bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on feline infectious peritonitis
Authors: Barker Emi , Tasker Séverine
Published: September 2020

Background

Feline coronavirus (FCoV) infection in cats is common, usually only causing mild intestinal signs, such as diarrhoea. It is highly infectious and found worldwide. A sequela of FCoV infection, feline infectious peritonitis (FIP), is a common cause of death in young cats, occurring in up to 10 per cent of cats infected with FCoV. Although suspicion of FIP is frequent in sick, particularly young, cats, obtaining a definitive diagnosis using non‐ or minimally‐invasive approaches is difficult.

Aim of the article

This article provides an update regarding diagnosing cases of FIP and guidance on current treatment recommendations.
Lesson of the month: novel method to quantify neutrophil uptake in early lung cancer using SPECT-CT
Authors: Farahi Neda , Gillett Daniel , Southwood Mark , Rassl Doris , Tregay Nicola , Hill Uta , Preston Stephen Denis , Loutsios Chrystalla , Lok Laurence Si Chong , Heard Sarah , Buscombe John , Rintoul Robert Campbell , Peters A Michael , Summers Charlotte , Chilvers Edwin R
Published: September 2020

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.
Tobacco use and access among 13 to 15 year olds in Kuna Yala, an indigenous region of Panama
Authors: Quintana Hedley , Roa Reina
Published: September 2020

Background

Panama has the lowest overall prevalence of tobacco use in the Americas, however rates are almost three times higher in the indigenous territory of Kuna Yala compared with the national average. Most people who smoke started during adolescence, making this a key period for tobacco control efforts.

Objective

We aimed to examine tobacco access and use among adolescents (13 to 15 years old) in Kuna Yala compared with nationwide Panama using data from the 2017 Global Youth Tobacco Survey, a standardised international tool for assessing key tobacco control indicators among adolescents.

Results

The prevalence of current tobacco use among 13 to 15 year olds in Kuna Yala was 14.0% (95% CI: 11.6% to 16.9%)—almost twice the national average of 7.8% (95% CI: 6.3% to 9.4%). Half of all adolescents in Kuna Yala estimated the cost of a 20-cigarette pack as less than US$0.75, compared with 16.2% of adolescents across of Panama (p value <0.01).

Conclusions

Kuna Yala is one of the few indigenous territories in Spanish-speaking countries where key tobacco control indicators have recently been assessed. Higher tobacco use and lower reported cigarette prices in that region may be linked with the presence of barter economy which may give adolescents more ready access to cigarettes than in other parts of Panama. There is a need for more indigenous-specific data to help build the evidence base to improve tobacco control and reduce commercial tobacco use among indigenous peoples.
Harry Macdonald Ross
Authors: Gunn George J. , Foster Geoffrey
Published: September 2020

A vet at Scotland’s Rural College, his practical knowledge and experience enabled him to support rural veterinary practices, as well as to foster his own interest in wildlife.
Water budget fluxes in catchments under grassland and Eucalyptus plantations of different ages
Authors: Ferreto Décio Oscar Cardoso , Reichert José Miguel , Cavalcante Rosane Barbosa Lopes , Srinivasan Raghavan
Published: September 2020

Planted forests are increasing in area worldwide in recent decades and play an important role in carbon sequestration programs. However, the effects of plantations on water resources are largely unknown. Here, we investigate the effects of Eucalyptus sp. plantations on water budget fluxes in the southern Brazilian grasslands biome. We evaluated green (canopy interception and evapotranspiration) and blue (discharge) water flows in three watersheds: two watersheds predominantly covered with eucalyptus, either in the first years after planting or at the end of the rotation, and one watershed with livestock-grazing grassland. We used field measurements of rainfall, streamflow, and throughfall and estimated canopy interception and evapotranspiration by water balance. Water flows in the monitored watersheds with eucalyptus plantations were influenced by forest developmental stage. Annual canopy interception and transpiration were always higher in the watersheds with eucalyptus than in the one with grassland, except for the transpiration in the first year after plantation in the watershed with young eucalyptus. An increase in evapotranspiration (green water flow) and the consequent decrease in streamflow (blue water flow) should be considered in local water resource management. Studies of catchment hydrology and forest management for improved water use efficiency and streamflow regulation are needed, particularly in understudied regions.
Stop search in SUSY SO(10) GUTs with nonuniversal Gaugino masses
Authors: Altın Zafer , Kırca Zerrin , Tanımak Tug̃çe , Salih Ün Cem
Published: September 2020

We explore the stop mass and its possible probe through a set of three different signal processes within a class of SUSY GUTs with non-universal gaugino masses. The stop mass can be realized in a wide range (0.4–8 TeV) consistent with the current experimental constraints. We consider the decay processes;$$\tilde{t}_{1}\rightarrow t\tilde{\chi }_{1}^{0}$$t~1→tχ~10,$$\tilde{t}_{1}\rightarrow b W^{\pm }\tilde{\chi }_{1}^{0}$$t~1→bW±χ~10and$$\tilde{t}_{1}\rightarrow b q{\bar{q}}^{\prime }\tilde{\chi }_{1}^{0}$$t~1→bqq¯′χ~10to be possible signals, and explore the impact of the current experimental results as well as the possible mass scales of stop, which can be probed in the future collider experiments. We find that the first and third signal processes can be tested in the current experiments, and significantly probed in future, while the second signal process is not available for the current experiments in this class of SUSY GUTs. We also comment that the second signal process can be available to be tested when the collider experiments are conducted at high center of mass energies and luminosity.
A Multi-Sensor Approach to Automatically Recognize Breaks and Work Activities of Knowledge Workers in Academia
Authors: Di Lascio Elena , Gashi Shkurta , Hidalgo Juan Sebastian , Nale Beatrice , Debus Maike E. , Santini Silvia
Published: September 2020

Personal informatics systems for the work environment can help improving workers' well-being and productivity. Using both self-reported data logged manually by the users and information automatically inferred from sensor measurements, such systems may track users' activities at work and help them reflect on their work habits through insightful data visualizations. They can further support interventions like, e.g., blocking distractions during work activities or suggest the user to take a break. The ability to automatically recognize when the user is engaged in a work activity or taking a break is thus a fundamental primitive such systems need to implement. In this paper, we explore the use of data collected from personal devices -- smartwatches, laptops, and smartphones -- to automatically recognize when users are working or taking breaks. We collect a data set of of continuous streams of sensor data captured from personal devices along with labels indicating whether a user is working or taking a break. We use multiple instruments to facilitate the collection of users' self-reported labels and discuss our experience with this approach. We analyse the available data -- 449 labelled activities of nine knowledge workers collected during a typical work week -- using machine learning techniques and show that user-independent models can achieve a (F1 score) of 94% for the identification of work activities and of 69% for breaks, outperforming baseline methods by 5-10 and 12-54 percentage points, respectively.
mSense
Authors: Wu Chenshu , Zhang Feng , Wang Beibei , Liu K. J. Ray
Published: September 2020

Target material sensing in ubiquitous contexts plays an important role in various applications. Recently, a few wireless sensing systems have been proposed for material identification. Yet, prior work usually requires to capture the signals penetrating a target (with devices set up on both sides of the target) or to instrument the target (e.g., by attaching an RFID tag), relies on multiple transceivers, and/or involves unexplainable feature engineering. In this paper, we explore the feasibility of material identification by analyzing only the signals reflected off the target, rather than those penetrating it, with a single RF radio. We present mSense, a mobile material sensing system using a single millimeter-wave (mmWave) radio. At the core of mSense is the insight that different materials reflect RF signals in distinct ways. We propose a novel and easy-to-measure material reflection feature that quantitatively characterizes the material's reflectivity. A set of techniques are then devised to achieve accurate and robust material identification despite various factors, including device mobility, hardware defects of commodity mmWave radios, environmental interferences, and etc. Experiments using commercial mmWave networking chipsets demonstrate an average accuracy of 93% in categorizing five common types of materials: aluminum, ceramic, plastic, wood, and water, regardless of their different sizes and thicknesses. The accuracy retains about 90% even in mobile scenarios (i.e., a user holds and moves the radio to perform sensing), which shows the great potential of mSense for mobile applications. A case study on 21 daily objects of various materials, shapes, and textures over different days further validates the performance in differentiating real-life objects.
VibroSense
Authors: Sun Wei , Chen Tuochao , Zheng Jiayi , Lei Zhenyu , Wang Lucy , Steeper Benjamin , He Peng , Dressa Matthew , Tian Feng , Zhang Cheng
Published: September 2020

Smart homes of the future are envisioned to have the ability to recognize many types of home activities such as running a washing machine, flushing the toilet, and using a microwave. In this paper, we present a new sensing technology, VibroSense, which is able to recognize 18 different types of activities throughout a house by observing structural vibration patterns on a wall or ceiling using a laser Doppler vibrometer. The received vibration data is processed and sent to a deep neural network which is trained to distinguish between 18 activities. We conducted a system evaluation, where we collected data of 18 home activities in 5 different houses for 2 days in each house. The results demonstrated that our system can recognize 18 home activities with an average accuracy of up to 96.6%. After re-setup of the device on the second day, the average recognition accuracy decreased to 89.4%. We also conducted follow-up experiments, where we evaluated VibroSense under various scenarios to simulate real-world conditions. These included simulating online recognition, differentiating between specific stages of a device's activity, and testing the effects of shifting the laser's position during re-setup. Based on these results, we discuss the opportunities and challenges of applying VibroSense in real-world applications.
OpenGPT-2
Authors: Cohen Vanya , Gokaslan Aaron
Published: September 2020

When OpenAI released its billion-parameter language model GPT-2, their attempts to withhold the model inspired two researchers to use open research practices to combat the misuse of machine learning.
The context in discourse analysis
Authors: Díaz Germán Alejandro Miranda
Published: September 2020

Inquiring about discourse can be an activity that is as specific as addressing its structure or as wide as analyzing discourse as an expression of culture considering its context in its minimal version as "what surrounds" or in the complexities of "to weave together."
Query Optimization for Faster Deep CNN Explanations
Authors: Nakandala Supun , Kumar Arun , Papakonstantinou Yannis
Published: September 2020

Deep Convolutional Neural Networks (CNNs) now match human accuracy in many image prediction tasks, resulting in a growing adoption in e-commerce, radiology, and other domains. Naturally, "explaining" CNN predictions is a key concern for many users. Since the internal workings of CNNs are unintuitive for most users, occlusion-based explanations (OBE) are popular for understanding which parts of an image matter most for a prediction. One occludes a region of the image using a patch and moves it around to produce a heatmap of changes to the prediction probability. This approach is computationally expensive due to the large number of re-inference requests produced, which wastes time and raises resource costs. We tackle this issue by casting the OBE task as a new instance of the classical incremental view maintenance problem. We create a novel and comprehensive algebraic framework for incremental CNN inference combining materialized views with multi-query optimization to reduce computational costs. We then present two novel approximate inference optimizations that exploit the semantics of CNNs and the OBE task to further reduce runtimes. We prototype our ideas in a tool we call Krypton. Experiments with real data and CNNs show that Krypton reduces runtimes by up to 5x (resp. 35x) to produce exact (resp. high-quality approximate) results without raising resource requirements.
Technical Perspective
Authors: Kanza Yaron
Published: September 2020

For many applications, data are worthy only if they are trustworthy. The concept of trust is sometimes elusive, and yet it is fundamental in data management. Even when not expressed explicitly, the correctness of computations and reliability of applications depend on trustworthy management of the data. These notions received new attention with the advent of blockchain and distributed ledger technology.
Revealing Every Story of Data in Blockchain Systems
Authors: Ruan Pingcheng , Anh Dinh Tien Tuan , Lin Qian , Zhang Meihui , Chen Gang , Chin Ooi Beng
Published: September 2020

The success of Bitcoin and other cryptocurrencies bring enormous interest to blockchains. A blockchain system implements a tamper-evident ledger for recording transactions that modify some global states. The system captures the entire evolution history of the states. The management of that history, also known as data provenance or lineage, has been studied extensively in database systems. However, querying data history in existing blockchains can only be done by replaying all transactions. This approach is feasible for large-scale, offline analysis, but is not suitable for online transaction processing.

We present LineageChain, a fine-grained, secure, and efficient provenance system for blockchains. LineageChain exposes provenance information to smart contracts via simple interfaces, thereby enabling a new class of blockchain applications whose execution logics depend on provenance information at runtime. LineageChain captures provenance during contract execution and stores it in a Merkle tree. LineageChain provides a novel skip list index that supports efficient provenance queries. We have implemented LineageChain on top of Hyperledger Fabric and a blockchainoptimized storage system called ForkBase. We conduct extensive evaluation, demonstrating benefits of LineageChain, its efficient querying, and its small storage overhead.
COVID-19 and hypertension: is the HSP60 culprit for the severe course and worse outcome?
Authors: Jakovac Hrvoje
Published: September 2020

The 60-kDa heat shock protein (HSP60) is a chaperone essential for mitochondrial proteostasis ensuring thus sufficient aerobic energy production. In pathological conditions, HSP60 can be translocated from the mitochondria and excreted from the cell. In turn, the extracellular HSP60 has a strong ability to trigger and enhance inflammatory response with marked proinflammatory cytokine induction, which is mainly mediated by Toll-like receptor binding. Previous studies have found increased circulating levels of HSP60 in hypertensive patients, as well as enhanced HSP60 expression and membrane translocation in the hypertrophic myocardium. These observations are of particular interest, since they could provide a possible pathophysiological explanation of the severe course and worse outcome of severe acute respiratory syndrome coronavirus 2 infection in hypertensive patients, repeatedly reported during the recent coronavirus disease 2019 (COVID-19) pandemic and related to hyperinflammatory response and cytokine storm development during the third phase of the disease. In this regard, pharmacological inhibition of HSP60 could attract attention to potentially ameliorate inappropriate inflammatory reaction in severe COVID-19 patients. Among HSP60 antagonizing drugs, mizoribine is the most intriguing, since it is clinically approved and exerts antiviral activity. However, this topic requires to be further scrutinized.
Endothelial function and shear stress in hypobaric hypoxia: time course and impact of plasma volume expansion in men
Authors: Tremblay Joshua C. , Ainslie Philip N. , Turner Rachel , Gatterer Hannes , Schlittler Maja , Woyke Simon , Regli Ivo B. , Strapazzon Giacomo , Rauch Simon , Siebenmann Christoph
Published: September 2020

Using a normoxic crossover study design, we examined the impact of hypobaric hypoxia (4 days; altitude equivalent, 3,500 m) and hemoconcentration on blood viscosity, shear stress, and endothelial function. Blood viscosity increased during the hypoxic exposure and was accompanied by elevated resting and exercising arterial shear stress. Flow-mediated dilation stimulated by reactive hyperemia and handgrip exercise was preserved throughout the hypoxic exposure. Plasma volume expansion reversed the hypoxia-associated hemoconcentration and selectively increased handgrip exercise flow-mediated dilation.
Finite Difference/Fourier Spectral for a Time Fractional Black–Scholes Model with Option Pricing
Authors: He Juan , Zhang Aiqing
Published: September 2020

We study the fractional Black–Scholes model (FBSM) of option pricing in the fractal transmission system. In this work, we develop a full-discrete numerical scheme to investigate the dynamic behavior of FBSM. The proposed scheme implements a known L1 formula for the α-order fractional derivative and Fourier-spectral method for the discretization of spatial direction. Energy analysis indicates that the constructed discrete method is unconditionally stable. Error estimate indicates that the 2−α-order formula in time and the spectral approximation in space is convergent with order OΔt2−α+N1−m, where m is the regularity of u and Δt and N are step size of time and degree, respectively. Several numerical results are proposed to confirm the accuracy and stability of the numerical scheme. At last, the present method is used to investigate the dynamic behavior of FBSM as well as the impact of different parameters.
Differential Immunogenicity and Protective Efficacy Elicited by MTO- and DMT-Adjuvanted CMFO Subunit Vaccines against Mycobacterium tuberculosis Infection
Authors: Ullah Nadeem , Hao Ling , Wu Yaqi , Zhang Yandi , Lei Qing , Banga Ndzouboukou Jo-Lewis , Lin Xiaosong , Fan Xionglin
Published: September 2020

Tuberculosis (TB) remains a major and global problem of public health. An effective TB subunit vaccine is urgently needed. Proper selection of the delivery system for the vaccine is crucial for inducing an appropriate immune response tailored to control the target pathogen. In this study, we compared the immunogenicity and protective efficacy of CMFO subunit vaccines against primary progressive TB in two different adjuvant systems: the MTO oil-in-water (O/W) emulsion composed of monophosphoryl lipid A (MPL), trehalose-6,60-dibehenate (TDB), and oil in water emulsion MF59 and the DMT liposome containing dimethyldioctadecylammonium bromide (DDA), monophosphoryl lipid A (MPL), and trehalose-6,60-dibehenate (TDB). Our results demonstrated that the DMT-adjuvanted CMFO could confer more significant protection against M. tuberculosis infection than the CMFO/MTO did in mice. In particular, the adjuvant DMT showed a stronger ability than the O/W emulsion to adjuvant CMFO subunit vaccine and enhanced protection, attributed to elicit Th1-biased responses, strong Th1/Th17 cytokine responses, and IFN-γ+ or IL-2+ T cell responses. Therefore, our findings demonstrate that the liposome delivery system shows more effectiveness to adjuvant TB subunit vaccine than O/W emulsion and highlight the importance of adjuvant formulation for the better efficacy of a protein vaccine.
A Novel Intelligent Method for Predicting the Penetration Rate of the Tunnel Boring Machine in Rocks
Authors: Zhang Yan , Wei Mingdong , Su Guoshao , Li Yao , Zeng Jianbin , Deng Xueqin
Published: September 2020

In the construction of rock tunnels, the penetration rate of the tunnel boring machine (TBM) is influenced by many factors (e.g., geomechanical parameters), some of which are highly uncertain. It is difficult to establish a precise model for predicting the penetration rate on the basis of the influencing factors. Thus, this work proposed a useful method, based on the relevance vector machine (RVM) and particle swarm optimization (PSO), for the prediction of the TBM penetration rate. In this method, the RVM played a vital role in establishing a nonlinear mapping relationship between the penetration rate and its influencing factors through training-related samples. Then, the penetration rate could be predicted using some collected data of the influencing factors. As for the PSO, it helped to find the optimum value of a key parameter (called the basis function width) that was needed in the RVM model. Subsequently, the validity of the proposed RVM-PSO method was checked with the data monitored from a rock tunnel. The results showed that the RVM-PSO method could estimate the penetration rate of the TBM, and it proved superior to the back-propagation artificial neural network, the least-squares support vector machine, and the conventional RVM methods, in terms of the prediction performance. Moreover, the proposed RVM-PSO method could be applied to identify the difference in the importance of the various factors affecting the TBM penetration rate prediction for a tunnel.
Comparison of Involved Field Radiotherapy versus Elective Nodal Irradiation in Stage IIIB/C Non-Small-Cell Lung Carcinoma Patients Treated with Concurrent Chemoradiotherapy: A Propensity Score Matching Study
Authors: Topkan Erkan , Ozdemir Yurday , Guler Ozan Cem , Kucuk Ahmet , Besen Ali Ayberk , Mertsoylu Huseyin , Sezen Duygu , Akdemir Eyub Yasar , Sezer Ahmet , Bolukbasi Yasemin , Pehlivan Berrin , Selek Ugur
Published: September 2020

Background. We retrospectively compared the incidence of isolated elective nodal failure (IENF) and toxicity rates and survival outcomes after elective nodal irradiation (ENI) versus involved-field RT (IFRT) by employing the propensity score matching (PSM) methodology in stage IIIB/C inoperable non-small-cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (C-CRT). Methods. Our PSM examination included 1048 stage IIIB/C NSCLC patients treated with C-CRT from January 2007 to December 2016: a total dose of 66 Gy (2 Gy/fraction) radiotherapy and 1–3 cycles of platinum-based doublet chemotherapy concurrently. The primary and secondary endpoints were the IENF and toxicity rates and survival outcomes after ENI versus IFRT, respectively. Propensity scores were calculated for each group to adjust for confounding variables and facilitate well-balanced comparability by creating 1 : 1 matched study groups. Results. The median follow-up was 26.4 months for the whole study accomplice. The PSM analysis unveiled 1 : 1 matched 646 patients for the ENI (N = 323) and IFRT (N = 323) cohorts. Intergroup comparisons discovered that the 5-year isolated ENF incidence rates (3.4% versus 4.3%; P=0.52) and median overall survival (25.2 versus 24.6 months; P=0.69), locoregional progression-free survival (15.3 versus 15.1 months; P=0.52), and progression-free survival (11.7 versus 11.2 months; P=0.57) durations were similar between the ENI and IFRT cohorts, separately. However, acute grade 3-4 leukopenia (P=0.0012), grade 3 nausea-vomiting (P=0.006), esophagitis (P=0.003), pneumonitis (P=0.002), late grade 3-4 esophageal toxicity (P=0.038), and the need for hospitalization (P<0.001) were all significantly higher in the ENI than in the IFRT group, respectively. Conclusion. Results of the present large-scale PSM cohort established the absence of meaningful IENF or survival differences between the IFRT and ENI cohorts and, consequently, counseled the IFRT as the elected RT technique for such patients since ENI increased the toxicity rates.
Physiologically Difficult Airway in the Patient with Severe Hypotension and Metabolic Acidosis
Authors: Capone Joseph , Gluncic Vicko , Lukic Anita , Candido Kenneth D.
Published: September 2020

The expertise to recognize and manage the difficult airway is essential in anesthesiology. Conventionally, this refers to anatomical concerns causing difficulties with facemask ventilation and/or with tracheal intubation. Severe derangements in patients’ physiology can make induction and intubation likewise difficult, and approximately 30% of critically ill patients had cardiovascular collapse subsequently to intubation. We present the case of a 58-year-old male with a past medical history of type II diabetes and hypertension who presented with altered mental status due to severe metabolic acidosis with a pH of 6.8 on admission to the intensive care unit. The anesthesia team was called to urgently intubate the patient. Upon arrival, the patient was localizing to pain and was hypocapnic, tachycardic, and hypotensive despite ongoing therapy with norepinephrine, vasopressin, and bicarbonate drips. Bedside point-of-care ultrasound showed hyperdynamic left ventricle with no other abnormalities. The patient was induced with IV ketamine, and dissociation occurred with maintenance of spontaneous respirations, which was followed by laryngoscopy and intubation causing only minimal hemodynamic changes. The patient was subsequently dialyzed and treated supportively. He was discharged from the hospital two weeks later—neurologically intact and at his baseline. Combination of hypotension and severe metabolic acidosis is particularly a challenging setting for airway management and a major risk factor for adverse events, including cardiopulmonary arrest. Hemodynamically stable induction agents should be preferred. In addition, sustaining spontaneous ventilation and avoiding periods of apnea in the peri-intubation period is paramount—any buildup of CO2 could push a critically low pH even lower and cause cardiovascular collapse. Sympathomimetic properties of ketamine make this induction agent a particularly appealing choice in this setting. This case report further supports the concept that severe physiologic perturbations—in which conventional induction techniques are not feasible—should be included in the current definition of a difficult airway.
Tribological Behavior of Tool Steel Substrate and Solid Films against 304 BA Austenitic Stainless Steel under Dry Sliding
Authors: Angsuseranee Natchanun , Watcharasresomroeng Bhadpiroon , Bunyawanichkul Pracha , Chartniyom Siradej
Published: September 2020

The objective of this work is to study the tribological behavior of the contacting surfaces of SKD11 grade hardened cold work tool steel against grade SUS304BA austenitic stainless steel. DLC, CrN, TiN, and TiCN films were coated on the surface of the tool material to test the tribological performance. Simulation testing with a pin-on-disk was used in this study. The study was done under dry conditions with sliding velocities at 50, 100, and 150 mm/s and contact pressures of 807, 1095, and 1280 MPa. The results show that the main problem is the adhesion of the workpiece material on the tool surface. The severity of the adhesion from the workpiece material is proportional to the sliding velocity and the contact pressure between the contacting surfaces. The coefficient of friction between the contacting surfaces has a positive relationship with the adhesion occurring on the tool surface. The hardness of the film coating is useful for preventing wear of the tool material, especially under high pressure between the contacting surfaces. However, it does not prevent the adhesion of workpiece material of low sliding velocity and low contact pressure conditions. Noncoated SKD11 tool steel has better effectiveness of adhesion performance than CrN, TiN, and TiCN film coatings.
Identification of Key Genes of Prognostic Value in Clear Cell Renal Cell Carcinoma Microenvironment and a Risk Score Prognostic Model
Authors: Zhao Enfa , Bai Xiaofang
Published: September 2020

Objective. We aimed at identifying the key genes of prognostic value in clear cell renal cell carcinoma (ccRCC) microenvironment and construct a risk score prognostic model. Materials and Methods. Immune and stromal scores were calculated using the ESTIMATE algorithm. A total of 539 ccRCC cases were divided into high- and low-score groups. The differentially expressed genes in immune and stromal cells for the prognosis of ccRCC were screened. The relationship between survival outcome and gene expression was evaluated using univariate and multivariate Cox proportional hazard regression analyses. A risk score prognostic model was constructed based on the immune/stromal scores. Results. The median survival time of the low immune score group was longer than that of the high immune score group (p=0.044). Ten tumor microenvironment-related genes were selected by screening, and a predictive model was established, based on which patients were divided into high- and low-risk groups with markedly different overall survival (p<0.0001). Multivariate Cox analyses showed that the risk score prognostic model was independently associated with overall survival, with a hazard ratio of 1.0437 (confidence interval: 1.0237–1.0641, p<0.0001). Conclusions. Low immune scores were associated with extended survival time compared to high immune scores. The novel risk predictive model based on tumor microenvironment-related genes may be an independent prognostic biomarker in ccRCC.
Ultimate Bearing Capacity of Strip Foundations in Unsaturated Soils considering the Intermediate Principal Stress Effect
Authors: Yan Qing , Zhao Junhai , Zhang Changguang , Wang Jintai
Published: September 2020

The reasonable determination of ultimate bearing capacity is crucial to an optimal design of shallow foundations. Soils surrounding shallow foundations are commonly located above the water table and are thus in an unsaturated state. The intermediate principal stress has an improving effect on the unsaturated soil strength. In this study, the ultimate bearing capacity formulation of strip foundations in unsaturated soils is presented by using Terzaghi’s theory. The unified shear strength equation of unsaturated soils under a plane strain condition is utilized to capture the intermediate principal stress effect. Furthermore, two profiles of matric suction are considered and a hyperbolic function of the friction angle related to matric suction (φb) is adopted to describe strength nonlinearity. The validity of this study is demonstrated by comparing it with model tests and a theoretical solution reported in the literature. Finally, parameter studies are conducted to investigate the effects of intermediate principal stress, matric suction, and base roughness on the ultimate bearing capacity of strip foundations. Besides, the effect of strength nonlinearity is discussed with two methods representing the angle φb.
Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors
Authors: Balmanoukian Ani S. , Infante Jeffrey R. , Aljumaily Raid , Naing Aung , Chintakuntlawar Ashish V. , Rizvi Naiyer A. , Ross Helen J. , Gordon Michael , Mallinder Philip R. , Elgeioushi Nairouz , González-García Ignacio , Standifer Nathan , Cann Jennifer , Durham Nicholas , Rahimian Shahram , Kumar Rakesh , Denlinger Crystal S.
Published: September 2020

Purpose:

The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.

Patients and Methods:

Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results:

Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.

Conclusions:

MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
Phase Ib Study of Ribociclib plus Fulvestrant and Ribociclib plus Fulvestrant plus PI3K Inhibitor (Alpelisib or Buparlisib) for HR+ Advanced Breast Cancer
Authors: Tolaney Sara M. , Im Young-Hyuck , Calvo Emiliano , Lu Yen-Shen , Hamilton Erika , Forero-Torres Andres , Bachelot Thomas , Maur Michela , Fasolo Angelica , Tiedt Ralph , Nardi Lisa , Stammberger Uz , Abdelhady Ahmed M. , Ruan Shiling , Lee Soo Chin
Published: September 2020

Purpose:

Resistance to treatment with endocrine therapy in patients with HR+, HER2− advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib.

Patients and Methods:

In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR+, HER2− ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant.

Results:

The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8–46.7).

Conclusions:

Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR+, HER2− ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation.

See related commentary by Clark et al., p. 371
Circulating T-cell Immunosenescence in Patients with Advanced Non–small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy
Authors: Ferrara Roberto , Naigeon Marie , Auclin Edouard , Duchemann Boris , Cassard Lydie , Jouniaux Jean-Mehdi , Boselli Lisa , Grivel Jonathan , Desnoyer Aude , Mezquita Laura , Texier Matthieu , Caramella Caroline , Hendriks Lizza , Planchard David , Remon Jordi , Sangaletti Sabina , Proto Claudia , Garassino Marina C. , Soria Jean-Charles , Marabelle Aurelien , Voisin Anne-Laure , Farhane Siham , Besse Benjamin , Chaput Nathalie
Published: September 2020

Purpose:

CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown.

Experimental Design:

The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.

Results:

In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.

Conclusions:

Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.

See related commentary by Salas-Benito et al., p. 374
Abstract 1020: Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor cells
Authors: Kato Kazunori , Kuroki Katsuhiro , Shimizu Yui
Published: September 2020

Ergothioneine (ERG) is a natural antioxidant nutrient containing in edible golden oyster mushroom, Pleurotus cornucopiae (Tamogitake). In previous AACR meeting, we reported that administration of ERG rich water extracts of p. cornucopiae to tumor-bearing mice could suppress the growth of subcutaneous tumors and reduce the number of regulatory T cells (Treg) in lymph node and spleen. However, the molecular events inducing antitumor and immunomodulatory effects are still unknown. Our aim is to identify the mechanism of ERG in tumor cells which secrete various immunomodulatory cytokines. We cocultured human tumor cell lines with ERG and tested cytokine concentration in culture supernatants and expression of immune checkpoint molecules on tumors. ERG could significantly inhibit the production of VEGF, CCL2 and TGF-β1 which are important in not only angiogenesis and tumor invasion but also Treg induction. Importantly, ERG also reduced the expression of some immune checkpoint molecules on tumor cells and prolonged the survival of IL-2-activated lymphocytes in vitro. Overall, ERG rich water extract of p. citrinopileatus might inhibit the induction of Treg in tumor-bearing host via suppression of VEGF and TGF-β1, indicating a novel immunomodulatory antioxidant nutrient in mushrooms

Citation Format: Kazunori Kato, Katsuhiro Kuroki, Yui Shimizu. Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1020.
Abstract 1027: Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma
Authors: Sun Xian , Li Chia-Wei , Wang Wei-Jan , Hung Mien-Chie
Published: September 2020

Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in phase III clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Tivantinib upregulates PD-L1 in NSCLC cells in dose and time-dependent manner. Mechanistically, inhibition of c-MET suppresses p-GSK3-beta, leading to the stabilization of PD-L1. Collectively, our findings suggest a potential crosstalk between c-Met inhibition and immune escape and provide a rationale for the combination therapy of c-Met inhibitors and immune checkpoint blockade in NSCLC.

Citation Format: Xian Sun, Chia-Wei Li, Wei-Jan Wang, Mien-Chie Hung. Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1027.
Abstract 1033: NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle
Authors: Oh Se Jin , Kim Tae Woo , Song Kwon-Ho , Kim Suyeon
Published: September 2020

T cell-based immunotherapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to presence of immune-refractory tumor cells that limits its clinical success by blocking amplification of anti-tumor immunity cycle. Previously, we found that immune selection by T-cell based immunotherapy drives the evolution of tumors toward immunotherapeutic refractoriness including multimodal resistant and stem-like phenotype via activation of NANOG-TCL1A-AKT axis. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and the refractoriness of immune-edited tumor cells by identifying HSP90AA1 as a novel NANOG transcriptional target. Furthermore, we found that TCL1A is a novel client of HSP90A, and demonstrated that HSP90A potentiates AKT activation through TCL1A stabilization and thereby contributes to refractoriness in NANOGhigh immune-edited tumor cells. Importantly, inhibition of HSP90A sensitizes immune-refractory tumor cells to T cell-based immunotherapy and elicits effective anti-tumor response by re-invigorating anti-tumor immune cycle of tumor-reactive T cells. Our findings implicate that the NANOG-HSP90A pathway is a central molecular axis and a potential target for immune-refractory tumor.

Citation Format: Se Jin Oh, Tae Woo Kim, Kwon-Ho Song, Suyeon Kim. NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1033.
Abstract 1057: Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress
Authors: Helleday Thomas
Published: September 2020

Summary

Thymidine synthesis pathways are upregulated pathways in cancer. Since the 1940s, targeting nucleotide and folate metabolism to induce thymineless death has remained first-line anti-cancer treatment. Recent discoveries that showing cancer cells have rewired networks and exploit unique enzymes for proliferation, have renewed interest in metabolic pathways. The cancer-specific expression of MTHFD2 has gained wide-spread attention and here we describe an emerging role for MTHFD2 in the DNA damage response (DDR). The folate metabolism enzyme MTHFD2 is one of the most consistently overexpressed metabolic enzymes in cancer and an emerging anticancer target. We show a novel role for MTHFD2 being essential for DNA replication and genomic stability in cancer cells. We describe first-in-class nanomolar MTHFD2 inhibitors (MTHFD2i), with protein co-crystal structures demonstrating binding in the active site of MTHFD2 and engaging with the target in cells and tumours. We show MTHFD2i reduce replication fork speed and induce replication stress, followed by S phase arrest, apoptosis and killing of a range of haematological and solid cancer cells in vitro and in vivo, with a therapeutic window spanning up to four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD2i prevent thymidine production leading to mis-incorporation of uracil into DNA and replication stress. As MTHFD2 expression is cancer specific there is a potential of MTHFD2i to synergize with other treatments. Here, we show MTHFD2i synergize with dUTPase inhibitors as well as other DDR inhibitors and demonstrate the mechanism of action. These results demonstrate a new link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically.

Keywords

MTHFD2, one-carbon metabolism, folate metabolism, DNA replication, replication stress, synthetic lethal, thymineless death, small-molecule inhibitor, DNA damage response

Citation Format: Thomas Helleday. Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1057.