bluuebunny/crossref_metadata_2025 huggingface dataset:
Myeloid-specific deletion of thrombospondin 1 protects against inflammation and insulin resistance in long-term diet-induced obese male mice
Authors: Memetimin Hasiyet , Li Dong , Tan Kaiyuan , Zhou Changcheng , Liang Ying , Wu Yadi , Wang Shuxia
Published: October 2018

Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Recent studies demonstrate that TSP1 is highly expressed in adipose tissue (AT) and positively associated with AT inflammation and insulin resistance (IR). In this study, the contribution of different cellular sources of TSP1 to obesity-induced metabolic complications is determined by using mice with either adipocyte or myeloid/macrophage-specific deletion of TSP1 in a diet-induced obese model. The results demonstrated that neither adipocyte nor myeloid/macrophage-specific deletion of TSP1 affected the development of long-term high-fat diet-induced obesity. Adipocyte-specific deletion of TSP1 did not protect mice from obesity-induced inflammation and IR. On the contrary, obese mice with myeloid/macrophage loss of TSP1 had reduced macrophage accumulation in AT, which was accompanied with reduced inflammation and improved glucose tolerance and insulin sensitivity compared with obese control mice. Reduced macrophage-derived-TGF-β1 signaling and adipose tissue fibrosis were also observed in long-term high-fat-fed mice with myeloid/macrophage-specific TSP1 deletion. Moreover, in vitro experiments demonstrated an autocrine effect of TSP1-mediated TGF-β activation in macrophages in obesity. Collectively this study highlights the critical contribution of myeloid/macrophage-derived TSP1 to obesity-associated chronic inflammation and IR, which may serve as a new therapeutic target for metabolic disease.
Rank-Two NMF Clustering for Glioblastoma Characterization
Authors: Bougacha Aymen , Njeh Ines , Boughariou Jihene , Kammoun Omar , Ben Mahfoudh Kheireddine , Dammak Mariem , Mhiri Chokri , Ben Hamida Ahmed
Published: October 2018

This study investigates a novel classification method for 3D multimodal MRI glioblastomas tumor characterization. We formulate our segmentation problem as a linear mixture model (LMM). Thus, we provide a nonnegative matrix M from every MRI slice in every segmentation process’ step. This matrix will be used as an input for the first segmentation process to extract the edema region from T2 and FLAIR modalities. After that, in the rest of segmentation processes, we extract the edema region from T1c modality, generate the matrix M, and segment the necrosis, the enhanced tumor, and the nonenhanced tumor regions. In the segmentation process, we apply a rank-two NMF clustering. We have executed our tumor characterization method on BraTS 2015 challenge dataset. Quantitative and qualitative evaluations over the publicly training and testing dataset from the MICCAI 2015 multimodal brain segmentation challenge (BraTS 2015) attested that the proposed algorithm could yield a competitive performance for brain glioblastomas characterization (necrosis, tumor core, and edema) among several competing methods.
Optimal Linear Estimators for Time-Delay Systems with Fading Measurements and Correlated Noises
Authors: Li Yazhou , Li Jiayi , Wang Xin
Published: October 2018

The optimal linear estimation problems are investigated in this paper for a class of discrete linear systems with fading measurements and correlated noises. Firstly, the fading measurements occur in a random way where the fading probabilities are regulated by probability mass functions in a given interval. Furthermore, time-delay exists in the system state and observation simultaneously. Additionally, the multiplicative noises are considered to describe the uncertainty of the state. Based on the projection theory, the linear minimum variance optimal linear estimators, including filter, predictor, and smoother are presented in the paper. Compared with conventional state augmentation, the new algorithm is finite-dimensionally computable and does not increase computational and storage load when the delay is large. A numerical example is provided to illustrate the effectiveness of the proposed algorithms.
No Modulatory Effects when Stimulating the Right Inferior Frontal Gyrus with Continuous 6 Hz tACS and tRNS on Response Inhibition: A Behavioral Study
Authors: Brauer Hannah , Kadish Navah Ester , Pedersen Anya , Siniatchkin Michael , Moliadze Vera
Published: October 2018

Response inhibition is the cognitive process required to cancel an intended action. During that process, a “go” reaction is intercepted particularly by the right inferior frontal gyrus (rIFG) and presupplementary motor area (pre-SMA). After the commission of inhibition errors, theta activity (4–8 Hz) is related to the adaption processes. In this study, we intend to examine whether the boosting of theta activity by electrical stimulation over rIFG reduces the number of errors and the reaction times in a response inhibition task (Go/NoGo paradigm) during and after stimulation. 23 healthy right-handed adults participated in the study. In three separate sessions, theta tACS at 6 Hz, transcranial random noise (tRNS) as a second stimulation condition, and sham stimulation were applied for 20 minutes. Based on behavioral data, this study could not show any effects of 6 Hz tACS as well as full spectrum tRNS on response inhibition in any of the conditions. Since many findings support the relevance of the rIFG for response inhibition, this could mean that 6 Hz activity is not important for response inhibition in that structure. Reasons for our null findings could also lie in the stimulation parameters, such as the electrode montage or the stimulation frequency, which are discussed in this article in more detail. Sharing negative findings will have (1) positive impact on future research questions and study design and will improve (2) knowledge acquisition of noninvasive transcranial brain stimulation techniques.
Design and Optimum of Dust Collector with Corrugated Plate for Underground Mine
Authors: Li Ming , Wu Chao , Zhou Zhi-yong , Lian Wei-chun , Chen Zhi-xiong
Published: October 2018

A set of dust collectors was designed with corrugated plate for an underground metal mine, which has low ventilation resistance, simple maintenance, and strong environmental adaptability. A three‐dimensional simulation model was built based on ANSYS‐Fluent software, and it was used to analyze the influence law of key parameters on the comprehensive dust removal efficiency; the angle of corrugated plate to the horizontal plane, the surface characteristics of plate, pressure loss and dust removal efficiency were discussed. The optimal design scheme of the dust collector was determined according to the simulation results. The dust collection was carried out in the Fankou lead‐zinc underground metal mine in China, and the total dust removal efficiency was more than 95%, and for respiratory dust, it was more than 85%. This dust collector can be widely used in similar underground metal mines.
Decrease in Intracellular Perforin Levels and IFN-γ Production in Human CD8+ T Cell Line following Long-Term Exposure to Asbestos Fibers
Authors: Kumagai-Takei Naoko , Nishimura Yasumitsu , Matsuzaki Hidenori , Lee Suni , Yoshitome Kei , Otsuki Takemi
Published: October 2018

Although the tumorigenicity of asbestos, which is thought to cause mesothelioma, has been clarified, its effect on antitumor immunity requires further investigation. We previously reported a decrease in the percentage of perforin+ cells of stimulated CD8+ lymphocytes derived from patients with malignant mesothelioma. Therefore, we examined the effects of long-term exposure to asbestos on CD8+ T cell functions by comparing long-term cultures of the human CD8+ T cell line EBT-8 with and without exposure to chrysotile (CH) asbestos as an in vitro model. Exposure to CH asbestos at 5 μg/ml or 30 μg/ml did not result in a decrease in intracellular granzyme B in EBT-8 cells. In contrast, the percentage of perforin+ cells decreased at both doses of CH exposure. CH exposure at 30 μg/ml did not suppress degranulation following stimulation with antibodies to CD3. Secreted production of IFN-γ stimulated via CD3 decreased by CH exposure at 30 μg/ml, although the percentage of IFN-γ+ cells induced by PMA/ionomycin did not decrease. These results indicate that long-term exposure to asbestos can potentially suppress perforin levels and the production of IFN-γ in human CD8+ T cells.
Empirical Approximation for the Stochastic Fundamental Diagram of Traffic Flow on Signalized Intersection
Authors: Zhang Nan , Yang Xiaoguang , Ma Wangjing
Published: October 2018

The wide scattering nature of the fundamental diagram (FD) with observed flow-density data may be associated with the dynamical traffic flow process, especially on signalized intersection. To describe the uncertainty of FD, in this work we established stochastic fundamental diagram (SFD) which is defined by the distributions of shockwave speed. Our approach is based on a two-level stochastic process of the traffic flow system in terms of the dynamics of traffic density and state mode associated with signal phases which is named switching linear dynamical systems (SLDS). Then, variational Bayesian learning method is adopted to compute the distributions of SFD parameter to approximate the experimental distributions of shockwave calculated by the observed flow-density data. Given traffic flow data from the NGSIM program, the verification result demonstrated that the SFD can be more helpful to capture the main features of the observed widely scattering of the flow-density data compared with FD. With the shockwave speed sampled from the SFD, the SLDS could describe the dynamic characteristics of traffic flow and be applied to the maximum likelihood estimation of traffic density or flow rate. Because it is simple and automatically calculated, the SFD provides an alternative description for fundamental diagram and its uncertainty in the traffic flow.
Role of Phytoremediation in Reducing Cadmium Toxicity in Soil and Water
Authors: Mahajan Pooja , Kaushal Jyotsna
Published: October 2018

Heavy metals are a noxious form of pollutants present in soil and water. A new plant-based solar energy driven technology, phytoremediation, emerges as eco-friendly and cost-effective approach to remove heavy metal from various media with the help of hyperaccumulating plant species. This review paper aims to provide information on phytoremediation and its mechanisms for heavy metal removal especially to focus on Cadmium (Cd) metal and highlights the role of various hyperaccumulating plants for Cd metal remediation in soil and water. It complies various field case studies which play the important role in understanding the Cd removal through various plants. Additionally, it pinpoints several sources and the effects of Cd and other technologies used for Cd remediation. This paper provides the recent development in mechanisms of Cd hyperaccumulation by different plants, in order to motivate further research in this field.
A Derivative-Free Trust Region Algorithm with Nonmonotone Filter Technique for Bound Constrained Optimization
Authors: Gao Jing , Cao Jian , Yang Yueting
Published: October 2018

We propose a derivative-free trust region algorithm with a nonmonotone filter technique for bound constrained optimization. The derivative-free strategy is applied for special minimization functions in which derivatives are not all available. A nonmonotone filter technique ensures not only the trust region feature but also the global convergence under reasonable assumptions. Numerical experiments demonstrate that the new algorithm is effective for bound constrained optimization. Locally, optimal parameters with respect to overall computational time on a set of test problems are identified. The performance of the best choice of parameter values obtained by the algorithm we presented which differs from traditionally used values indicates that the algorithm proposed in this paper has a certain advantage for the nondifferentiable optimization problems.
Intrabullous Adhesion Pexia (IBAP) by Percutaneous Pulmonary Bulla Centesis: An Alternative for the Surgical Treatment of Giant Pulmonary Bulla (GPB)
Authors: Li Wei-Liang , Li Yong-Hua , Yang Yu-Bo , Lv Li-Hui
Published: October 2018

Background and Objective. Most patients with giant pulmonary bulla (GPB) are treated by surgery; however, there is a subset for whom surgery is not a viable option, such as those with contraindications, or those unwilling to undergo operation. Therefore, an alternative minimally invasive method is desired for this subpopulation. The aim of this study was to explore an alternative procedure for treating GPB. Methods. This was a prospective, nonrandomized, single-arm, unblinded study evaluating the efficacy and safety of intrabulla adhesion pexia (IBAP) procedure in GPB patients. The study was conducted between December 2004 and April 2017. Results. There were 38 cases in 36 patients (33 males and 3 females) with the target GPB cavities varying in size (range, 10 cm × 7 cm × 5 cm to 15 cm × 8 cm × 30 cm (anteroposterior diameter × medial-lateral diameter × superoinferior diameter)). After IBAP treatment, the closure ratio of GPB in one month was 86.84% (33/38), while the dyspnea index significantly decreased from 4.11 ± 1.11 to 2.24 ± 1.15 (P<0.01). In addition, the mean FEV1 (L) increased from 1.06 ± 0.73 to 1.57 ± 1.13 (P<0.01), while RV (L) decreased from 2.77 ± 0.54 to 2.36 ± 0.38 (P<0.01) and TLC (L) decreased from 6.46 ± 1.21 to 5.86 ± 1.08 (P<0.01). Moreover, PaO2 (mmHg) increased from 52.18 ± 8.31 to 68.29 ± 12.34, while the 6 MWD increased by 129.36% from 131.58 ± 105.24 to 301.79 ± 197.90 (P<0.01). Collectively, these data indicated significant improvement in pulmonary function and exercise tolerance after IBAP treatment. Furthermore, no deaths occurred during IBAP treatment, and no cases of aggravated GPB relapse were reported during the 12-month follow-up period. Conclusions. IBAP is a promising strategy for the treatment of GPB. Our findings demonstrated that IBAP had a noteworthy therapeutic effect, desirable safety, and ideal long-term efficacy for GPB.
Synthesis of Zeolites Materials Using Fly Ash and Oil Shale Ash and Their Applications in Removing Heavy Metals from Aqueous Solutions
Authors: Hamadi A. , Nabih K.
Published: October 2018

Fly ash and oil shale ash generated from power plants can be transformed to suitable materials usable for removal of heavy metals. Due to their high silica content, fly ash and oil shale ash have been considered as the main stone of zeolite synthesis. In this work, we synthesized zeolites from class F fly ash (FA) and modified oil shale ash (MOSA) by alkaline fusion followed by refluxing. Our synthesis process focused on the effect of quantity of NaOH on the crystallinity of the reaction products: Na-P1 and Na-P2 type zeolites synthesized, respectively, from FA and MOSA. The effect of NaOH mass (1, 2, 4, and 8 g) was investigated with the following synthesis conditions: 2 h fusion at 650°C, 2 h agitation, and refluxing for 12 hours. The experimental results demonstrated that the crystallinity of Na-p1 and Na-P2 zeolites increased with increasing the mass of NaOH. The resulting products were characterized with X-ray diffraction, FTIR, and scanning electron microscopy. The reaction products ZV4 and ZM4 synthesized, respectively, from FA and MOSA and containing main zeolite phases with a crystallinity of 92.7% of Na-P1 and 83.6% of Na-P2, respectively, were chosen as adsorbents for the adsorption experiments. Series of experiments were carried out to study the removal of lead, zinc, and chromium by ZV4 and ZM4. The results allowed us to know the optimal conditions of adsorption for the three heavy metals. Adsorption data have been interpreted in terms of Langmuir and Freundlich isotherms. The results showed that lead has a higher affinity for ZM4 than ZV4 and zinc has similar adsorption efficiency for both sorbents that was remarkably reduced for chromium. The results of the present work suggest that zeolites synthesized from MOSA may be considered as effective as those synthesized from FA for heavy metals adsorption.
Chemostat Model of Competition between Plasmid-Bearing and Plasmid-Free Organism with the Impulsive State Feedback Control
Authors: Tao Fengmei , Zhao Zhong , Chen Lansun
Published: October 2018

In this paper, we propose a chemostat model of competition between plasmid-bearing and plasmid-free organism with the impulsive state feedback control. The sufficient condition for existence of the positive period-1 solution is obtained by means of successor function and the qualitative properties of the corresponding continuous system. We show that the impulsive control system is more effective than the corresponding continuous system if we choose a suitable threshold value of the state feedback control in the process of manufacturing the desired products through genetically modified techniques. Furthermore, a new method of proving the stability of the order-1 periodic solution is given based on the theory of the limit cycle of the continuous dynamical system. Finally, mathematical results are justified by some numerical simulations.
Increased Corneal Toricity after Long-Term Orthokeratology Lens Wear
Authors: Chen Zhi , Zhou Jiaqi , Xue Feng , Zhou Xingtao , Qu Xiaomei
Published: October 2018

Purpose. To investigate the change in corneal toricity and associated refractive astigmatism after discontinuation of long-term orthokeratology (ortho-k) lens wear. Methods. This study investigated 136 subjects aged between 6 and 14 (9.1 ± 1.5) years old at the commencement of ortho-k treatment, who had been undergoing overnight ortho-k treatment for 24 to 72 (37.4 ± 11.9) months. Corneal refractive power and manifest refraction were measured and compared before ortho-k and 1 month after discontinuation of ortho-k lens wear. Changes in corneal curvature were analyzed. Corneal curvature data from a historical longitudinal study were used as control. Results. Compared to pre-ortho-k values, the corneal curvature became significantly flatter in the flatter meridian (−0.22 ± 0.27 D, P<0.001) and steeper in the steeper meridian (0.06 ± 0.34 D, P=0.032) after cessation of ortho-k lens wear, resulting in a significant increase in corneal toricity (0.28 ± 0.43 D, P<0.001), which is associated with an increase in refractive astigmatism (0.57 ± 0.57 D, r=0.465, P<0.001). The amount of residual corneal flattening in the flatter meridian is significantly affected by the length of ortho-k treatment (t=−2.965, P=0.004) and the baseline age of subject (t=−2.841, P=0.005), but not by the baseline spherical or cylindrical refractive error (both P>0.05). In the historical control group, there is no significant change in the corneal curvature over two years in children wearing spectacle lenses (both meridians, P>0.05). Change of corneal toricity was more significant in the ortho-k group than in the spectacle control group (P=0.001). Conclusions. Long-term ortho-k lens wear increases corneal toricity after discontinuation of the treatment, which is associated with an increase in refractive astigmatism. A more pronounced change in corneal toricity was found in subjects who were younger to start ortho-k and have been in a longer period of treatment. This trial is registered with http://www.chictr.org.cn (ChiCTR-TNRC-11001210).
A Challenging Diagnosis of Ascites: A Case Report of Peritoneal Tuberculosis
Authors: Ruiz Jose , Ganji Maedeh , Canha Catarina , Isache Carmen
Published: October 2018

Approximately 2 billion people, which is about one third of the world’s population, are infected with tuberculosis (TB). Around 10% of infected people will develop active TB at one point in their lifetime. We present a rare case of a 68-year-old male who presented to the emergency department with a 2-week progressive dyspnea. In addition, the patient complained of generalized weakness, subjective fevers, and abdominal pain in the right upper quadrant. Ascites was noted on physical exam, and the patient underwent a diagnostic paracentesis with initial workup that was unrevealing for underlying etiology. Abdominal computed tomography was done, which revealed peritoneal carcinomatosis. He underwent omental biopsy which showed necrotizing granulomatous inflammation with rare acid-fast bacilli. Repeat biopsy was culture positive for mycobacterium tuberculosis complex. The patient was started on rifampin, isoniazid, pyrazinamide, and ethambutol with improvement of his symptoms days after treatment was started. This case demonstrates how the diagnosis of peritoneal tuberculosis can be elusive. Physicians must be aware of this disease and its behavior in high risk patients, also of the current diagnostic limitations.
Contrast-Enhanced Magnetic Resonance Angiography Using a Novel Elastin-Specific Molecular Probe in an Experimental Animal Model
Authors: Reimann Carolin , Brangsch Julia , Kaufmann Jan Ole , Adams Lisa C. , Onthank David C. , Robinson Simon P. , Botnar Rene M. , Collettini Federico , Makowski Marcus R.
Published: October 2018

Objectives. The aim of this study was to test the potential of a new elastin-specific molecular agent for the performance of contrast-enhanced first-pass and 3D magnetic resonance angiography (MRA), compared to a clinically used extravascular contrast agent (gadobutrol) and based on clinical MR sequences. Materials and Methods. Eight C57BL/6J mice (BL6, male, aged 10 weeks) underwent a contrast-enhanced first-pass and 3D MR angiography (MRA) of the aorta and its main branches. All examinations were on a clinical 3 Tesla MR system (Siemens Healthcare, Erlangen, Germany). The clinical dose of 0.1 mmol/kg was administered in both probes. First, a time-resolved MRA (TWIST) was acquired during the first-pass to assess the arrival and washout of the contrast agent bolus. Subsequently, a high-resolution 3D MRA sequence (3D T1 FLASH) was acquired. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated for all sequences. Results. The elastin-specific MR probe and the extravascular imaging agent (gadobutrol) enable high-quality MR angiograms in all animals. During the first-pass, the probes demonstrated a comparable peak enhancement (300.6 ± 32.9 vs. 288.5 ± 33.1, p>0.05). Following the bolus phase, both agents showed a comparable intravascular enhancement (SNR: 106.7 ± 11 vs. 102.3 ± 5.3; CNR 64.5 ± 7.4 vs. 61.1 ± 7.2, p>0.05). Both agents resulted in a high image quality with no statistical difference (p>0.05). Conclusion. The novel elastin-specific molecular probe enables the performance of first-pass and late 3D MR angiography with an intravascular contrast enhancement and image quality comparable to a clinically used extravascular contrast agent.
Only Surgical Treatment to Be Considered for Adhesive Small Bowel Obstruction: A New Paradigm
Authors: Tabchouri Nicolas , Dussart David , Giger-Pabst Urs , Michot Nicolas , Marques Frederic , Khalfallah Meriem , Bucur Petru , Barbier Louise , Kraemer-Bucur Aurore , Nayeri Mihane , Thiery Julien , Bourbao-Tournois Celine , Bourlier Pascal , Salamé Ephrem , Ouaïssi Mehdi
Published: October 2018

Background. Adhesive small bowel obstruction (SBO) represents a heavy burden in healthcare systems worldwide and is associated with significant morbidity and mortality. Although conservative treatment alone can lead to SBO resolution in most cases, its optimal duration is still a matter of debate. The aim of this study was to analyze different SBO evolution patterns in order to further determine when to switch to surgical treatment. Study Design. All patients who were admitted for adhesive SBO between 2011 and 2016 were reviewed. Patients who had immediate surgery (IS), a successful medical treatment (SMT), and a failed medical treatment (FMT) were compared in terms of overall morbidity, mortality, and SBO recurrence. Results. Overall 154 patients were identified, including 23 (14.9%) in IS, 27 (17.5%) in FMT, and 104 (67.6%) in SMT groups. In terms of comorbidities, patients were similar in all groups. Overall morbidity rates were highest in IS and FMT groups (30% and 33%, respectively, vs. 4% in the SMT group, p<0.001) whereas mortality rate was highest in the FMT group (22% vs. 0% and 0% in IS and SMT groups, respectively, p<0.001). SBO recurrence rate was highest in the SMT group (22% vs. 4% and 7% in IS and FMT groups, respectively, p=0.042). Conclusion. FMT seems to be associated with similar overall morbidity compared with IS but with increased postoperative mortality. Patient frailty seems to be worsened by prolonged inefficient medical treatment.
SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer
Authors: Tao Zhen , McCall Neal S. , Wiedemann Norbert , Vuagniaux Grégoire , Yuan Zhiyong , Lu Bo
Published: October 2018

Purpose:

Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.

Experimental Design:

To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.

Results:

ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.

Conclusions:

Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell–dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.
Serum Nardilysin, a Surrogate Marker for Epithelial–Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection
Authors: Yoh Tomoaki , Hatano Etsuro , Kasai Yosuke , Fuji Hiroaki , Nishi Kiyoto , Toriguchi Kan , Sueoka Hideaki , Ohno Mikiko , Seo Satoru , Iwaisako Keiko , Taura Kojiro , Yamaguchi Rina , Kurokawa Masato , Fujimoto Jiro , Kimura Takeshi , Uemoto Shinji , Nishi Eiichiro
Published: October 2018

Purpose:

Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC.

Experimental Design: We measured serum NRDC levels in 98 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 patients with ICC. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing.

Results:

High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n = 79) and validation (n = 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman ρ = 0.413; P = 0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown of NRDC was also accompanied by significant changes in the expression of several epithelial–mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1, in surgical specimens from patients with ICC.

Conclusions:

Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.
Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530
Authors: Locatelli Silvia L. , Careddu Giuseppa , Serio Simone , Consonni Francesca M. , Maeda Akihiro , Viswanadha Srikant , Vakkalanka Swaroop , Castagna Luca , Santoro Armando , Allavena Paola , Sica Antonio , Carlo-Stella Carmelo
Published: October 2018

Purpose:

Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed–Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response.

Experimental Design:

Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts.

Results:

In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%–76%).

Conclusions:

Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.
Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target
Authors: Grellety Thomas , Callens Celine , Richard Elodie , Briaux Adrien , Vélasco Valérie , Pulido Marina , Gonçalves Anthony , Gestraud Pierre , MacGrogan Gaetan , Bonnefoi Hervé , Cardinaud Bruno
Published: October 2018

Purpose:

Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.

Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer–associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo.

Results:

Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy.

Conclusions:

This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.
Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14–mutant Non–small Cell Lung Cancer
Authors: Suzawa Ken , Offin Michael , Lu Daniel , Kurzatkowski Christopher , Vojnic Morana , Smith Roger S. , Sabari Joshua K. , Tai Huichun , Mattar Marissa , Khodos Inna , de Stanchina Elisa , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Lockwood William W. , Drilon Alexander , Ladanyi Marc , Somwar Romel
Published: October 2018

Purpose:

MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear.

Experimental Design:

We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models.

Results:

Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models.

Conclusions:

KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.
Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment
Authors: Wang Hexuan , Mislati Reem , Ahmed Rifat , Vincent Phuong , Nwabunwanne Solumtochukwu F. , Gunn Jason R. , Pogue Brian W. , Doyley Marvin M.
Published: October 2018

Purpose:

High tissue pressure prevents chemotherapeutics from reaching the core of pancreatic tumors. Therefore, targeted therapies have been developed to reduce this pressure. While point probes have shown the effectiveness of these pressure-reducing therapies via single-location estimates, ultrasound elastography is now widely available as an imaging technique to provide real-time spatial maps of shear modulus (tissue stiffness). However, the relationship between shear modulus and the underlying tumor microenvironmental causes of high tissue pressure has not been investigated. In this work, elastography was used to investigate how shear modulus influences drug delivery in situ, and how it correlates with collagen density, hyaluronic acid content, and patent vessel density—features of the tumor microenvironment known to influence tissue pressure.

Experimental Design:

Intravenous injection of verteporfin, an approved human fluorescent drug, was used in two pancreatic cancer xenograft models [AsPC-1 (n = 25) and BxPC-3 (n = 25)].

Results:

Fluorescence intensity was higher in AsPC-1 tumors than in BxPC-3 tumors (P < 0.0001). Comparing drug uptake images and shear wave elastographic images with histologic images revealed that: (i) drug delivery and shear modulus were inversely related, (ii) shear modulus increased linearly with increasing collagen density, and (iii) shear modulus was marginally correlated with the local assessment of hyaluronic acid content.

Conclusions:

These results demonstrate that elastography could guide targeted therapy and/or identify patients with highly elevated tissue pressure.

See related commentary by Nia et al., p. 2024
Targeting Resistance to Targeted Therapies: Combating a Resilient Foe
Authors: Devarakonda Siddhartha , Govindan Ramaswamy
Published: October 2018

While the advent of third-generation therapies has dramatically changed the treatment paradigm for EGFR-mutated lung cancer, resistance to these agents inevitably emerges. Understanding resistance mechanisms and their genomic underpinnings is crucial for developing innovative strategies that are capable of meaningfully prolonging patient survival.

See related article by Le et al., p. 6195
Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women
Authors: Serrano Davide , Gandini Sara , Guerrieri-Gonzaga Aliana , Feroce Irene , Johansson Harriet , Macis Debora , Aristarco Valentina , Bonanni Bernardo , DeCensi Andrea
Published: October 2018

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.
Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women
Authors: Toriola Adetunji T. , Appleton Catherine M. , Zong Xiaoyu , Luo Jingqin , Weilbaecher Katherine , Tamimi Rulla M. , Colditz Graham A.
Published: October 2018

The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (Ptrend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (Ptrend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (Ptrend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.
Interventions to Reduce Future Cancer Incidence from Diesel Engine Exhaust: What Might Work?
Authors: Carey Renee N. , Fritschi Lin , Driscoll Timothy R. , Peters Susan , Glass Deborah C. , Benke Geza , Reid Alison
Published: October 2018

Exposure to diesel engine exhaust (DEE) contributes appreciably to the burden of occupational cancer. This study aims to estimate the potential impact of a range of interventions on the future burden of cancer from occupational exposure to DEE in Australia. The future excess fraction method, a novel method based on the lifetime risk approach, was used to model changes in the future burden of cancer among the Australian working age population exposed to DEE at work in 2012 under various intervention strategies. The interventions modeled were based on the widely accepted hierarchy of control model. At baseline, 600 (0.4%) future bladder and 4,450 (0.6%) future lung cancer cases over the lifetime of the cohort were estimated to be attributable to occupational exposure to DEE in those exposed in 2012. Up to 2,000 of these cases were estimated to be avoidable through the use of various interventions. Exhaust hoses (engineering controls) were estimated to be particularly effective. This study provides an indication of which intervention strategies may be most useful in reducing the future burden of cancer associated with occupational DEE exposure. These results show the potential effect of changing current exposure, rather than focusing on past exposures, and thus provide relevant information for policy planning.
Effect of Lignocaine Concentration on Human Fibroblasts Growth in Eyes Undergoing Trabeculectomy: An in vitro Study
Authors: Janani Madhuravasal Krishnan , Jaichandran Venkatakrishnan , Madhavan Hajib Narahari Rao , Vijaya Lingam , George Ronnie Jacob , Ambastha Priyam Shrikant , Manu Abhijeet , Malathi Jambulingam
Published: October 2018

Purpose: To evaluate the effect of lignocaine on growth and apoptosis indication of primary human Tenon’s capsule fibroblast (HTFs) in an in vitro model. Patients and Methods: Tenon’s capsule tissue obtained from patients undergoing trabeculectomy were grown in cell culture medium. The effect of different concentrations of lignocaine (0.5, 1.0, 1.5, and 2%) on the morphology and growth of the fibroblasts was studied using microscopy, cell viability, and proliferation assay, and apoptosis was detected using the FITC Annexin V Apoptosis Kit. Results: Morphological changes similar to those of apoptotic cells, including cytoplasmic vacuolation, shrinkage, and rounding were visualized in the cells treated with concentrations greater than 1.0% (i.e., 1.5, 2.0%). Though proliferation inhibition was found with all four concentrations (0.5–2.0%), the viability of cells decreased from 1.0% lignocaine. Conclusion: 0.5% lignocaine prevents proliferation of fibroblasts without causing apoptosis in vitro.
Evaluating the Demand for Integrative Medicine Practices in Breast and Gynecological Cancer Patients
Authors: Schuerger Nikolas , Klein Evelyn , Hapfelmeier Alexander , Kiechle Marion , Brambs Christine , Paepke Daniela
Published: October 2018

Introduction: Integrative medicine is becoming increasingly relevant to modern oncology. The present study aims to assess the demand for integrative therapeutic approaches including complementary and alternative medicine (CAM), body and mind practices, nutritional counseling, and psychological assistance among breast and gynecological cancer patients. Methods: From April to July 2017, a pseudo-anonymous questionnaire was distributed to cancer patients at the Department of Gynecology and Obstetrics, Technical University of Munich. Patterns of CAM use and demand for integrative health approaches were investigated by generating descriptive statistics. Results: 182 (90%) of 203 patients participated in the survey. 59% indicated the use of CAM practices in general, and 41% specifically in relation to their oncological disease. Most frequently used modalities were herbal supplements (32%), homeopathy (29%), vitamins (28%), and selenium (21%). Integrative health approaches that patients would have desired alongside conventional oncological treatment were CAM (54%), relaxation therapies (44%), and dietary counseling (43%). Conclusion: There is a considerable demand for integrative medicine among breast and gynecological cancer patients. Our results underline the need for the implementation of evidence-based integrative treatments in cancer care in order to meet the standards of modern oncology.
Long-Term Mortality and Bone Safety in Patients with End-Stage Renal Disease Receiving Lanthanum Carbonate
Authors: Hutchison Alastair , Whelton Andrew , Thadhani Ravi , Achenbach Heinrich , Vergani Andrea , Wu Jingyang , Hall Gillian
Published: October 2018

Background/Aims: This post-marketing observational study assessed the long-term safety of lanthanum carbonate (LaC) in US patients with end-stage renal disease (NCT00567723). Methods: Patients (≥18 years old) undergoing dialysis, who had Medicare as their primary healthcare payer, and records in the United States Renal Data System were followed-up for 5 years. Patients who had received LaC for at least 12 consecutive weeks formed the exposed cohort. During the same time period, patients who had undergone dialysis for at least 12 consecutive weeks and had been treated with any other phosphate binder formed the primary comparator cohort. A historical cohort was also evaluated. Primary outcomes were all-cause mortality, and time to and incidence of first bone-fracture event requiring hospitalization. Secondary outcomes were time to first occurrence of and incidence of specific gastrointestinal (GI) disease, liver disease, malignancy, and major infectious episode requiring hospitalization. ­Results: 2,026 and 8,094 patients were included in the exposed and primary comparator cohorts, respectively. A Cox proportional hazards model showed that patients receiving LaC were not at increased risk of all-cause mortality (adjusted hazard ratio 0.94; 95% CI 0.88–1.01; p = 0.078), bone fractures (0.86; 0.71–1.05; p = 0.130), specific GI disease (0.86; 0.76–0.97; p = 0.015), liver disease (0.88; 0.70–1.09; p = 0.236), malignancy (0.85; 0.54–1.34; p = 0.496), or major infectious episodes (0.87; 0.80–0.94; p < 0.001) requiring hospitalization compared with primary comparator patients. Conclusions: LaC was not associated with increased risk of mortality, bone fractures, or any secondary outcome.