bluuebunny/crossref_metadata_2025 huggingface dataset:
UK guidance for the pathological reporting of serrated lesions of the colorectum
Authors: Bateman Adrian C , Shepherd Neil A
Published: May 2015

Bowel cancer screening programmes have highlighted to endoscopists and clinicians the spectrum of serrated colorectal lesions. One of the most significant developments has been the recognition that sessile serrated lesions (SSLs), while bearing histological resemblance to hyperplastic polyps (HPs), may be associated with the enhanced development of epithelial dysplasia and colorectal adenocarcinoma. Different minimum criteria exist for the diagnosis of SSLs and their differentiation from HPs. Furthermore, the spectrum of terminology used to describe the entire range of serrated lesions is wide. This variability has impaired interobserver agreement during their histopathological assessment. Here, we provide guidance for the histopathological reporting of serrated lesions, including a simplified nomenclature system. Essentially, we recommend use of the following terms: HP, SSL, SSL with dysplasia, traditional serrated adenoma (TSA) and mixed polyp. It is hoped that this standardisation of nomenclature will facilitate studies of the biological significance of serrated lesions in terms of the relative risk of disease progression.
Infective endocarditis in the Pacific: clinical characteristics, treatment and long-term outcomes
Authors: Mirabel Mariana , André Romain , Barsoum Mikhaïl Paul , Colboc Hester , Lacassin Flore , Noël Baptiste , Robert Jacques , Nadra Marie , Braunstein Corinne , Gervolino Shirley , Marijon Eloi , Iung Bernard , Jouven Xavier
Published: May 2015

Introduction

Data on clinical characteristics and outcomes of infective endocarditis (IE) in the Pacific are scarce.

Methods

Retrospective hospital-based study in New Caledonia, a high-income country, on patients aged over 18 years with definite IE according to the modified Duke criteria (2005–2010).

Results

51 patients were included: 31 (60.8%) men; median age of 52.4 years (IQR 33.0–70.0). Left-sided IE accounted for 47 (92.2%) patients: native valve IE in 34 (66.7%) and prosthetic valve IE in 13 (25.5%). The main underlying heart disease included: rheumatic valve disease in 19 (37.3%), degenerative heart valve disease in 12 (23.5%) and congenital heart disease in 6 (11.8%). Significant comorbidities (Charlson's score >3) were observed in 20 (38.7%) patients. Infection was community acquired in 43 (84.3%) patients. Leading pathogens includedStaphylococcus aureusin 16 (31.4%) andStreptococcusspp in 15 (29.4%) patients. Complications were noted in 33 patients (64.7%) and 24 (47.1%) were admitted to the intensive care unit. Cardiac surgery was eventually performed in 22 of 40 (55.0%) patients with a theoretical indication. None underwent emergent cardiac surgery (ie, first 24 h); 2 (3.9%) were operated within 7 days; and 20 (39.2%) beyond 7 days. 11 (21.6%) patients died in hospital and 21 (42.9%) were dead after a median follow-up of 28.8 months (IQR 4.6–51.2). Two (3.9%) were lost to follow-up.

Conclusions

In New Caledonia, IE afflicts relatively young patients with rheumatic heart disease, and carries high complication and mortality rates. Access to heart surgery remains relatively limited in this remote archipelago.
The impact of patient heterogeneity and socioeconomic factors on abatacept retention in rheumatoid arthritis across nine European countries
Authors: Finckh A , Neto D , Iannone F , Loza E , Lie E , van Riel P , Hetland M L , Pavelka K , Gottenberg J E , Canhão H , Mariette X , Turesson C
Published: May 2015

Background

There are substantial differences in accessibility to biological disease modifying antirheumatic drugs (bDMARDs) across countries. The objective of this study was to analyse the impact of patient demographics, disease characteristics and gross domestic product (GDP) on abatacept (ABA) retention in patients with rheumatoid arthritis (RA) treated in clinical practice.

Methods

Data from nine European observational RA cohorts of patients treated with ABA were pooled. Kaplan-Meier analysis was used to compare drug retention across registries. Specific causes of drug retention were investigated using competing risks multivariate Cox regression.

Results

A total of 3961 patients treated with ABA, with 6188 patient-years of follow-up, were included. Patients in the different national registries had similar demographic features, but varied in baseline disease characteristics. ABA drug retention differed between countries, with median drug retention rates ranging from 1.2 to more than 6 years. The differences in drug retention were marginally explained by disparities in disease characteristics, while the national GDP per capita was strongly associated with drug retention (correlation coefficient −0.74; p=0.02).

Conclusions

Patient characteristics at ABA initiation vary across Europe, probably reflecting differences in eligibility criteria and prescription patterns. However, the difference in ABA drug retention between countries was not primarily explained by disparities in patient characteristics. Lower ABA retention was observed in countries with a more liberal access to bDMARDs and higher GDP. National differences need to be accounted for when pooling data on treatment with bDMARDs from various countries.
Epidemiological survey of Angiostrongylus vasorum in dogs and slugs around a new endemic focus in Scotland
Authors: Helm J. , Roberts L. , Jefferies R. , Shaw S. E. , Morgan E. R.
Published: May 2015

The nematode parasite Angiostrongylus vasorum is an increasingly important cause of respiratory and other diseases in dogs. Geographical spread from previously limited endemic foci has occurred rapidly. This paper investigates parasite epidemiology around the location of the first reported case in Scotland in 2009: by detection of A vasorum ‐specific DNA in gastropod intermediate hosts, and in dogs circulating DNA and specific antibodies, and first stage larvae in faeces. Overall prevalence in gastropods was 6.7 per cent (16/240), with parasite DNA found in slugs in the Arion ater and Arion hortensis species aggregates and the snail Helix aspersa (syn. Cornu aspersum). Of 60 dogs presenting with clinical signs compatible with angiostrongylosis, none tested positive using PCR on peripheral blood or Baermann test on faeces, and none of 35 tested for circulating anti‐A vasorum antibodies were positive. PCR prevalence in gastropods was highest (11 per cent) in the park frequented by the canine angiostrongylosis index case. Molecular survey for infection in gastropods is a potentially informative and efficient method for characterising the distribution of A vasorum and therefore local risk of canine infection. However, there appears to be a complex relationship between prevalence in gastropods and emergence of canine clinical disease, which requires further work to advance understanding of parasite transmission and geographical disease spread.
Delay-Induced Double Hopf Bifurcations in a System of Two Delay-Coupled van der Pol–Duffing Oscillators
Authors: Jiang Heping , Zhang Tonghua , Song Yongli
Published: May 2015

In this paper, we investigate the codimension-two double Hopf bifurcation in delay-coupled van der Pol–Duffing oscillators. By using normal form theory of delay differential equations, the normal form associated with the codimension-two double Hopf bifurcation is calculated. Choosing appropriate values of the coupling strength and the delay can result in nonresonance and weak resonance double Hopf bifurcations. The dynamical classification near these bifurcation points can be explicitly determined by the corresponding normal form. Periodic, quasi-periodic solutions and torus are found near the bifurcation point. The numerical simulations are employed to support the theoretical results.
A Study on the Ricochet of Concrete Debris Against Soil
Authors: Xu J. , Lee C. K. , Fan S. C.
Published: May 2015

In this study, the impact responses of concrete debris against soil are investigated. Three types of concrete debris are shot at soil with different incident conditions in experiments. A numerical modeling for the impact process is established and calibrated by the experimental results. A further study on the effect of debris size is then carried out based on the calibrated numerical modeling. A set of formulation is presented to predict the outgoing velocity and the outgoing angle in terms of the incident velocity and the incident angle. Critical lethality curves are derived based on the assumption of a critical kinetic energy of 79 J.
The singular values of the GOE
Authors: Bornemann Folkmar , La Croix Michael
Published: May 2015

As a unifying framework for examining several properties that nominally involve eigenvalues, we present a particular structure of the singular values of the Gaussian orthogonal ensemble (GOE): the even-location singular values are distributed as the positive eigenvalues of a Gaussian ensemble with chiral unitary symmetry, while the odd-location singular values, conditioned on the even-location ones, can be algebraically transformed into a set of independent χ-distributed random variables. We discuss three applications of this structure: first, there is a pair of bidiagonal square matrices, whose singular values are jointly distributed as the even- and odd-location ones of the GOE; second, the magnitude of the determinant of the GOE is distributed as a product of simple independent random variables; third, on symmetric intervals, the gap probabilities of the GOE can be expressed in terms of the Laguerre unitary ensemble. We work specifically with matrices of finite order, but by passing to a large matrix limit, we also obtain new insight into asymptotic properties such as the central limit theorem of the determinant or the gap probabilities in the bulk-scaling limit. The analysis in this paper avoids much of the technical machinery (e.g. Pfaffians, skew-orthogonal polynomials, martingales, Meijer G-function, etc.) that was previously used to analyze some of the applications.
Empire, Health, and Health Care: Perspectives at the End of Empire as We Have Known It
Authors: Waitzkin Howard , Jasso-Aguilar Rebeca
Published: May 2015

Health and health care have played important roles during the rise of empire and during its subsequent decline. Research has emphasized the underdevelopment of health in less developed countries, the opening of new markets for medical products manufactured in dominant nations, the contribution of public health in enhancing the productivity of labor, the impact of medicine in reinforcing international class relations, and the adverse effects of military interventions on health and mental health. Latin American social medicine, especially work by Salvador Allende, has clarified the social origins of illness and early death in the context of empire. Connections among empire, health, and health care have operated through key mediating institutions: trade agreements and international financial institutions, foundations, and international public health organizations. Several popular struggles show a diminishing tolerance among the world's peoples for the health policies of empire and a growing demand for health systems grounded in solidarity rather than profitability.
Modulation of endothelial cell phenotype by physical activity: impact on obesity-related endothelial dysfunction
Authors: Bender Shawn B. , Laughlin M. Harold
Published: May 2015

Increased levels of physical activity are associated with reduced cardiovascular disease (CVD) risk and mortality in obesity and diabetes. Available evidence suggests that local factors, including local hemodynamics, account for a significant portion of this CVD protection, and numerous studies have interrogated the therapeutic benefit of physical activity/exercise training in CVD. Less well established is whether basal differences in endothelial cell phenotype between/among vasculatures related to muscle recruitment patterns during activity may account for reports of nonuniform development of endothelial dysfunction in obesity. This is the focus of this review. We highlight recent work exploring the vulnerability of two distinct vasculatures with established differences in endothelial cell phenotype. Specifically, based largely on dramatic differences in underlying hemodynamics, arteries perfusing soleus muscle (slow-twitch muscle fibers) and those perfusing gastrocnemius muscle (fast-twitch muscle fibers) in the rat exhibit an exercise training-like versus an untrained endothelial cell phenotype, respectively. In the context of obesity, therefore, arteries to soleus muscle exhibit protection from endothelial dysfunction compared with vulnerable arteries to gastrocnemius muscle. This disparate vulnerability is consistent with numerous animal and human studies, demonstrating increased skeletal muscle blood flow heterogeneity in obesity coincident with reduced muscle function and exercise intolerance. Mechanistically, we highlight emerging areas of inquiry exploring novel aspects of hemodynamic-sensitive signaling in endothelial cells and the time course of physical activity-associated endothelial adaptations. Lastly, further exploration needs to consider the impact of endothelial heterogeneity on the development of endothelial dysfunction because endothelial dysfunction independently predicts CVD events.
Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice
Authors: Kim Jungsil , Procknow Jesse D. , Yanagisawa Hiromi , Wagenseil Jessica E.
Published: May 2015

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 ( Fbln4−/−) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4−/−and Fbln4+/+mice. Fbln4−/−AA has increased diameters compared with Fbln4+/+AA and Fbln4−/−DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4−/−aortas. Fbln4−/−aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4−/−aortas compared with Fbln4+/+. Additional genes in both pathways, as well as matrix metalloprotease-8 ( Mmp8), are upregulated specifically in Fbln4−/−AA compared with Fbln4+/+AA and Fbln4−/−DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4−/−AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.
Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus
Authors: Orgeig Sandra , McGillick Erin V. , Botting Kimberley J. , Zhang Song , McMillen I. Caroline , Morrison Janna L.
Published: May 2015

Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130–135 ( n = 19) and 139–145 ( n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain ( PHD) 2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α ( HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.
Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH
Authors: Rhodes Julie , Saxena Deeksha , Zhang GuangFeng , Gittes George K. , Potoka Douglas A.
Published: May 2015

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 ( E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH.
Quantized State Based Simulation of Time Invariant and Time Varying Continuous Systems
Authors: Song Xiao , Ma Yaofei , Zhang Wei , Wang Jiangyun
Published: May 2015

Continuous system can be discretized for computer simulation. Quantized state systems (QSS) method has been used to discretize time invariant systems based on the discretization of the state space. A HLA based QSS method is proposed in this paper to address issues of real-time advancements in simulation and an aircraft control example was introduced to illustrate our method. Moreover, to simulate time varying systems, a novel approach is also proposed and exemplified with a practical case.
A Novel Frequency Domain Iterative Image Registration Algorithm Based on Local Region Extraction
Authors: Qu Xiujie , Huo Haili , Lian Sitong , Zhao Fei
Published: May 2015

Because of the differences of imaging time, position between sensor and target position, scaling, rotation, translation, and other transformations between the series of images will be generated by the imaging system. The conventional phase correlation algorithm has been widely applied because of its advantages of high speed, precision, and weak influence of the geometric distortion when computing these changing parameters. However, when the scaling factor and the rotation angle are too large, it is difficult to use the conventional phase correlation method for high precision registration. To solve this problem, this paper presents a novel method, which combines the speeded up robust features algorithm and the phase correlation method under the log polar. Through local region extraction and reusing a two-step iterative phase correlation algorithm, this method avoids excessive computation and the demand of characteristics of the image and effectively improves the accuracy of registration. A plurality of visible light image simulation verifies that this is a fast, accurate, and robust algorithm, even when the image has large angle rotation and large multiple scaling.
Seasonal Dynamics of N, P, and K in an Organic and Inorganic Fertilized Willow Biomass System
Authors: Quaye Amos K. , Volk Timothy A. , Schoenau Jeff J.
Published: May 2015

The seasonal variations in soil nutrient supply and bioavailability were assessed in a willow biomass crop (Salix miyabeana, SX64) treated with 150 and 200 kg available N ha−1of commercial fertilizer (CF), biosolid compost (BC), dairy manure (DM), and control (CT0) at Delhi, NY. Plant root simulator probes were used to measure nutrient supply (inside) and bioavailability (outside) of root exclusion cylinders. Measurements were made in September 2008 and May, August, and October of 2009. Soil moisture content (θd)and foliar nutrient concentrations were also determined. The BC treatments increased soil P supply more than CF and CT0. The supply ofNH4+and K in the soil increased in August but their bioavailability increased in May and October. SoilNO3-and P supply and bioavailability were both high in May. Foliar N and K concentrations were significantly high in May and low in August which could be due to dilution effect caused by increased soil moisture foliar dry weight. Foliar P concentrations increased in September and October. The observed higher soilNO3-mineralization and plant uptake in May suggest that in high soilNO3-conditions willow biomass crops can level and minimize leaching out of the root zone into groundwater.
Effectiveness of Extractants for Bioavailable Phosphorus in Tropical Soils Amended with Sewage Sludge
Authors: Nogueirol Roberta Corrêa , Melo Wanderley José de , Bertoncini Edna Ivani , Alleoni Luís Reynaldo Ferracciú
Published: May 2015

Urban wastes such as sewage sludge can be an economically viable alternative source for providing macro- and micronutrients to plants in tropical conditions. Sewage sludge is normally rich in phosphorus (P), which is present in soils mainly in organic forms, so that it is very important to establish methods for estimating its availability to plants. This study aimed to test three extractants that simulate P-uptake by maize (Zea mays) cropped in plots after 13 consecutive years of fertilization with sewage sludge, in a cycle of fertilized sugarcane (SaccharumL.) amended with sewage sludge and organic compost. Soil samples were collected at depths of 0–10, 10–20, and 20–40 cm in March 2010 from the two experimental areas. Soil P was extracted via ion exchange resin, Mehlich-I, and 0.025 M H2SO4and determined via colorimetry. Maize and sugarcane diagnostic leaves were collected in the experiments, subjected to nitric-perchloric digestion, and the leaf-P content was determined via colorimetry. No significant correlations were found between phosphorus extracted from soils and phosphorus concentrations in diagnostic leaves. Resin extracted larger amounts of P in the short-term experiment, while acidic extractants yielded larger amounts in the long-term experiment.
The Impact of Vitamin D3Supplementation on Mechanisms of Cell Calcium Signaling in Chronic Kidney Disease
Authors: Lajdova Ingrid , Spustova Viera , Oksa Adrian , Kaderjakova Zuzana , Chorvat Dusan , Morvova Marcela , Sikurova Libusa , Marcek Chorvatova Alzbeta
Published: May 2015

Intracellular calcium concentration in peripheral blood mononuclear cells (PBMCs) of patients with chronic kidney disease (CKD) is significantly increased, and the regulatory mechanisms maintaining cellular calcium homeostasis are impaired. The purpose of this study was to examine the effect of vitaminD3on predominant regulatory mechanisms of cell calcium homeostasis. The study involved 16 CKD stages 2-3 patients with vitamin D deficiency treated with cholecalciferol 7000–14000 IU/week for 6 months. The regulatory mechanisms of calcium signaling were studied in PBMCs and red blood cells. After vitaminD3supplementation, serum concentration of 25(OH)D3increased (P<0.001) and[Ca2+]idecreased (P<0.001). The differences in[Ca2+]iwere inversely related to differences in 25(OH)D3concentration (P<0.01). VitaminD3supplementation decreased the calcium entry through calcium release activated calcium (CRAC) channels and purinergic P2X7channels. The function of P2X7receptors was changed in comparison with their baseline status, and the expression of these receptors was reduced. There was no effect of vitaminD3on P2X7pores and activity of plasma membrane Ca2+-ATPases. VitaminD3supplementation had a beneficial effect on[Ca2+]idecreasing calcium entry via CRAC and P2X7channels and reducing P2X7receptors expression.
Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D
Authors: Jeong Youngtae , Swami Srilatha , Krishnan Aruna V. , Williams Jasmaine D. , Martin Shanique , Horst Ronald L. , Albertelli Megan A. , Feldman Brian J. , Feldman David , Diehn Maximilian
Published: May 2015

The anticancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and preclinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here, we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor–initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors and estrogen receptors (ER) and exhibited calcitriol-induced molecular responses including ER downregulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D–supplemented diet caused a striking delay in tumor appearance and growth, whereas a vitamin D–deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies may enhance anticancer activity and improve therapeutic outcomes. Mol Cancer Ther; 14(8); 1951–61. ©2015 AACR.
AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody–Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML
Authors: Pereira Daniel S. , Guevara Claudia I. , Jin Liqing , Mbong Nathan , Verlinsky Alla , Hsu Ssucheng J. , Aviña Hector , Karki Sher , Abad Joseph D. , Yang Peng , Moon Sung-Ju , Malik Faisal , Choi Michael Y. , An Zili , Morrison Kendall , Challita-Eid Pia M. , Doñate Fernando , Joseph Ingrid B.J. , Kipps Thomas J. , Dick John E. , Stover David R.
Published: May 2015

CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody–drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34+CD38− leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML. Mol Cancer Ther; 14(7); 1650–60. ©2015 AACR.
Abstract 1459: miR-221: A potential therapeutic target for hepatocellular carcinoma
Authors: Lee Edmund C. , Xu Jessica , Vincent Thomas , Chen Jie , Nelson Michael , Huang Xinqiang , Marcusson Eric , Androsavich John , Davis Scott , Pavlicek Adam , Gibson Neil , Zabludoff Sonya
Published: May 2015

microRNAs, which control post-transcriptional gene expression by repressing mRNA translation and/or causing mRNA degradation, play important roles in human cancers. miR-221 is one of the two microRNAs in the miR-221/222 cluster located in chromosome-X, targets key cancer pathways and inhibit translation of several tumor suppressors including p27, p57, and PTEN. miR-221 is up-regulated by >2-fold in 55% and >5-fold in 14% of human hepatocellular carcinoma (HCC) tumor samples. Importantly, it has been shown in preclinical HCC models that miR-221 overexpression accelerated tumorigenesis, while miR-221 inhibition reduced tumor growth. To identify novel microRNA antagonists that specifically inhibit miR-221 (refer to as miR-221 anti-miRs) for the treatment of HCC, we have generated a number of chemically-modified oligonucleotides and screened for their ability to inhibit miR-221 functions. A number of potent and metabolically stable miR-221 anti-miRs devoid of proinflammatory potential were identified. These miR-221 anti-miRs were tested in a number of human HCC cell lines that highly express miR-221 compare to normal adult human hepatocytes. We demonstrated the de-repression of both p27 mRNA and p27 protein in HCC cells following treatment with miR-221 anti-miRs. We also showed in HCC cells the de-repression of a novel miR-221 target gene recently identified through an argonuate pull-down assay (Ago-IP), alongside with the enrichment of global miR-221 target seeds (as defined by TargetScan) following miR-221 anti-miRs treatment. We then sought to determine the biologic consequences following miR-221 inhibition in HCC cells. In standard cell proliferation assays, we demonstrated that HCC cells responded to miR-221 anti-miRs treatment with IC50s of 125 to 500nM under free-uptake conditions and IC50s of 5 to 75 nM under transfection conditions. In addition, we also showed that miR-221 anti-miRs treatment disrupted HCC cell cycle transition. Altogether, our data showed that miR-221 inhibition de-repressed p27, blocked cell cycle progression and reduced cell proliferation in HCC cells, and supports the notion of miR-221 as a potential therapeutic target for the treatment of HCC. Further preclinical testing of our miR-221 anti-miRs is currently in progress.

Citation Format: Edmund C. Lee, Jessica Xu, Thomas Vincent, Jie Chen, Michael Nelson, Xinqiang Huang, Eric Marcusson, John Androsavich, Scott Davis, Adam Pavlicek, Neil Gibson, Sonya Zabludoff. miR-221: A potential therapeutic target for hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1459. doi:10.1158/1538-7445.AM2014-1459
Abstract 1671: Immunosuppressive myeloid-derived suppressor cells expressing PDL1 are increased in human melanoma tumor tissue
Authors: Jordan Kimberly Rae , Borges Virginia , McCarter Martin D.
Published: May 2015

Despite the ability to elicit active immune responses, most immunotherapies fail to eliminate tumors in human cancer patients. One reason immunotherapy has not met expectations may be due to immunosuppression in the local environment of the tumor. Immunosuppressive myeloid-derived suppressor cells (MDSCs) are increased in the peripheral blood of melanoma patients and the frequency of MDSCs correlates with overall survival and disease progression. Furthermore, cytokines related to the recruitment and differentiation of MDSCs are also increased in melanoma patient serum and changes in these cytokine levels may correlate with disease progression. We find an increased frequency of regulatory T cells, PD-1-expressing T cells, and PD-L1 expressing MDSCs in primary melanoma tumors, suggesting that PD-1/PD-L1 interactions may play a role in immunosuppression in the microenvironment of the tumor. We are currently investigating the mechanisms of immunosuppression used by human MDSCs and whether the suppressive function of MDSCs can be blocked with antibodies targeting PD-L1. In conclusion, we have established MDSCs as an important player in immunosuppression in melanoma patients suggesting that combinatorial treatments that reduce the frequency or activity of MDSCs may improve the effectiveness of future immunotherapies.

Citation Format: Kimberly Rae Jordan, Virginia Borges, Martin D. McCarter. Immunosuppressive myeloid-derived suppressor cells expressing PDL1 are increased in human melanoma tumor tissue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2014-1671
Abstract 1760: Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition
Authors: Moore Zachary , Boothman David A.
Published: May 2015

Cancer cells require increased NAD+ synthesis to support anabolic metabolism, to sustain signaling processes such as sirtuin activity and ADP-ribosylation, and to maintain redox balance. Inhibitors of Nicotinamide phosphoribosyltransferase (NamPT), the rate-limiting step in NAD+ biosynthesis, have modest anti-tumor activity in monotherapy in vitro and in vivo, but failed clinical trials due to a lack of tumor specificity attributed to the necessity of NAD+ synthesis in normal proliferating cells. We found that the tumor specificity and efficacy of NamPT inhibition can be greatly increased when small molecule NamPT inhibitors, such as FK866, are used in combination with the NQO1 bioactivated therapeutic ß-lapachone (ß-lap). Most solid tumor cells overexpress NQO1, which catalyzes a futile redox cycle with ß-lap, resulting in the formation of a burst of reactive oxygen species (ROS). This results in substantial DNA single strand breaks and base damage in a tumor-specific manner, which hyperactivates poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme that utilizes NAD+ to generate poly(ADP-ribose) (PAR)-protein moieties. Rapid NAD+ and ATP loss occurs and tumor cells die through programmed necrosis. PARP-1-mediated NAD+ depletion caused by ß-lap treatment synergizes with reduced NAD+ synthesis as a result of FK866-mediated NamPT inhibition. Enhanced cancer cell death in terms of loss of viability and clonogenicity at lower ß-lap doses was noted, while tumor specificity for NQO1 overexpressing cells was maintained. With combination treatment, cells are primed for ROS-mediated damage due to reduced glutathione and NAD(P)+ levels, they are unable to recover ATP, NAD+, and NADP+ synthesis even after only a 2 hour treatment, and they rapidly die through a caspase-independent mechanism. This therapeutic approach is highly effective against a variety of tumor cell lines from pancreatic, breast, and non-small cell lung, and is expected to improve the efficacy and tumor specificity of both of these drugs by allowing their use at lower doses in vivo. These studies were supported by an AACR/PanCan Innovator Award and NIH R01 CA102972 to DAB.

Citation Format: Zachary Moore, David A. Boothman. Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1760. doi:10.1158/1538-7445.AM2014-1760
Abstract 1882: The expression phenotype of SNPs linked to the risk for prostate cancer
Authors: Chen Xin , Jia Zhenyu , McClelland Michael , Rahmatpanah Farah , Mercola Dan
Published: May 2015

Numerous Genome Wide Association (GWA) studies of large populations have provided limited biomarkers for cancer and few linkages to phenotype. We investigated whether SNPs that are known to be associated with prostate cancer (PCa) affect expression in prostate stroma. The stroma of prostate tumors provides genetically homogenous tissue type with hundreds of tumor-dependent expression changes [1] which favors linkage identification. We surveyed published GWA studies covering a total of ∼90,000 patients and selected the most significant 35 susceptibility loci for further linkage analysis. We also selected 4030 transcripts previously associated with PCa diagnosis and prognosis. We then investigated 47 PCa cases using genetic variations in nontumor DNA (Illumina Human1M-Duov3_B snp arrays) and correlating the genotypes with RNA gene expression data from the same patients (U133 plus 2.0 arrays). A novel eQTL (Expression Quantitative Trait Loci) analysis was carried out by a modified BAYES method to analyze the associations between the risk variants and expressed transcripts jointly in a single model. The model assumed that a risk variant can be associated with multiple RNA expression changes and vice versa. We observed 47 significant linkages between 8 risk variants and 46 significant expression changes. The false discovery rates of two resampling studies are 0.03 and 0.05, respectively, which indicated the 47 linkages are significant. All linkages are “trans' linkages indicating remote effects of key SNPs on expressing genes. This is the first study to identify trans-linkages between multiple SNPs and multiple significant expression changes identified in cancer stroma. The linkages also associated with trends in clinical phenotypes. The strongest trend is between linkage rs9623117(C)-FOXD1 and biochemical relapse (p=0.01). The study reveals links between SNPs associated with PCa risk and transcription, which may identify the subset of patients where these genotypes may affect relevant phenotypes.

[1] Jia et al., Cancer Research 2011; 71:2476-2487.

Citation Format: Xin Chen, Zhenyu Jia, Michael McClelland, Farah Rahmatpanah, Dan Mercola. The expression phenotype of SNPs linked to the risk for prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2014-1882
Abstract 2624: The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model
Authors: Niemann Carsten U. , Montraveta Arnau , Herman Sarah E. M. , Ingallinera Tim , Barf Tjeerd , Colomer Dolors , Wiestner Adrian
Published: May 2015

Background: Targeting Bruton's tyrosine kinase (BTK), an essential kinase in the B cell receptor (BCR) pathway in patients with chronic lymphocytic leukemia (CLL) has proven very effective. For the first generation BTK inhibitor ibrutinib, clinical response rates >70% and 75% progression free survival >2 years have been reported for previously treated patients (Byrd, NEJM, 2013). ACP-196 is a novel, second generation, irreversible BTK inhibitor that may show advantages in terms of binding specificity and drug-drug interactions compared to the first generation BTK inhibitor. Survival and proliferation of CLL cells is highly dependent on microenvironment interaction, which must be taken into consideration when testing new drugs for CLL. We have previously shown that human CLL cells engrafted in the spleen of NSG mice have comparable tumor biology to human lymph node resident CLL cells (Herman, Leukemia, 2013). We here demonstrate the in vivo effects of ACP-196 monotherapy against CLL cells in the NSG xenograft model.

Methods: Peripheral blood mononuclear cells from previously untreated CLL patients were injected intravenously into NSG mice. Mice received ACP-196 through the drinking water. The effect of ACP-196 on xenografted CLL cells from peripheral blood and spleen was assessed by flow cytometry.

Results: At all dose levels tested, ACP-196 significantly inhibited proliferation of human CLL cells in the spleens of NSG mice, as measured by Ki67 expression (P=0.002). The mean Ki67 decrease was 58%, 70% and 73%, respectively for the low, intermediate, and high dose level compared with vehicle. Tumor burden in spleens from mice treated with the high dose of ACP-196 decreased compared with the vehicle treated group (P=0.007). As seen with other BCR inhibitors, ACP-196 transiently increased CLL cell counts in the peripheral blood in a dose dependent manner (p=0.01). ACP-196 inhibited BCR signaling in vivo, as demonstrated by reduced phosphorylation of PLCγ2.

Conclusions: Results presented here for ACP-196 are in accordance with the expected profile of an irreversible BTK inhibitor. The NSG CLL xenograft model will be used for comparative testing of different BTK inhibitors and exploration of combination therapies.

Citation Format: Carsten U. Niemann, Arnau Montraveta, Sarah E. M. Herman, Tim Ingallinera, Tjeerd Barf, Dolors Colomer, Adrian Wiestner. The novel Bruton's tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2014-2624
Abstract 2640: RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors
Authors: Liu Shu-Hui , Strop Pavel , Tran Thomas-Toan , Dorywalska Magdalena , Delaria Katherine , Ho Wei-Hsien , Dushin Russell , Pons Jaume , Rajpal Arvind , Shelton Dave
Published: May 2015

Human trophoblast cell surface antigen-2 (Trop-2), also known as TACSTD2, EGP-1, GA733-1 and MS1, is expressed on a variety of human carcinomas and its expression is often associated with poor prognosis of the diseases. Trop-2 is frequently detected in many tumor types at high levels, however, it is also present on the epithelium of a number of normal tissues. A comprehensively designed Trop-2-targeting ADC, balancing both efficacy and toxicity, is necessary to achieve clinical utility. We developed a site-specific cleavable Trop-2-ADC (RN927C) using a novel transglutaminase-mediated enzymatic conjugation method and a proprietary MTI (microtubule inhibitor) linker-payload. Our site-specific conjugation technology enables a precise drug-loading ratio of two and thus a better control of desired potency. Robust in vitro cytotoxicity of RN927C was observed selectively on multiple Trop-2 expressing tumor cell lines, with IC50 generally in the sub-nM range. Upon binding to surface Trop-2, RN927C internalized quickly and trafficked to the lysosomal compartment, as visualized by the co-localization of RN927C with lysosomal marker LAMP-2. As expected for a MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple tumor models including pancreatic, NSCLC, and ovarian cell line and patient-derived xenograft models. Single dose administration of RN927C at 1.5 mg/kg was generally sufficient to induce sustained regression of Trop-2 expressing tumors and showed superior efficacy over standard treatment with paclitaxol or Gemcitabine. Furthermore, addition of RN927C to Gemcitiabine greatly enhanced its in vivo efficacy. RN927C was well-tolerated in non-human primates upon repeat dosing at 6mg/kg q2w, with non-severe toxicity observed primarily in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues. Importantly, only minimal off-target hematological toxicity was observed in monkeys. Based on the combined efficacy and safety results, RN927C is expected to have a favorable therapeutic index and clinical development is currently underway.

Citation Format: Shu-Hui Liu, Pavel Strop, Thomas-Toan Tran, Magdalena Dorywalska, Katherine Delaria, Wei-Hsien Ho, Russell Dushin, Jaume Pons, Arvind Rajpal, Dave Shelton. RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2640. doi:10.1158/1538-7445.AM2014-2640