bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathologic characterization of the process of Marssonina brunnea infection in poplar leaves
Authors: Zhang Yanfeng , He Wei , Yan Dong-Hui
Published: August 2018

Marssonina brunnea (Ellis & Everh.) Magnus, the causative pathogen of Marssonina leaf spot of poplars (MLSP), can lead to complete defoliation and tree death. Although MLSP has been studied for over 30 years, its precise process of infection is currently unclear. In this study, we present the process of M. brunnea infection in detail using several types of microscopy. When the conidia came into contact with the poplar leaves, they developed germ tubes to attach to the leaf surface. During the first 2 days post inoculation (dpi), infection vesicles (IV) and primary hyphae (PH) formed within host cells. The plasma membranes of the host cells penetrated by IV remained unbroken and intact organelles were visible, indicating that the IV did not kill the host cell. At 3 dpi, secondary hyphae (SH) began to appear within and outside the host cells. The ultrastructural evidence indicated that the SH could kill the host cells rapidly, producing black spots on the surfaces of the leaves. These results collectively suggested that M. brunnea is a typical hemibiotrophic fungus. In addition, M. brunnea could develop intercellular infective hyphae (IH) for expansion. Our findings also confirmed that the germ tubes, IV, and SH are crucial structures for the disease interactions and showed that the two formae speciales of M. brunnea share the same infection histopathological features. This provides important insight for further research into M. brunnea.
Comprehensive compensation method for thermal error of vertical drilling center
Authors: Kang Cheng Ming , Zhao Chun Yu , Liu Kuo , Li Tie Jun , Yang Bo
Published: August 2018

To eliminate the influence of thermally induced error from a machine tool on machining accuracy, a comprehensive error compensation method for thermal displacement of the screw shaft and spindle is put forward. Based on a heat transfer mechanism and experimental analysis, a model of screw thermal expansion error is built. Modeling of spindle thermal growth that depends on speed variations is also proposed. Thermal tests for studying thermal behavior of the spindle and screw axis are carried out on the vertical drilling center TC500R. Finally, the compensation effect of the robust model is validated via experimental tests and machining. Experimental results show that thermal displacement variations are controlled within 2 μm when the compensation system is activated. The suggested model can achieve high accuracy and good applicability in different moving states. Machining results indicate that dimensional accuracy of the workpiece is significantly improved after implementation of compensation. Feasibility of the thermal error compensation system is satisfactory in applications for drilling operations.
Direct detection of axion-like particles in Bismuth-based topological insulators
Authors: Liang Tairan , Zhu Bin , Ding Ran , Li Tianjun
Published: August 2018

In recent years, a new field emerged in dark matter community and immediately attracted a multitude of theorists and experimentalists, that of light dark matter direct detection in electronic systems. The phenomenon is similar to nuclear recoil in elastic scattering between dark matter and nucleus but with different kinematics. Due to the small energy gap, the electronic system can probe sub-GeV dark matter rather than nucleus target. In particular, the absorption into materials can even detect ultralight dark matter within mass around meV. In terms of the equivalence between optical conductivity and absorption cross-section, axion detection can be computed in Bismuth-based topological insulators. It is found that topological insulator has strong sensitivity on axion and provides a complementary direct detection to superconductor and semiconductors. The novelty of topological insulator is that the thin film could even obtain the same sensitivity as a superconductor.
Anomalies in finite amplitudes: Two-dimensional single and triple axial-vector triangles
Authors: Battistel O. A. , Traboussy F. , Dallabona G.
Published: August 2018

An explicit and detailed investigation about the two-dimensional (2D) single and triple axial-vector triangles is presented. Such amplitudes are related to the 2D axial-vector two-point function (AV) through contractions with the external momenta. Given this fact, before considering the triangles, we give a clear point of view for the AV anomalous amplitude. Such point of view is constructed within the context of an alternative strategy to handle the divergences typical of the perturbative solutions of quantum field theory. In the referred procedure all amplitudes in all theories, formulated in odd and even space–time dimensions, renormalizable or not, are treated on the same footing. After performing, in a very detailed way, all the calculations, we conclude that the same phenomenon occurring in the AV amplitude is present also in the finite single and triple axial-vector triangles. The conclusion gives support to the thesis that the phenomenon is present in pseudo-amplitudes belonging to a chain where the divergent AV one is only the simplest structure. It is expected that the same must occur in all even space–time dimensions. In particular, in four dimensions, the single and triple axial box amplitudes must exhibit anomalies too.
The hierarchical Green’s function approach to the two-dimensional Hubbard model
Authors: Liu Yu-Liang
Published: August 2018

By introducing multiple-site correlation functions, we propose a hierarchical Green’s function approach, and apply it to study the characteristic properties of a two-dimensional (2D) square lattice Hubbard model by solving the equation of motions of a one-particle Green’s function and related multiple-site correlation functions. Under a cut-off approximation and taking the Fourier representation of multiple-site correlation functions, we obtain an analytical expression of one-particle Green’s function with static correlation functions. Then we calculate the spectral density function of electrons, and obtain that besides two main peaks corresponding to the lower and upper Hubbard bands in the spectral density function, there emerge some novel states between these two main peaks, and the total spectral weight of these emerged states is proportional to the hole doping concentration [Formula: see text]. Meanwhile, there also emerge some collective modes related to possible charge/spin density wave and/or electronic pairing density wave ordering states. This calculation is completely consistent with the spectroscopy observations of the cuprate superconductors in normal states. On the other hand, the appearance of the static correlation functions in the one-particle Green’s function can be used to describe the intertwined orders observed in the normal state of the cuprate superconductors.
Characteristics of acoustic phonon transport and thermal conductance in multi-frame graphene nanoribbons
Authors: Bao Bengang , Li Fei , Zhou Xin
Published: August 2018

Using non-equilibrium Green’s function method and maintaining the zigzag carbon chains unchanged, we investigate the transmission rate of acoustic phonon and the reduced thermal conductance through multi-frame graphene nanoribbons (GNRs). The results show that the reduced thermal conductance approaches [Formula: see text] in the limit [Formula: see text]. Due to the fact that only long wavelength acoustic phonons with zero cutoff frequency are excited at such low temperatures, the scattering influence on the long wavelength acoustic phonons by the multi-frame in GNRs can be ignored and these phonons can go through the scattering region perfectly. As the temperature goes up, the reduced thermal conductance decreases. This is because the high-frequency phonons are excited and these high-frequency phonons are scattered easily by the scattering structures. With the further rise in temperature, acoustic phonon modes with the cutoff frequency greater than zero are excited, which leads to a rapid increase of the reduced thermal conductance. This study shows that changing the frame structure by a small length can lead to a significant change of transmission probability. In the higher frequency region, the transmission spectra display complex peak-dip structures, which results from the fact that in higher frequency region more phonon modes are excited and scattered in the middle scattering region with multi-frames, and the scattering phonons are coupled with the incident phonons, with the increase of the length of frame structure, the scattering of the phonon is also enhanced, which leads to the decrease in the phonon transmission; by changing the frame structure, the parameters can effectively adjust the position of low-frequency phonon transmission valley. The frame structure can induce high-frequency phonon blocking effect and the blocking effect depending on the structure parameter of the frame. When the single frame and double frame GNRs are narrowest, the scattering from low-frequency phonons by the scattering structure is largest, which leads to the fact that the reduced thermal conductance is smallest at low temperatures; however, at high temperature, the reduced thermal conductance is biggest when the single frame and double frame GNRs are narrowest. This is because the scattering from high-frequency phonons by the scattering structure is the smallest. When the length of the frame structure is unchanged, a graphite chain is inserted in which the reduced thermal conductance is always reduced. These results provide an effective theoretical basis for designing the thermal transport quantum devices based on GNRs.
A Robust Multi-Circle Detector Based on Horizontal and Vertical Search Analysis Fitting with Tangent Direction
Authors: Li Shaodong , Du Zhijiang , Yu Hongjian , Yi Jiafu
Published: August 2018

In this paper, we propose an efficient Multi-Circle detector which follows the fixed search order. The method makes use of horizontal and vertical search to realize circle detection, which is named as HVCD. First, this method computes edge areas in a given image. The edge areas could be divided into some regions by means of region growing. Each of regions could be efficiently searched to achieve not only one-pixel wide edges but edge segments as well. Next, the candidate circles can be extracted from every edge segment. Finally, the circle candidates could be validated with the help of Helmholtz principle. Experimental results demonstrate that HVCD could effectively detect circles on synthetic and natural images on the one hand; on the other hand, HVCD here could solve the weakness in the process of circle Hough transform implementation and EDcircles implementation.
The motion of color-charged particles as a means of testing the non-Abelian dark matter model
Authors: Dzhunushaliev Vladimir , Folomeev Vladimir , Protsenko Nina
Published: August 2018

A possibility is discussed to experimentally test a dark matter model supported by a classic non-Abelian SU(3) Yang–Mills gauge field. Our approach is based on the analysis of the motion of color-charged particles in the background of color electric and magnetic fields using the Wong equations. Estimating the magnitudes of the color fields near the edge of a galaxy, we employ them in obtaining the general analytic solutions to the Wong equations. Using the latter, we calculate the magnitude of the extra acceleration of color-charged particles related to the possible presence of the color fields in the neighborhood of Earth.
GOLD-PLATED TITANIUM VS CARBON-IMPLANTED TITANIUM AS MATERIAL FOR BIPOLAR PLATES IN PEM FUEL CELLS
Authors: VLASKIN M. S. , GRIGORENKO A. V. , SHKOLNIKOV E. I. , ILYUKHIN A. S.
Published: August 2018

Three different types of current-collecting plates for air-hydrogen PEM fuel cell were manufactured and tested: unmodified titanium plates; gold-plated titanium plates and titanium plates treated by carbon ions implantation. It was shown that the applied surface modifications reduce contact resistance between titanium plate and carbon gas diffusion layer. Total ohmic resistance of fuel cell is reduced by 1.8 and 1.4 times in case of gold-plated titanium and carbon-implanted titanium, respectively, in comparison with uncoated titanium. Although gold plating turned out to be more profitable than carbon ion implantation in terms of electrical characteristics, in the last case, the performance enhancement was reached without using precious metals, which at mass production must play more important role. This technology promises to reduce the cost of bipolar plates manufacturing, while maintaining high electrical performance of PEM fuel cells.
A Hida–Malliavin white noise calculus approach to optimal control
Authors: Agram Nacira , Øksendal Bernt
Published: August 2018

The classical maximum principle for optimal stochastic control states that if a control [Formula: see text] is optimal, then the corresponding Hamiltonian has a maximum at [Formula: see text]. The first proofs for this result assumed that the control did not enter the diffusion coefficient. Moreover, it was assumed that there were no jumps in the system. Subsequently, it was discovered by Shige Peng (still assuming no jumps) that one could also allow the diffusion coefficient to depend on the control, provided that the corresponding adjoint backward stochastic differential equation (BSDE) for the first-order derivative was extended to include an extra BSDE for the second-order derivatives. In this paper, we present an alternative approach based on Hida–Malliavin calculus and white noise theory. This enables us to handle the general case with jumps, allowing both the diffusion coefficient and the jump coefficient to depend on the control, and we do not need the extra BSDE with second-order derivatives. The result is illustrated by an example of a constrained linear-quadratic optimal control.
A quantum probabilistic approach to Hecke algebras for 𝔭-adic PGL2
Authors: Hasegawa Takehiro , Saigo Hayato , Saito Seiken , Sugiyama Shingo
Published: August 2018

The subject of the present paper is an application of quantum probability to [Formula: see text]-adic objects. We give a quantum-probabilistic interpretation of the spherical Hecke algebra for [Formula: see text], where [Formula: see text] is a [Formula: see text]-adic field. As a byproduct, we obtain a new proof of the Fourier inversion formula for [Formula: see text].
Lévy–Khintchine decompositions for generating functionals on algebras associated to universal compact quantum groups
Authors: Das Biswarup , Franz Uwe , Kula Anna , Skalski Adam
Published: August 2018

We study the first and second cohomology groups of the [Formula: see text]-algebras of the universal unitary and orthogonal quantum groups [Formula: see text] and [Formula: see text]. This provides valuable information for constructing and classifying Lévy processes on these quantum groups, as pointed out by Schürmann. In the case when all eigenvalues of [Formula: see text] are distinct, we show that these [Formula: see text]-algebras have the properties (GC), (NC) and (LK) introduced by Schürmann and studied recently by Franz, Gerhold and Thom. In the degenerate case [Formula: see text], we show that they do not have any of these properties. We also compute the second cohomology group of [Formula: see text] with trivial coefficients — [Formula: see text] — and construct an explicit basis for the corresponding second cohomology group for [Formula: see text] (whose dimension was known earlier, thanks to the work of Collins, Härtel and Thom).
Approximation of a free Poisson process by systems of freely independent particles
Authors: Bożejko Marek , Luís da Silva José , Kuna Tobias , Lytvynov Eugene
Published: August 2018

Let [Formula: see text] be a non-atomic, infinite Radon measure on [Formula: see text], for example, [Formula: see text] where [Formula: see text]. We consider a system of freely independent particles [Formula: see text] in a bounded set [Formula: see text], where each particle [Formula: see text] has distribution [Formula: see text] on [Formula: see text] and the number of particles, [Formula: see text], is random and has Poisson distribution with parameter [Formula: see text]. If the particles were classically independent rather than freely independent, this particle system would be the restriction to [Formula: see text] of the Poisson point process on [Formula: see text] with intensity measure [Formula: see text]. In the case of free independence, this particle system is not the restriction of the free Poisson process on [Formula: see text] with intensity measure [Formula: see text]. Nevertheless, we prove that this is true in an approximative sense: if bounded sets [Formula: see text] ([Formula: see text]) are such that [Formula: see text] and [Formula: see text], then the corresponding particle system in [Formula: see text] converges (as [Formula: see text]) to the free Poisson process on [Formula: see text] with intensity measure [Formula: see text]. We also prove the following [Formula: see text]-limit: Let [Formula: see text] be a deterministic sequence of natural numbers such that [Formula: see text]. Then the system of [Formula: see text] freely independent particles in [Formula: see text] converges (as [Formula: see text]) to the free Poisson process. We finally extend these results to the case of a free Lévy white noise (in particular, a free Lévy process) without free Gaussian part.
Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension
Authors: Diaz-Otero Janice M. , Yen Ting-Chieh , Fisher Courtney , Bota Daniel , Jackson William F. , Dorrance Anne M.
Published: August 2018

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16−18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg−1·min−1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg−1·day−1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5–14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10−9–10−5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10−5 mol/l) and indomethacin (10−4 mol/l). We used GSK2193874 (10−7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension.

NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.
Attenuated forearm vascular conductance responses to rhythmic handgrip in young African-American compared with Caucasian-American men
Authors: Barbosa Thales C. , Kaur Jasdeep , Stephens Brandi Y. , Akins John D. , Keller David M. , Brothers R. Matthew , Fadel Paul J.
Published: August 2018

Previous studies have demonstrated that African-American (AA) individuals have heightened vasoconstrictor and reduced vasodilator responses under resting conditions compared with Caucasian-American (CA) individuals. However, potential differences in vascular responses to exercise remain unclear. Therefore, we tested the hypothesis that, compared with CA subjects, AA subjects would present an attenuated increase in forearm vascular conductance (FVC) during rhythmic handgrip exercise. Forearm blood flow (FBF; duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured in healthy young CA ( n = 10) and AA ( n = 10) men during six trials of rhythmic handgrip performed at workloads of 4, 8, 12, 16, 20, and 24 kg. FVC (calculated as FBF/MAP), FBF, and MAP were similar between groups at rest (FVC: 63 ± 7 ml·min−1·100 mmHg−1 in CA subjects vs. 62 ± 7 ml·min−1·100 mmHg−1 in AA subjects, P = 0.862). There was an intensity-dependent increase in FVC during exercise in both groups; however, AA subjects presented lower FVC (interaction P < 0.001) at 8-, 12-, 16-, 20-, and 24-kg workloads (e.g., 24 kg: 324 ± 20 ml·min−1·100 mmHg−1 in CA subjects vs. 241 ± 21 ml·min−1·100 mmHg−1 in AA subjects, P < 0.001). FBF responses to exercise were also lower in AA subjects (interaction P < 0.001), whereas MAP responses did not differ between groups (e.g., ∆MAP at 24 kg: +19 ± 2 mmHg in CA subjects vs. +19 ± 2 mmHg in AA subjects, interaction P = 0.950). These findings indicate lower hyperemic responses to rhythmic handgrip exercise in AA men compared with CA men.

NEW & NOTEWORTHY It is known that African-American individuals have heightened vasoconstriction and reduced vasodilation under resting conditions compared with Caucasian-American individuals. Here, we identified that the hyperemic response to moderate and high-intensity rhythmic handgrip exercise was lower in healthy young African-American men.
Abstract A067: Salinomycin kills not only circulating epithelial tumor cells (CETCs) but also circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with breast cancer
Authors: Pizon Monika , Schott Dorothea , Pachmann Ulrich , Pachmann Katharina , Szalus Norbert
Published: August 2018

Background: Recently the hypothesis has been proposed that a more aggressive subpopulation of circulating tumor cells, circulating cancer stem cells, are the source of metastatic spread from the primary tumor. These cells are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. The antibiotic salinomycin isolated from Streptomyces albus is the best established cancer stem cell inhibitor and has been shown to reduce the expression of markers for stemness and spheroid-forming ability. The mechanisms of the anticancer effects remain unclear. In this study, we evaluated the cytotoxic effect of salinomycin on CETCs and tumorspheres cultured from cCSC. Methods: 20 patients with breast cancer in different stages of disease were included. The determination of CETCs and cCSC was performed using Maintrac® method and tumorsphere forming assay, respectively. To evaluate the cytotoxic effect of salinomycin on CETCs and spheroids, they were exposed to different concentrations of salinomycin in short time culture for different periods of time. Results: 79% of patients had detectable CETCs and sphere formation was observed in 74% of breast cancer patients. Interestingly, growth of spheroids was detected also in patients without CETCs. The number of tumorspheres increased significantly with tumor progression, especially with presence of metastasis. Treatment with salinomycin showed an 80% reduction in spheroid formation compared with control. Salinomycin reduced the viability of spheroids in a dose-dependent manner. Salinomycin had a stronger cytotoxic effect on CETCs in nonmetastatic as compared to metastatic patients (median of dead CETCs 85% vs. 34%, p<0.001). Similarly, patients without chemotherapy responded better to salinomycin treatment than patients after several lines of chemotherapy (median of dead CETCs 87%vs.35%, p<0.001). Conclusion: Using a method for cultivation of tumorspheres from peripheral blood of cancer patients and an effective in vitro platform for screening anticancer stem cells drugs was developed. Thus it could be shown that salinomycin targets not only more differentiated circulating cancer cells but also cancer stem cells from peripheral blood. It may evolve as a novel and promising therapeutic strategy for future cancer treatment.

Citation Format: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann, Norbert Szalus. Salinomycin kills not only circulating epithelial tumor cells (CETCs) but also circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A067.
Abstract A131: Comparison of next-generation sequencing results between brain metastasis and blood in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation
Authors: Lee Hee Yeon , Kim Jeong-Oh , Kang Jin-Hyoung
Published: August 2018

Background: Mechanisms of acquired resistance for EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) has been studied broadly, and T790M mutation, bypass signaling, and phenotype change have been suggested. Questions remain in terms of the selection of sub-clones according to the sites during EGFR TKI therapy, especially in brain due to blood-brain barrier. Three metastatic NSCLC patients harboring sensitive EGFR mutation were treated with EGFT TKI with good response but became refractory and symptomatic brain oligo-metastasis occurred. Metastectomy was done and next-generation sequencing (NGS) was done with the brain tissue and blood. Methods: Fresh brain metastasis tissue was obtained during surgery and frozen in liquid nitrogen. Blood sampling was done within a week of the surgery and plasma was used for NGS. Amplicon sequencing (Thunderbolt) was performed. Library preparation and quality control sequencing amplicon libraries were prepared using ThunderBolts Cancer Panel, according to the manufacturer's instructions. The ThunderBolts Cancer Panel uses 230 amplicons to interrogate mutations and hotspots in 50 oncogenes, tumor suppressors, and drug resistance markers. Results: All 3 brain tissues had the same sensitive EGFR mutation (exon 19 deletion) as initial presentation, with PDGFRA, APC and TP53 mutations, while in the plasma, PDGFRA and APC mutations were identified in the 3 patients. From case 1, PDGFRA, APC, MLH1, and EGFR mutations were identified in the plasma, and additional PIK3CA, KDR, TP53, ERBB2, and GNA11 mutations were found in the brain. From case 2, PDGFRA, APC, EGFR, MET, PTEN, HRAS, and TP53 mutations were found in the plasma, and in the brain, PIK3CA, KDR, and ERBB2 mutations were identified in addition. From case 3, PDGFRA, APC, HRAS, and TP53 mutations in the plasma, and additional EGFR mutation in the brain. Conclusions: Our data identified several additional mutations in brain metastasis compared to the plasma from patients with acquired EGFR TKI resistance, other than T790M mutation. Every mutation in the blood sample was identified in the brain tissue, while additional mutations were found in the brain tissue.

Citation Format: Hee Yeon Lee, Jeong-Oh Kim, Jin-Hyoung Kang. Comparison of next-generation sequencing results between brain metastasis and blood in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A131.
Abstract A143: Repurposing disulfiram as a potential novel treatment of drug-resistant metastatic colorectal cancer
Authors: Stenvang Jan , Keinicke Helle , Nielsen Signe L. , Jandu Haatisha , Bartek Jiri , Brünner Nils
Published: August 2018

Introduction: Drug repurposing has emerged as an attractive alternative to the classical pipeline of drug development for novel anticancer drugs. We have selected disulfiram, which was FDA approved for treatment of alcoholism already in 1951. Disulfiram has been examined in various in vitro cancer model systems and has demonstrated several different mechanistic types of anticancer effects. The consensus is that coadministration of divalent metal ions, especially copper, is required for the maximal anticancer effect of disulfiram. Disulfiram has also been investigated in a few clinical trials but with a difference in efficacy. However, there are no data on the clinical effects of disulfiram in patients with colorectal cancer, and no studies on disulfiram in colorectal cancer can be found at www.clinicaltrials.org. Methods: We have established a research platform consisting of isogenic pairs of parental (sensitive) and drug-resistant human colorectal cancer cell lines (HT-29, HCT-116, LoVo) with resistance to either oxaliplatin or SN-38 (the active metabolite of irinotecan) (Jensen et al., Mol Oncol 2015 9(6):1169-85). We have tested disulfiram ± copper in this panel. MTT assay was used to estimate cell number. Results: In all 9 cell lines it was observed that addition of copper to disulfiram resulted in increased cell cell viability inhibition. Even more importantly, when combining disulfiram and copper with oxaliplatin or SN38, an additive or synergistic viability inhibitory effect was observed with oxaliplatin in SN-38 resistant cell lines and with SN-38 in oxaliplatin resistant cell lines. Conclusions: Based on these in vitro results, we are now planning a clinical phase 2 study using Simon’s two-stage min/max design enrolling metastatic colorectal cancer patients having failed first-line treatment with either oxaliplatin- or irinotecan-containing treatment. The patients will as second-line treatment receive irinotecan- or oxaliplatin-containing treatment (depending on their first-line treatment) plus disulfiram and copper. Endpoint will be objective response rate according to RECIST version 1.1.

Citation Format: Jan Stenvang, Helle Keinicke, Signe L. Nielsen, Haatisha Jandu, Jiri Bartek, Nils Brünner. Repurposing disulfiram as a potential novel treatment of drug-resistant metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A143.
Abstract A203: Generation of human TIM3 knock-in mice for preclinical efficacy assessment of therapeutic antibodies
Authors: Zheng Lei , Huang Xuesong , Ouyang Wenyi , Chen Gang , An Annie Xiaoyu , Dong Xin , Liu Jay , Wery Jean Pierre , Shi Qian , Ouyang Davy Xuesong
Published: August 2018

Immune checkpoint inhibitors, i.e., PD1 and CTLA4 antibody therapeutics, have led to long-term survival in many late-stage solid tumor patients. Despite this revolutionary clinical impact, the overall response rate is still low. One major roadblock is that compensatory immune inhibitory pathways were turned on to protect tumor cells from being attacked by T cells. T cell immunoglobulin- and mucin domain-containing molecule 3 (Tim-3) is a type I transmembrane protein expressed in T cells, monocytes, macrophages, and dendritic cells. PD-1 and Tim-3 coexpression is often associated with an exhausted phenotype of tumor-infiltrating lymphocyte (TIL) in various tumor types. TIM-3 expression has been reported as a compensatory mechanism in the PD1 nonresponsive patients. Simultaneously targeting PD1 and TIM3 is now being actively tested in clinical trials. However, we still do not have an animal model that can efficiently evaluate the efficacy of therapeutic TIM3 antibodies or combinations. Here we report generation of a human TIM3 knock-in C57BL/6 mouse model, in which we replaced mouse exon 2-5 of HAVCR2 gene with human counterparts. The engineered knock-in mice express a chimeric TIM3 where its extracellular and transmembrane domains are human sequence, while the signal peptide and intracellular domain are kept intact. We confirmed that homozygous knock-in mice only express this chimeric TIM3, recognizable by human TIM3 antibody in NK cells, macrophages, and stimulated T cells. In an efficacy study, we inoculated the TIM3 knock-in mice with MC38 syngeneic tumor cells. Treating the mice with 5 mg/kg of human TIM3 antibody resulted in modest tumor growth inhibition (TGI), while in combination with anti-mouse PD1 antibody, the TGI improved to 62% following 2 weeks of treatment. We are now breeding the human PD1 and human TIM3 double knock-in mice to test the combinatory therapeutic antibodies. We have also developed human PD-L1 expressing MC38 cells, so that when inoculated in human TIM3 knock-in mice, PD-L1 and TIM3 therapeutic combination can be evaluated.

Citation Format: Lei Zheng, Xuesong Huang, Wenyi Ouyang, Gang Chen, Annie Xiaoyu An, Xin Dong, Jay Liu, Jean Pierre Wery, Qian Shi, Davy Xuesong Ouyang. Generation of human TIM3 knock-in mice for preclinical efficacy assessment of therapeutic antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A203.
Abstract B005: FPT155, a novel therapeutic CD80-Fc fusion protein with potent antitumor activity in preclinical models
Authors: Barbee Susannah D. , Sennino Barbara , De La Torre Jacqueline , Macal Monica , Walker Quinn , Jabon Marc R. , Chen Amanda , Busha David A. , Best Margaret , Pierce Kristen L. , Borges Luis , Baker Kevin P. , Brennan Thomas
Published: August 2018

Optimal activation of T cells requires both antigen-specific signaling and induction of costimulatory pathways. Costimulatory pathways are upregulated by foreign antigenic challenge but are not active in the normal immune state, thus maintaining peripheral tolerance to self-antigens. The absence of costimulatory signaling may likewise play a role in tolerance to cancer cells. Five Prime has developed a CD80 (B7.1) extracellular domain (ECD)-Fc fusion protein (FPT155) as a costimulatory molecule that can stimulate T-cell activation and break tumor immune tolerance. In vitro studies show that FPT155 induces T-cell activation and cytokine production via CD28. FPT155 activity requires T-cell receptor engagement, which indicates that FPT155 is not a CD28 “superagonist” that can drive T-cell activation independently of antigenic stimulation. To investigate the impact of CD80-Fc in preclinical models, we generated murine FPT155 (mFPT155), a surrogate fusion protein, composed of the mouse CD80 ECD fused with the murine Fc region of IgG2a. mFPT155 is well tolerated in mice and has potent efficacy in syngeneic tumor models, including the induction of complete tumor regression in the CT26 model. mFPT155 promotes the infiltration of T cells into the tumor core and increases the effector T:Treg ratio, thus inducing a favorable microenvironment for an effective antitumor immune response. Furthermore, combination of mFPT155 and anti-PD1 therapy leads to stronger antitumor efficacy compared to either therapy alone. Together these results indicate that mFPT155 is a potent T-cell costimulator with strong antitumor activity in mouse tumor models. We are currently performing IND-enabling studies and plan to initiate a clinical study with FPT155 in 2018.

Citation Format: Susannah D. Barbee, Barbara Sennino, Jacqueline De La Torre, Monica Macal, Quinn Walker, Marc R. Jabon, Amanda Chen, David A. Busha, Margaret Best, Kristen L. Pierce, Luis Borges, Kevin P. Baker, Thomas Brennan. FPT155, a novel therapeutic CD80-Fc fusion protein with potent antitumor activity in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B005.
Abstract B148: Activity of the TAM kinase-targeting compound, SLC-391, is mediated by the engagement of the immune system in CT-26 syngeneic mouse model
Authors: Lai Shenshen , Li Rick , Raha Paromita , Hu Yuxiang , Yan Jun , Zhang Hong , Marotta Anthony , Zhang Zaihui
Published: August 2018

Overexpression of TAM family receptor tyrosine kinases such as Axl has been reported in numerous types of human cancer, and found to correlate with tumor progression and prognosis, metastasis, and drug resistance. Aside from the role in cell growth and survival, TAM kinases have long been recognized for their immunosuppressive activity as well. Hence, downregulation of their activity is expected to unleash antitumor immunity in the tumor microenvironment. As one of the several TAM-targeting small-molecule inhibitors identified, SLC-391 displays a relatively strong activity against Axl, as evidenced by the reductions of phosphotransferase activity in radiometric biochemical assay and the level of Axl Y779 phosphorylation in the cell-based assay. Contradictorily, proliferation of CT-26 murine colon carcinoma cells seemed to be unaffected by the compound in the thymidine incorporation assay with an IC50 of ~10 μM. Interestingly, SLC-391 inhibited CT-26 tumor growth by 37% in a 15-day efficacy study in which the compound was administered at 50 mg/kg p.o.. In comparison, a PD-1 antibody delayed tumor growth by 27%. Tumor-infiltrating lymphocyte phenotyping revealed increases in the number of NK cells and the ratio of M1/M2-polarized macrophages in SLC-391 treatment group, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of proinflammatory innate immune response and adaptive immune response. In addition, a synergistic antitumor effect was observed when the anti-PD-1 insensitive CT-26 syngeneic model was treated with a combination of SLC-391 and an anti-PD-1 antibody and the overall survival rate of the combination group was prolonged dramatically in comparison with the vehicle control group. To summarize, the antitumor activity of SLC-391 is at least in part mediated by reversing the immunosuppressive tumor microenvironment in CT-26 colon carcinoma model.

Citation Format: Shenshen Lai, Rick Li, Paromita Raha, Yuxiang Hu, Jun Yan, Hong Zhang, Anthony Marotta, Zaihui Zhang. Activity of the TAM kinase-targeting compound, SLC-391, is mediated by the engagement of the immune system in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B148.
Abstract LB-A03: Allele specific HLA loss and immune escape in lung cancer evolution
Authors: McGranahan Nicholas , Rosenthal Rachel , Hiley Crispin T. , Rowan Andrew J. , Watkins Thomas B.K. , Wilson Gareth A. , Birkbak Nicolai J. , Veeriah Selvaraju , Loo Peter Van , Herrero Javier , Swanton Charles
Published: August 2018

Cancer cells adopt a variety of mechanisms to evade the immune system and avoid T-cell recognition. Disruption of human leukocyte antigen (HLA), which may lead to reduced neoantigen presentation, has been proposed as an immune escape strategy in many cancers, including lung cancer. Mutations in HLA class I genes are infrequent in early stage non-small cell lung cancers (NSCLC), suggesting alternative mechanisms of HLA disruption may be common. To date, the polymorphic nature of the locus has precluded copy number analysis and exploration of HLA loss. To investigate the prevalence and importance of HLA disruption, we present LOHHLA (Loss Of Heterozygosity in Human Leukocyte Antigen), a computational tool to determine HLA allele-specific copy number from sequencing data. Building upon previous work imputing HLA haplotypes from sequencing data (Shukla, 2015; Szolek, 2014) and utilizing previously published datasets (Jamal-Hanjani, 2017; Brastianos, 2015), we endeavored to address the prevalence and timing of HLA LOH in lung cancer and its impact on tumor evolution and neoantigen presentation. Using LOHHLA, we find HLA LOH occurs in 40% of NSCLCs and is associated with a high subclonal neoantigen burden, APOBEC mediated-mutagenesis, upregulation of cytolytic activity and PD-L1 positivity. The focal nature of these alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggest that HLA LOH is an immune escape mechanism, selected later in NSCLC tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for immunotherapeutic approaches targeting neoantigens.

Citation Format: Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton. Allele specific HLA loss and immune escape in lung cancer evolution [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A03.
Abstract LB-B30: First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors
Authors: Sullivan Ryan J. , Mehnert Janice , Tawbi Hussain , Lawrence Donald , Flaherty Keith , Chen Helen , Takabe Naoko , Davies Michael
Published: August 2018

Combined BRAF and MEK inhibitor therapy is associated with responses in patients (pts) with BRAF mutant solid tumors. Preclinically, the addition of the BH3 mimetic navitoclax improves the efficacy of BRAF inhibitor therapy to BRAF mutant cell lines. CTEP study P9466 (NCT01989585) is a clinical trial designed to test the safety of the combination of dabrafenib, trametinib, and navitoclax (DTN) in patients with BRAF mutant solid tumors.

The primary objective of this dose escalation trial was to determine the recommended phase 2 dose (RP2D) of DTN. From March 2014 to August 2017, 25 pts were enrolled, using a 3+3 design, at three dose levels (DL). A one week lead-in of navitoclax 150 mg QD was used to limit thrombocytopenia.

Dose limiting toxicities (DLTs) occurred at every dose level and included Grade 3 (Gr) alkaline phosphatase, Gr 3 Rash, Gr 4 thrombocytopenia, and Gr 3 fever. The RP2D was determined to be D 150 mg BID, T 2 mg QD, N 225 mg QD. Severe adverse events (SAEs) occurred in 10 pts. There was one Gr 5 SAE that was possibly related to study drugs (acute kidney injury). Twenty-two of 25 pts were eligible for preliminary efficacy assessment at the time of this submission. Best response, per RECIST1.1, was complete (CR) or partial (PR) response in 6 pts, stable disease (SD) in 7 pts, and disease progression (PD) in 8 pts. Of note, PD was the best response for all 5 pts with melanoma (mel) previously treated with a BRAF inhibitor. In the 6 mel pts who had not received a prior BRAF inhibitor, 5 had a PR or CR (1). Disease control (PR or SD) was seen in most colon cancer (3 of 5) and thyroid cancer (4 of 5) pts.

DTN at the RP2D was determined to be safe with preliminary efficacy in pts with BRAF mutant solid tumors. Based on this preliminary data, the randomized phase II portion of this trial of DTN compared to DT in BRAF mutant naïve patients is opening in the ETCTN in the Fall of 2017.

Citation Format: Ryan J. Sullivan, Janice Mehnert, Hussain Tawbi, Donald Lawrence, Keith Flaherty, Helen Chen, Naoko Takabe, Michael Davies. First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B30.
Abstract 1155: The SRGTM rat: A novel SCID rat for humanization studies
Authors: Noto Fallon K. , Towobola Bisoye , Arey Angela , Narla Goutham , Chengelis Christopher , Yeshi Tseten
Published: August 2018

In vivo modeling of human cancer in genetically engineered rodents can provide insights into tumor kinetics, genetics and molecular biology, and allow for the testing of drug efficacy. Over the recent years, studies have demonstrated that immunodeficient mice, such as the NSG, reconstituted with functional human immune cells, such as peripheral blood mononuclear cells (PBMCs), are promising models for immuno-oncology efficacy studies. Immune humanized mice engrafted with human cancer cells show human-specific immune responses when treated with drugs that target immune pathways, such as CTLA-4 and PD-1, leading to the inhibition of tumor growth. These models provide a critical platform to study how the immune system can be engaged to drive anti-cancer efficacy.

Although the NSG and similar immunodeficient mouse strains have been beneficial for human immuno-oncology studies, there are many caveats to performing these studies in mice, including inconsistent tumor kinetics, small tumor size for downstream analyses, limited blood for PK/PD studies due to the small size of the mouse, and graft vs. host disease (GvHD) onset around 4-6 weeks post-engraftment. Humanized rat models would allow for the development of larger tumors and the ability to perform serial blood sampling on a routine basis throughout the course of treatment. We have created a Rag2 null, Il2rg null rat on the Sprague Dawley background (SRGTM) that lacks B, T, and NK cells and supports the growth of multiple human cancer cell lines, including lines that do not engraft or grow well in existing mouse models: HCT-116, H358, and VCaP. The SRGTM rat is also permissive to immune humanization with PBMCs. PBMC-engrafted SRGTM rats have a significant amount of human CD45+ lymphocytes in peripheral blood, of which the majority are T cells, comparable to immune-humanized NSG and NOG mice. Some animals also show significant levels of circulating human B cells. Interestingly, the incidence of GvHD is delayed to 12-14 weeks post-engraftment in the immune humanized SRG™ rat.

We are currently assessing functionality of the PBMC-immune humanized SRG™ rat in immuno-oncology studies as well as characterizing the ability of the SRG™ rat to support the growth of human patient derived xenografts (PDX). The generation of this novel humanized SRG™ rat model could allow for a more permissive host system to test existing and novel immunomodulatory strategies for the treatment of human disease.

Citation Format: Fallon K. Noto, Bisoye Towobola, Angela Arey, Goutham Narla, Christopher Chengelis, Tseten Yeshi. The SRGTM rat: A novel SCID rat for humanization studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1155.