bluuebunny/crossref_metadata_2025 huggingface dataset:
The Segmentation-Thickness Tradeoff in Online Marketplaces
Authors: Alijani Reza , Banerjee Siddhartha , Gollapudi Sreenivas , Kollias Kostas , Munagala Kamesh
Published: March 2020

A core tension in the operations of online marketplaces is between segmentation (wherein platforms can increase revenue by segmenting the market into ever smaller sub-markets) and thickness (wherein the size of the sub-market affects the utility experienced by an agent). An important example of this is in dynamic online marketplaces, where buyers and sellers, in addition to preferences for different matches, also have finite patience (or deadlines) for being matched. We formalize this trade-off via a novel optimization problem that we term as 'Two-sided Facility Location': we consider a market wherein agents arrive at nodes embedded in an underlying metric space, where the distance between a buyer and seller captures the quality of the corresponding match. The platform posts prices and wages at the nodes, and opens a set of virtual clearinghouses where agents are routed for matching. To ensure high match-quality, the platform imposes a distance constraint between an agent and its clearinghouse; to ensure thickness, the platform requires the flow to any clearinghouse be at least a pre-specified lower bound. Subject to these constraints, the goal of the platform is to maximize the social surplus subject to weak budget balance, i.e., profit being non-negative. Our work characterizes the complexity of this problem by providing both hardness results as well as algorithms for this setting; in particular, we present an algorithm that for any constant ε > 0 yields a (1 + ε ) approximation for the gains from trade, while relaxing the match quality (i.e., maximum distance of any match) by a constant factor.
Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway
Authors: Yang Chun , Sun Shengnan , Zhang Qi , Guo Jia , Wu Tengfei , Liu Ying , Yang Min , Zhang Yan , Peng Yinghua
Published: March 2020

Postoperative cognitive dysfunction (POCD) is a severe complication of cardiopulmonary bypass (CPB) and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cells (MSCs) are multipotent cells that have therapeutic potentials mainly through paracrine action via secreting growth factors and cytokines. Exosomes are one of the important paracrine factors and have been reported as potential cell-free therapy for the treatment of autoimmune and central nervous system disorders. In this study, we examined exosomes derived from antler MSCs (AMSCs) of POCD rats after CPB and evaluated their potential regulatory mechanisms. AMSC-derived exosomes reduced neurological damage and brain damage and prevent apoptosis in CPB rats. Furthermore, AMSC-derived exosomes were found to reduce hippocampal neuronal apoptosis and the expression of TLR2, TLR4, MyD88, and NF-κB in CPB rats. However, the above effects of AMSC-derived exosomes on CPB rats were abolished partially by toll-like receptor 2/4 (TLR2/TLR4) agonist (LPS-EB). In conclusion, AMSC-derived exosomes can improve cognitive function in CPB rats through inhibiting the TLR2/TLR4 signaling pathway.
Could Obesity be a Triggering Factor for Endometrial Tubal Metaplasia to be a Precancerous Lesion?
Authors: El-Saka Ayman M. , Zamzam Yomna A. , Zamzam Yosra A. , El-Dorf Ayman
Published: March 2020

Background & Aims. Endometrial tubal metaplasia (ETM) is mostly described in conjunction with unopposed estrogen levels, and its association with endometrial hyperplasia and endometrial carcinoma (EC) is striking. Obesity is a risk factor for endometrial hyperplasia and EC development. The aim of this study is to investigate the impact of BMI and serum estradiol level on expression of PAX-2, H-TERT, P16, Ki-67, and P53 in studied ETM in reference to benign endometrium and EC. Methods. The study was conducted on the following groups: group (1) consists of 57 cases that had endometrial biopsies with histologically demonstrable ETM (typical or atypical) and all were subjected to serum estradiol levelling and body mass index (BMI) evaluation; group (2) had adjacent benign endometrial tissue as control; group (3) consists of 52 cases of conventional endometrial carcinoma and 16 serous carcinoma paraffin blocks which were collected and reevaluated. All included groups were immunostained for PAX-2, H-TERT, p16, ki67, and p53. Results. The relation between BMI and serum estradiol level in group 1 and PAX-2, H-TERT, P16, and p53 was statistically significant, while their relation with atypia and ki67 expression was insignificant. Twenty-three ETM cases (40.4%) out of group 1 were all (100%) obese, 87% had high serum estradiol level, and 73.9% were postmenopausal and had a similar immunohistochemical profile as EC cases (group 3). Conclusions. The presence of ETM regardless of the histologic atypia in obese postmenopausal patients with high serum estradiol level is an alarming sign. This implies that ETM might not be as benign as generally accepted, as under certain clinical conditions, it may turn into a potential premalignant lesion.
Microstructure, Tensile Property, and Surface Quality of Glass Fiber-Reinforced Polypropylene Parts Molded by Rapid Heat Cycle Molding
Authors: Liu Feng , Li Taidong , Xu Fuyu , Li Jiquan , Jiang Shaofei
Published: March 2020

The microstructure of a molded product considerably influences its macroscopic properties. In this study, the influence of molding process on microstructure, tensile property, and surface quality was explored on the glass fiber-reinforced polypropylene (GFRPP) parts molded by rapid heat cycle molding (RHCM) and conversion injection molding (CIM). Tensile strength and surface gloss were chosen to measure macroscopic properties of the molded parts. The microstructure including multilayer, fiber orientation, crystallinity, and fiber-matrix bonding strength were analyzed by simulations, scanning electron microscopy, wide-angle X-ray diffraction, and dynamic mechanical analysis. The relationship between the macroscopic properties and microstructure of the RHCM samples was also discussed. The results indicate that as the mold cavity surface temperature increases, the tensile strength increases firstly and decreases thereafter. The tensile strength of RHCM parts reached the maximum at the mold heating temperature of 60°C. It is also observed that the surface gloss of the sample increases as the mold cavity surface temperature rises, and the increase of surface gloss decreases distinctly with the mold heating temperature higher than 90°C.
The Roles of Skin Fibroblasts at Local Acupoints in Chrono-Acupuncture
Authors: Liu Nannan , Zhao Zhengyu , Zhou Qizhi , Zhang Xiaohong , Wang Yu , Huang Shiqi , Cai Dingjun
Published: March 2020

Objective. The aim of this study was to demonstrate the peripheral mechanisms of chrono-acupuncture by observing acupuncture at different time points affecting relative proteins to regulate the cytoskeleton of fibroblasts differently. Methods. A total of 108 male SD rats (180–220 g) that have basic pain threshold within 3–10 s were selected and randomly divided into group A (n = 72) and control group (n = 36). After the succession of modeling with CFA injection, the rats in group A were randomly divided into model group and acupuncture group, each group containing 36 rats. Then according to the different treatment time, each group was randomly classified into 6 subgroups (ZT0, ZT4, ZT8, ZT12, ZT16, and ZT20), each subgroup containing 6 rats (n = 6). On the second day of successful modeling, the rats in the acupuncture group received acupuncture treatment at the corresponding time point, while the control group and the model group were only tied up at the corresponding time point without any treatments. Methods of operation: use 0.5-inch needles, puncture the rats’ “Zusanli” on the affected limb, with Twirling manipulation for a minute after every five minutes; the treatment lasts thirty minutes in total. After 7 days of treatments, the skin and subcutaneous tissue of rats’ acupoint area of “Zusanli” on the affected limb were taken and then stained by immunofluorescence double staining method to observe the expression of the fibroblast cytoskeleton F-actin and β-tubulin under the LSCM while using western blot to observe the expression of P38MAPK/P-P38MAPK. Results. The expression of the cytoskeleton F-actin and β-tubulin at acupoint area in the acupuncture group was significantly higher than that in the control and model group. The effect of acupuncture on the restructure of the fibroblast cytoskeleton is different at different time points, the most effective time point was at ZT12 while the least at ZT16. Acupuncture can decrease the high expression of P-P38MAPK/P38MAPK in the model group, and the effect has time differences. The expression of P-P38MAPK/P38MAPK increased more significantly at ZT16 than ZT12. Conclusion. The remodeling difference of fibroblast cytoskeleton after receiving acupuncture treatment could be one of the peripheral bases of the chrono-acupuncture.
A Rare Case of Nonsyndromic Generalized Radiculomegaly with a Literature Review
Authors: Al-Obaida Mohammad
Published: March 2020

Radiculomegaly is a rare condition involving elongated tooth roots. This condition has significant clinical implications and has been associated with syndromes such as oculofaciocardiodental syndrome. However, only a few nonsyndromic cases of radiculomegaly have been reported. Here, we report a case of nonsyndromic radiculomegaly in a Saudi individual. A subsequent review of the literature suggests endodontic management modalities for individuals with the dental findings demonstrated in the present case.
Roux-en-Y Gastric Bypass in Obese Diabetic Rats Promotes Autophagy to Improve Lipid Metabolism through mTOR/p70S6K Signaling Pathway
Authors: Ma Nanxi , Ma Rui , Tang Kaixin , Li Xuesong , He Bing
Published: March 2020

Purpose. To investigate the effects of Roux-en-Y gastric bypass (RYGB) surgery on markers of liver mitochondrial dynamics and find new therapeutic basis on obese type 2 diabetes mellitus (T2DM) patients. Materials and Methods. Thirty-two rats were divided into nondiabetic group, diabetic group, sham group, and RYGB group. The Dual-energy X-ray absorptiometry (DEXA) was used to detect short-term curriculum vitae for rat body component and fat and lean mass. Hepatic lipid content and triglyceride levels were detected by Oil Red O staining. Western blotting was used to examine autophagy and mammalian target of rapamycin/P70S6 kinase (mTOR/p70S6K) pathway-related proteins. The carbon dioxide production from the oxidation of [14C] oleate was measured. Plasma glucose was measured by glucose oxidase assay. The insulin and C-peptide were detected. Triacylglyceride (TG) and free fat acid (FFA) in plasma were determined by enzymatic colorimetric assays. Results. RYGB improved metabolic parameters and enhanced plasma GLP-1 level, ameliorated the lipopexia, and increased insulin sensitivity in the liver; RYGB promoted the hepatic autophagy and inhibited the mTOR/p70S6K signaling pathway. GLP-1 reduced fat load and increased fatty acid β-oxidation by activated autophagy to regulate the hepatic lipid pathway through mTOR/p70S6K signaling pathway. Conclusions. RYGB may reduce liver lipid toxicity and improve insulin sensitivity through activating the hepatic fat hydrolysis pathway and inhibiting the liver fat synthesis pathway. However, the transport pathway of liver fat does not play a key role.
Laser Treatment for Strengthening of Thin Sheet Steel
Authors: Kapustynskyi Oleksandr , Višniakov Nikolaj
Published: March 2020

This paper presents the results of computer simulations and experimental studies, aiming to increase the mechanical strength of sheet metal parts manufactured from high‐quality structural carbon steel by means of local laser processing. The effects of laser processing on the strength of steel sheet plates and their ability to resist bend load after laser treatment were studied. The results of bending experiments and computer simulations of elastoplastic deformation establish that local laser processing with surface melting can be used to increase the mechanical strength of structural elements made from thin sheet steel C22E and to decrease its deflection under similar workload, as an alternative to the application of complex geometric shapes, additional strengthening elements, or heat treatment.
Can Superabsorbent Polymers Improve Plants Production in Arid Regions?
Authors: Jahan Mohsen , Nassiri Mahallati Mehdi
Published: March 2020

Superabsorbent polymers (SAPs) have shown to be quite effective and useful in acting as a reservoir for water and some nutrients in arid and semiarid regions. There are many studies in Iran that have been performed in relation to SAPs and their useful application in agriculture; however, there is still a lack of its applied definition in arid regions. Therefore, this study was conducted with the aim of doing a meta-analysis of the results of studies conducted in Iran and answering a general question about whether the application of SAPs has been effective in enhancing the production or not, and if so, how much of SAP is recommended. To conduct this research, articles published during 2006–2016 on the subject of the effects of different rates of SAP application on yield and yield components of crops (including cereals, legumes, and medicinal and grassland plants) were investigated. The results of the meta-analysis showed that the mean consumption rate of SAPs for cereals, legumes, and medicinal and grassland plants was 83, 322, 1031, and 210 kg ha−1, respectively, and that, at these SAP application rates, the mean seed yield in cereals, medicinal plants, and legumes increased by 15.2, 12.6, and 38% (equivalent to 1059, 345, and 452 kg ha−1), respectively, compared with the control. Dry matter response to superabsorbent application was slower compared with the seed yield response. The mean consumption of 83 kg ha−1 of superabsorbent for cereals increased seed yield by 15.2% on average. According to the results, it seems that the application of 100 kg SAP ha−1 is the most appropriate rate for increasing seed and dry matter yields and satisfying economic aspects. These study findings may shed light on the environment and socioeconomic concerns and improve efficacy and reduction of costs.
Maximizing E-Tailers’ Sales Volume through the Shipping-Fee Discount and Product Recommendation System
Authors: Guo Yan , Hu Xiaonan , Zou Yu , Li Shouwei , Cheng Wenchuan , Li Zhiyong
Published: March 2020

E-tailers can impact customers’ order incidence and cart size by offering an attractive shipping fee; they can also influence customers to purchase other products using a recommendation system. This article provides a combined model in which the shipping-fee discount and product recommendations occur jointly to maximize the sales volume of e-tailers. Selection of recommended products and discount of shipping fee are the dynamic issues involving the complexity of business environments. The proposed model first determines the optimal shipping-fee discount to attract customers and then establishes the most suitable product recommendation list to encourage customers to spend more money on other products. Through the use of a shipping-fee discount and simultaneous product recommendations, e-tailers maximize the sales volume. As for consumers, they can always get additional savings from the subsequent shopping process because the product’s shipping fee is lower than the original shipping costs. Experimental results indicate that the proposed approach is feasible and better than alternative methods for achieving sales volume maximization. Furthermore, sensitivity analysis validates the stability of the proposed model in the face of an uncertain environment. Therefore, using the shipping-fee discount and product recommendation system as a united marketing strategy can maximize e-tailers’ sales volume.
Optimization of Injection-Molding Process Parameters for Weight Control: Converting Optimization Problem to Classification Problem
Authors: Zhao Peng , Dong Zhengyang , Zhang Jianfeng , Zhang Yi , Cao Mingyi , Zhu Zhou , Zhou Hongwei , Fu Jianzhong
Published: March 2020

Product weight is one of the most important properties for an injection-molded part. The determination of process parameters for obtaining an accurate weight is therefore essential. This study proposed a new optimization strategy for the injection-molding process in which the parameter optimization problem is converted to a weight classification problem. Injection-molded parts are produced under varying parameters and labeled as positive or negative compared with the standard weight, and the weight error of each sample is calculated. A support vector classifier (SVC) method is applied to construct a classification hyperplane in which the weight error is supposed to be zero. A particle swarm optimization (PSO) algorithm contributes to the tuning of the hyperparameters of the SVC model in order to minimize the error between the SVC prediction results and the experimental results. The proposed method is verified to be highly accurate, and its average weight error is 0.0212%. This method only requires a small amount of experiment samples and thus can reduce cost and time. This method has the potential to be widely promoted in the optimization of injection-molding process parameters.
Complexity to Forecast Flood: Problem Definition and Spatiotemporal Attention LSTM Solution
Authors: Wu Yirui , Ding Yukai , Zhu Yuelong , Feng Jun , Wang Sifeng
Published: March 2020

With significant development of sensors and Internet of things, researchers nowadays can easily know what happens in physical space by acquiring time-varying values of various factors. Essentially, growing data category and size greatly contribute to solve problems happened in physical space. In this paper, we aim to solve a complex problem that affects both cities and villages, i.e., flood. To reduce impacts induced by floods, hydrological factors acquired from physical space and data-driven models in cyber space have been adopted to accurately forecast floods. Considering the significance of modeling attention capability among hydrology factors, we believe extraction of discriminative hydrology factors not only reflect natural rules in physical space, but also optimally model iterations of factors to forecast run-off values in cyber space. Therefore, we propose a novel data-driven model named as STA-LSTM by integrating Long Short-Term Memory (LSTM) structure and spatiotemporal attention module, which is capable of forecasting floods for small- and medium-sized rivers. The proposed spatiotemporal attention module firstly explores spatial relationship between input hydrological factors from different locations and run-off outputs, which assigns time-varying weights to various factors. Afterwards, the proposed attention module allocates temporal-dependent weights to hidden output of each LSTM cell, which describes significance of state output for final forecasting results. Taking Lech and Changhua river basins as cases of physical space, several groups of comparative experiments show that STA-LSTM is capable to optimize complexity of mathematically modeling floods in cyber space.
Global Dynamics of the Chaotic Disk Dynamo System Driven by Noise
Authors: Feng Chunsheng , Li Lijie , Liu Yongjian , Wei Zhouchao
Published: March 2020

The disk dynamo system, which is capable of chaotic behaviours, is obtained experimentally from two disk dynamos connected together. It models the geomagnetic field and is used to explain the reversals in its polarity. Actually, the parameters of the chaotic systems exhibit random fluctuation to a greater or lesser extent, which can carefully describe the disturbance made by environmental noise. The global dynamics of the chaotic disk dynamo system with random fluctuating parameters are concerned, and some new results are presented. Based on the generalized Lyapunov function, the globally attractive and positive invariant set is given, including a two-dimensional parabolic ultimate boundary and a four-dimensional ellipsoidal ultimate boundary. Furthermore, a set of sufficient conditions is derived for all solutions of the stochastic disk dynamo system being global convergent to the equilibrium point. Finally, numerical simulations are presented for verification.
Predictors of Low Birth Weight at Lumbini Provincial Hospital, Nepal: A Hospital-Based Unmatched Case Control Study
Authors: Shrestha Saneep , Shrestha Sandeep , Shakya Shrestha Upasana , Gyawali Kamala
Published: March 2020

Background. Low birth weight (LBW) is defined as the birth weight of live born infants below 2500 g, regardless of gestational age. It is a public health problem caused by factors that are potentially modifiable. The purpose of this study was to determine the socioeconomic, obstetric, and maternal factors associated with LBW in Lumbini Provincial Hospital, Nepal. Methods. The study was conducted using case control study design with 1 : 2 case control ratio. A total of 105 cases and 210 controls were taken in this study. Data were entered on Epi data software version 3.1 and exported to Statistical Package for Social Science (SPSS) software version 25 for analysis. Characteristics of the sample were described using mean and standard deviation. Bivariate analysis was done to assess the association between dependent and independent variables. The ultimate measure of association was odds ratio. Variables found to be associated with bivariate analysis were entered into a multivariable logistic regression model to identify predictors of LBW. Results. The mean age of the participants was 25.98 years with ±4.40 standard deviation. Mothers with literate educational background (AOR 0.32, 95% CI 0.13–0.81), housewife (AOR 2.63, 95% CI 1.11–6.20), vaginal mode of delivery (AOR 0.45, 95% CI 0.25–0.82), gestational age <37 weeks (AOR 2.51, 95% CI 1.15–5.48), history of LBW (AOR 5.12, 95% CI 1.93–13.60), and maternal weight <50 kilograms (AOR 2.23, 95% CI 1.23–4.02) were significantly associated with LBW. Conclusion. Educational and occupational status, mode of delivery, gestational age, maternal weight, and history of LBW were found to be independent predictors of LBW. There is need of developing coordination with education sector for increasing educational status of mothers and adolescent girls. Social determinants of health need to be considered while developing interventional programs. Similarly, interventional programs need to be developed considering identified predictors of low birth weight.
Acute and Subchronic Oral Toxicity Study of Polyherbal Formulation Containing Allium sativum L., Terminalia bellirica (Gaertn.) Roxb., Curcuma aeruginosa Roxb., and Amomum compactum Sol. ex. Maton in Rats
Authors: Sholikhah E. N. , Mustofa M. , Nugrahaningsih D. A. A. , Yuliani F. S. , Purwono S. , Sugiyono S. , Widyarini S. , Ngatidjan N. , Jumina J. , Santosa D. , Koketsu M.
Published: March 2020

The polyherbal formulation containing Allium sativum L., Terminalia bellirica (Gaertn.) Roxb., Curcuma aeruginosa Roxb., and Amomum compactum Sol ex. Maton has been used for hypertension treatment empirically. Our previous study showed its blood pressure‐lowering effect on a rat model of hypertension. However, toxicity data were not available for this polyherbal formulation. This study is aimed at evaluating the acute and subchronic oral toxicity of the polyherbal formulation in rats. The acute toxicity study was conducted on 6 female Wistar rats using the fixed‐dose method for the treatment group and 5 female Wistar rats for the control. The single dose of 2,000 mg/kg of the polyherbal formulation was given orally. There were no significant toxic effects and no death observed until the end of the study, and it was showed that the lethal dose 50% (LD50) of the polyherbal formulation was estimated to be more than 2,000 mg/kg. The macroscopic and microscopic examination of vital organs showed no symptoms of toxicity. At the subchronic toxicity study, the polyherbal formulation with 3 dose variations of 252 mg/kg, 1,008 mg/kg, and 4,032 mg/kg was administered for 91 days orally. The lowest dose of 252 mg/kg is equivalent to the daily recommended dose for a human. There were no significant toxic effects observed at all doses on physical sign and symptoms, weight gain, food intake, hematological parameters, biochemical parameters, and macroscopic and microscopic examination of organs. These findings showed that the short‐ and long‐term oral administration of the polyherbal formulation is safe to use within its dose recommendation.
Comparison of Functional Movement Screen, Star Excursion Balance Test, and Physical Fitness in Junior Athletes with Different Sports Injury Risk
Authors: Chang Wen-Dien , Chou Li-Wei , Chang Nai-Jen , Chen Shuya
Published: March 2020

Objectives. The aim of this study was to assess the relationships between functional movement screen (FMS), star excursion balance test (SEBT), agility T test, and vertical jump test scores and sports injury risk in junior athletes. We compared these assessments and the differences between groups with high and low risks of sports injury. Subjects and Methods. Eleven volleyball, 12 basketball, and 9 handball athletes were recruited. All participants followed the routine training in school sports teams. Weekly training schedules followed a similar pattern. The 32 junior athletes (age = 16.06 ± 0.21 years; height = 167.28 ± 6.32 cm; and body mass = 68.45 ± 9.67 kg) were assessed using the FMS, SEBT, agility T test, and vertical jump test in random order. The correlations of composite and individual item scores of these assessments were analyzed, and the differences between groups with high and low risks of sports injury were compared. Results. All participants completed the study protocol. No significant differences were observed between FMS, SEBT, agility T test, and vertical jump test scores in groups with high and low risks of sports injuries. Fair and moderate‐to‐good correlations were observed for anterior reach maximum of SEBT and deep squat (r = 0.47, P = 0.02) as well as inline lunge (r = 0.53, P = 0.01) of FMS. The hurdle step of FMS also exhibited moderate‐to‐good (r = 0.52, P = 0.01) and fair (r = 0.42, P = 0.04) correlations with posterior medial and posterior lateral reach maximum of SEBT, respectively. A fair correlation was observed between posterior lateral reach maximum of SEBT and rotary stability of FMS (r = −0.23, P = 0.03). Fair and moderate‐to‐good correlations were identified for agility T test and maximum anterior reach in the SEBT (r = −0.42, P = 0.04) and trunk stability push‐up in the FMS, respectively (r = −0.57 and P = 0.006). Conclusions. Junior athletes with a high risk of sports injury did not exhibit differences in terms of FMS, SEBT, and physical fitness test scores. Deep squat, hurdle step, inline lunge, and rotary stability scores in the FMS were correlated with the item scores in the SEBT, which may be due to the use of similar movement patterns. Scores for anterior reach maximum in the SEBT and trunk stability push‐up in the FMS were correlated with agility T test scores, suggesting a similar task requirement of trunk stability and dynamic weight shifting ability.
Fiscal Decentralization and Environmental Pollution: A Spatial Analysis
Authors: Chen Xia , Liu Jianmin
Published: March 2020

Based on annual data over the period 2003 to 2017 covering 31 provinces in China, the environmental pollution index and environmental regulation index are constructed. Moran’s I, the widely used spatial autocorrelation index, is used to analyze the spatial distribution of environmental pollution, which provides a fairly high stability of the positive spatial correlation of environmental pollution. Then, the 0-1 matrix, distance weighting matrix, and economic distance mixed matrix are carried out to weigh space separately. To analyze the impact of fiscal decentralization on environmental pollution, the spatial Durbin model is employed. In the meanwhile, fiscal decentralization is measured from the perspective of both fiscal expenditure decentralization and fiscal revenue decentralization. The results show that the impact of fiscal decentralization on environmental pollution is positive and appears the phenomenon of “race to bottom.” To improve environmental quality, appropriate environmental regulation target, implementing green GDP accounting, and adjusting economic structure should be adopted.
Natural Habitat, Housing, and Restraint of Six Selected Neotropical Animals in Trinidad and Tobago with the Potential for Domestication
Authors: Lall Kavita Ranjeeta , Jones Kegan Romelle , Garcia Gary Wayne
Published: March 2020

This paper highlights the natural habitat, housing, and restraint needs of 6 Neotropical animals that are found in Trinidad and Tobago with the potential for domestication: agouti (Dasyprocta leporina), lappe/paca (Cuniculus paca/Agouti paca), capybara (Hydrochoerus hydrochaeris), manicou/opossum (Didelphis marsupialis insularis), collared peccary (Tayassu tajacu/Pecari tajacu), and red brocket deer (Mazama americana). The year of the earliest reference cited was 1950 and the most recent was 2018, with over 100 references being used. The average density, home range size, social group, and housing requirements were also examined as these factors would play a role in designing enclosures. A number of different physical and chemical restraint techniques were also discussed. Information from other species within the same genus was incorporated as some of the animals did not have sufficient literature.
Abstract A002: Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities
Authors: Chen Tai-Lin , Jain Vicky , Patel Anilkumar S. , Lin Yi-Wen , Su Tsann-Long , Lee Te-Chang
Published: March 2020

Angiogenesis plays a critical role in sustaining the microenvironment, growth, and metastatic potential of a variety of tumors, such as lung cancer, colorectal cancer, and renal cancer. However, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits. To improve the therapeutic efficacy, the designed dual functional inhibitors, composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety), were synthesized. We first demonstrated that 1,2-bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazines displayed dual functions, inducing DNA crosslinking and inhibiting angiogenesis. By aid of DIVAA, we confirmed the in vivo anti-angiogenetic activity. They were cytotoxic to a panel of cancer cell lines, including leukemia, colorectal, renal, and lung cancer cells. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from subnanomolar to micromolar. Significantly, we observed tumor suppression by treatment of compound 8 in a given formulation at the dose of 20 mg/kg (10 times in 2 weeks) in SCLC H526, squamous lung cancer H520 and renal cancer 786-O xenograft models. In addition, orally admission of 60 mg/kg compound 8 daily for 14 days was also more potent than cisplatin in suppression of growth of SCLC H526 xenografts. Importantly, compound 8 at the dose given did not cause body weight lost. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids are potent than anticancer agents against a wide spectrum of cancers. They deserve our further development.

Citation Format: Tai-Lin Chen, Vicky Jain, Anilkumar S. Patel, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Discovery of bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives as orally bioavailable antitumor agents with anti-angiogenic and DNA cross-linking activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A002. doi:10.1158/1535-7163.TARG-19-A002
Abstract A005: Clinicopathological factors associated with establishment of gastric cancer PDXs and cell lines
Authors: Kuwata Takeshi
Published: March 2020

Background: Patient-derived xenograft (PDX) models has been widely accepted as a suitable preclinical model. However, the number of PDX models as well as cell-lines from gastric cancer (GC) are limited. We started our DEF study project on May 2013 for establishing new GC PDX models and cell lines for accelerating the development of new therapeutics for GC. Methods: Two hundred and fifty (250) patients, including 233 patients underwent gastrectomy and 17 patients received cell-free and concentrated ascites reinfusion therapy (CART) in our hospitals, were enrolled. We subcutaneously engrafted 232 surgically resected gastric cancer tissues into immune-deficient NOG mice. Primary or PDX tumor tissues or ascites from CART patients were cultivated for establishing GC cell lines. Results and Discussion: From 233 surgically resected tumor tissues, we have successfully established 35 gastric cancer PDX models. PDX-establishment rate was 15.1%, and differentiated type adenocarcinomas (DAs) were more effectively established than poorly differentiated type adenocarcinomas (PDAs). The histology of PDX resembled their primary tumors, and the concordance of histological differentiation grade between primary tumors and PDXs was significant (28/35, p<0.01). Twenty-three (23) GC cell lines have been established from surgically resected primary or subsequently transplanted PDX tissues. Another 2 GC lines were established by cultivating primary GC tissues directly. Among 25 GC cell lines, 24 lines could develop subcutaneous tumors (CDXs) in SCID mice. In contrast to PDX, the concordance of histological differentiation grade between primary tumors and CDXs was not significant. In addition, we have also established 7 GC cell lines from ascites from 17 patients received CART, and six of them could develop CDXs. All of the CDXs from CART cases showed PD histology. As the results, we have established both PDX and Cell lines simultaneously from 21 patients, which allowed us to invest a direct histological and molecular comparison between primary, PDX, and CDX tumors. We would also like to discuss about lymphoproliferative lesions, most of which showed proliferation of B cell with various cytological atypia, encountered during the PDX establishment process.

Citation Format: Takeshi Kuwata. Clinicopathological factors associated with establishment of gastric cancer PDXs and cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A005. doi:10.1158/1535-7163.TARG-19-A005
Abstract A007: A Rag2/Il2rg double-knockout rat supports engraftment of human immune system for immunotherapy-based cancer efficacy studies
Authors: Noto Fallon K , Adedeji Bisoye Towobola , Agarwal Yash , Beatty Cole , Ho Sara , Das Antu , Salunke Rajeev , Bility Moses , Jamling Tseten Yeshi
Published: March 2020

Immune humanized mice have been valuable in the development of novel cancer immunotherapies and have demonstrated stronger efficacy when combined with standard of care chemotherapy. An immune humanized rat could provide several advantages over the currently available humanized mouse models, including supporting the growth of larger tumors for serial fine needle biopsies to assess immune infiltration and serial blood draws for assessing human immune development and tumor biomarkers in real-time throughout an efficacy study. We developed a novel autologous human skin and immune cells-humanized rat model by co-engrafting full-thickness human-fetal skin and autologous fetal lymphoid organoids under the kidney capsule along with intravenous injection of autologous fetal-liver derived hematopoietic stem cells, thus termed, human skin-immune system humanized rat model (hSIS-humanized rat). hSIS-humanized rat support development of adult-like, full-thickness human skin and human lymphoid organoids along with human immune cells. Methicillin-resistant Staphylococcus aureus inoculation in the human skin results in infection and skin pathology, thus recapitulating clinical outcomes. This model will enable in vivo mechanistic studies for development and evaluation of novel therapeutics for skin infectious disease and may also provide a model for establishing skin grafts of patient-derived melanoma tumors to investigate melanoma metastasis and response to therapies. In addition, engrafting the rat with human lymphoid organs and human immune cells may provide a similar platform to the BLT mouse for immunotherapy studies. Finally, we have demonstrated humanization of the rat immune system using human PBMCs. Human CD45+, CD3+, and CD20+ cells can be found in the peripheral blood, spleen, and bone marrow of engrafted rats. These immune humanized rat models may be beneficial for evaluating immunotherapies in human cancer models, including assessment of immune cell infiltration through fine needle biopsies.

Citation Format: Fallon K Noto, Bisoye Towobola Adedeji, Yash Agarwal, Cole Beatty, Sara Ho, Antu Das, Rajeev Salunke, Moses Bility, Tseten Yeshi Jamling. A Rag2/Il2rg double-knockout rat supports engraftment of human immune system for immunotherapy-based cancer efficacy studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A007. doi:10.1158/1535-7163.TARG-19-A007
Abstract A014: Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization
Authors: Becker Michael , Brzezicha Bernadette , Conrad Theresia , Rolff Jana , Linnebacher Michael , Treese Christoph , Rau Beate , Walther Wolfgang , Hoffmann Jens
Published: March 2020

Gastric cancer is a common malignant disease representing the fifth common cancer worldwide. Its prognosis is determined by the stage and localization (distal vs. proximal), making gastric cancer the third most lethal cancer type. In early and localized stages, the therapeutic aim is curative, in metastatic stages however, palliative treatment is the only option. Despite some progress in the last 10 years, mortality for late stage gastric cancer is still high due to late diagnosis of the disease. Therefore, we have established patient-derived xenograft models (PDX) of gastric cancer to determine their potential as a preclinical tool to improve diagnosis and therapies of this cancer. For PDX generation, tumor tissue specimens were collected from the gastric cancers immediately after surgery and transplanted subcutaneously into immunodeficient mice. Each PDX was serially passaged for at least three times. Established PDX models were treated in monotherapy with standard of care drugs, inter alia, from the European FLOT standard (5-FU, leucovorine, oxaliplatin and docetaxel). PDX tumor tissue was collected for immunohistochemistry as well as for next generation RNA sequencing and a comprehensive transcriptome analysis was performed. We established 7 new PDX models of gastric cancer and stably expanded them for further analyses. The histology of the primary tumor was preserved in the PDX model proven by histopathological evaluation. Treatment with standard of care drugs such as 5-FU, docetaxel, or oxaliplatin showed an individual response towards these drugs. The mutational and gene expression landscape of the PDX models resembles the pattern known from public gastric cancer data sets. In conclusion, the newly established gastric cancer PDX panel represents a tool for preclinical analyses of molecular mechanisms of drug sensitivity and resistance. They further provide a clinically relevant platform to identify new biomarkers and to develop novel therapies.

Citation Format: Michael Becker, Bernadette Brzezicha, Theresia Conrad, Jana Rolff, Michael Linnebacher, Christoph Treese, Beate Rau, Wolfgang Walther, Jens Hoffmann. Gastric cancer PDX models for predictive preclinical studies: Establishment, drug sensitivity, and genomic characterization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A014. doi:10.1158/1535-7163.TARG-19-A014
Abstract A026: An automated biomarker discovery platform based on in vitro pharmacology raw data
Authors: Xue Jia , Li Henry QX , Guo Sheng
Published: March 2020

In vitro pharmacology studies using cultures of biological models, such as cancer cell lines or lately organoids in the oncology field, are commonly used to assess drug efficacy. The baseline genetic or epigenetic features, including those reflective of the original patient tissue, can be characterized by genomic profiling of the respective models, and correlated to the efficacy observed during pharmacology studies to discover potential predictive biomarkers. On the other hand, the changes of these features following specific treatment (pharmacodynamic changes) can be used to explore the drug mechanism of action (MOA) or potential drug targets. Discovery and/or validation of relevant biomarkers using these in vitro preclinical pharmacology studies are obviously critical in drug discovery/development. Although important, the biomarker discovery and validation process can be complex and labor intensive, and currently there are few robust tools that can be used readily to take on the task of automated computation discovery. To this end, we have established an automated biomarker discovery platform for in vitro preclinical pharmacology studies by implementing a variety of machine learning algorithms and statistical methods, combining them with Shiny package in R, an integrated suite of software facilities for data manipulation, calculation and graphical display. This platform is user-friendly and efficiently manages raw data uploads, data conversions, drug efficacy overview, biomarker discovery analysis as well as data report generation. In conclusion, our platform provides a new solution for precision biomarker discovery in preclinical, especially immune-oncology studies.

Citation Format: Jia Xue, Henry QX Li, Sheng Guo. An automated biomarker discovery platform based on in vitro pharmacology raw data [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A026. doi:10.1158/1535-7163.TARG-19-A026
Abstract A034: The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751
Authors: Pant Shubham , Lamar Maria , Kazakin Julia , Savage Ronald , Schwartz Brian , hall terence
Published: March 2020

Background: AKT, a critical node in the PI3K/AKT/mTOR pathway, is one of the most frequently activated protein kinases in human cancers. ARQ 751 is a potent and highly selective pan-AKT inhibitor against AKT1, AKT2, and AKT3, and is currently in a phase 1b clinical trial as a single agent, or combination with paclitaxel or fluvestrant. Inhibition of the PI3K/AKT pathway is known to cause increases in serum glucose and insulin in patients. Recent advances in next generation sequencing technologies are providing physicians and researchers with access to tumor genomic data, including circulating tumor DNA (ctDNA), to support and evaluate treatment strategies. Methods: Samples were collected for pharmacokinetic, pharmacodynamic, and genetic analysis. PK samples were collected on Days 1 and 22 to generate PK profiles. Samples were analyzed, and PK parameters generated, including Cmax, AUC, and t1/2 (where possible). Biomarkers evaluated for target engagement were serum glucose and insulin. Finally, whole blood was collected and mutational status of ctDNA was analyzed using Guardant360. Results: The Recommended Phase 2 Dose (RP2D) of ARQ 751 was determined to be 75 mg QD, with a mean Cmax of 263 ng/mL and an AUClast 2240 h*ng/mL on Day 22. Changes in both serum insulin and glucose were observed, and these increases correlated with ARQ 751 exposure. In patients with detectable levels of ctDNA (matching tumor); 6 (1PR, 4SD, 1PD) showed a decrease between Cycle 1, Day 1 and Cycle, 2 Day 1, and 3 showed an increase (1PR, 1SD, 1 PD). Conclusions: Preliminary PK, PD, and ctDNA data support the selection of 75 mg QD as the RP2D for ARQ 751. ARQ 751 plasma levels at this dose produced increases in both serum insulin and glucose, confirming target engagement. Additionally, an evaluation of a limited set of pre and post treatment ctDNA data provides interesting new insights on patient’s responses to therapy. Additional data to be presented at the meeting.

Citation Format: Shubham Pant, Maria Lamar, Julia Kazakin, Ronald Savage, Brian Schwartz, terence hall. The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A034. doi:10.1158/1535-7163.TARG-19-A034
Abstract A097: Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models
Authors: Burke Patrick J , Hamilton Joseph Z , Pires Thomas A , Emmerton Kim K , Senter Peter D , Jeffrey Scott C
Published: March 2020

As antibody-drug conjugates (ADCs) find increasing clinical application, treatment-related resistance mechanisms may eventually impact efficacy. One resistance mechanism that emerges following prolonged exposure to auristatin-based ADCs such as brentuximab vedotin and polatuzumab vedotin involves upregulation of efflux pumps that confer the multidrug resistance positive (MDR+) phenotype. New payload technologies that retain activity in this context may be important for next-generation anti-tubulin ADCs. The tubulysins are a potent class of tubulin binders consisting of natural products and designed analogues which have become a compelling cytotoxic payload for drug targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express MDR-conferring transporters. Recently, we developed the quaternary ammonium linker system to conjugate tertiary amine-containing payloads and applied it to the tubulysins. In this work, β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads for activity in MDR+ models. The resulting conjugates displayed high potency in multiple MDR+ models at well-tolerated doses, including those resistant to MMAE-based ADCs. In addition to potency in resistant models, the tubulysin conjugates also retained bystander activity - a property in common with vedotin-based conjugates and important for indications characterized by heterogeneous antigen expression. Thus, the glucuronide-tubulysin M linker could enable future ADC programs designed for the treatment of resistant tumors due to emergence of MDR transporters.

Citation Format: Patrick J Burke, Joseph Z Hamilton, Thomas A Pires, Kim K Emmerton, Peter D Senter, Scott C Jeffrey. Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A097. doi:10.1158/1535-7163.TARG-19-A097