new direction for faster knowledge discovery in a bug repository. Another objective of the work is to demonstrate that intelligent summary of a bug can be generated from description of bug using topic modeling techniques. In this work, topic modeling techniques are used to generate meaningful terms for framing the bug summary of software bugs which can be utilized for faster knowledge discovery. Topic modeling techniques can be utilized efficiently for generating intelligent summary from description of a software bugs and then the knowledge discovery can be performed using the intelligent summary only since it will reduce the volume of data for knowledge discovery. To demonstrate the presented approach, experiments are performed on three popular bug repositories namely, Android, Mozilla and MySql. Comparative analysis is carried using various performance parameters and in order to analyze the impact of present work, two knowledge discovery tasks namely, bug classification and duplicate bug identification are presented in this study.
Novel Research on a Fibration Knowledge-Based Solution for Engineered Surface Tolerances within the Modern GPS Context
Authors: Xu Yuanping , Scott Paul J. , Zheng Jiaoling
Published: July 2016

Geometrical product specification and verification (GPS) is the only worldwide tolerancing specification language available for unambiguously communicating functional requirements and precisely expressing geometrical tolerances of workpieces on technical drawings. Although the understanding and application of GPS are of vital importance for modern manufacturing industry, the latest GPS standards contain huge amounts of data, information and knowledge that are obscurely linked together, so they are very difficult for designers, engineers and metrologists to understand, remember and comprehensively use them. This is especially true for surface texture that is one of the most complicated geometrical characteristics in GPS domain. To overcome the implementation barrier of GPS surface texture, a novel knowledge-based solution supported formally by a unified knowledge modeling of the complete GPS surface texture standard chain has been researched. This knowledge model can serve as a formal basis for developing more intelligent and reliable tolerance design and measurement systems. This paper starts with an introduction on how to build up a formal knowledge model based on category theory, called categorical fibration model, to unified acquisition and representation of all surface texture knowledge. It then moves on to define a recursive knowledge refinement process for the devised model to enable the recursive multi-level GPS knowledge transformations and refinements. This knowledge model is validated naturally by checking rules identified from category theoretic notions. Finally, this paper presents a general framework for applying the modeled GPS knowledge in practice, from the aspects of the integrated and complete modeling of all surface texture knowledge, detailed knowledge acquisition and modeling examples for four sub-knowledge bases of the proposed software solution, core functional features of this software, and a comprehensive case study for testing its validity and usability. This knowledge-based solution facilitates life cycle collaboration and integration of the complete GPS surface texture chain to reduce product development cost and lead time, and to ensure functional requirements of geometrical workpieces.
Quintom cosmological model and some possible solutions using Lie and Noether symmetries
Authors: Dutta Sourav , Lakshmanan Muthusamy , Chakraborty Subenoy
Published: July 2016

The present work deals with a quintom model of dark energy in the framework of a spatially flat isotropic and homogeneous Friedmann–Lemaitre–Robertson–Walker (FLRW) universe. At first, Lie point symmetry is imposed to the system and the unknown coupled potential of the model is determined. Then Noether symmetry, which is also a point like symmetry of the Lagrangian, is imposed on the physical system and the potential takes a general form. It is shown that the Lie algebra of Noether symmetry is a sub-algebra of the corresponding Lie algebra of the Lie symmetry. Finally, a point transformation in the three-dimensional augmented space is performed suitably so that one of the variables become cyclic and as a result there is considerable simplification to the physical system. Hence, conserved quantities (i.e. constants of motion) are expressed in a compact form and cosmological solutions are evaluated and analyzed in the present context.
Measurement of the Root Mean Square (RMS) Temperature Fluctuations of a Turbulent Plane Jet Using an Optical Method
Authors: Borji S. , Benzirar M. , Sabri L. , Bouabdellaoui M.
Published: July 2016

The purpose of this paper is to reach the root mean square (RMS) value of the fluctuating temperature along a jet plane by examining only the impact produced by a laser beam after having traversed the heated jet of air. This model is based on the Einstein–Fokker–Planck–Kolmogorov (EFPK) equation, which helped us to determine the value of the jet diffusion coefficient defined as a proportionality factor between the mean square of the deflection angle fluctuations and the length of the corresponding finite laser beam path. The numerical method of calculation in our work uses the value of the localized diffusion coefficient. This plays an essential role in measuring along the RMS of the temperature fluctuations. The obtained values are compared to the experimental measurements.
Classical and quantum dynamics of the sphere
Authors: Lasukov Vladimir , Moldovanova Evgeniia , Abdrashitova Maria , Malik Hitendra , Gorbacheva Ekaterina
Published: July 2016

In Minkowski space, there has been developed the mathematic quantum model of the real particle located on the sphere evolving owing to the negative pressure inside the sphere. The developed model is analogous to the geometrodynamic model of the Lemaitre–Friedmann primordial atom in superspace-time, whose spatial coordinate is the scale factor functioning as a radial coordinate. There is a formulation of quantum geometrodynamics in which the spatial coordinate is an offset of the scale factor and wave function at the same time. With the help of the Dirac procedure for extracting the root from the Hamiltonian operator we have constructed a Dirac quantum dynamics of the sphere with fractional spin.
CHANGING INNOVATION ROLES OF FOREIGN SUBSIDIARIES FROM THE MANUFACTURING INDUSTRY IN CHINA
Authors: ZHOU WENQIAN , VELAMURI VIVEK K. , DAUTH TOBIAS
Published: July 2016

Based on the observation of higher internationalisation of innovation activities of multinational companies towards emerging markets, this paper aims to provide insights on how foreign subsidiaries from the manufacturing industry are changing their innovation roles in China. Based on in-depth expert interviews conducted from the subsidiary perspective in China, this paper affirms that foreign subsidiaries are moving towards higher innovative activities. The study contributes to extant literature by revealing three characteristics, namely innovation capabilities, organisational structures, and interaction with the headquarters that differentiate subsidiaries’ innovation roles with regard to their geography and magnitude of innovation. This study illustrates how these distinctive characteristics and their underlying elements advance as subsidiaries move towards greater innovation roles and discusses implications for managerial practice.
Palaeomagnetism in fold and thrust belts: use with caution
Authors: Pueyo E. L. , Sussman A. J. , Oliva-Urcia B. , Cifelli F.
Published: July 2016

The application of palaeomagnetism in fold and thrust belts is a unique way to obtain kinematic information regarding the evolution of these systems. However, since many potential problems can affect the reliability of palaeomagnetic datasets and their interpretations, such data should be used with caution. In this paper, we thoroughly review the sources of error from palaeomagnetism with a particular focus on deciphering vertical-axis rotations and the assumptions behind the method. Recent investigations have demonstrated that the age of the magnetization and syn-folding results from the fold test must also be carefully examined: factors such as internal deformation, deficient isolation of components (i.e. overlapping) or incorrect restoration procedures may produce apparent syn-folding results. In fact, the restoration procedure used to return the palaeomagnetic signal to the palaeogeographic coordinate system may itself inhibit accurate estimations of vertical-axis rotations when complex deformation histories induce different, non-coaxial, deformation axes. We recommend the auxiliary use of the inclination v. dip diagram as an efficient tool for identifying many errors. Finally, to determine accurate vertical axis rotations, the reference direction should honour standard reliability criteria and would ideally be measured within the undeformed foreland of the thrust system. In this paper, we review five decades of palaeomagnetic research in fold and thrust belts by concentrating on maximizing standard reliability criteria procedures to reduce uncertainty and increase confidence when applying palaeomagnetic data to unravel the tectonic evolution of fold and thrust belts.
Evolution and architectural styles of a forced-regressive Holocene delta and megafan, Mitchell River, Gulf of Carpentaria, Australia
Authors: Lane T. I. , Nanson R. A. , Vakarelov B. K. , Ainsworth R. B. , Dashtgard S. E.
Published: July 2016

The monsoonal Mitchell River delta and megafan shows minimal anthropogenic disturbance and thus provides a unique opportunity to examine the autogenic and allogenic controls on the evolution of deltas and fluvial megafans. Detailed mapping, vibracoring, trenching and topographic surveying were used to characterize the palaeodistributary channel belts on the megafan and the depositional elements that comprise the delta. Chronological analyses of these data facilitated the reconstruction of the megafan and delta evolution and enabled the identification of discrete periods of delta progradation within the last 6000 years. These results indicate that sediment distribution is controlled primarily by two types of avulsion: (1) delta avulsions, which are frequent (>16/1000 years), typically backwater-mediated and associated with local shifts in sedimentation loci; and (2) megafan avulsions, which are less frequent (>3/1000 years), but which are also associated with more significant shifts in depositional loci. These links between megafan and delta processes and geomorphology in the Mitchell River region were integrated to develop a new model of channel belt facies associated with fluvial (
F
), fluvial backwater-affected (
F
BW
), fluvial-dominated, tide-influenced (Ft) and tide-dominated, fluvial-influenced (Tf) channels. This model enables improved predictions of channel belt composition in modern and ancient marginal-marine systems by providing sedimentological and ichnological criteria for distinguishing between channel types.

Supplementary material:
Mitchell River region optically stimulated luminescence (OSL) dating methodology and results are available at
https://doi.org/10.6084/m9.figshare.c.3280949
Multimodular Text Normalization of Dutch User-Generated Content
Authors: Schulz Sarah , Pauw Guy De , Clercq Orphée De , Desmet Bart , Hoste Véronique , Daelemans Walter , Macken Lieve
Published: July 2016

As social media constitutes a valuable source for data analysis for a wide range of applications, the need for handling such data arises. However, the nonstandard language used on social media poses problems for natural language processing (NLP) tools, as these are typically trained on standard language material. We propose a text normalization approach to tackle this problem. More specifically, we investigate the usefulness of a multimodular approach to account for the diversity of normalization issues encountered in user-generated content (UGC). We consider three different types of UGC written in Dutch (SNS, SMS, and tweets) and provide a detailed analysis of the performance of the different modules and the overall system. We also apply an extrinsic evaluation by evaluating the performance of a part-of-speech tagger, lemmatizer, and named-entity recognizer before and after normalization.
Mechanisms of ATP-Dependent Chromatin Remodeling Motors
Authors: Zhou Coral Y. , Johnson Stephanie L. , Gamarra Nathan I. , Narlikar Geeta J.
Published: July 2016

Chromatin remodeling motors play essential roles in all DNA-based processes. These motors catalyze diverse outcomes ranging from sliding the smallest units of chromatin, known as nucleosomes, to completely disassembling chromatin. The broad range of actions carried out by these motors on the complex template presented by chromatin raises many stimulating mechanistic questions. Other well-studied nucleic acid motors provide examples of the depth of mechanistic understanding that is achievable from detailed biophysical studies. We use these studies as a guiding framework to discuss the current state of knowledge of chromatin remodeling mechanisms and highlight exciting open questions that would continue to benefit from biophysical analyses.
Intestinal brush-border Na+/H+exchanger-3 drives H+-coupled iron absorption in the mouse
Authors: Shawki Ali , Engevik Melinda A. , Kim Robert S. , Knight Patrick B. , Baik Rusty A. , Anthony Sarah R. , Worrell Roger T. , Shull Gary E. , Mackenzie Bryan
Published: July 2016

Divalent metal-ion transporter-1 (DMT1), the principal mechanism by which nonheme iron is taken up at the intestinal brush border, is energized by the H+-electrochemical potential gradient. The provenance of the H+gradient in vivo is unknown, so we have explored a role for brush-border Na+/H+exchanger (NHE) isoforms by examining iron homeostasis and intestinal iron handling in mice lacking NHE2 or NHE3. We observed modestly depleted liver iron stores in NHE2-null (NHE2−/−) mice stressed on a low-iron diet but no change in hematological or blood iron variables or the expression of genes associated with iron metabolism compared with wild-type mice. Ablation of NHE3 strongly depleted liver iron stores, regardless of diet. We observed decreases in blood iron variables but no overt anemia in NHE3-null (NHE3−/−) mice on a low-iron diet. Intestinal expression of DMT1, the apical surface ferrireductase cytochrome b reductase-1, and the basolateral iron exporter ferroportin was upregulated in NHE3−/−mice, and expression of liver Hamp1 (hepcidin) was suppressed compared with wild-type mice. Absorption of59Fe from an oral dose was substantially impaired in NHE3−/−compared with wild-type mice. Our data point to an important role for NHE3 in generating the H+gradient that drives DMT1-mediated iron uptake at the intestinal brush border.
Exercise and Prostate Cancer: Evidence and Proposed Mechanisms for Disease Modification
Authors: Hayes Brian D. , Brady Lauren , Pollak Michael , Finn Stephen P.
Published: July 2016

Exercise has many potential benefits in relation to cancer. Apart from primary prevention, these include improvement of nonspecific cancer-related symptoms, amelioration of symptoms and cardiovascular risk factors related to cancer treatment, and improvements in various quality-of-life–related factors. Increasing evidence also points toward improved cancer-free and overall survival in cancer patients who undertake regular exercise, findings which should encourage further research in this area. Obesity is known to be associated with a proinflammatory, prothrombotic humoral milieu, which may promote aggressiveness in prostate cancer through interactions with NK-cell–mediated killing of circulating tumor cells, through platelet-circulating tumor cell interactions, and through alterations in adipokine and myokine profile among others. Physical activity reduces levels of systemic inflammatory mediators and so exercise may represent an accessible and cost-effective means of ameliorating the proinflammatory effects of obesity in cancer patients. This review outlines the evidence for the benefits of exercise in these patients, focusing on prostate cancer, and delineates current theories of the underlying biological mechanisms. Cancer Epidemiol Biomarkers Prev; 25(9); 1281–8. ©2016 AACR.
Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility
Authors: Künkele Annette , Taraseviciute Agne , Finn Laura S. , Johnson Adam J. , Berger Carolina , Finney Olivia , Chang Cindy A. , Rolczynski Lisa S. , Brown Christopher , Mgebroff Stephanie , Berger Michael , Park Julie R. , Jensen Michael C.
Published: July 2016

Purpose: The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)–redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody.

Experimental Design: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed.

Results: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 × 108/kg CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity.

Conclusions: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466–77. ©2016 AACR.
Bortezomib Treatment Sensitizes Oncolytic HSV-1–Treated Tumors to NK Cell Immunotherapy
Authors: Yoo Ji Young , Jaime-Ramirez Alena Cristina , Bolyard Chelsea , Dai Hongsheng , Nallanagulagari Tejaswini , Wojton Jeffrey , Hurwitz Brian S. , Relation Theresa , Lee Tae Jin , Lotze Michael T. , Yu Jun-Ge , Zhang Jianying , Croce Carlo M. , Yu Jianhua , Caligiuri Michael A. , Old Matthew , Kaur Balveen
Published: July 2016

Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)–expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy.

Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA–targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou–Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy.

Results: Combination treatment with bortezomib- and oHSV-induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy.

Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients. Clin Cancer Res; 22(21); 5265–76. ©2016 AACR.

See related commentary by Suryadevara et al., p. 5164
Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer
Authors: Chen Long , Li Jie , Farah Elia , Sarkar Sukumar , Ahmad Nihal , Gupta Sanjay , Larner James , Liu Xiaoqi
Published: July 2016

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) reactivation is responsible for the recurrence of prostate cancer after ADT. Thus, targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSP) are chaperones that modify stability and activity of their client proteins. HSP90, a major player in the HSP family, regulates stability of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events. Further, HSP90 is overexpressed in different cancers, including prostate cancer. Herein, we show that cotreatment of prostate cancer with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that cotargeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that cotargeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC. Mol Cancer Ther; 15(9); 2107–18. ©2016 AACR.
Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin
Authors: Ganesh Shanthi , Koser Martin L. , Cyr Wendy A. , Chopda Girish R. , Tao Junyan , Shui Xue , Ying Bo , Chen Dongyu , Pandya Purva , Chipumuro Edmond , Siddiquee Zakir , Craig Kevin , Lai Chengjung , Dudek Henryk , Monga Satdarshan P. , Wang Weimin , Brown Bob D. , Abrams Marc T.
Published: July 2016

The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143–54. ©2016 AACR.
Postoperative Quality of Life in Patients with Ileal Neobladder at Short-, Intermediate- and Long-Term Follow-Up
Authors: D'Agostino Daniele , Racioppi Marco , Pugliese Dario , Ragonese Mauro , Di Gianfrancesco Luca , Filianoti Alessio , Palermo Giuseppe , Belgrano Emanuele , Siracusano Salvatore , Niero Mauro , Imbimbo Ciro , Iafrate Massimo , Artibani Walter , Cerruto Maria Angela , Talamini Renato , Bassi PierFrancesco
Published: July 2016

Background: To evaluate the difference at different steps of follow-up of the postoperative quality of life (QoL) in patients who had undergone radical cystectomy and ileal orthotopic neobladder derivation. Patients and Methods: A multicentric, cross-qualitative study was performed in 5 Italian centers of reference for the treatment of bladder cancer. One hundred seventy one patients who underwent radical cystectomy and creation of ileal orthotopic neobladder according to ‘Vescica Ileale Padovana' between 2006 and 2011 have been analyzed. The validated and dedicated questionnaires EORTC QLQ-C30, IOB-PRO and EORTC QLQ-BLM30 were used. Results: All data gathered were then processed, specifically means ± SD were included for comparison during 4 periods of follow-up (quartile): the first ranging from 1 to 18 months; the second ranging from 19 to 36 months; the third from 37 to 72 months and the fourth >72 months. Cancer-specific and health-related factors were analyzed separately, and the change was determined during follow-up. Conclusions: The global QoL, highlighted by validated cancer-specific and health-related questionnaires, is certainly on a satisfactory level. Thus, the education of the patient, the exploration of the pros and cons of an orthotopic neobladder and the active participation in treatment decision seem to be the keys to better improve the post-operative QoL during the follow-up period.
Long-Term Pulmonal Therapy of Cystic Fibrosis-Patients with Amitriptyline
Authors: Adams Constantin , Icheva Vanya , Deppisch Caroline , Lauer Josefine , Herrmann Gloria , Graepler-Mainka Ute , Heyder Susanne , Gulbins Erich , Riethmueller Joachim
Published: July 2016

Background/Aims: Several recent clinical studies revealed an accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis (CF). Degradation of ceramide concentrations in lungs of CF patients employing the functional acid sphingomyelinase inhibitor amitriptyline revealed a benefit in lung function, weight and exacerbation rates. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed two phase II randomised, double-blind, placebo-controlled studies. CF patients were treated with 25 mg amitriptyline twice daily, i.e. a total dose of 50 mg/d. After those two studies part of the patients used amitriptyline in an off-lable-use for routine treatment. These patients were observed after one, two and three years after continuous use of amitriptyline and were matched with those patients who were not treated. These patients were used as a control group. Results: After one year of treatment, forced expiratory volume in 1 sec predicted (FEV1) increased significantly by 7.6±7.0%, p=<0.001, and weight increased by 2.1±2.3kg, p=<0.001 in the amitriptyline population (n=20), whereas FEV1 decreased significantly in the control group by 1.8±3.3%, p=0.010, and weight increased by 1.1±2.7kg, p=0.010 (n=14). After two years of treatment, FEV1 increased significantly by 5.6±10.3%, p=0.009, and weight increased by 3.6±2.9kg, p=<0.001 in the amitriptyline population (n=12). In contrast, FEV1 decreased in the control group by 2.1±3.7%, p=0.051 and weight increased by only 0.4±2.9kg, p=0.31 (n=10). After three years of treatment, FEV1 increased significantly by 7.7±8%, p=0.050, and weight increased by 7.3±3.8kg, p=0.016, in the amitriptyline population (n=5), whereas FEV1 decreased in the control group by 1.0±1.3%, p=0.075 and weight increased by 0.4±1.5kg, p=0.29 (n=5). Conclusion: Amitriptyline significantly increases FEV1, reduces ceramide in lung cells and increases weight of CF patients.
Micafungin-Induced Suicidal Erythrocyte Death
Authors: Peter Thomas , Bissinger Rosi , Signoretto Elena , Mack Andreas F. , Lang Florian
Published: July 2016

Background/Aims: The antifungal drug Micafungin is used for the treatment of diverse fungal infections including candidiasis and aspergillosis. Side effects of Micafungin treatment include microangiopathic hemolytic anemia and thrombocytopenia with microvascular thrombosis. The development of thrombosis may be fostered by stimulation of eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated protein kinase C (PKC), casein kinase 1α or p38 kinase and activated caspases. The present study explored, whether Micafungin induces eryptosis. Methods: Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Hemolysis was quantified by measuring haemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to Micafungin (10 - 25 µg/ml) significantly increased hemolysis and the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Micafungin (25 µg/ml) did not significantly modify Fluo3-fluorescence, DCFDA fluorescence, or ceramide abundance. The effect of Micafungin on annexin-V-binding was not significantly modified by removal of extracellular Ca2+, by PKC inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase 1α inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM). Conclusions: Micafungin triggers hemolysis and eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane.
FoxP1 Protein Shows Differential Layer Expression in the Parahippocampal Domain among Bird Species
Authors: Garcia-Calero Elena , Martinez Salvador
Published: July 2016

Different bird orders show diversity in neural capabilities supported by variations in brain morphology. The parahippocampal domain in the medial pallium, together with the hippocampus proper, plays an important role in memory skills. In the present work, we analyze the expression pattern of the FoxP1 protein in the parahippocampal area of four different bird species: the nonvocal learner birds quail and chicken (Galliformes) and two vocal learner birds, i.e. the zebra finch (Passeriformes) and the budgerigar (Psittaciformes), at different developmental and adult stages. We also analyze the expression of the calbindin protein in quails and zebra finches. We observed differences in the FoxP1 parahippocampal layer among bird species. In quails, chickens, and budgerigar, FoxP1 cells were located in the outer layers of the lateral and caudolateral parahippocampal sectors. In contrast, FoxP1 immunoreactive cells appeared in the inner layer of the same sectors in the zebra finch parahippocampal domain. These differences suggest two possibilities: either the FoxP1-positive cells described in quails, chickens, and budgerigars are a different population than the one described in the zebra finch, or there are changes in the pattern of radial migration in the parahippocampal area among birds. In the present study, we show that FoxP1 expression is more similar between quails, chickens, and budgerigars than between budgerigars and zebra finches in the parahippocampal area. This result contrasts with previous data in other telencephalic structures, like the calbindin-positive projection neurons described in the striatum of budgerigars and zebra finches but not in quails and chickens. All of these data point to diversity in the evolution of different morphological characters and, therefore, a mosaic model for telencephalic evolution in birds.
TREMOR12: An Open-Source Mobile App for Tremor Quantification
Authors: Kubben Pieter L. , Kuijf Mark L. , Ackermans Linda P.C.M. , Leentjes Albert F.G. , Temel Yasin
Published: July 2016

Background: Evaluating the effect of treatment of tremor is mostly performed with clinical rating scales. Mobile applications facilitate a more rapid, objective, and quantitative evaluation of treatment effect. Existing mobile apps do not offer raw data access, which limits algorithm development. Objective: To develop a novel open-source mobile app for tremor quantification. Methods: TREMOR12 is an open-source mobile app that samples acceleration, rotation, rotation speed, and gravity, each in 3 axes and time-stamped in a frequency up to 100 Hz. The raw measurement data can be exported as a comma-separated value file for further analysis in the TREMOR12P data processing module. The app was evaluated with 3 patients suffering from essential tremor, who were between 55 and 71 years of age. Results: This proof-of-concept study shows that the TREMOR12 app is able to detect and register tremor characteristics such as acceleration, rotation, rotation speed, and gravity in a simple and nonburdensome way. The app is compatible with current regulatory oversight by the European Union (MEDDEV regulations) and the Food and Drug Administration (FDA) guidance on mobile medical applications. Conclusion: TREMOR12 offers low-cost tremor quantification for research purposes and algorithm development, and may help to improve treatment evaluation.
Brown Heroin-Associated Candida albicans Ventriculitis and Endopthalmitis Treated with Voriconazole
Authors: Elfiky Nora , Baldwin Kelly
Published: July 2016

Chronic meningitis and ventriculitis are defined as inflammatory pleocytoses in the cerebrospinal fluid (CSF) and ependyma that persists for at least 1 month without spontaneous resolution. Because the CSF communicates directly with the posterior compartments of the eye, fungal infections in the brain often cause secondary ophthalmologic complications. We report a 23-year-old male who presented to the emergency room with progressive severe headaches associated with insidious monocular vision loss. After extensive workup and a multidisciplinary team effort, the patient was diagnosed with ventriculitis and endogenous endopthalmitis. The etiology is suspected to be due to brown heroin use with secondary disseminated Candida albicans.