bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing and studying the dynamical behavior of a nonlinear mathematical model for cancers with tumor by considering immune system role
Authors: Alishzadeh Khoei Amir , Zakerzadeh Mohammadreza , Ayati Moosa , Soleimani Neda
Published: June 2020

We are constrained by widespread cancerous diseases to improve treatment methods which save patients and provide better living conditions during and after the treatment period. Because of the complexity of the treatment process, mathematical models need to be used in order to have a better understanding of the process. However, deriving an adequate complex model that can capture the disease pattern which could be confirmed by simulations and experiments has its own barriers. In this paper, a new mathematical model is developed concerning immune system effect on cancer. The model is introduced using nonlinear ordinary differential equations. Also, the qualitative behavior of the proposed system is studied in order to examine the extent of the model with respect to the nature of tumor evolution. Thus, number and status of equilibria points in line with the existence of limit cycles are obtained for sub-systems and the whole system. Meanwhile, possible bifurcations are mentioned, and the consequent evolutions are described. It is shown that the model conforms well to natural possibilities, cancer growth or remission. Thus, the model would be fit for further studies for prediction and contemplating treatment method, especially for immune stimulating drugs and immunotherapy.
Use of pore pressure data from the Norwegian Continental Shelf to characterize fluid-flow processes in geological timescales
Authors: Riis Fridtjof , Wolff Anke
Published: June 2020

A dataset with pore pressures from more than 1000 exploration wells has been used to investigate the dynamics of aquifer systems in the Norwegian Continental Shelf (NCS). Variations in aquifer pressures reflect flow of porewater through permeable rocks over geological time. Strongly overpressured regimes are formed within confined aquifers in subsiding areas, where fluid flow out of the aquifer is controlled by vertical seepage. In transitional pressure regimes, fluid flows within permeable beds towards areas with hydrostatic pressures. In the hydrostatic regime, pressure differences result from density differences due to varying formation water salinity and by hydrocarbon columns. An underpressured regime has been encountered in confined aquifers in the platform areas of the Barents Sea, and is related to net uplift and erosion. In the case studies, pressure differences are interpreted in the context of the relevant pressure regime, and with a dynamic approach where segment boundaries and cap rocks are regarded as low-permeability restrictions rather than barriers. The present distribution of pressure regimes was developed over the last few million years due to rapid Pleistocene sedimentation and erosion processes.
SlimCache
Authors: Jia Yichen , Shao Zili , Chen Feng
Published: June 2020

Flash-based key-value caching is becoming popular in data centers for providing high-speed key-value services. These systems adopt slab-based space management on flash and provide a low-cost solution for key-value caching. However, optimizing cache efficiency for flash-based key-value cache systems is highly challenging, due to the huge number of key-value items and the unique technical constraints of flash devices. In this article, we present a dynamic on-line compression scheme, called
SlimCache
, to improve the cache hit ratio by virtually expanding the usable cache space through data compression. We have investigated the effect of compression granularity to achieve a balance between compression ratio and speed, and we leveraged the unique workload characteristics in key-value systems to efficiently identify and separate hot and cold data. To dynamically adapt to workload changes during runtime, we have designed an adaptive hot/cold area partitioning method based on a cost model. To avoid unnecessary compression, SlimCache also estimates data compressibility to determine whether the data are suitable for compression or not. We have implemented a prototype based on Twitter’s Fatcache. Our experimental results show that SlimCache can accommodate more key-value items in flash by up to 223.4%, effectively increasing throughput and reducing average latency by up to 380.1% and 80.7%, respectively.
On Measuring Global Poverty
Authors: Ravallion Martin
Published: June 2020

This article critically assesses prevailing measures of global poverty. A welfarist interpretation of global poverty lines is augmented by the idea of normative functionings, the cost of which varies across countries. In this light, current absolute measures are seen to ignore important social effects on welfare, while popular, strongly relative measures ignore absolute levels of living. It is argued that a new hybrid measure is called for, combining absolute and weakly relative measures consistent with how national lines vary across countries. Illustrative calculations indicate that we are seeing a falling incidence of poverty globally over the past 30 years. This is mainly due to lower absolute poverty counts in the developing world. While fewer people are poor by the global absolute standard, more are poor by the country-specific relative standard. The vast bulk of poverty, both absolute and relative, is now found in the developing world.
Coordinated alpha-crystallin B phosphorylation and desmin expression indicate adaptation and deadaptation to resistance exercise-induced loading in human skeletal muscle
Authors: Jacko Daniel , Bersiner Käthe , Schulz Oliver , Przyklenk Axel , Spahiu Fabian , Höhfeld Jörg , Bloch Wilhelm , Gehlert Sebastian
Published: June 2020

Skeletal muscle is a target of contraction-induced loading (CiL), leading to protein unfolding or cellular perturbations, respectively. While cytoskeletal desmin is responsible for ongoing structural stabilization, in the immediate response to CiL, alpha-crystallin B (CRYAB) is phosphorylated at serine 59 (pCRYABS59) by P38, acutely protecting the cytoskeleton. To reveal adaptation and deadaptation of these myofibrillar subsystems to CiL, we examined CRYAB, P38, and desmin regulation following resistance exercise at diverse time points of a chronic training period. Mechanosensitive JNK phosphorylation (pJNKT183/Y185) was determined to indicate the presence of mechanical components in CiL. Within 6 wk, subjects performed 13 resistance exercise bouts at the 8–12 repetition maximum, followed by 10 days detraining and a final 14th bout. Biopsies were taken at baseline and after the 1st, 3rd, 7th, 10th, 13th, and 14th bout. To assess whether potential desensitization to CiL can be mitigated, one group trained with progressive and a second with constant loading. As no group differences were found, all subjects were combined for statistics. Total and phosphorylated P38 was not regulated over the time course. pCRYABS59 and pJNKT183/Y185 strongly increased following the unaccustomed first bout. This exercise-induced pCRYABS59/pJNKT183/Y185 increase disappeared with the 10th until 13th bout. As response to the detraining period, the 14th bout led to a renewed increase in pCRYABS59. Desmin content followed pCRYABS59 inversely, i.e., was up- when pCRYABS59 was downregulated and vice versa. In conclusion, the pCRYABS59 response indicates increase and decrease in resistance to CiL, in which a reinforced desmin network could play an essential role by structurally stabilizing the cells.
IL-6 induced upregulation of T-type Ca2+ currents and sensitization of DRG nociceptors is attenuated by MNK inhibition
Authors: Jeevakumar Vivek , Al Sardar Aysha Khalid , Mohamed Farah , Smithhart Clay Matthew , Price Theodore , Dussor Gregory
Published: June 2020

In this study, we show that the MNK inhibitor and anti-tumor agent eFT508 (tomivosertib) is effective in attenuating IL-6 induced sensitization of dorsal root ganglion (DRG) nociceptors. Pretreatment with eFT508 in DRG cultures from mice helps mitigate the development of hyperexcitability in response to IL-6. Furthermore, our data reveal that the upregulation of T-type voltage-gated calcium channels following IL-6 application can be blocked by eFT508, implicating the MNK-eIF4E signaling pathway in membrane trafficking of ion channels.
Acute changes in nerve excitability following oxaliplatin treatment in mice
Authors: Makker Preet G. S. , White Daniel , Lees Justin G. , Parmar Jasneet , Goldstein David , Park Susanna B. , Howells James , Moalem-Taylor Gila
Published: June 2020

We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.
Quantile Regression Analysis of Depression and Clinical Symptom Degree in Chinese Patients with Spinocerebellar Ataxia Type 3
Authors: Chen Xiaoping , Zheng Lihui , Yao Jianqi
Published: June 2020

Spinal cerebellar ataxia type 3 is a common SCA subtype in the world. It is a neurodegenerative disease characterized by ataxia. Patients exhibit common neuropsychological symptoms such as depression and anxiety. Some patients have suicidal tendencies when they are severely depressed. So, it is very important to study the severity of depression and clinical symptoms (SARA), to find out the patient’s psychological state in time and to help patients actively respond to treatment. A total of 97 Chinese SCA3 patients were enrolled in the study. The Beck Depression Scale was used to investigate the prevalence of depression in the confirmed patients. The distribution of depression data in these patients was investigated. Then, the quantifier was used to model the depression status of Chinese SCA3 patients. An analysis was conducted to identify the key factors affecting depression under different quantiles. Studies have shown that SARA and gender are important factors affecting depression; the effect of initial SARA is small, then the degree of influence increases, and the degree of influence decreases in the later period, but it is always positively correlated with depression; the development of women’s SARA is gentler than that of men, and the degree of depression is lower than that of men.
A Semianalytical Solution for Passively Loaded Piles Adjacent to Surcharge Load
Authors: Zhang Hao , Shi Minglei , Yang Lei , Guo Yuancheng
Published: June 2020

Piles adjacent to a surcharge load commonly support not only active loads from superstructures but also the passive loads caused by soil lateral movement. To investigate the influence of passive load and the response along pile shafts of existing actively loaded piles, a load transfer model for analyzing the soil‐pile interaction was developed based on plastic deformation theory and the triparameter soil model. An analytical solution for the deformation and internal force of such piles was proposed using the transfer matrix method, in which the transfer matrix coefficients for piles in free, plastic, and elastic zones were analytically obtained by considering the second‐order axial force effect caused by lateral loading and soil yielding based on the triparameter soil model. The proposed methodology was validated by comparing its predictions with field measurements and previously published results. A good match between model predictions, field measurements, and previously published results implies that the proposed method can be used to evaluate the response of passive piles adjacent to a surcharge load. Parametric studies were also carried out to investigate the influence of surcharge pressure, soil resistance, and boundary conditions on the behavior of passively loaded piles adjacent to a surcharge load.
Experimental Analysis of Residual Stress and Bending Strength of Gear Tooth Surface after Shot Peening Treatment
Authors: Liang Dong , Meng Sheng , Chen Yi , Hua Chengli
Published: June 2020

The fatigue strength of a gear tooth surface is affected by various factors, which subsequently impacts the transmission performance of gears. Usually, shot peening treatment is carried out during processing to improve the performance of gears. Most current studies focus on theoretical descriptions and simulation analyses of shot peening treatment. However, in this paper, the relationships among shot peening treatment, residual stress, and bending fatigue strength of a gear tooth surface are discussed, through experimental methods. Based on X-ray stress analysis, at select locations on the test samples, the residual stresses on gear tooth surfaces with and without shot peening treatment are determined and contrasted. The results show that shot peening treatment can effectively increase the residual stress on gear tooth surfaces. In addition, an electromagnetic resonance fatigue tester is used to analyze the bending fatigue strength of gear tooth surfaces. The test results indicate that the bending fatigue strength of the gear teeth with shot peening is higher than that of the gear teeth without shot peening. The obtained conclusions lay the foundation for further practical engineering applications of gears.
Enhancing Accuracy in a Touch Operation Biometric System: A Case on the Android Pattern Lock Scheme
Authors: Ng’ang’a Allan , Musuva Paula M. W.
Published: June 2020

The main objective of this research study is to enhance the functionality of an Android pattern lock application by determining whether the time elements of a touch operation, in particular time on dot (TOD) and time between dot (TBD), can be accurately used as a biometric identifier. The three hypotheses that were tested through this study were the following–H1: there is a correlation between the number of touch stroke features used and the accuracy of the touch operation biometric system; H2: there is a correlation between pattern complexity and accuracy of the touch operation biometric system; H3: there is a correlation between user training and accuracy of the touch operation biometric system. Convenience sampling and a within-subjects design involving repeated measures were incorporated when testing an overall sample size of 12 subjects drawn from a university population who gave a total of 2,096 feature extracted data. Analysis was done using the Dynamic Time Warping (DTW) Algorithm. Through this study, it was shown that the extraction of one-touch stroke biometric feature coupled with user training was able to yield high average accuracy levels of up to 82%. This helps build a case for the introduction of biometrics into smart devices with average processing capabilities as they would be able to handle a biometric system without it compromising on the overall system performance. For future work, it is recommended that more work be done by applying other classification algorithms to the existing data set and comparing their results with those obtained with DTW.
Preserving Data Privacy in the Internet of Medical Things Using Dual Signature ECDSA
Authors: Cano Maria-Dolores , Cañavate-Sanchez Antonio
Published: June 2020

The disclosure of personal and private information is one of the main challenges of the Internet of Medical Things (IoMT). Most IoMT-based services, applications, and platforms follow a common architecture where wearables or other medical devices capture data that are forwarded to the cloud. In this scenario, edge computing brings new opportunities to enhance the operation of IoMT. However, despite the benefits, the inherent characteristics of edge computing require countermeasures to address the security and privacy issues that IoMT gives rise to. The restrictions of IoT devices in terms of battery, memory, hardware resources, or computing capabilities have led to a common agreement for the use of elliptic curve cryptography (ECC) with hardware or software implementations. As an example, the elliptic curve digital signature algorithm (ECDSA) is widely used by IoT devices to compute digital signatures. On the other hand, it is well known that dual signature has been an effective method to provide consumer privacy in classic e-commerce services. This article joins both approaches. It presents a novel solution to enhanced security and the preservation of data privacy in communications between IoMT devices and the cloud via edge computing devices. While data source anonymity is achieved from the cloud perspective, integrity and origin authentication of the collected data is also provided. In addition, computational requirements and complexity are kept to a minimum.
miR-7-5p Promotes Hepatic Stellate Cell Activation by Targeting Fibroblast Growth Factor Receptor 4
Authors: Tian Shuxia , Chen Min , Wang Bing , Han Yonglong , Shang Haonan , Chen Junming
Published: June 2020

Aims. Fibroblast growth factor receptor 4 (FGFR4) is a key mediator that protects the liver from chronic injury. MicroRNA-7 (miR-7) is a tumor suppressor and associated with lipid homeostasis in the liver. This study was designed to examine the role of the miR-7-5p/FGFR4 axis in liver fibrogenesis. Methods. TargetScan was employed to predict microRNAs that targeted FGFR4 on the 3′-untranslated region (3′-UTR). miR-7-5p and FGFR4 expression in pathological liver tissues and LX-2 cells was determined using qRT-PCR and an immunoblotting assay. A dual-luciferase assay was conducted to validate the target prediction. A Cell Counting Lit-8 assay was performed to assess the proliferation ability of LX-2 cells. Hydroxyproline content in LX-2 cells was measured using a hydroxyproline assay. The expression of hepatic stellate cell (HSC) activation markers was examined using qRT-PCR and an immunoblotting assay. Results. FGFR4 was a putative target of miR-7-5p. In LX-2 cells, miR-7-5p targeted FGFR4 by binding to 3′-UTR. FGFR4 was downregulated, but miR-7-5p was markedly enhanced in the liver samples as the degree of liver fibrosis rose. miR-7-5p was negatively associated with FGFR4 expression in liver tissues. The miR-7-5p inhibitor blocked the lipopolysaccharide-induced proliferation and activation of LX-2 cells, and FGFR4 overexpression inhibited LX-2 cell proliferation and activation triggered by miR-7-5p. Conclusion. miR-7-5p promotes HSC proliferation and activation by downregulating FGFR4.
Excitation Functions of Related Parameters from Transverse Momentum (Mass) Spectra in High-Energy Collisions
Authors: Li Li-Li , Liu Fu-Hu , Waqas Muhammad , Al-Yusufi Rasha , Mujear Altaf
Published: June 2020

Transverse momentum (mass) spectra of positively and negatively charged pions and of positively and negatively charged kaons, protons, and antiprotons produced at mid-(pseudo)rapidity in various collisions at high energies are analyzed in this work. The experimental data measured in central gold-gold, central lead-lead, and inelastic proton-proton collisions by several international collaborations are studied. The (two-component) standard distribution is used to fit the data and extract the excitation function of effective temperature. Then, the excitation functions of kinetic freeze-out temperature, transverse flow velocity, and initial temperature are obtained. In the considered collisions, the four parameters increase with the increase of collision energy in general, and the kinetic freeze-out temperature appears at the trend of saturation at the top Relativistic Heavy Ion Collider and the Large Hadron Collider.
Evaluation of Relationships between Menopause Onset Age and Bone Mineral Density and Muscle Strength in Women from South‐Western Poland
Authors: Fugiel Jarosław , Ignasiak Zofia , Skrzek Anna , Sławińska Teresa
Published: June 2020

Introduction. The onset of the menopause entails numerous changes, both physical and mental, in the functioning of the bodies of women. Moreover, the early menopause increases the risk of occurrence of many civilization‐related diseases. Major factors contributing to health deficits include lowered bone mineral density and sarcopenia, which can result in serious functional limitations and the acceleration of ageing processes in the body. The aim of this study was to determine how the menopause onset age is linked with bone mineral density and the strength of selected muscles of the limbs and the trunk. Material and Methods. 756 women aged 50‐80 years were subjected to tests. The subjects were divided into three groups: (I) from 50 to 59 years, (II) from 60 to 69 years, and (III) from 70 to 79 years. Each of the women specified the age when her final menstrual period occurred. On this basis, groups of women with (1) the early menopause—before the 50th year of life—and (2) with the late menopause—after the 50th year of life—were distinguished. Bone mineral density (BMD), dominant hand grip strength, knee extensor and flexor strength, and functional upper and lower body muscle strength were determined in each of the women. Results. The test results indicate differences in levels of muscle strength and BMD between the 50‐year‐old early‐ and late‐menopausal women. The late‐menopausal women score better motor ability test results and higher BMD values. The differences decrease in the groups of 60‐year‐old women, whereas the 70‐year‐old early‐ and late‐menopausal women score similar results. Conclusions. A higher percentage of women with a lowered bone mass and a lower strength level was found in the group of early‐menopausal subjects. The rate of decline in hand grip strength, the functional efficiency of the upper and lower limbs, and BMD is faster in the late‐menopausal women, whereby the two groups of 70‐year‐old women score similar test results.
On Regular Black Holes at Finite Temperature
Authors: Ulhoa S. C. , Spaniol E. P. , Gomes R. , Santos A. F. , Santana A. E.
Published: June 2020

The Thermo Field Dynamics (TFD) formalism is used to investigate the regular black holes at finite temperature. Using the Teleparalelism Equivalent to General Relativity (TEGR), the gravitational Stefan-Boltzmann law and the gravitational Casimir effect at zero and finite temperature are calculated. In addition, the first law of thermodynamics is considered. Then, the gravitational entropy and the temperature of the event horizon of a class of regular black holes are determined.
Vibration Control Method of an Electromagnetic Isolation System Based on LQR and Coevolutionary NGA
Authors: Zhang Lei , Zhuan Xiangtao
Published: June 2020

An electromagnetic isolation system can dynamically adjust the output characteristic parameters of the system in real time through the active control strategy, which has strong adaptability to the external environment. In order to control the electromagnetic vibration isolation system effectively, an active control method is presented based on the linear quadratic regulator (LQR) approach and the coevolutionary niche genetic algorithm (NGA). In this paper, the dynamical equation and state equation of the electromagnetic isolation system are built, which include the nonlinear relationship between electromagnetic force and coil current and gap. The LQR approach is employed to maintain a steady state of an isolated object on the vibration isolation system. Meanwhile, a coevolutionary niche genetic algorithm is put forward to optimize the parameters in Q and R matrices. Simulation and experimental results demonstrate that the electromagnetic isolation system with the LQR approach and coevolutionary NGA can effectively isolate the vibration and maintain a steady state for an isolated object in comparison with the passive isolation system.
A Data Mining Approach on Lorry Drivers Overloading in Tehran Urban Roads
Authors: Ayazi Ehsan , Sheikholeslami Abdolreza
Published: June 2020

The aim of this study is to identify the important factors influencing overloading of commercial vehicles on Tehran’s urban roads. The weight information of commercial freight vehicles was collected using a pair of portable scales besides other information needed including driver information, vehicle features, load, and travel details by completing a questionnaire. The results showed that the highest probability of overloading is for construction loads. Further, the analysis of the results in the lorry type section shows that the least likely occurrence of overloading is among pickup truck drivers such that this likelihood within this group was one-third among Nissan and small truck drivers. Also, the results of modeling the type of route showed that the highest likelihood of overloading is for internal loads (origin and destination inside Tehran), and the least probability of overloading is for suburban trips (origin and destination outside of Tehran). Considering the type of load packing as a variable, the results of binary regression model analysis showed that the most probability of overloading occurs for packed (boxed) loads. Finally, it was concluded that drivers are 18 times more likely to commit overloading on weekends than on weekdays.
Detection of Extended‐Spectrum β‐Lactamases (ESBL) Producing Enterobacteriaceae from Fish Trapped in the Lagoon Area of Bizerte, Tunisia
Authors: Hassen Bilel , Jouini Ahlem , Elbour Monia , Hamrouni Safa , Maaroufi Abderrazek
Published: June 2020

Extended‐spectrum β‐lactamase and their molecular mechanism in Enterobacteriaceae were analyzed in 126 fish samples of 9 various wild species, living in the lagoon of Bizerte in Tunisia. Fifty‐nine (59) Gram‐negative strains were isolated and identified as Escherichia coli (n = 24), Klebsiella pneumonia (n = 21), Citrobacter freundii (n = 8), and Shigella boydii (n = 6). Forty‐seven ESBL producers were identified using the synergic test. β‐Lactamase genes detected were blaCTX-M-1 (E. coli/15; K. pneumonia/8; C. freundii/1; Sh. boydii/1), blaCTX-M-1+ blaOXA-1 (E. coli/4; K. pneumonia/3), blaCTX-M-1+ blaTEM-1-a (K. pneumonia/2), blaCTX-M-15+ blaTEM-1-a (K. pneumonia/1; Sh. boydii/1), blaCTX-M-15+ blaOXA-1 (K. pneumonia/1), blaCTX-M-15 (E. coli/3; K. pneumonia/1; Sh. boydii/3), and blaCTX-M-9 (C. freundii/3). Most strains (84.7%) showed a multiresistant phenotype. qnrA and qnrB genes were identified in six E. coli and in ten E. coli+one K. pneumonia isolates, respectively. The resistance to tetracycline and sulfonamide was conferred by the tet and sul genes. Characterization of phylogenic groups in E. coli isolates revealed phylogroups D (n = 20 strains), B2 (n = 2), and A (n = 2). The studied virulence factor showed prevalence of fimA genes in 9 E. coli isolates (37.5%). Similarly, no strain revealed the three other virulence factors tested (eae, aer, and cnf1). Our findings confirmed that the lagoons of Bizerte may be a reservoir of multidrug resistance/ESBL‐producing Enterobacteriaceae. This could lead to indisputable impacts on human and animal health, through the food chain.
Numerical and Experimental Study on Soil Plug Resistance of Open‐Ended Pipe Pile with a Restriction Plate
Authors: Guo Yuan , Dong Shaoyang , Li Jiale , Yu Xiong (Bill)
Published: June 2020

The end bearing capacity of open‐ended pipe piles is highly dependent upon the soil plugging behavior inside the pipe wall. For large‐diameter open‐ended pipe piles, the arching effect due to inner soil‐pile friction may be insufficient to generate a fully plugged condition, which compromises the end bearing capacity after the pile installation. Here, we propose two innovatively designed restriction plates installed inside the pipe to facilitate the soil plugging process, that is, a restriction plate with one circular hole and a restriction plate with four semisized circular holes. By use of the discrete element method, the mechanical behaviors of soil plugs in cohesionless soils with different restriction plates are analyzed. The numerical model has been validated by comparing the simulations to the results of a series of laboratory‐scale experiments over different pile diameters, plug length‐diameter ratios, and different types of restriction plates. It is shown that the numerical model can accurately predict the soil plug resistance and the particle‐scale force transmission. Both numerical simulations and experiments validate that the arching effect is significantly enhanced by the restriction plate, especially with the four‐hole restriction plate. Furthermore, the geotechnical centrifuge principle is adopted into the DEM model to study the mechanical behavior of large‐diameter soil plugs. It is found that the effectiveness of restriction plate decreases as the pile diameter increases. However, even for the 2 m in diameter soil plugs, the plug resistance is increased by 252% with one‐hole restriction plate and 281% with four‐hole restriction plate compared to that of traditional pipe piles.
A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors
Authors: Qiu Zhaojun , Fa Pengyan , Liu Tao , Prasad Chandra B. , Ma Shanhuai , Hong Zhipeng , Chan Ernest R. , Wang Hongbing , Li Zaibo , He Kai , Wang Qi-En , Williams Terence M. , Yan Chunhong , Sizemore Steven T. , Narla Goutham , Zhang Junran
Published: June 2020

There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non–small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC in vitro and in vivo and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors.

Significance:

This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
Genome Instability Profiles Predict Disease Outcome in a Cohort of 4,003 Patients with Breast Cancer
Authors: Lischka Annette , Doberstein Natalie , Freitag-Wolf Sandra , Koçak Ayla , Gemoll Timo , Heselmeyer-Haddad Kerstin , Ried Thomas , Auer Gert , Habermann Jens K.
Published: June 2020

Purpose:

The choice of therapy for patients with breast cancer is often based on clinicopathologic parameters, hormone receptor status, and HER2 amplification. To improve individual prognostication and tailored treatment decisions, we combined clinicopathologic prognostic data with genome instabilty profiles established by quantitative measurements of the DNA content.

Experimental Design:

We retrospectively assessed clinical data of 4,003 patients with breast cancer with a minimum postoperative follow-up period of 10 years. For the entire cohort, we established genome instability profiles. We applied statistical methods, including correlation matrices, Kaplan–Meier curves, and multivariable Cox proportional hazard models, to ascertain the potential of standard clinicopathologic data and genome instability profiles as independent predictors of disease-specific survival in distinct subgroups, defined clinically or with respect to treatment.

Results:

In Cox regression analyses, two parameters of the genome instability profiles, the S-phase fraction and the stemline scatter index, emerged as independent predictors in premenopausal women, outperforming all clinicopathologic parameters. In postmenopausal women, age and hormone receptor status were the predominant prognostic factors. However, by including S-phase fraction and 2.5c exceeding rate, we could improve disease outcome prediction in pT1 tumors irrespective of the lymph node status. In pT3-pT4 tumors, a higher S-phase fraction led to poorer prognosis. In patients who received adjuvant endocrine therapy, chemotherapy or radiotherapy, or a combination, the ploidy profiles improved prognostication.

Conclusions:

Genome instability profiles predict disease outcome in patients with breast cancer independent of clinicopathologic parameters. This applies especially to premenopausal patients. In patients receiving adjuvant therapy, the profiles improve identification of high-risk patients.
Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers
Authors: Lee Soo-Chin , Shimasaki Noriko , Lim Joline S.J. , Wong Andrea , Yadav Kritika , Yong Wei Peng , Tan Lip Kun , Koh Liang Piu , Poon Michelle L.M. , Tan Sing Huang , Ow Samuel G.W. , Bharwani Lavina , Yap Yoon Sim , Foo Mabel Z.Q. , Coustan-Smith Elaine , Sundar Raghav , Tan Hon Lyn , Chong Wan Qin , Kumarakulasinghe Nesaretnam Barr , Lieow Jedidah L.M. , Koe Priscillia J.X. , Goh Boon Cher , Campana Dario
Published: June 2020

Purpose:

Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.

Patients and Methods:

In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.

Results:

In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.

Conclusions:

NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
Pathogenic Germline Mutations in Chinese Patients with Gastric Cancer Identified by Next-Generation Sequencing
Authors: Zhou Jing , Zhao Zhengyi , Zhang Yuzi , Bao Celimuge , Cui Longgang , Cai Shangli , Bai Yuezong , Shen Lin , Zhang Xiaotian
Published: June 2020

Background: Gastric cancer (GC) is one of the leading causes of cancer death in China, while the nature of genetic factors related to GC has not been well-studied. Objectives: To assess the inherited genetic factors regarding pathogenic germline mutations in Chinese GC population. Methods: Genomic profiling of DNA was performed through next-generation sequencing with 381 cancer-related genes on tissue from patients with GC between January 1, 2017, and May 7, 2019. Results: 470 GC patients were included for analysis. A total of 28 (6.0%) patients were identified to harbor 25 different pathogenic or very likely pathogenic germline mutations in 15 genes. The variants fell most frequently in BRCA2 (n = 6, 1.28%), CHEK2 (n = 5, 1.06%), MUTYH (n = 3, 0.64%), CDH1 (n = 2, 0.43%), and ATM (n = 2, 0.43%). Of all the germline-mutated genes, 66.7% (n = 10) lay in the DNA damage repair pathways. Seven patients were identified to have a high TMB status, among whom two were also identified as MSI-H. Overall, 20 out of the 28 patients (71.4%) carried clinically actionable mutations. Conclusions: Our study has depicted the spectrum of pathogenic germline mutations in Chinese GC patients, which may provide valuable clues for the assessment of the genetic susceptibility and clinical management in GC.
Utility of Easy Z-Score Imaging System-Assisted SPECT in Detecting Onset Age-Dependent Decreases in Cerebral Blood Flow in the Posterior Cingulate Cortex, Precuneus, and Parietal Lobe in Alzheimer’s Disease with Amyloid Accumulation
Authors: Hayashi Hiroshi , Kobayashi Ryota , Kawakatsu Shinobu , Morioka Daichi , Otani Koichi
Published: June 2020

Background: Easy Z-score imaging system (eZIS)-assisted SPECT accurately detects decreases in cerebral blood flow in the posterior cingulate cortex (PCC), precuneus, and parietal lobe, the cerebral regions deeply implicated in Alzheimer’s disease (AD). Several studies suggested onset age-dependent decreases in cerebral blood flow in these regions in AD, but these studies did not screen for amyloid accumulation, suggesting inclusion of non-AD patients in their subjects. Objective: By applying eZIS-SPECT to patients with amyloid deposition, it was the aim of this study to clarify onset age-dependent decreases in cerebral blood flow in the regions critical to AD. Methods: We retrospectively analyzed eZIS-SPECT data on 34 AD patients with amyloid retention confirmed by 11C-Pittsburgh compound B-PET. The subjects were divided into an early-onset group (n = 16) and a late-onset group (n = 18). The three indicators of the eZIS that had discriminated between AD patients and normal controls in previous studies were compared between the two groups. Results: The mean values for the respective indicators were significantly higher in the early-onset group than in the late-onset group. Also, the proportion of patients with abnormalities in all indicators was significantly higher in the early-onset group (93.8%) than in the late-onset group (50.0%). Conclusions: The present study, applying eZIS-SPECT to amyloid-positive AD patients, suggests that reduced cerebral blood flow in the PCC, precuneus, and parietal lobe is more pronounced in the early-onset type than in the late-onset type of the disease.
Immunotherapy in Gastrointestinal Cancers
Authors: Güthle Melanie , Ettrich Thomas , Seufferlein Thomas
Published: June 2020

Background: Gastrointestinal malignancies have both a high incidence rate and a high mortality rate. Immuno-oncological treatment approaches are becoming increasingly established in the treatment of gastrointestinal cancers. Summary: In this review, we give an overview of the types and effects of immunotherapies. We focus on recent studies on immunotherapies with special attention to immune checkpoint inhibition in carcinomas of the esophagus and stomach, the hepato-pancreatico-biliary system, and the colorectum including the anal channel in the metastatic setting, and we show their achievements but also their limitations. In an outlook, we discuss new approaches in immunotherapy like CAR T-cell therapy and oncolytic viruses. Key Messages: Gastrointestinal cancers show overall moderate response rates to immunotherapy. Nevertheless, subgroups such as DNA mismatch repair-deficient or microsatellite-instable tumors particularly benefit from the immune checkpoint blockade. Further studies are ongoing.
What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review
Authors: Żorniak Michał , Sirtl Simon , Mayerle Julia , Beyer Georg
Published: June 2020

Background: Alcoholic pancreatitis is a serious medical concern worldwide and remains to be one of the common causes of pancreatic disease. Summary: While alcohol consumption causes direct damage to pancreatic tissue, only a small percentage of active drinkers will develop pancreatitis. An explanation of this phenomenon is probably that alcohol increases pancreatic vulnerability to damage; however, the simultaneous presence of additional risk factors and pancreatic costressors is required to increase the risk of pancreatitis and its complications caused by alcohol misuse. Recently, a number of important genetic as well as environmental factors influencing the risk of alcoholic pancreatitis have been described. Key Messages: In brief, this review reports established factors for the development of alcoholic pancreatitis and summarizes recent progress made in basic and clinical research.
Prevalence, Resistance Rates, and Risk Factors of Pathogens in Routine Bile Cultures Obtained during Endoscopic Retrograde Cholangiography
Authors: Reiter Florian P. , Obermeier Wolfgang , Jung Jette , Denk Gerald , Mahajan Ujjwal M. , De Toni Enrico N. , Schirra Jörg , Mayerle Julia , Schulz Christian
Published: June 2020

Introduction and Objective: Acute cholangitis is a life-threatening condition. The early initiation of antibiotic therapy significantly impacts the course of disease. Only few data are available on distribution and resistance profiles of bile pathogens. Here, we report on an analysis of routinely acquired bile specimens and provide an overview of the prevalence, resistance rates, and risk factors for the presence of pathogens in bile. Methods: Bile cultures obtained from 388 endoscopic retrograde cholangiographies (ERCs) with corresponding clinical data were analysed in 208 patients. Results: The majority (84.8%) of cultures yielded positive for at least 1 organism. Abundance was highest for Enterococcus faecalis, Enterococcus faecium, and Escherichia coli. Multiresistant organisms were present in 14.9%. The initial antibiotic regimen was changed in 44.1%, which increased the length of hospital stay significantly (***p < 0.001). Pre-existing papillotomy (EPT) or biliary drainage was associated with higher frequency of bile pathogens (**p < 0.01) in a univariate analysis. Multivariate analysis confirmed these results for EPT and revealed significantly more positive results for pathogens, gram-negative bacteria, and fungi in patients with biliary drainage. Significant differences in the prevalence of pathogens were observed between relevant subgroups of ERC indications. The highest susceptibility rates were observed for linezolid and tigecycline in gram-positive bacteria and for meropenem and gentamicin in gram-negative bacteria. Conclusions: Our study provides a comprehensive analysis of the distribution, resistance profiles, and risk factors for the detection of bile pathogens. The frequent change in initial antibiotic treatment highlights the importance of routine bile culture and indicates that current schemas of empirical treatment might not cover the contemporary spectrum of pathogens in bile.
Optimal Use of Vasodilators for Diagnosis of Microvascular Angina in the Cardiac Catheterization Laboratory
Authors: Rahman Haseeb , Demir Ozan M. , Ryan Matthew , McConkey Hannah , Scannell Cian , Ellis Howard , Webb Andrew , Chiribiri Amedeo , Perera Divaka
Published: June 2020

Background:

Among patients with angina and nonobstructive coronary artery disease, those with coronary microvascular dysfunction have a poor outcome. Coronary microvascular dysfunction is usually diagnosed by assessing flow reserve with an endothelium-independent vasodilator like adenosine, but the optimal diagnostic threshold is unclear. Furthermore, the incremental value of testing endothelial function has never been assessed before. We sought to determine what pharmacological thresholds correspond to exercise pathophysiology and myocardial ischemia in patients with coronary microvascular dysfunction.

Methods:

Patients with angina and nonobstructive coronary artery disease underwent simultaneous acquisition of coronary pressure and flow during rest, supine bicycle exercise, and pharmacological vasodilatation with adenosine and acetylcholine. Adenosine and acetylcholine coronary flow reserve were calculated as vasodilator/resting coronary blood flow (CFR and AchFR, respectively). Coronary wave intensity analysis was used to quantify the proportion of accelerating wave energy; a normal exercise response was defined as an increase in accelerating wave energy from rest to peak exercise. Ischemia was assessed by quantitative 3-Tesla stress perfusion cardiac magnetic resonance imaging and dichotomously defined by a hyperemic endo-epicardial gradient <1.0.

Results:

Ninety patients were enrolled (58±10 years, 77% female). Area under the curve using receiver-operating characteristic analysis demonstrated optimal CFR and AchFR thresholds for identifying exercise pathophysiology and ischemia as 2.6 and 1.5, with positive and negative predictive values of 91% and 86%, respectively. Fifty-eight percent had an abnormal CFR (of which 96% also had an abnormal AchFR). Of those with a normal CFR, 53% had an abnormal AchFR, and 47% had a normal AchFR; ischemia rates were 83%, 63%, and 14%, respectively.

Conclusions:

The optimal CFR and AchFR diagnostic thresholds are 2.6 and 1.5, with high-positive and negative predictive values, respectively. A normal CFR value should prompt the measurement of AchFR. A stepwise algorithm incorporating both vasodilators can accurately identify an ischemic cause in patients with nonobstructive coronary artery disease.