bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydration Mimicry by Membrane Ion Channels
Authors: Chaudhari Mangesh I. , Vanegas Juan M. , Pratt L.R. , Muralidharan Ajay , Rempe Susan B.
Published: March 2020

Ions transiting biomembranes might pass readily from water through ion-specific membrane proteins if these protein channels provide environments similar to the aqueous solution hydration environment. Indeed, bulk aqueous solution is an important reference condition for the ion permeation process. Assessment of this hydration mimicry concept depends on understanding the hydration structure and free energies of metal ions in water in order to provide a comparison for the membrane channel environment. To refine these considerations, we review local hydration structures of ions in bulk water and the molecular quasi-chemical theory that provides hydration free energies. In doing so, we note some current views of ion binding to membrane channels and suggest new physical chemical calculations and experiments that might further clarify the hydration mimicry concept.
Climate Change and Society
Authors: Dietz Thomas , Shwom Rachael L. , Whitley Cameron T.
Published: March 2020

Climate change is one of the greatest ecological and social challenges of the twenty-first century. Sociologists have made important contributions to our knowledge of the human drivers of contemporary climate change, including better understanding of the effects of social structure and political economy on national greenhouse gas emissions, the interplay of power and politics in the corporate sector and in policy systems, and the factors that influence individual actions by citizens and consumers. Sociology is also poised to make important contributions to the study of climate justice across multiple lines of stratification, including race, class, gender, indigenous identity, sexuality and queerness, and disability, and to articulate the effects of climate change on our relationship to nonhuman species. To realize its potential to contribute to the societal discourse on climate change, sociology must become theoretically integrated, engage with other disciplines, and remain concerned with issues related to environmental and climate inequalities.
Chronic Corynebacterium striatum Septic Arthritis in a Patient Referred for Total Knee Arthroplasty
Authors: Hollnagel Katharine , Willen Jacob , Ellis Michael , Soleimanifard Yalda , Booth Robert , Nandi Sumon
Published: March 2020

Background. While Corynebacterium striatum and other Corynebacterium species were historically considered contaminants, they are recently being identified as pathogens with increasing frequency. Case Summary. We report the case of a 78-year-old gentleman with a three-year history of knee pain and established diagnosis of osteoarthritis referred for consideration for total knee arthroplasty. He had no knee pain with passive range-of-motion. Plain films demonstrated bony erosions atypical for osteoarthritis. Joint aspiration white blood cell count was 30,548/mm3, but multiple cultures were positive for C. striatum. The infection was successfully treated with open irrigation and debridement, complete synovectomy, and six weeks of intravenous daptomycin. Conclusion. To our knowledge, this is the first report of chronic C. striatum septic arthritis of a native joint and only the third case of C. striatum septic arthritis of the knee.
Early Recurrence of Ovarian Cancer during Pregnancy after Primary Staging Surgery in the First Trimester
Authors: Akazawa Munetoshi , Hashimoto Kazunori
Published: March 2020

Cancer during pregnancy is rare. However, even during pregnancy, there is the possibility of recurrence for the patients. We present the case of recurrence of ovarian cancer during pregnancy regardless of primary staging surgery performed in the first trimester of the same pregnancy. The patient was a 29-year-old woman who underwent fertility-sparing surgery at 15 weeks of pregnancy for ovarian cancer (mucinous adenocarcinoma, FIGO stage IC). Omitting adjuvant chemotherapy during pregnancy, we continued the prenatal checkups in the outpatient. At 31 weeks of gestation, massive ascites emerged and oliguria/anuria developed acutely. We performed emergent cesarean section, diagnosing acute kidney injury during pregnancy. On surgical finding, there were a number of 1 cm sized nodules in the small bowel wall and peritoneum. The infant was appropriate for gestational age without any abnormalities. Oliguria continued due to rapid accumulation of ascites in the early postpartum period. After two cycles of chemotherapy, ascites decreased gradually and the markers gradually decreased. However, after six courses of chemotherapy, she suddenly complained of nausea and anorexia. CT imaging showed cancerous ileus and ascites fluids. The patient chose palliative care. Even in the case of nonadvanced cancer, it has the potential to be an extremely aggressive malignancy under the irregular hormonal environment of pregnancy.
Optimization of Subway Advertising Based on Neural Networks
Authors: Sun Ling , Yang Yanbin , Fu Xuemei , Xu Hao , Liu Wei
Published: March 2020

Subway advertising has become a regular part of our daily lives. Because the target audiences are high-level consumers, subway advertising can promote the return on investment. Such advertising has taken root in various countries and regions. However, a lack of appropriate oversight, a single-track operating mode of subway advertising, and unclear price standards significantly reduced the expected advertising effects and the reasonableness of advertising quotations. The shared biking services have gained a great amount of attention in the past few years. Besides, more citizens get involved in using public transportation, which provides a basis for analyzing subway passenger characteristics. First, we examined the use of shared bikes around subway stations to obtain the information on passengers’ age. Then, using daily passenger flow volume, transfer lines, and the original subway advertising quotes, we trained backpropagation neural networks and used the results to provide new quotations. Finally, we combined passenger age structure and different passenger groups’ preferences in every station to identify the most suitable advertisement type. Our goal was to make full use of transportation big data to optimize advertising quotations and advertisement selection for subway stations. We also proposed the using of electronic advertising board to help increase the subway advertising profits, decrease the financial pressure of operations, and boost the public transportation development.
Experimental Study of a Humidification-Dehumidification Seawater Desalination System Combined with the Chimney
Authors: Cao Fei , Liu Qingjun , Xiao Hong
Published: March 2020

The solar humidification-dehumidification system is of high significance to the freshwater supply in remote areas. In the present study, a humidification-dehumidification seawater desalination system combined with the chimney is designed and experimentally evaluated. Main parameters influencing its freshwater productivity are analyzed. It is found from this study that the cooling tower is required to obtain long-term steady freshwater generation. Raising the temperature difference between the evaporation and condensation chambers would lead to the rise of the freshwater productivity. There is a turning wind speed, beyond which increasing the wind speed would lead to the decline of both the freshwater productivity and the thermal efficiency. The turning wind speed is relevant to the ambient humanity and the heating power. Decreasing the heat power would increase the turning wind speed. When the heating power is 4.9 kW, the highest freshwater productivity and the highest efficiency are 48 g/min and 32.14%, respectively.
An Enhanced Grasshopper Optimization Algorithm to the Bin Packing Problem
Authors: Feng Hangwei , Ni Hong , Zhao Ran , Zhu Xiaoyong
Published: March 2020

The grasshopper optimization algorithm (GOA) is a novel metaheuristic algorithm. Because of its easy deployment and high accuracy, it is widely used in a variety of industrial scenarios and obtains good solution. But, at the same time, the GOA algorithm has some shortcomings: (1) original linear convergence parameter causes the processes of exploration and exploitation unbalanced; (2) unstable convergence speed; and (3) easy to fall into the local optimum. In this paper, we propose an enhanced grasshopper optimization algorithm (EGOA) using a nonlinear convergence parameter, niche mechanism, and the β-hill climbing technique to overcome the abovementioned shortcomings. In order to evaluate EGOA, we first select the benchmark set of GOA authors to test the performance improvement of EGOA compared to the basic GOA. The analysis includes exploration ability, exploitation ability, and convergence speed. Second, we select the novel CEC2019 benchmark set to test the optimization ability of EGOA in complex problems. According to the analysis of the results of the algorithms in two benchmark sets, it can be found that EGOA performs better than the other five metaheuristic algorithms. In order to further evaluate EGOA, we also apply EGOA to the engineering problem, such as the bin packing problem. We test EGOA and five other metaheuristic algorithms in SchWae2 instance. After analyzing the test results by the Friedman test, we can find that the performance of EGOA is better than other algorithms in bin packing problems.
The Centrosymmetric Matrices of Constrained Inverse Eigenproblem and Optimal Approximation Problem
Authors: Shen Jinrong , Liu Wei , Wang Baiyu , Peng Xiangyang
Published: March 2020

In this paper, a kind of constrained inverse eigenproblem and optimal approximation problem for centrosymmetric matrices are considered. Necessary and sufficient conditions of the solvability for the constrained inverse eigenproblem of centrosymmetric matrices in real number field are derived. A general representation of the solution is presented for a solvable case. The explicit expression of the optimal approximation problem is provided. Finally, a numerical example is given to illustrate the effectiveness of the method.
Polytrauma in Older Adults Leads to Significantly Increased TIMP-1 Levels in the Early Posttraumatic Period
Authors: Braunstein Mareen , Kusmenkov Thomas , Mutschler Wolf , Kammerlander Christian , Böcker Wolfgang , Bogner-Flatz Viktoria
Published: March 2020

Background. Patients after polytrauma regularly suffer from posttraumatic immune system destabilization, which closely influences the further clinical development. Increasing age has recently been identified as an isolated risk factor for an adverse outcome after major trauma. Higher rates and intensity of acute inflammation following severe injury suggest that deregulated inflammation may contribute to these higher rates of posttraumatic morbidity and mortality in older adults. MMP-9 and TIMP-1 have been found to play a major role in posttraumatic immune disorder in a previous genome-wide mRNA analysis. Objective. The aim of this study was to evaluate the differences in serum protein dynamics in older and younger polytraumatized adults. Methods. Blood samples were drawn immediately within 90 minutes after trauma and subsequently after 6, 12, 24, 48, and 72 h. Serum levels of TIMP-1 and MMP-9 were quantified using ELISA. Age groups were divided according to a cutoff of 60 years. Results. 60 polytrauma patients (ISS>16) were included (<60 years, n=49; ≥60 years, n=11). Serum TIMP-1 and MMP-9 levels showed a highly significant serum dynamic in young and old polytrauma patients (p<0.001). Patients≥60 years showed significantly higher overall TIMP-1 levels (p=0.008). TIMP-1 levels showed a significant maximum after 72 h in the older study population. MMP-9 levels were nonsignificantly higher during the whole observational period in older polytrauma patients when compared to younger patients. Conclusion. The posttraumatic immune response is characterized by significantly higher TIMP-1 levels in older polytrauma patients. This significant association between TIMP-1 levels and patients’ age indicates a more extensive immune dysregulation following major trauma in older adults.
Apolipoprotein E Gene Polymorphism, Glycated Hemoglobin, and Peripheral Arterial Disease Risk in Chinese Type 2 Diabetic Patients
Authors: Hu Yujing , Ling Tinghuan , Yu Min , Bai Yang , Feng Tongbao , Zhang Ping , Wang Yan
Published: March 2020

Background. The apolipoprotein E (ApoE) gene polymorphism has been found to influence plasma lipid concentration, and its correlation with peripheral arterial disease (PAD) has been investigated. However, it is unclear whether ApoE is associated with PAD in Chinese type 2 diabetes mellitus (T2DM) patients. Therefore, our study is aimed at investigating the relationship between the ApoE gene polymorphism and PAD in Chinese T2DM patients. Methods. A total of 192 T2DM patients were divided into two groups: T2DM and T2DM with PAD. The clinical and biochemical parameters were obtained. Polymerase chain reaction was used to identify the genotypes of ApoE. The multivariable logistic regression analysis was used to identify the possible risk factor for PAD. Results. There were no significant differences in the genotype and allele frequencies of ApoE between the T2DM and T2DM with PAD groups. However, the T2DM with PAD group tended to have more ε4/ε3 genotypes (21.5% vs. 11.3%) than the T2DM group. The multivariate logistic regression showed that smoking, age, disease duration, TG, LDL, and HbA1c were risk factors for PAD. Conclusions. These results demonstrated that there was no evidence of a relationship between ApoE and PAD.
Diagnosis and Management of Lemierre’s Syndrome Presented with Multifocal Pneumonia and Cerebral Venous Sinus Thrombosis
Authors: Sattar Yasar , Susheela Ammu Thampi , Karki Bibek , Liaqat Adnan , Ullah Waqas , Zafrullah Fnu
Published: March 2020

A 27-year-old female patient initially presented with fever, myalgia, sore throat that progressed to multifocal pneumonia, and cerebral sinus venous thrombosis. A combination of upper respiratory symptoms with tooth infection, positive blood culture for Fusobacterium nucleatum, computed tomography (CT) chest finding of multifocal pneumonia, and magnetic resonance imaging (MRI) finding of internal jugular vein thrombosis (IJVT) and cerebral venous sinus thrombosis (CVST) suggested Lemierre syndrome. The patient was managed with fluids, antibiotics, and anticoagulants. The patient survived and discharged from the hospital. The patient’s symptoms improved at 2 months of follow-up.
Linear Complexity of a New Class of Quaternary Generalized Cyclotomic Sequence with Period 2pm
Authors: Ke Pinhui , Zhong Yan , Zhang Shengyuan
Published: March 2020

Sequences with high linear complexity property are of importance in applications. In this paper, based on the theory of generalized cyclotomy, new classes of quaternary generalized cyclotomic sequences with order 4 and period 2pm are constructed. In addition, we determine their linear complexities over finite field F4 and over ℤ4, respectively.
Mobile Robot Path Planning Based on a Generalized Wavefront Algorithm
Authors: Wu Sifan , Du Yu , Zhang Yonghua
Published: March 2020

This study develops a generalized wavefront algorithm for conducting mobile robot path planning. The algorithm combines multiple target point sets, multilevel grid costs, logarithmic expansion around obstacles, and subsequent path optimization. The planning performances obtained with the proposed algorithm, the A∗ algorithm, and the rapidly exploring random tree (RRT) algorithm optimized using a Bézier curve are compared using simulations with different grid map environments comprising different numbers of obstacles with varying shapes. The results demonstrate that the generalized wavefront algorithm generates smooth and safe paths around obstacles that meet the required kinematic conditions associated with the actual maneuverability of mobile robots and significantly reduces the planned path length compared with the results obtained with the A∗ algorithm and the optimized RRT algorithm with a computation time acceptable for real-time applications. Therefore, the generated path is not only smooth and effective but also conforms to actual robot maneuverability in practical applications.
Different Incidence of Early-Onset Gastric Carcinoma Depending on Ethnicity: Preliminary Results of a Hospital in Liangshan
Authors: Li Shen , Rexin Peter , Qin Zhang , Changbo Chen , Guanghui Chen , Luyao Wang , Voelker Hans-Ullrich , Stauch Gerhard
Published: March 2020

Background. In China, the incidence of cancer has significantly decreased over the last two decades. In contrast, the incidence of gastric carcinoma (GC) has risen in young patients. Methods. We reevaluated the histopathological results of 4,353 endoscopic gastroscopies from the Department of Pathology at No 1 Hospital of Liangshan. The ethnic groups Han and Yi were almost equally distributed in this cohort. Over a five-year period, 1407 GC were diagnosed. Results. In 171 of these cases (12%), the patients were ≤40 years old (early-onset GC, EOGC). Out of this cohort, 9 patients were aged ≤25 years. 54% of these patients were male and showed marked predominance (92%) of the Yi-minority. Using the classification of Lauren, 103 GC (60%) were of diffuse type, 27 (16%) of intestinal type, and 41 (24%) of mixed type. In the remaining 1,236 cases of patients ≥41 years (88%), 1,014 patients (82%) belonged to the Yi-minority. Helicobacter pylori (HP) were found in 46% of all cases. Familial clustering was found in 14 patients (18%; in first degree relatives, 12%, and in second degree relatives, 6%). Follow-up was not possible. Conclusion. This study demonstrates the unequal manifestation of EOGC within the two ethnic groups of Han and Yi. However, familial clustering was infrequent. Further investigations are necessary to discover relevant risk factors apart from hereditary predisposition.
How to Choose Platelet-Rich Plasma or Hyaluronic Acid for the Treatment of Knee Osteoarthritis in Overweight or Obese Patients: A Meta-Analysis
Authors: Luo Pan , Xiong Zhencheng , Sun Wei , Shi Lijun , Gao Fuqiang , Li Zirong
Published: March 2020

Objective. The purpose of this meta-analysis was to determine whether platelet-rich plasma (PRP) was better than hyaluronic acid (HA) for the treatment of knee osteoarthritis (OA) in overweight or obese patients.Design. Two reviewers independently used the keywords combined with free words to search English-based electronic databases according to Cochrane Collaboration guidelines, such as PubMed, Embase, ScienceDirect, and Cochrane library. The pooled data were analyzed using RevMan 5.3.Results. Ten randomized controlled trials (RCTs) with 1096 patients were included. During the first two months of follow-up, there was no significant difference between the two groups. At the 3rd, 6th, and 12th months of follow-up, the pooled analysis showed that PRP was better than HA for the treatment of knee OA in overweight or obese patients. There were significant differences between the two groups at Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (3 months: MD = −1.35, [95% CI: −2.19 to −0.50],P=0.002,I2 = 0%; 6 months: MD = −7.62, [95% CI: −13.51 to −1.72],P=0.01,I2 = 88%; 12 months: MD = −12.11, [95% CI: −20.21 to −4.01],P=0.003,I2 = 94%).Conclusions. For overweight or obese patients with knee OA, intra-articular injection of PRP in a short time was not necessarily superior to HA, but long-term use was better than HA in pain and functional relief.
The Improved Value-at-Risk for Heteroscedastic Processes and Their Coverage Probability
Authors: Syuhada Khreshna
Published: March 2020

A risk measure commonly used in financial risk management, namely, Value-at-Risk (VaR), is studied. In particular, we find a VaR forecast for heteroscedastic processes such that its (conditional) coverage probability is close to the nominal. To do so, we pay attention to the effect of estimator variability such as asymptotic bias and mean square error. Numerical analysis is carried out to illustrate this calculation for the Autoregressive Conditional Heteroscedastic (ARCH) model, an observable volatility type model. In comparison, we find VaR for the latent volatility model i.e., the Stochastic Volatility Autoregressive (SVAR) model. It is found that the effect of estimator variability is significant to obtain VaR forecast with better coverage. In addition, we may only be able to assess unconditional coverage probability for VaR forecast of the SVAR model. This is due to the fact that the volatility process of the model is unobservable.
Successful Treatment of Crizotinib-Induced Fulminant Liver Failure: A Case Report and Review of Literature
Authors: Kreitman Kyle , Nair Satheesh P. , Kothadia Jiten P.
Published: March 2020

Crizotinib is a first-line tyrosine kinase inhibitor used for the treatment of metastatic lung cancer. Crizotinib-induced hepatotoxicity is a rare event. We report a case of a 46-year-old female with a history of metastatic lung cancer who presented with acute liver failure after being on crizotinib for two months. The medication was discontinued, and she was treated with N-acetylcysteine for seven days. Her liver function tests returned to normal limits after 26 days after admission. The precise mechanism and risk factors of crizotinib-induced hepatotoxicity remain unknown. Physicians should be aware of the potentially lethal side effect caused by crizotinib.
Evaluation Method of Multiobjective Functions’ Combination and Its Application in Hydrological Model Evaluation
Authors: Huo Jiuyuan , Liu Liqun
Published: March 2020

Parameter optimization of a hydrological model is intrinsically a high dimensional, nonlinear, multivariable, combinatorial optimization problem which involves a set of different objectives. Currently, the assessment of optimization results for the hydrological model is usually made through calculations and comparisons of objective function values of simulated and observed variables. Thus, the proper selection of objective functions’ combination for model parameter optimization has an important impact on the hydrological forecasting. There exist various objective functions, and how to analyze and evaluate the objective function combinations for selecting the optimal parameters has not been studied in depth. Therefore, to select the proper objective function combination which can balance the trade-off among various design objectives and achieve the overall best benefit, a simple and convenient framework for the comparison of the influence of different objective function combinations on the optimization results is urgently needed. In this paper, various objective functions related to parameters optimization of hydrological models were collected from the literature and constructed to nine combinations. Then, a selection and evaluation framework of objective functions is proposed for hydrological model parameter optimization, in which a multiobjective artificial bee colony algorithm named RMOABC is employed to optimize the hydrological model and obtain the Pareto optimal solutions. The parameter optimization problem of the Xinanjiang hydrological model was taken as the application case for long-term runoff prediction in the Heihe River basin. Finally, the technique for order preference by similarity to ideal solution (TOPSIS) based on the entropy theory is adapted to sort the Pareto optimal solutions to compare these combinations of objective functions and obtain the comprehensive optimal objective functions’ combination. The experiments results demonstrate that the combination 2 of objective functions can provide more comprehensive and reliable dominant options (i.e., parameter sets) for practical hydrological forecasting in the study area. The entropy-based method has been proved that it is effective to analyze and evaluate the performance of different combinations of objective functions and can provide more comprehensive and impersonal decision support for hydrological forecasting.
Dynamics of Unilateral and Bilateral Control Systems with State Feedback for Renewable Resource Management
Authors: Huang Mingzhan , Liu Shouzong , Song Xinyu , Chen Lansun
Published: March 2020

In this paper, mathematical models for the management of biological resources based on a given predator-prey relationship are proposed, and two types of control strategies, unilateral and bilateral control with impulsive state feedback, are studied. The existence of the order-1 homoclinic orbit, order-1 periodic solution, and bifurcation of homoclinic of the unilateral control system are obtained, and the attraction region of this system is also discussed. Besides, sufficient conditions for the existence and stability of the order-1 and order-2 periodic solutions of the bilateral control system are also gained. A series of numerical simulations including bifurcation diagrams of periodic solution are performed, which not only verify the theoretical results we get but also reveal some peculiar dynamical phenomena, such as the appearance of high-order periodic solutions and existence of parameter intervals with drastic order change of periodic solution. By comparing the two management strategies, our study encourages bilateral control rather than unilateral control for the risk of predator extinction.
Quantitative Evaluation of Visual Aesthetics of Human-Machine Interaction Interface Layout
Authors: Deng Li , Wang Guohua
Published: March 2020

The current research on human-machine interaction interface layout focused on ergonomic analysis, while the research on aesthetics and aesthetic degree calculation of interface layout was insufficient. In order to objectively evaluate the aesthetic degree of interface layout, this paper put forward an aesthetic degree evaluation method of interface design based on Kansei engineering. Firstly, the perceptual image structure of interface aesthetic degree was analyzed from the perspective of aesthetic cognition. Six aesthetic image factors affecting interface aesthetic degree, including proportion, conciseness, order, rhythm, density, and equilibrium, were extracted by factor analysis method, and the variance contribution rate of each factor was taken as the weight. Secondly, according to the six aesthetic degree indexes, the calculation system of interface aesthetic degree was constructed, and the aesthetic degree value of aesthetic image factor was calculated by the corresponding aesthetic degree evaluation mathematical formula. Then, Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method was used to analyze the order of aesthetic degree superiority of design schemes, and the comprehensive aesthetic degree evaluation was carried out. Finally, the aesthetic degree evaluation of human-machine interaction interface layout of the driller’s console of an AC variable frequency drilling rig was taken as an example to verify that this method was helpful for designers to optimize the design scheme. The experimental results showed that the proposed method was feasible and effective compared with the method of paired comparison commonly used in psychophysics.
Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity
Authors: Sun Linlin , Li Chia-Wei , Chung Ezra M. , Yang Riyao , Kim Yong-Soo , Park Andrew H. , Lai Yun-Ju , Yang Yi , Wang Yu-Han , Liu Jielin , Qiu Yufan , Khoo Kay-Hooi , Yao Jun , Hsu Jennifer L. , Cha Jong-Ho , Chan Li-Chuan , Hsu Jung-Mao , Lee Heng-Huan , Yoo Stephen S. , Hung Mien-Chie
Published: March 2020

Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.

Significance:

These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.
ICOS Is an Indicator of T-cell–Mediated Response to Cancer Immunotherapy
Authors: Xiao Zunyu , Mayer Aaron T. , Nobashi Tomomi W. , Gambhir Sanjiv S.
Published: March 2020

Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell–mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer.

Significance:

ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.

See related commentary by Choyke, p. 2975
RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome
Authors: Rooney Nicholas , Mason Susan M. , McDonald Laura , Däbritz J. Henry M. , Campbell Kirsteen J. , Hedley Ann , Howard Steven , Athineos Dimitris , Nixon Colin , Clark William , Leach Joshua D.G. , Sansom Owen J. , Edwards Joanne , Cameron Ewan R. , Blyth Karen
Published: March 2020

The recurring association of specific genetic lesions with particular types of cancer is a fascinating and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where, although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown protumorigenic role for the RUNX genes in this disease setting. Analysis of patient tumor biopsies together with loss-of-function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared with patients with low expression. This was functionally relevant, as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability in vitro and in vivo. Transcriptional profiling of RUNX1-CRISPR–deleted cells revealed a gene signature dominated by extracellular matrix remodeling, notably affecting STMN3, SERPINH1, and EPHRIN signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC.

Significance:

These data reveal a novel unexplored oncogenic role for RUNX genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC.
Evaluation of p16/Ki-67 Dual-Stained Cytology in Triaging HPV-Positive Women during Cervical Cancer Screening
Authors: Hu Yuan , Hong Zubei , Gu Liying , Xie Li , Yang Binlie , Dai Haiyan , Chen Hua , Zhang Baohua , Huang Lixia , Liu Zhou , Cheng Jingxin , Zhang Yu , Zhang Yu , Lin Jianhua , Qiu Lihua , Di Wen
Published: March 2020

Background:

We aimed to evaluate the utility of p16/Ki-67 dual-stained cytology for triaging human papillomavirus (HPV)-positive women.

Methods:

HPV-positive women ages ≥ 21 years were recruited in a multicenter prospective observational study between May 2016 and May 2017. The clinical performance of dual-stained cytology, with or without HPV16/18 genotyping, was evaluated for all HPV-positive women to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Results:

846 HPV-positive women ages ≥ 21 years with valid cervical biopsies were enrolled for this study. For CIN2+ detection, dual-stained cytology showed statistically higher specificity (85.28%) than Pap cytology (80.00%, P < 0.001) and HPV16/18 genotyping (72.36%, P < 0.001), while the sensitivity of dual-stained cytology (63.49%) remained comparable with that of Pap cytology (61.90%, P = 0.832) and HPV16/18 genotyping (61.90%, P = 0.897). HPV16/18 genotyping in combination with dual-stained cytology was more specific (62.50% vs. 58.06%, P < 0.001), while it showed similar sensitivity (86.51% vs. 85.71%, P = 1.000), as compared with HPV16/18 genotyping in combination with Pap cytology. Similar patterns were also observed for CIN3+.

Conclusions:

p16/Ki-67 dual-stained cytology, either alone or in combination with HPV16/18 genotyping, showed a good stratification with high specificity and comparable sensitivity for HPV-positive women.

Impact:

This is one of the few studies that has evaluated the performance of dual-stained cytology for triaging HPV-positive women in China. The higher specificity and comparable sensitivity of dual-stained cytology in comparison with Pap cytology in the detection of CIN2+ or CIN3+ is of vital importance to developing countries, where Pap cytology faces many challenges.
Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia
Authors: Danilov Alexey V. , Herbaux Charles , Walter Harriet S. , Hillmen Peter , Rule Simon A. , Kio Ebenezer A. , Karlin Lionel , Dyer Martin J.S. , Mitra Siddhartha S. , Yi Ping Cheng , Humeniuk Rita , Huang Xi , Zhou Ziqian , Bhargava Pankaj , Jürgensmeier Juliane M. , Fegan Christopher D.
Published: March 2020

Purpose:

Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.

Patients and Methods:

Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20–150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day).

Results:

Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study.

Conclusions:

Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).
GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer
Authors: O’Kane Grainne M. , Grünwald Barbara T. , Jang Gun-Ho , Masoomian Mehdi , Picardo Sarah , Grant Robert C. , Denroche Robert E. , Zhang Amy , Wang Yifan , Miller Jessica K. , Lam Bernard , Krzyzanowski Paul M. , Lungu Ilinca M. , Bartlett John M.S. , Peralta Melanie , Vyas Foram , Khokha Rama , Biagi James , Chadwick Dianne , Ramotar Stephanie , Hutchinson Shawn , Dodd Anna , Wilson Julie M. , Notta Faiyaz , Zogopoulos George , Gallinger Steven , Knox Jennifer J. , Fischer Sandra E.
Published: March 2020

Purpose:

To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.

Experimental Design:

Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored.

Results:

Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature.

Conclusions:

The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.

See related commentary by Collisson, p. 4715
Inhibition of Importin β1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-resistant Tumor Cells
Authors: Kojima Yuko , Nishina Takashi , Nakano Hiroyasu , Okumura Ko , Takeda Kazuyoshi
Published: March 2020

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.
Elucidation of Pelareorep Pharmacodynamics in A Phase I Trial in Patients with KRAS-Mutated Colorectal Cancer
Authors: Goel Sanjay , Ocean Allyson J. , Parakrama Ruwan Y. , Ghalib Mohammad H. , Chaudhary Imran , Shah Umang , Viswanathan Sengottuvel , Kharkwal Himanshu , Coffey Matthew , Maitra Radhashree
Published: March 2020

KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150–180 mg/m2) and pelareorep (1 × 1010 TCID50–3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1–5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral “homing” in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.
Three Aral Sea Films and the Soviet Ecology
Authors: Brookes Alec
Published: March 2020

Drawing on analysis of three films that converge on the Aral Sea and span from 1929 to 1988, Alec Brookes engages with Marxist scholarship on the Anthropocene and Capitalocene to argue that the Soviet ecology rested on the same fundamental principle of the Capitalist world ecology: the alienation of indigenous producers from land in waves of primitive accumulation. The Forty-First (1956) and Turksib (1929) both show how, alongside other devices, the dialectics of film form as theorized by Sergei Eisenstein were repurposed to reframe the conquest of “Man” over “Nature” and ultimately to appropriate land from producers within an ostensibly Marxist framework. In The Needle (1988), on an already desiccated Aral Sea, director Rashid Nugamov suggests that the restoration of Asian land to Asian producers provides a way forward after the decay and depravation of the Soviet ecology. The analysis here suggests that to confront the Capitalist world ecology in the present we must work to restore land to indigenous producers and promote indigenous ecological relations.
Folds in the Fabric: Robert Morris in the 1980s
Authors: Lotery Kevin
Published: March 2020

At the beginning of the 1980s, Robert Morris took a decisive and shocking turn. Abandoning the strategies of agency reduction, abstraction, and indeterminacy that had guided his practice since the 1960s, he began to make paintings instead. Architectural in scale and gaudy in their depictions of eviscerated human remains and post-apocalyptic landscapes, the new paintings trafficked in those myths of painting that Neo-Expressionism was just then resurrecting as bankable signs for a consumerist decade: expressivity, figuration, and narrative, among them. What, then, could unite the theorist of anti form—maker of the process-based, anti-object folds, tangles, and mounds of felt and thread waste—with the painter of the baroque, Neo-Expressionist daubs? This paper argues that the paintings of the 1980s, despite their seeming reversals, provide a key for understanding Morris's way of working from his earliest lead and felt projects forward. What they reveal, in short, is an oeuvre guided by a baroque logic of “the fold,” an aesthetic of non-invention that aimed, not at creating but at commandeering and multiplying, for better or worse, existing aesthetic and discursive structures, be they those of Conceptual art, post-Minimalism, or Neo-Expressionism.
Heritage and Debt
Authors: Joselit David
Published: March 2020

In a brief excerpt from his book Heritage and Debt: Art in Globalization (MIT, Spring 2020), David Joselit discusses how global contemporary art reanimates the past as a resource for the present, combating modern art's legacy of Eurocentrism.
What Would Douglas Crimp Say?
Authors: Lawler Louise
Published: March 2020

What would Douglas Crimp Say?
The Authenticity of Paracelsus’ Astronomia Magna and Brief an die Wittenberger Theologen: Towards a Diagnostic Rubric Clarifying Authentic and Spurious Elements in Paracelsus’ Oeuvre on the Basis of Theological Motifs
Authors: Daniel Dane T.
Published: March 2020

The paper is an evaluation of differing opinions regarding the authenticity of two of Paracelsus’ works, the Astronomia Magna (1537/1538) and Brief an die Wittenberger Theologen (1525). Karl Sudhoff – the exceptionally erudite and prolific Paracelsus scholar and editor – considered Paracelsus’ letter to Luther and the Wittenberg theologians to be spurious. Others have questioned the extent to which the Astronomia Magna (often considered to be Paracelsus’ Meisterstück) should be placed among the genuine texts of the Paracelsian corpus. Based on historical and conceptual data, and focusing on Paracelsus’ theology, the author argues that both works under consideration are authentic. The study thus highlights the need to develop a diagnostic rubric for evaluating the authenticity of works in the Paracelsian oeuvre and suggests ideas toward this end on the basis of theological motifs prevalent within Paracelsus’ clearly authentic works.
The Astronomia Olympi novi and the Theologia Cabalistica: Two Pseudo-Paracelsian Works of the Philosophia Mystica (1618)
Authors: Žemla Martin
Published: March 2020

The Astronomia Olympi novi and the Theologia Cabalistica were published as part of the Philosophia Mystica (1618). This influential collection of Paracelsian and Weigelian texts was among the first to include a publication of the theologica of Paracelsus. Both of these short pseudo-Paracelsian works were written by Adam Haslmayr (1560-1630), the propagator of the “Theophrastia Sancta,” a philosophical theology of Paracelsus mixed with Weigelian and alchemical influences. These works, taken in the Philosophia Mystica, are among the very few of his texts that appeared in print in his lifetime. In this paper, the content of both pseudepigrapha is analyzed and related to ideas found in both the authentic and the pseudepigraphic works of Paracelsus, as well as in relevant works of some Paracelsians (Khunrath, Figulus, Weigel, Croll, Siebmacher and Mögling). Specifically, the notions of the “Olympus novus” and the “cabalistic principles” are discussed in a wider context.