bluuebunny/crossref_metadata_2025 huggingface dataset:
PREHOSPITAL RISK STRATIFICATION USING A MODIFIED THROMBOLYSIS IN MYOCARDIAL INFARCTION (PRISM TIMI) SCORE: A RETROSPECTIVE MEDICAL RECORD REVIEW
Authors: Reed Ashley
Published: August 2016

Background

Paramedics convey patients with non-ST elevation acute coronary syndrome (NSTEACS) to emergency departments (EDs). The patient should be risk stratified using a risk stratification model (RSM) in the ED to determine the risk of death or adverse cardiovascular events. This determines if the patient should be transferred to a specialist heart attack centre (HAC) for an invasive procedure. If paramedics were to risk stratify the patients in the prehospital environment using a Modified Thrombolysis in Myocardial Infarction (MTIMI) RSM this could result in primary triage to an appropriate hospital. This could reduce secondary transfers, decrease demand on EDs, provide better patient care, reduce length of hospital stay and could provide cost savings to the National Health Service.

Aim

To determine if paramedics' use of a MTIMI RSM is more accurate than current practice at identifying and risk stratifying patients suffering from suspected high risk NSTEACS.

Methods

A retrospective medical record review.

Results

108 patient notes were used in this study, 84 from the ED and 24 from the HAC. Current practice produced a c-statistic (c) of 0.73 (95% Confidence Interval (CI) 0.62 to 0.85) and the MTIMI RSM (c=0.72, 0.61 to 0.83). The best RSM overall was the abbreviated MTIMI RSM with only three variables identified through logistic regression [diabetes mellitus, over 65 years and the electrocardiogram (ECG)] (c=0.79, 0.68 to 0.89).

Conclusions

The main reason that current practice was similar to the MTIMI RSM was that they both used the ECG variable, which alone was approximately twelve times more prognostic than any other variable. The need to identify a RSM with a good prognostic power that can be used in the prehospital environment still exists. Therefore, other RSMs should be explored in a prospective study.
Orthopaedic interventions in patients with psoriatic arthritis: a descriptive report from the SPAR cohort
Authors: Haque Naba , Lories Rik J , de Vlam Kurt
Published: August 2016

Objectives

To evaluate the current needs for joint surgery in patients with psoriatic arthritis (PsA).

Methods

The patient database at the Rheumatology Department of the University Hospitals Leuven, was cross-sectionally analysed using demographic, medical, laboratory, radiological and surgical data of 269 patients with PsA. Patients were grouped by the presence or absence of orthopaedic surgery and compared for gender, age, mean health assessment questionnaire (HAQ) score, current medication and disease duration. The data were assessed using descriptive statistics and Student's t-tests.

Results

Overall 48.33% of the patients underwent 1 or more orthopaedic surgeries at some point of time. A total of 280 surgical interventions were flagged in the database, including both joint sacrificing and non-joint sacrificing procedures. Mean disease duration±SD at the time of surgery was 1.58 years±12.05. Age of the patients with surgeries was 54.13 years±11.03 SD and not different from those without surgeries (53.73 years±12.81 SD; p=0.78). 41.54% of the patients underwent a single surgery while 58.46% had multiple surgeries. A significant difference in the mean HAQ score was observed among the patients with and without surgeries (p<0.001). Of all the surgeries 63.92% were performed after diagnosis whereas 36.07% were performed before a diagnosis of PsA was made. Among the surgeries performed before diagnosis 40.59% were arthroscopies including 9.90% of diagnostic arthroscopies.

Conclusions

The number of surgical interventions has significantly increased in patients with PsA compared with historical cohorts even with a relatively shorter disease duration. There was a significant difference in HAQ score between the patients with or without surgeries.
Investigations of gamma ray and fast neutron shielding properties of tellurite glasses with different oxide compositions
Authors: Sayyed M.I.
Published: August 2016

In the present paper, the basic radiation parameters of tellurite glasses with different forming oxides (B2O3, BaO, K2O, V2O5, WO3, and ZnO) have been studied over a wide photon energy range from 1 keV to 100 GeV, using WinXCom program. These parameters are the mass attenuation coefficient (μ/ρ), effective atomic number (Zeff), and electron density (Ne,eff). In addition, the macroscopic effective removal cross sections (ΣR) for fast neutrons have been calculated. The dependence of different parameters on incident photon energy and chemical content has been discussed. Among the selected glass systems TeO2–WO3 and TeO2–B2O3 showed superior shielding properties for gamma-ray and neutrons, respectively. It is shown that the selected glass systems have higher values of the mass attenuation coefficients (μ/ρ) than concretes and 0.7SiO2:0.3BaO glass. These results indicate that tellurite glasses can be used as radiation shielding materials.
One-loop nonlinear correction for QED
Authors: Furtado J. S. N. , Silva G. R.
Published: August 2016

In this work, we study the generation of a nonlinear correction for QED, namely, the Euler–Heisenberg effective action. In order to achieve this, we consider two methods. The first method employed consists in make use of Feynman parametrization to solve the integrals properly, while in the second method a derivative expansion in the external momentum was considered.
Single-mode cylindrical graphene plasmon waveguide
Authors: Yang Jianfeng , Yang Jingjing , Huang Ming
Published: August 2016

A cylindrical graphene plasmon waveguide (CGPW) which consists of two rolled graphene ribbons, a dielectric core and a dielectric interlayer is proposed. An analytical model for the single-mode condition and cutoff frequency of high-order graphene surface plasmon (GSP) modes is presented and verified by finite element method (FEM) simulations. Single-mode operation region of CGPW is identified in the frequency–radius space. By varying the separation between two graphene sheets and the Fermi level of graphene, a large tunability of the mode behavior is also demonstrated. The proposed structure may provide a new freedom to manipulate GSPs, and would lead to novel applications in optics.
Natural Language Acquisition: State Inferring and Thinking
Authors: Wang Dongshu , Duan Yihai
Published: August 2016

Natural language understanding plays an important role in our daily life. It is very significant to study how to make the computer understand the human language and produce the corresponding action or response. Most of the prior language acquisition models adopt handcrafted internal representation, and they are not sufficiently brain-based and not sufficiently comprehensive to account for all branches in psychology and cognitive science. An emergent developmental network (DN) is used to learn, infer and think a knowledge base represented as a finite automaton, from sensory and motor experience grounded in this operational environments. This work is different in the sense that we emphasize on the mechanism that enable a system to develop its emergent representations from its operational experience. By emergent, we mean a pattern of responses of multiple elements that corresponds to an event outside the closed skull but each element (e.g. pixel, muscle, neuron) of the pattern typically does not have a meaning. In this work, internal unsupervised neurons of the DN are used to represent short contexts, and the competitions among internal neurons enable them to represent different short contexts. By internal, we mean that all the neurons inside a brain are not directly supervised by the external environment — outside the brain skull. In this work, we analyze how internal neurons represent temporal contexts and how the feature neurons of the DN represent earlier contexts. Accuracy of Z state inferring and $X$ thinking of a relative complex training sequence (denoted as DN-2 in this work) can reach 100% and 75%, respectively. Comparative experiment results between this emergent method and the symbolic method, their corresponding Z state inferring and $X$ thinking accuracy are 100% and 82.1%, 85.7% and 75%, respectively (taking DN-6 in this work as the example), demonstrate the efficiency of the DN on natural language inferring and thinking. Complexity of the finite automaton is low and so is the temporal contexts, but the same principle is potentially applicable to more complex cases.
Geometry of Legendrian knots
Authors: Pancholi Dishant M. , Pandit Suhas
Published: August 2016

We study the extrinsic geometry of Legendrian knots in the standard tight contact structure on [Formula: see text] In particular, we show that the total curvature of a Legendrian knot [Formula: see text] in [Formula: see text] is bounded below by [Formula: see text] times, the total number of cusps in the front projection of [Formula: see text]. We also show that a Legendrian [Formula: see text]-torus knot has the total curvature bounded below by [Formula: see text] while that of the Legendrian knots [Formula: see text] is bounded below by [Formula: see text]. Furthermore, we find an explicit relation between the Thurston–Bennequin number of a Legendrian knot [Formula: see text] and the geometric self-linking number, the curvature and the torsion of the knot [Formula: see text].
Second-order concentration on the sphere
Authors: Bobkov Sergey G. , Chistyakov Gennadiy P. , Götze Friedrich
Published: August 2016

Sharpened forms of the concentration of measure phenomenon for classes of functions on the sphere are developed in terms of Hessians of these functions.
Unstable CMC spheres and outlying CMC spheres in AF 3-manifolds
Authors: Ma Shiguang
Published: August 2016

In this paper, we introduce a nonlinear ODE method to construct constant mean curvature (CMC) surfaces in Riemannian manifolds with symmetry. As an application, we construct unstable CMC spheres and outlying CMC spheres in asymptotically Schwarzschild manifolds with metrics like [Formula: see text]. The existence of unstable CMC spheres tells us that the stability condition in Qing–Tian’s work [On the uniqueness of the foliation of spheres of constant mean curvature in asymptotically flat 3-manifolds, J. Amer. Math. Soc. 20(4) (2007) 1091–1110] cannot be removed generally.
Exceptional collections and the bicanonical map of Keum’s fake projective planes
Authors: Di Brino Gennaro , Di Cerbo Luca F.
Published: August 2016

We apply the recent results of Galkin et al. [Derived categories of Keum’s fake projective planes, Adv. Math. 278 (2015) 238–253] to study some geometrical features of Keum’s fake projective planes. Among other things, we show that the bicanonical map of Keum’s fake projective planes is always an embedding. Moreover, we construct a nonstandard exceptional collection on the unique fake projective plane [Formula: see text] with [Formula: see text].
Hom-structures on simple graded Lie algebras of finite growth
Authors: Xie Wenjuan , Liu Wende
Published: August 2016

A Hom-structure on a Lie algebra [Formula: see text] is a linear map [Formula: see text] satisfying the Hom–Jacobi identity: [Formula: see text] for all [Formula: see text]. A Hom-structure is referred to as multiplicative if it is also a Lie algebra homomorphism. In this paper, using a classification theorem due to Mathieu, we determine explicitly all the Hom-structures on the simple graded Lie algebras of finite growth. As a direct consequence, all the Hom-structures on any simple graded Lie algebras of finite growth constitute a Jordan algebra in the usual way.
The Eastern Mediterranean Messinian salt-depth imaging and velocity analysis considerations
Authors: Feng Ye E. , Reshef Moshe
Published: August 2016

Newly acquired 3D seismic datasets over the Eastern Mediterranean Basin are used to image the massive Messinian salt body. Accurate imaging of this salt body is critical to the precise definition of the prospective pre-salt geological section. The availability of recent well logs, which are the only ones to date to have penetrated the entire Messinian salt sequence, enables a clear definition of the highly deformed clastic units within the salt. This study shows that these highly reflective clay units cause a significant reduction in the overall seismic velocity of the salt. It also demonstrates why 3D pre-stack depth migration, including a tomographical velocity update inside the salt body, is recommended as the preferred imaging technique.
The barren Messinian Tripoli in Sicily and its palaeoenvironmental evolution: suggestions on the exploration potential
Authors: Catalano Raimondo , Di Stefano Enrico , Sprovieri Rodolfo , Lena Gabriele , Valenti Vera
Published: August 2016

New observations on the Sicily Messinian Tripoli have yielded a variably thick diatomitic, calcareous and shaly rock interval marked by an upwards disappearance of calcareous and siliceous plankton (barren lithosome), coexisting with a variability in vegetal remains and significant amounts of amorphous organic matter (AOM). Facies analysis associated with biostratigraphy and palaeoecology of the several field and borehole sections has been framed in a well-accepted chronological scheme that points to this barren interval coinciding with the stratigraphic upper and younger part of some Tripoli sections (bituminous Tripoli) located in the northern part of the study area.

Biostratigraphically, the barren lithosome falls within the Non-Distinctive Zone (NDZ) and is generally younger than the First Common Occurrence (FCO) of
T
.
multiloba
. The age of its diachronous base appears older than the Messinian salinity crisis (MSC) deposits, because is well constrained by the calcareous plankton biostratigraphic markers along the underlying portions of the Tripoli. The top boundary of the barren rock interval, that is not always identifiable, could be age dated, following the proposed stratigraphic criteria. We infer that the Tripoli initial open-marine environment became, in more inner areas, progressively confined, with freshwater floodings alternating with short marine-water incursions in a shallow-water to continental domain. The collected information appears useful in addressing further exploration.
History of hydrothermal fluid flow in the midcontinent, USA: the relationship between inverted thermal structure, unconformities and porosity distribution
Authors: King Bradley D. , Goldstein Robert H.
Published: August 2016

A comprehensive study of the Cambrian–Ordovician Arbuckle Group suggests that multiple fluid migration events have affected reservoir porosity via fractures and preferred stratigraphic horizons. Fluid inclusion homogenization temperatures from late-stage precipitates yield temperatures higher than can be explained by burial conditions or an elevated geothermal gradient. Fluid inclusion melting temperatures yield salinity values that indicate multiple fluids evolving through time. Hydrocarbon fluid inclusions in late-stage baroque dolomite suggest oil migration concurrent with hydrothermal fluid flow. Depleted δ
13
C and δ
18
O values provide evidence for a high-temperature basinal fluid source as well as for the preferential flow of hydrothermal fluids through permeable zones in the Mississippian and Arbuckle Group, where pore systems related to paleokarst are overlain by less permeable units. Radiogenic strontium isotopic data support fluid–rock interaction with siliciclastic material or basement rock at some point during the fluid migration history. Variable
87
Sr/
86
Sr values suggest multiple sources for the fluids responsible for the cements and a transition from an advective fluid flow system to a vertical fluid flow system. The ancient aquifer system was vertically connected during migration of hydrothermal fluids, and a temperature-controlled vertical density gradient appears to have played an important role in late-stage porosity evolution, focusing the hottest fluids in the upper sections of permeable layers.
Catalytic iron and acute kidney injury
Authors: Leaf David E. , Swinkels Dorine W.
Published: August 2016

Acute kidney injury (AKI) is a common and often devastating condition among hospitalized patients and is associated with markedly increased hospital length of stay, mortality, and cost. The pathogenesis of AKI is complex, but animal models support an important role for catalytic iron in causing AKI. Catalytic iron, also known as labile iron, is a transitional pool of non-transferrin-bound iron that is readily available to participate in redox cycling. Initial findings related to catalytic iron and animal models of kidney injury have only recently been extended to human AKI. In this review, we discuss the role of catalytic iron in human AKI, focusing on recent translational studies in humans, assay considerations, and potential therapeutic targets for future interventional studies.
Physiological insights into novel therapies for nephrogenic diabetes insipidus
Authors: Sands Jeff M. , Klein Janet D.
Published: August 2016

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high.
Developmental restoration of LTP deficits in heterozygous CaMKIIα KO mice
Authors: Goodell Dayton J. , Benke Tim A. , Bayer K. Ulrich
Published: August 2016

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory and cognition. The heterozygous CaMKIIα isoform KO (CaMKIIα+/−) mice have a schizophrenia-related phenotype, including impaired working memory. Here, we examined synaptic strength and plasticity in two brain areas implicated in working memory, hippocampus CA1 and medial prefrontal cortex (mPFC). Young CaMKIIα+/−mice (postnatal days 12–16; corresponding to a developmental stage well before schizophrenia manifestation in humans) showed impaired hippocampal CA1 LTP. However, this LTP impairment normalized over development and was no longer detected in older CaMKIIα+/−mice (postnatal weeks 9–11; corresponding to young adults). By contrast, the CaMKIIα+/−mice failed to show the developmental increase of basal synaptic transmission in the CA1 seen in wild-type (WT) mice, resulting in impaired basal synaptic transmission in the older CaMKIIα+/−mice. Other electrophysiological parameters were normal, including mPFC basal transmission, LTP, and paired-pulse facilitation, as well as CA1 LTD, depotentiation, and paired-pulse facilitation at either age tested. Hippocampal CaMKIIα levels were ∼60% of WT in both the older CaMKIIα+/−mice and in the younger WT mice, resulting in ∼30% of adult WT expression in the younger CaMKIIα+/−mice; levels in frontal cortex were the same as in hippocampus. Thus, in young mice, ∼30% of adult CaMKIIα expression is sufficient for normal LTD and depotentiation, while normal LTP requires higher levels, with ∼60% of CaMKIIα expression sufficient for normal LTP in adult mice.
Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney
Authors: Stowasser Michael , Gordon Richard D.
Published: August 2016

In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extra-adrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.
A Cross-Sectional Population-Based Survey of Trachoma among Migrant School Aged Children in Shanghai, China
Authors: Xue Wenwen , Lu Lina , Zhu Jianfeng , He Xiangui , He Jiangnan , Zhao Rong , Zou Haidong
Published: August 2016

We investigated the prevalence of clinical trachoma in 154,265 children aged 6 to 16 years in 206 Shanghai migrant schools. Clean water availability in school, each child’s facial cleanliness, eyelids, corneas, and the presenting distance visual acuities were examined. Trachoma was clinically diagnosed in accordance with the World Health Organization simplified classification. Eyes diagnosed with trachoma were swabbed to test for ocularChlamydia trachomatisinfections (OCTI) with a rapid latex immunochromatographic test. Among 153,977 students, no blindness was found related to trachoma. Trachoma was diagnosed in 8029 children (5.2%). In 87 schools clinical trachoma prevalence was higher than 5%. OCTI was confirmed in 2073 of 6823 trachoma diagnosed children (30.4%). Clinical trachoma prevalence was higher among females than males (p<0.001), but gender comparison showed no statistical difference in the prevalence of OCTI (p=0.077). Age and clinical trachoma (r=-0.014;p<0.001) or OCTI (r=-0.026;p=0.031) prevalence were negatively correlated. Clinical trachoma was different in different districts and counties (p<0.001). Trachoma warrants close attention in Shanghai migrant children because the condition remains endemic in some schools.
Giant Cell Tumor of Bone: Documented Progression over 4 Years from Its Origin at the Metaphysis to the Articular Surface
Authors: Burke Colin , Link Thomas , O’Donnell Richard J. , Cho Soo-Jin , Motamedi Daria
Published: August 2016

The exact location of origin for giant cell tumors of bone (GCTB) remains controversial, as lesions are not routinely imaged early but rather late when the tumor is large and clinically symptomatic. At the time of diagnosis, GCTB are classically described as lucent, eccentric lesions with nonsclerotic margins, located within the epiphysis to a greater extent than the metaphysis. Here we present a case of a biopsy proven GCTB initially incidentally seen on MRI as a small strictly metaphyseal lesion, which over the course of several years expanded across a closed physis to involve the epiphysis and abut the articular surface/subchondral bone plate.
Improving the Performance of Somatic Mutation Identification by Recovering Circulating Tumor DNA Mutations
Authors: Fu Yu , Jovelet Cécile , Filleron Thomas , Pedrero Marion , Motté Nelly , Boursin Yannick , Luo Yufei , Massard Christophe , Campone Mario , Levy Christelle , Diéras Véronique , Bachelot Thomas , Garrabey Julie , Soria Jean-Charles , Lacroix Ludovic , André Fabrice , Lefebvre Celine
Published: August 2016

DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53. We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell–free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954–61. ©2016 AACR.
Targeting Alpha-Fetoprotein (AFP)–MHC Complex with CAR T-Cell Therapy for Liver Cancer
Authors: Liu Hong , Xu Yiyang , Xiang Jingyi , Long Li , Green Shon , Yang Zhiyuan , Zimdahl Bryan , Lu Jingwei , Cheng Neal , Horan Lucas H. , Liu Bin , Yan Su , Wang Pei , Diaz Juan , Jin Lu , Nakano Yoko , Morales Javier F. , Zhang Pengbo , Liu Lian-xing , Staley Binnaz K. , Priceman Saul J. , Brown Christine E. , Forman Stephen J. , Chan Vivien W. , Liu Cheng
Published: August 2016

Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide–MHC complexes can be targets for CAR T-cell therapy against solid tumors.

Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158–166 peptide complexed with human leukocyte antigen (HLA)-A*02:01.

Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP158-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6).

Conclusions: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478–88. ©2016 AACR.
PD-1 Inhibitor–Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course
Authors: Nishino Mizuki , Ramaiya Nikhil H. , Awad Mark M. , Sholl Lynette M. , Maattala Jennifer A. , Taibi Myriam , Hatabu Hiroto , Ott Patrick A. , Armand Philippe F. , Hodi F. Stephen
Published: August 2016

Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor–related pneumonitis in advanced cancer patients.

Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis.

Results: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.

Conclusions: PD-1 inhibitor–related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients. Clin Cancer Res; 22(24); 6051–60. ©2016 AACR.

See related commentary by Castanon, p. 5956
In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia
Authors: Hagemann Urs B. , Wickstroem Katrine , Wang Ellen , Shea Adam O. , Sponheim Kristine , Karlsson Jenny , Bjerke Roger M. , Ryan Olav B. , Cuthbertson Alan S.
Published: August 2016

The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, 223RaCl2), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (223Ra), the parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter 227Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G2 phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422–31. ©2016 AACR.
Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia
Authors: Kühn Michael W.M. , Song Evelyn , Feng Zhaohui , Sinha Amit , Chen Chun-Wei , Deshpande Aniruddha J. , Cusan Monica , Farnoud Noushin , Mupo Annalisa , Grove Carolyn , Koche Richard , Bradner James E. , de Stanchina Elisa , Vassiliou George S. , Hoshii Takayuki , Armstrong Scott A.
Published: August 2016

Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin–MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1mut AML. Combined pharmacologic inhibition of menin–MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia.

Significance: MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166–81. ©2016 AACR.

See related commentary by Hourigan and Aplan, p. 1087.

This article is highlighted in the In This Issue feature, p. 1069
Evaluation of Dying Vocal Fold Epithelial Cells by Ultrastructural Features and TUNEL Method
Authors: Novaleski Carolyn K. , Mizuta Masanobu , Rousseau Bernard
Published: August 2016

Cell death is a regulated mechanism of eliminating cells to maintain tissue homeostasis. This study described 2 methodological procedures for evaluating cell death in the epithelium of immobilized, approximated and vibrated vocal folds from 12 New Zealand white breeder rabbits. The gold standard technique of transmission electron microscopy evaluated high-quality ultrastructural criteria of cell death and a common immunohistochemical marker, the terminal deoxynucleotidyl transferase dUTP nick end labeling method, to confirm cell death signaling. Results revealed that ultrastructural characteristics of apoptotic cell death, specifically condensed chromatin and apoptotic bodies, were observed after vocal fold vibration and approximation. Although episodes of necrosis were rare, few enlarged cell nuclei were present after vibration and approximation. The vocal fold expresses an immunohistochemical marker for apoptosis along the apical surface of the epithelium. This study provides a solid foundation for future investigations regarding the role of cell death in vocal fold health and disease.
Redifferentiation of High-Throughput Generated Fibrochondrocyte Micro-Aggregates: Impact of Low Oxygen Tension
Authors: Berneel Elke , Philips Charlot , Declercq Heidi , Cornelissen Ria
Published: August 2016

In meniscus tissue engineering strategies, enhancing the matrix quality of the neomeniscal tissue is important. When the differentiated phenotype of fibrochondrocytes is lost, the quality of the matrix becomes compromised. The objective of this study was to produce uniform fibrochondrocyte micro-aggregates with desirable phenotype and tissue homogeneity in large quantities using a simple and reproducible method. Furthermore, we investigated if hypoxia could enhance the matrix quality. Porcine fibrochondrocytes were expanded at 21% oxygen until passage 3 (P3) and a gene expression profile was determined. P3 fibrochondrocytes were cultivated in chondrogenic medium at 5 and 21% oxygen in high-throughput agarose chips containing 2,865 microwells 200 µm in diameter. Evaluation included live/dead staining, histological examination, immunohistochemistry, dimethylmethylene blue assay and real-time reverse transcriptase quantitative polymerase chain reaction of the micro-aggregates. Gene expression analysis showed a drastic decline in collagen II and high expression of collagen I during monolayer culture. After 4 days, uniform and stable micro-aggregates could be produced. The redifferentiation and matrix quality of the hypoxic cultured micro-aggregates were enhanced relative to the normoxic cultures. Sulfated glycosaminoglycan synthesis was significantly higher, and collagen II expression and the collagen II/collagen I ratio were significantly upregulated in the hypoxic cultures. High-throughput production of uniform microtissues holds promise for the generation of larger-scale tissue engineering constructs or optimization of redifferentiation mechanisms for clinical applications.
Pretreatment Cognitive Profile Likely to Benefit from Donepezil Treatment in Dementia with Lewy Bodies: Pooled Analyses of Two Randomized Controlled Trials
Authors: Mori Etsuro , Ikeda Manabu , Nakagawa Masaki , Miyagishi Hideaki , Kosaka Kenji
Published: August 2016

Background/Aims: Based on Mini-Mental State Examination (MMSE) subitem scores, in dementia with Lewy bodies (DLB), we aimed to delineate features of cognitive impairment, identify cognitive domains improved by donepezil, and define a pretreatment cognitive profile likely to benefit from donepezil. Methods: Pooled data were used from two randomized controlled trials of donepezil in DLB (n = 235). Baseline MMSE subitem scores were calculated for all patients. Mean changes in subitem scores at week 12 were compared between the placebo and the active group. Finally, the subgroup identification based on differential effect search (SIDES) method was applied. Results: Baseline subitem scores were relatively low for serial 7's, delayed recall, and copying. Significant improvement by donepezil was found for orientation, serial 7's, repetition, 3-step command, and copying. The subgroup with pretreatment scores of serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 were the best responders. MMSE change in subgroups increased as more of these three conditions were fulfilled. Conclusion: Cognitive domains characteristically impaired in DLB are particularly improved by donepezil. The number of fulfilled conditions for serial 7's = 1, 2, or 3, delayed recall ≥1, and copying = 0 (likely to benefit score) may predict the response to donepezil in DLB patients.
The Suppression of Kallistatin on High-Glucose-Induced Proliferation of Retinal Endothelial Cells in Diabetic Retinopathy
Authors: Xing Qian , Zhang Guowei , Kang Lihua , Wu Jian , Chen Hui , Liu Gaoqin , Zhu Rongrong , Guan Huaijin , Lu Peirong
Published: August 2016

Background: Diabetic retinopathy (DR) is a severe ocular complication of diabetes. Kallistatin has multiple biological functions including anti-inflammation and antiangiogenesis. Our aim was to detect the level of kallistatin in the vitreous of proliferative DR (PDR) and its effect on proliferation, migration, and tube formation of human retinal endothelial cells (HRECs) under high glucose in an in vitro model. Methods: Vitreous humor samples were obtained through pars plana vitrectomy from 7 nondiabetic patients with idiopathic macular holes or idiopathic preretinal membranes and 10 PDR patients. The vitreous levels of kallistatin were measured by ELISA. HRECs were cultured with different concentrations of glucose and 1,000 nM kallistatin. The proliferation of HRECs was evaluated by a Cell Counting Kit-8 assay. Cell migration was assessed by using Transwell chambers. Cell sprouting was detected by tube formation assay. The RNA interference technique was used to create the knockdown of the kallistatin gene in HRECs for evaluating its effect on the proliferation, migration, and tube formation of HRECs. Results: The vitreous levels of kallistatin were significantly lower in PDR patients in comparison with nondiabetic control patients (p < 0.05). Compared with 5 mM of normal glucose treatment, high glucose (30 mM) in culture significantly increased the proliferation and migration of HRECs, which was attenuated by 1,000 nM kallistatin. In addition, 1,000 nM kallistatin was shown to suppress high-glucose-induced tube formation and the expression of vascular endothelial growth factor of HRECs. Furthermore, the knockdown of kallistatin enhanced the proliferation, migration, and tube formation of HRECs. Conclusions: Our data indicated that kallistatin might be a potent inhibitory factor for PDR. The molecule plays its role by inhibiting high-glucose-induced proliferation of HRECs. The findings suggest that the upregulation of kallistatin might be an effective strategy for PDR prevention.
α-Solanine Modulates the Radiosensitivity of Esophageal Cancer Cells by Inducing MicroRNA 138 Expression
Authors: Wang Yuanyuan , Wu Jianbo , Guo Wei , Sun Qianqian , Chen Xiaonan , Zang Wenqiao , Dong Ziming , Zhao Guoqiang
Published: August 2016

Background: Esophageal cancer (EC) is one of the most common malignant tumors in the world. Due to difficulties with performing the operation, most patients choose to have palliative treatment instead. Radiotherapy is one of the main palliative treatments of EC. However, the clinical efficacy of radiotherapy is not satisfactory α-Solanine is a bioactive component of steroidal glycoalkaloids which has been demonstrated to exhibit anti-metastasis activity in different cancers. In the present study, we determined the effect of α-solanine on the radiosensitivity of EC cells and priliminarily explored the underlying molecular mechanisms. Methods: Cell Counting Kit-8 (CCK-8) assay was conducted to found the cytotoxic effect of α-solanine on EC cells. CCK-8 assay and colony-forming survival assays were performed to explore the effect of α-solanine on cell viability and proliferation of EC cells after irradiation. Immunofluorescence and comet assays were used to detect the effect of α-solanine on DNA repair capacity of EC cells after irradiation. The flow cytometry (FCM) and Hoechst/PI staining were conductd to study the effect of α-solanine on apoptosis of EC cells after irradiation. Results: The cytotoxic effect of α-solanine to EC cells was dose-dependent. The results of CCK-8, colony-forming survival assay, immunofluorescence, comet assay, FCM and Hoechst/PI staining showed that α-solanine could enhance the radiosensitivity of EC cells. α-Solanine could downregulate Survivin expression level by upregulating miR-138 expression in EC cells. Upregulation of miR-138 and knock down Survivin both enhanced the radiosensitivity of EC cells. Moreover, Survivin could restore the effect of α-solanine and miR-138 on radiosensitivity of EC cells. Conclusions: α-solanine could enhance the radiosensitivity of esophageal cancer cells by inducing microRNA-138 expression, and probably be an effective radiosensitizer in treating EC.
Prospective, Randomized Study on the Efficacy and Safety of Local UV-Free Blue Light Treatment of Eczema
Authors: Keemss Kim , Pfaff Stephanie C. , Born Matthias , Liebmann Jörg , Merk Hans F. , von Felbert Verena
Published: August 2016

Background: Blue light was shown to reduce the activation of T cells and modulate cytokine release in vitro. Therefore, we investigated the efficacy of blue light in the treatment of eczema. Methods: A sample of 21 patients with mild to moderate eczema were locally treated with blue LED light (light-emitting diode, emission maximum: 453 nm). They received light treatment 3 times per week for 4 weeks. A contralateral control lesion remained untreated. Results: A total of 20 patients completed the trial with a compliance rate of 100%. The blue light treatment was safe with no adverse events and no side effects. The primary end point change from baseline in the mean sum score of the local Eczema Severity Index (local ESI) was more pronounced for the treated area than for the control area (-1.9 ± 2.02 vs. -1.3 ± 2.24). The treatment difference was statistically significant (p = 0.0152, paired t test, two-sided). Conclusion: In this study UV-free blue light was safe and effective in the reduction of eczema lesions.
Diffusion Tensor Imaging-Based Thalamic Segmentation in Deep Brain Stimulation for Chronic Pain Conditions
Authors: Kim Won , Chivukula Srinivas , Hauptman Jason , Pouratian Nader
Published: August 2016

Background/Aims: Thalamic deep brain stimulation (DBS) for the treatment of medically refractory pain has largely been abandoned on account of its inconsistent and oftentimes poor efficacy. Our aim here was to use diffusion tensor imaging (DTI)-based segmentation to assess the internal thalamic nuclei of patients who have undergone thalamic DBS for intractable pain and retrospectively correlate lead position with clinical outcome. Methods: DTI-based segmentation was performed on 5 patients who underwent sensory thalamus DBS for chronic pain. Postoperative computed tomography images obtained for electrode placement were fused with preoperative magnetic resonance images that had undergone DTI-based thalamic segmentation. Sensory thalamus maps of 4 patients were analyzed for lead positioning and interpatient variability. Results: Four patients who experienced significant pain relief following DBS demonstrated contact positions within the DTI-determined sensory thalamus or in its vicinity, whereas 1 patient who did not respond to stimulation did not. Only 4 voxels (2%) within the sensory thalamus were mutually shared among patients; 108 voxels (58%) were uniquely represented. Conclusions: DTI-based segmentation of the thalamus can be used to confirm thalamic lead placement relative to the sensory thalamus and may serve as a useful tool to guide thalamic DBS electrode implantation in the future.
Major Depression and Psoriasis: A Psychodermatological Phenomenon
Authors: Tohid Hassaan , Aleem Daniyal , Jackson Chantal
Published: August 2016

Objective: The aim of this paper was to highlight the mechanisms involved and the relationship between depression and psoriasis. Method: A comprehensive literature search was performed in various databases, and finally 88 studies were deemed relevant. Results: A significant link was found between depression and psoriasis, primarily through immune mechanisms related but not limited to the actions of inflammatory cytokines such as tumor necrosis factor-α, interleukin 1 (IL-1), IL-2, IL-10, interferon-γ, IL-1β, prostaglandin E2, C-reactive protein, IL-6, and IL-8. Conclusion: Various neuroimmunological studies point towards the notion that depression and psoriasis are associated with each other. Melatonin has also been found to be associated with both conditions. A possibility exists that both conditions can cause each other due to the possible bidirectional relationship of psoriasis and major depression. However, if this is the case, then why all depressed patients fail to develop psoriasis and why all psoriatic patients fail to develop depression remains a question unanswered. We believe that future studies will unmask this mystery.