bluuebunny/crossref_metadata_2025 huggingface dataset:
DOING IT RIGHT, BUT GETTING IT WRONG: BEST PRACTICES FOR REFUGEE FOCUSED INCUBATORS
Authors: NEWMAN ARIELLE BADGER , CHRISTENSEN LISA JONES
Published: September 2021

In response to the rising numbers of refugees worldwide, many aid organizations suggest entrepreneurship as a preferred route to refugee economic self-reliance in a new country. Incubators have long provided assistance to nascent entrepreneurs and are utilized worldwide to offer support to entrepreneurial businesses. Yet, little research examines refugee-focused incubators or considers refugee-specific constraints. Herein, we argue that refugee status has specific implications for how refugee entrepreneurs accumulate and deploy human, social and financial capital. Thus, refugee status affects the types of services transitioning refugees require from incubators. This paper considers refugee-specific resources and uses a case study approach to investigate resource provision in a refugee-focused incubator in the United States. We find that even when an incubator follows best practices in terms of service provision, it may still miss the mark in terms of meeting key resource needs of refugees. Specifically, this paper illuminates how refugee entrepreneurs need (more) incubator support in terms of (1) addressing mental health in service provision, (2) building community within the incubator and (3) balancing financial tradeoffs associated with culturally-based businesses. Findings are novel when tied to a resource-based lens and help build theory regarding entrepreneurship among less-served populations.
Study of Fear Effect on Prey–Predator Model with Ivlev-Type Functional Response in Fuzzy Environment
Authors: Das Soumya , Biswas Suvankar , Das Pritha
Published: September 2021

A prey–predator model with Ivlev-type functional response and the fear effect on prey species by the predator have been considered for the first time in a crisp as well as fuzzy environment. The effects of fear have been investigated on the stability of the system. Granular function derivative concept has been used to do fuzzy mathematics. For the first time, proper model analysis, positivity, bounds and uniform persistence are studied for our proposed model in fuzzy environment. The conditions of stability of all co-existing equilibrium points and Hopf bifurcation analysis have also been studied in fuzzy environment. Analytical results have been justified by numerical simulation with proper table and graphical presentation in crisp and fuzzy environment both.
Enhanced Photocatalytic Degradation of Organic Pollutants Under Visible Light Using Ag-Modified TiO2 on Activated Carbon Fibers
Authors: Zhang Wenrui , Wang Yonghui , Hao Meilu , Zhang Huawei , Liang Peng
Published: September 2021

Ag-modified TiO2 on activated carbon fibers (ACF) was synthesized and successfully used for the photocatalytic degradation of organic pollutants in this work. The physical properties of the materials were characterized using various methods such as X-ray diffraction, scanning electron microscope, Brunauer–Emmett–Teller, Fourier transform infrared, UV–Vis, electrochemical impedance spectroscopy and reusability tests. Besides, the effects of reaction parameters on photodegradation such as silver loading, light source, organic pollutant species and initial pollutant concentration were investigated. The results showed that Ag significantly increased the number of surface adsorption sites, improved the electron transmission rate and suppressed the complexation of e− and h[Formula: see text]. Under visible light, 1.5-Ag-TiO2/ACF [Formula: see text] revealed the best catalytic activity and reusability for dye removal and toluene adsorption. Based on the experimental results, a possible photocatalytic mechanism of Ag-TiO2/ACF was proposed. This study will provide a theoretical basis for the application of Ag-TiO2/ACF photocatalyst in the field of organic pollutants treatment.
Decorating Pt nanoparticles on oxygen vacancies incorporated hematite photoanode for enhanced water oxidation
Authors: Lv Xiaoxin , Deng Zixiao , Wang Menglian
Published: September 2021

Pt-treatment and oxygen vacancies incorporation as effective strategies had been extensively used to improve the photoelectrochemical (PEC) water splitting performance of hematite. Herein, by coupling Pt-decoration and oxygen vacancies incorporation through a facile solution route, an efficient hematite photoanode for PEC water splitting was fabricated. PEC measurements indicated that the photocurrent density was increased from 0.80 mA/cm2 at 1.23 V versus RHE for the pristine Fe2O3 film to 1.15 mA/cm2 at 1.23 V versus RHE for the co-modified sample. Based on various characterizations, this improvement could be attributed to the cumulative effect of Pt-decoration and oxygen vacancies incorporation, in which the incorporation of oxygen vacancies could increase the donor density and consequently promote the charge transport in the bulk hematite, while the excellent electrical conductivity of Pt was beneficial for facilitating the charge transfer across hematite/electrolyte interface. This study provides a feasible approach for the development of high-performance hematite photoanodes.
Optimization of 16-Element Quantum Search on IBMQ
Authors: Zi Wei , Yang Shuai , Guo Cheng , Sun Xiaoming
Published: September 2021

Unstructured searching, which is to find the marked element from a given unstructured data set, is a widely studied problem in computer science. It is well known that Grover algorithm provides a quadratic speedup to solve unstructured search problem compared with the classical algorithm. This algorithm has received a lot of attention due to the strong versatility. In this manuscript, we report experimental results of searching a unique target from 16 elements on five different quantum devices of IBM quantum Experience (IBMQ). We first implement the original Grover algorithm on these devices. However, the experiment probability of success of finding the correct target is almost the same as random choice. We then optimize the quantum circuit size of the search algorithm. The oracle operator and diffusion operator are two of the most costly operators in Grover algorithm. For the 16-element quantum search algorithm, both the oracle operator and diffusion operator consist of a triple controlled [Formula: see text] gate ([Formula: see text]) and some single-qubit gates. So we optimize the implementation of the [Formula: see text] gate according to the qubits layout of different quantum devices. On the ibmq_santiago, the experimental success rate of the 16-element quantum search algorithm is increased to [Formula: see text] by the optimization, which is better than all the published experiments implemented on IBMQ devices. For other IBMQ devices, the experimental success rate of 16-element quantum search also has been significantly improved. We then try to further reduce the size of the quantum circuit by modifying the Grover algorithm, with a tolerable loss of the theoretical success probability. On ibmq_quito, the experimental success rate is further improved from 25.23% to 27.56% after optimization. These experimental results show the importance of circuit optimization and algorithm optimization in the Noisy-Intermediate-Scale Quantum (NISQ) era.
Quantum Newton’s Method for Solving the System of Nonlinear Equations
Authors: Xue Cheng , Wu Yuchun , Guo Guoping
Published: September 2021

While quantum computing provides an exponential advantage in solving the system of linear equations, there is little work to solve the system of nonlinear equations with quantum computing. We propose quantum Newton’s method (QNM) for solving [Formula: see text]-dimensional system of nonlinear equations based on Newton’s method. In QNM, we solve the system of linear equations in each iteration of Newton’s method with quantum linear system solver. We use a specific quantum data structure and [Formula: see text] tomography with sample error [Formula: see text] to implement the classical-quantum data conversion process between the two iterations of QNM, thereby constructing the whole process of QNM. The complexity of QNM in each iteration is [Formula: see text]. Through numerical simulation, we find that when [Formula: see text], QNM is still effective, so the complexity of QNM is sublinear with [Formula: see text], which provides quantum advantage compared with the optimal classical algorithm.
India’s China Challenge: Foreign Policy Dilemmas Post-Galwan and Post-Covid
Authors: SCOTT DAVID
Published: September 2021

The paper analyzes the challenge to India from China, and the dilemmas faced by India in shaping an appropriate response. A two-level theory analysis indicates that some diminishing cooperation is possible at the global level, for example over environmental issues. However, regionally, this has been overtaken structurally by increasing sharp confrontation along the Himalayas and by rising geopolitical and geo-economic competition across Asia and the Indo-Pacific. This has been overlaid in 2020–2021 by the particularly negative effect on Indian relations with China of the clashes and casualties at Galwan and the impact of Covid-19. Given this sharpening challenge, the paper finds that India’s cherished axiom of full strategic autonomy now has to be tempered in its response by balancing dictates, particularly in the light of Stephen Walt’s balance of threat model. India’s responses pose various dilemmas in terms of effectiveness and counter-productiveness. Geopolitically, dilemmas continue to revolve for India around how far to invoke a Tibet Card and a Taiwan Card in its One China policy; and how far India can shape an immediate web (in effect around China) through strengthening security links with Vietnam, Mongolia and South Korea. Dilemmas also follow from how far India should pursue tighter security/military arrangements with more powerful China-concerned states like Australia, Japan, France, and above all, the United States. Geo-economically, India’s dilemmas revolve around how to respond to the Regional Comprehensive Economic Partnership (RCEP) and to China’s Maritime Silk Road scheme. Looking forward, an important factor will be how far India pulls away from Covid-19 disruption to the economy, and how far it will need to divert long-term economic funding away from immediate short-term military projects.
Spontaneous Aggregation of Convective Storms
Authors: Muller Caroline , Yang Da , Craig George , Cronin Timothy , Fildier Benjamin , Haerter Jan O. , Hohenegger Cathy , Mapes Brian , Randall David , Shamekh Sara , Sherwood Steven C.
Published: September 2021

Idealized simulations of the tropical atmosphere have predicted that clouds can spontaneously clump together in space, despite perfectly homogeneous settings. This phenomenon has been called self-aggregation, and it results in a state where a moist cloudy region with intense deep convectivestorms is surrounded by extremely dry subsiding air devoid of deep clouds. We review here the main findings from theoretical work and idealized models of this phenomenon, highlighting the physical processes believed to play a key role in convective self-aggregation. We also review the growing literature on the importance and implications of this phenomenon for the tropical atmosphere, notably, for the hydrological cycle and for precipitation extremes, in our current and in a warming climate.
Rotating Horizontal Convection
Authors: Gayen Bishakdatta , Griffiths Ross W.
Published: September 2021

Global differences of temperature and buoyancy flux at the ocean surface are responsible for small-scale convection at high latitudes, global overturning, and the top-to-bottom density difference in the oceans. With planetary rotation the convection also contributes to the large-scale horizontal, geostrophic circulation, and it crucially involves a 3D linkage between the geostrophic circulation and vertical overturning. The governing dynamics of such a surface-forced convective flow are fundamentally different from Rayleigh–Bénard convection, and the role of buoyancy forcing in the oceans is poorly understood. Geostrophic balance adds to the constraints on transport in horizontal convection, as illustrated by experiments, theoretical scaling, and turbulence-resolving simulations for closed (mid-latitude) basins and an annulus or reentrant zonal (circumpolar) channel. In these geometries, buoyancy drives either horizontal mid-latitude gyre recirculations or a strong Antarctic Circumpolar Current, respectively, in addition to overturning. At large Rayleigh numbers the release of available potential energy by convection leads to turbulent mixing with a mixing efficiency approaching unity. Turbulence-resolving models are also revealing the relative roles of wind stress and buoyancy when there is mixed forcing, and in future work they need to include the effects of turbulent mixing due to energy input from tides.
Endoscopic Approaches to Obesity Management
Authors: Dolan Russell D. , Schulman Allison R.
Published: September 2021

The field of endoscopic bariatric and metabolic therapy has rapidly evolved from offering endoscopic treatment of weight regain following bariatric surgery to providing primary weight loss options as alternatives to pharmacologic and surgical interventions. Gastric devices and remodeling procedures were initially designed to work through a mechanism of volume restriction, leading to earlier satiety and reduced caloric intake. As the field continues to grow, small bowel interventions are evolving that may have some effect on weight loss but focus on the treatment of obesity-related comorbidities. Future implementation of combination therapy that utilizes both gastric and small bowel interventions offers an exciting option to further augment weight loss and alleviate metabolic disease. This review considers gastric devices and techniques including space-occupying intragastric balloons, aspiration therapy, endoscopic tissue suturing, and plication interventions, followed by a review of small bowel interventions including endoluminal bypass liners, duodenal mucosal resurfacing, and endoscopically delivered devices to create incisionless anastomoses.
E-Cigarette Toxicology
Authors: Gordon Terry , Karey Emma , Rebuli Meghan E. , Escobar Yael-Natalie H. , Jaspers Ilona , Chen Lung Chi
Published: September 2021

Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic cigarette (e-cigarette) vaping has surpassed conventional cigarette smoking among adolescents and young adults in the United States and beyond. This review describes the experimental and clinical evidence of e-cigarette toxicity and deleterious health effects. Adverse health effects related to e-cigarette aerosols are influenced by several factors, including e-liquid components, physical device factors, chemical changes related to heating, and health of the e-cigarette user (e.g., asthmatic). Federal, state, and local regulations have attempted to govern e-cigarette flavors, manufacturing, distribution, and availability, particularly to underaged youths. However, the evolving e-cigarette landscape continues to impede timely toxicological studies and hinder progress made toward our understanding of the long-term health consequence of e-cigarettes.
A Case Report on Life-Threatening Lower Gastrointestinal Bleeding: A Rare Presentation of Mucinous Adenocarcinoma of the Appendix
Authors: Wijayaratne H. W. T. D. , Fernando K. J. A. , Matheeshan T.
Published: September 2021

Introduction. A life-threatening lower gastrointestinal bleeding from mucinous adenocarcinoma of the appendix is a rare occurrence. Diagnosing and management of such a condition are challenging. Case Presentation. A 73-year-old male with a history of type 2 diabetes mellitus and hypertension presented with intermittent per rectal bleeding for two weeks, which progressed to the passage of a large number of blood clots and fresh blood. He had features of class III shock on admission. An endoscopic evaluation followed initial resuscitation to locate the source of bleeding. Colonoscopy revealed a large blood clot at the opening of the appendicular orifice with no active bleeding. Oesophagoduodenoscopy, contrast-enhanced CT abdomen, and CT angiogram findings were unremarkable. Due to repeated episodes of rebleeding leading to haemodynamic instability, an exploratory laparotomy was performed. A retrocaecal appendix was noticed with a macroscopically suspicious-looking dilated tip adhered to the posterior caecal wall. Right hemicolectomy was performed as the lesion was suspicious and to stop bleeding from the site. Ileocolic side-to-side hand-sewn anastomosis was performed using 3/0 polyglactin. Postoperatively, per rectal bleeding was settled. Microscopy revealed appendiceal mucinous adenocarcinoma with AJCC staging of pT3NoMx. The patient was discharged on postoperative day seven and referred to oncological management. He was offered six cycles of chemotherapy with capecitabine and oxaliplatin. At the six-month follow-up visit, the patient had no features of recurrence clinically. Conclusion. Mucinous adenocarcinoma of the appendix can rarely present as life-threatening lower GI bleeding. Prompt resuscitation, endoscopic evaluation, and operative management with right hemicolectomy and chemotherapy provided a good outcome.
Application of a Stress‐Fractional Model for Capturing the Stress‐Strain Behavior of Granular Soils
Authors: Lu Wei , Yang Jiangong , Wang Jinan
Published: September 2021

Granular soils usually serve as the filler material in geotechnical engineering. This study presents the development and application of a stress‐fractional model for granular soils with different initial material states. To capture the plastic loading and flow behaviors, a subloading surface with the fractional stress gradient is used. The developed model contains twelve parameters which can be determined through triaxial tests. To validate the developed model, the well‐documented test results of Firoozkuh No. 161 sand and crushed basalt are simulated and discussed. It is found that the stress‐fractional model can reasonably simulate the undrained and drained behaviors of granular soils consolidated with different densities and mean effective pressures.
[Retracted] Exchange Rate Forecasting Based on Deep Learning and NSGA‐II Models
Authors: Chen Jun , Zhao Chenyang , Liu Kaikai , Liang Jingjing , Wu Huan , Xu Shiyan
Published: September 2021

Today, the global exchange market has been the world’s largest trading market, whose volume could reach nearly 5.345 trillion US dollars, attracting a large number of investors. Based on the perspective of investors and investment institutions, this paper combines theory with practice and creatively puts forward an innovative model of double objective optimization measurement of exchange forecast analysis portfolio. To be more specific, this paper proposes two algorithms to predict the volatility of exchange, which are deep learning and NSGA‐II‐based dual‐objective measurement optimization algorithms for the exchange investment portfolio. Compared with typical traditional exchange rate prediction algorithms, the deep learning model has more accurate results and the NSGA‐II‐based model further optimizes the selection of investment portfolios and finally gives investors a more reasonable investment portfolio plan. In summary, the proposal of this article can effectively help investors make better investments and decision‐making in the exchange market.
Research on Modeling and Scheduling Methods of an Intelligent Manufacturing System Based on Deep Learning
Authors: Lan Xiaoyi , Chen Hua
Published: September 2021

Under the background of intelligent manufacturing, the modeling and scheduling of an intelligent manufacturing system driven by big data have attracted increasing attention from all walks of life. Deep learning can find more hidden knowledge in the process of feature extraction of the hierarchical structure and has good data adaptability in domain adaptation. From the perspective of the manufacturing system, intelligent scheduling is irreplaceable in intelligent production when the manufacturing quantity of workpieces is small or products are constantly changing. This paper expounds the outstanding advantages of deep learning in intelligent manufacturing system modeling, which provides an effective way and powerful tool for intelligent manufacturing system design, performance analysis, and running status monitoring and provides a clear direction for selecting, designing, or implementing the deep learning architecture in the field of intelligent manufacturing system modeling and scheduling. The scheduling of the intelligent manufacturing system should integrate intelligent scheduling of part processing and intelligent planning of product assembly, which is suitable for intelligent scheduling of any kind and quantity of products and resources.
Using Improved XGBoost Algorithm to Obtain Modified Atmospheric Refractive Index
Authors: Mai Yanbo , Sheng Zheng , Shi Hanqing , Liao Qixiang
Published: September 2021

Atmospheric refraction is a special meteorological phenomenon mainly caused by gas molecules and aerosol particles in the atmosphere, which can change the propagation direction of electromagnetic waves in the atmospheric environment. Atmospheric refractive index, an index to measure atmospheric refraction, is an important parameter for electromagnetic wave. Given that it is difficult to obtain the atmospheric refractive index of 100 meters (m)–3000°m over the ocean, this paper proposes an improved extreme gradient boosting (XGBoost) algorithm based on comprehensive learning particle swarm optimization (CLPSO) operator to obtain them. Finally, the mean absolute percentage error (MAPE) and root mean-squared error (RMSE) are used as evaluation criteria to compare the prediction results of improved XGBoost algorithm with backpropagation (BP) neural network and traditional XGBoost algorithm. The results show that the MAPE and RMSE of the improved XGBoost algorithm are 39% less than those of BP neural network and 32% less than those of the traditional XGBoost. Besides, the improved XGBoost algorithm has the strongest learning and generalization capability to calculate missing values of atmospheric refractive index among the three algorithms. The results of this paper provide a new method to obtain atmospheric refractive index, which will be of great reference significance to further study the atmospheric refraction.
A Modified Customization Strategy in a Dual-Channel Supply Chain Model with Price-Sensitive Stochastic Demand and Distribution-Free Approach
Authors: Chauhan Ruchi , Kumar Varun , Jana Tapas Kumar , Majumder Arunava
Published: September 2021

With the advancement of technology, many companies provide customization facilities to customers. This facility provides a vast variety to customers which enhances the level of customer satisfaction. This approach helps various technologically advanced companies to increase their profit. In this paper, a dual-channel supply chain model is developed with the aforementioned customization strategy with the target of increasing the profit of the firm. In dual-channel, the core or standard product is provided to the customer through a traditional retail channel, whereas the customized product is made available through the online channel. This article incorporates a modification in the existing dual-channel policy on the number of customers that switch between the offline and online channels. Moreover, a preassigned threshold value is also assumed which signifies the decrease in demand that takes place if the difference between the selling price of offline and online channels crosses a fixed specified threshold value. In addition to that, due to fluctuation and uncertainty of demand, both variability and randomness may occur simultaneously. Thus, the price-sensitive stochastic demand is considered to develop the dual-channel centralized supply chain model with customization. A max-min distribution-free approach is applied to deal with the randomness and variability of demand. The model is analyzed and validated with numerical experiments and graphical analysis. Consequently, the article concluded that it is better to adopt a dual-channel supply chain policy for better profitability than the traditional single-channel supply chain as this firm will be able to provide customized products to customers. Moreover, if the difference between the selling prices of the offline and online channels is greater than the preassigned threshold value, then the shifting of customers takes place depending upon the factor that which channel’s selling is less in comparison to another.
Handwashing Knowledge, Attitudes, and Practices among Students in Eastern Province Schools, Saudi Arabia
Authors: Almoslem Munthir M. , Alshehri Talal A. , Althumairi Arwa A. , Aljassim Mohammed T. , Hassan Mohamed E. , Berekaa Mahmoud M.
Published: September 2021

Background. Lack of knowledge about appropriate handwashing practices has caused great concerns for human health, especially in the risk of many communicable diseases. The objective of the current study is to determine the level of handwashing knowledge, attitudes, and practices among school students in Eastern Province Schools, Saudi Arabia. A cross-sectional survey was recruited from November 2019 to March 2020 to assess the level of the students’ handwashing knowledge. A reliable questionnaire was prepared (Cronbach’s alpha = 0.608) and conducted using a two-stage sampling technique. A total of 271 students participated in the study from primary, middle, and high schools; 80% were boys, most of whom displayed an acceptable level of knowledge on hand hygiene. Nearly 75% and 74% of boys and girls, respectively, gained knowledge about hand hygiene practices from their parents. Only 46% of the students thought that handwashing is a potential protective measure against diseases, whereas 34% thought it only removes dirt. Prevalence of handwashing with soap after using the toilet was recognized among 52% of the students. Additionally, 93% of the students used water and soap to wash their hands (

p

value < 0.001) and 97% suggested that soap and water are the best methods to wash their hands (

p

value < 0.001). There was a positive correlation between the mother’s education and hand hygiene practices (

p

value = 0.044). Results collectively indicated that handwashing knowledge and practices among school students in the Eastern Province are acceptable interventions in preventing the transmission of infectious diseases such as COVID-19. Indeed, further improvement conducted through specific health education programs to emphasize the role of handwashing in health hygiene is highly recommended.
Experimental Study on Thermal Conductivity of Organic-Rich Soils under Thawed and Frozen States
Authors: He Ruixia , Jia Ning , Jin Huijun , Wang Hongbo , Li Xinyu
Published: September 2021

Thermal properties are important for featuring the water-heat transfer capacity of soil. They are also key to many processes in earth sciences, such as the land surface processes and ecological and geoenvironmental dynamics and their changes in permafrost regions. With loose and porous structures, the organic matter layer in soil strata substantially influences soil thermal conductivity. So far, thermal conductivity of mineral soils has been explored extensively and in depth, but there are only limited studies on that of organic soils. In this study, influences of soil temperature, soil moisture saturation (SMS), and soil organic matter (SOM) content on soil thermal conductivity were analyzed on the basis of laboratory experiments on the silt-organic soil mixtures of varied mixing ratios. Results show that soil thermal conductivity declines slowly with the lowering temperatures from 10 to 0°C; however, it increases and finally stabilizes when temperature further lowers from 0 to -10°C. It is important to note that thermal conductivity peaks in the temperature range of -2~0°C (silty and organic-poor soil) and -5~0°C (organic-rich soil), possibly due to phase changes of ice/water in warm permafrost. Under both thawed and frozen states, soil thermal conductivity is positively related with SMS. However, with rising SOM content, the growth rate of soil thermal conductivity with SMS slows gradually. Given the same SMS, soil thermal conductivity declines exponentially with increasing SOM content. Based on the experimental and theoretical analyses, a new empirical computational formula of soil thermal conductivity is established by taking into account of the SOM content, SMS, and soil temperature. The results may help better parameterize in simulating and predicting land surface processes and for optimizing frozen soil engineering designs and provide theoretical bases for exploring the dynamic mechanisms of environmental changes in cold regions under a changing climate.
Medicinal Plants and Zinc: Impact on COVID-19 Pandemic
Authors: Jalal Zineb , Bakour Meryem , Lyoussi Badiaa
Published: September 2021

The world is currently grappling with the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection can cause fever, a dry cough, fatigue, severe pneumonia, respiratory distress syndrome, and in some cases death. There is currently no effective antiviral SARS-CoV-2 drug. To reduce the number of infections and deaths, it is critical to focus on strengthening immunity. This review aims to conduct a comprehensive search on the previous studies using Google Scholar, ScienceDirect, Medline, PubMed, and Scopus for the collection of research papers based on the role of zinc in the immune system, the antiviral activity of zinc, the effect of zinc supplementation in respiratory infections, the therapeutic approaches against viral infections based on medicinal plants, and the role of plants’ bioactive molecules in fighting viral infections. In conclusion, we highlighted the pivotal role of zinc in antiviral immunity and we suggested the bioactive molecules derived from medicinal plants as a search matrix for the development of anti-SARS-CoV-2 drugs.
Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment
Authors: Hashimoto Masakazu , Konda John David , Perrino Stephanie , Celia Fernandez Maria , Lowy Andrew M. , Brodt Pnina
Published: September 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti–PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.
Phosphoproteomics Identifies PI3K Inhibitor–selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance
Authors: Cintas Célia , Douche Thibault , Dantes Zahra , Mouton-Barbosa Emmanuelle , Bousquet Marie-Pierre , Cayron Coralie , Therville Nicole , Pont Frédéric , Ramos-Delgado Fernanda , Guyon Camille , Garmy-Susini Barbara , Cappello Paola , Burlet-Schiltz Odile , Hirsch Emilio , Gomez-Brouchet Anne , Thibault Benoît , Reichert Maximilian , Guillermet-Guibert Julie
Published: September 2021

The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kβ, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
Heme Sequestration as an Effective Strategy for the Suppression of Tumor Growth and Progression
Authors: Wang Tianyuan , Ashrafi Adnin , Konduri Purna Chaitanya , Ghosh Poorva , Dey Sanchareeka , Modareszadeh Parsa , Salamat Narges , Alemi Parinaz Sadat , Berisha Eranda , Zhang Li
Published: September 2021

Heme is an essential nutritional, metabolic, and signaling molecule in living organisms. Pathogenic microbes extract heme from hosts to obtain metallonutrient, while heme fuels mitochondrial respiration and ATP generation in lung tumor cells. Here, we generated small heme-sequestering proteins (HeSPs) based on bacterial hemophores. These HeSPs contain neutral mutations in the heme-binding pocket and hybrid sequences from hemophores of different bacteria. We showed that HeSPs bind to heme and effectively extracted heme from hemoglobin. They strongly inhibited heme uptake and cell proliferation and induced apoptosis in non–small cell lung cancer (NSCLC) cells, while their effects on nontumorigenic cell lines representing normal lung cells were not significant. HeSPs strongly suppressed the growth of human NSCLC tumor xenografts in mice. HeSPs decreased oxygen consumption rates and ATP levels in tumor cells isolated from treated mice, while they did not affect liver and blood cell functions. IHC, along with data from Western blotting and functional assays, revealed that HeSPs reduced the levels of key proteins involved in heme uptake, as well as the consumption of major fuels for tumor cells, glucose, and glutamine. Further, we found that HeSPs reduced the levels of angiogenic and vascular markers, as well as vessel density in tumor tissues. Together, these results demonstrate that HeSPs act via multiple mechanisms, including the inhibition of oxidative phosphorylation, to suppress tumor growth and progression. Evidently, heme sequestration can be a powerful strategy for suppressing lung tumors and likely drug-resistant tumors that rely on oxidative phosphorylation for survival.
Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors
Authors: Sheikh Tahir N. , Chen Xiao , Xu Xinjing , McGuire John T. , Ingham Matthew , Lu Chao , Schwartz Gary K.
Published: September 2021

Chondrosarcomas are inherently resistant to chemotherapy and radiotherapy, pointing to an unmet need for new treatment options. Immune checkpoint inhibitors, which have shown remarkable promise in multiple solid cancer types, have limited efficacy in chondrosarcomas. Mutations in IDH1/2 genes, which result in progressive increases in DNA and histone methylation, are observed in 50% of conventional chondrosarcomas, suggesting that epigenetic dysregulation represents a potential barrier for tumor progression and target for therapeutic intervention. Here, we demonstrated that combined treatment of FDA-approved inhibitors of DNA methyltransferases (DNMTs) 5-aza-2′-deoxycytidine (5-aza), and histone deacetylases (HDACs) suberanilohydroxamic acid (SAHA) impaired the proliferation of chondrosarcoma cell lines in vitro and in xenograft studies. Transcriptomic analysis reveals that chondrosarcoma cells treated with 5-aza and SAHA markedly elevated the expression of IFN-stimulated genes including PD-L1, indicating that these epigenetic drugs induced a potent innate immune response. We demonstrated that 5-aza and SAHA resulted in both genomic and epigenomic instability, as shown by elevated DNA damage response and derepression of retrotransposons, respectively, which in turn activated pattern recognition receptors (PRRs) and the downstream IFN signaling pathways. Importantly, the cytotoxic effects of 5-aza and SAHA can be rescued by depletion of PRRs such as cGAS and MAVS, and potentiated by depletion of the RNA-editing enzyme ADAR1. Together, our results demonstrate preclinical activity of combined DNMT and HDAC inhibition against chondrosarcomas and suggest that targeted epigenetic therapies could represent a new therapeutic approach in the treatment of chondrosarcomas, and this is being tested in an ongoing clinical trial (NCT04340843).
Repurposing Vandetanib plus Everolimus for the Treatment ofACVR1-Mutant Diffuse Intrinsic Pontine Glioma
Authors: Carvalho Diana M. , Richardson Peter J. , Olaciregui Nagore , Stankunaite Reda , Lavarino Cinzia , Molinari Valeria , Corley Elizabeth A. , Smith Daniel P. , Ruddle Ruth , Donovan Adam , Pal Akos , Raynaud Florence I. , Temelso Sara , Mackay Alan , Overington John P. , Phelan Anne , Sheppard David , Mackinnon Andrew , Zebian Bassel , Al-Sarraj Safa , Merve Ashirwad , Pryce Jeremy , Grill Jacques , Hubank Michael , Cruz Ofelia , Morales La Madrid Andres , Mueller Sabine , Carcaboso Angel M. , Carceller Fernando , Jones Chris
Published: September 2021

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.

Significance:

Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.

This article is highlighted in the In This Issue feature, p. 275
Placental Abruption after Fetoscopic Laser Surgery in Twin-Twin Transfusion Syndrome: The Role of the Solomon Technique
Authors: Knijnenburg Patricia J.C. , Lopriore Enrico , Ge Yuchun , Scholl Irene M. , van Klink Jeanine M.M. , Haak Monique C. , Middeldorp Johanna M. , Klumper Frans J.C.M. , Oepkes Dick , Sun Luming , Slaghekke Femke
Published: September 2021

Introduction: Twin-twin transfusion syndrome (TTTS) is a complication in monochorionic twin pregnancies which is preferably treated with fetoscopic laser surgery. A few small studies suggested a possible association between the Solomon laser technique and placental abruption. Methods: The objective of this study is to compare the rate of and to explore potential risk factors for placental abruption in TTTS treated with fetoscopic laser surgery according to the Selective and Solomon laser technique. We conducted a large retrospective cohort study of consecutive TTTS-cases treated with fetoscopic laser surgery in Shanghai, China, and Leiden, The Netherlands treated with either the Selective laser technique (Selective group) or Solomon laser technique (Solomon group). Results: The rate of placental abruption in the Selective group versus the Solomon group was 1.7% (5/289) and 3.4% (15/441), respectively (p = 0.184). No risk factors for placental abruption were identified. Placental abruption was associated with lower gestational age at birth (p = 0.003) and severe cerebral injury (p = 0.003). Conclusion: The prevalence of placental abruption in TTTS after fetoscopic laser surgery is low, although it appears higher than in the overall population. Placental abruption is associated with a lower gestational age at birth, which is associated with severe cerebral injury. The rate of placental abruption was not significantly increased with the use of the Solomon technique. Continued research of placental abruption in TTTS is necessary to determine why the rate is higher than in the overall population.
Pharmacokinetics of Baclofen in a Full-Term Newborn after Intrauterine Exposure: A Case Report
Authors: Balakirouchenane David , Khoudour Nihel , Chouchana Laurent , Chevillard Lucie , Parat Sophie , Declèves Xavier
Published: September 2021

Intrauterine exposure to baclofen can lead to syndrome of withdrawal during the first days of the newborn. We report the case of a full-term baby exposed to baclofen during pregnancy. The mother was treated with baclofen 10 mg 4 times daily. Blood samples were collected from the mother before entering labor and from the baby at H0, H11, H31, and H102 after birth to measure baclofen concentrations and monitor its elimination. Baclofen maternal and neonate pharmacokinetics (PK) and placental transfer were assessed using a physiologically based PK model. Baclofen PK in the neonate after birth followed a monoexponential elimination with a half-life of 10 h, 3-fold longer than that in adults. The newborn was monitored for 11 days without experiencing any symptoms of withdrawal. Reducing baclofen dosing regimen of the mother to the lowest and therefore reducing fetal exposure to baclofen is essential. This case reports for the first time the baclofen pharmacokinetic profile in a newborn.
Lower Cranial Nerve Palsies in the COVID-19 Pandemic: A 10-Case Series of Intensive Care Unit Patients
Authors: Decavel Pierre , Nahmias Olympe , Petit Carine , Tatu Laurent
Published: September 2021

Introduction: A number of neurological complications of COVID-19 have been identified, including cranial nerve paralyses. We present a series of 10 patients with lower cranial nerve involvement after severe COVID-19 infection requiring hospitalization in an intensive care unit. Methods: We conducted a retrospective, observational study of patients admitted to the post-intensive care unit (p-ICU) of Besançon University Hospital (France) between March 16 and May 22, 2020. We included patients with confirmed COVID-19 and cranial neuropathy at admission to the p-ICU. All these patients were treated by orotracheal intubation, and all but one underwent prone-position ventilation therapy. Results: Of the 88 patients admitted to the p-ICU, 10 patients (11%) presented at least 1 cranial nerve palsy. Of these 10 patients, 9 had a hypoglossal nerve palsy and 8 of these also had a deficit in another cranial nerve. The most frequent association was between hypoglossal and vagal palsies (5 patients). None of the patients developed neurological signs related to a global neuropathy. We found no correlation between the intensity of the motor limb weakness and the occurrence of lower cranial nerve palsies. All but 2 of the patients recovered within less than a month. Conclusion: The mechanical compressive hypothesis, linked to the prone-position ventilation therapy, appears to be the major factor. The direct toxicity of SARS-CoV-2 and the context of immune dysfunction induced by the virus may be involved in a multifactorial etiology.
Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI–Mediated High-Density Lipoprotein Uptake
Authors: Xu Hao , Thomas Michael J. , Kaul Sushma , Kallinger Rachel , Ouweneel Amber B. , Maruko Elisa , Oussaada Sabrina M. , Jongejan Aldo , Cense Huib A. , Nieuwdorp Max , Serlie Mireille J. , Goldberg Ira J. , Civelek Mete , Parks Brian W. , Lusis Aldons J. , Knaack Darcy , Schill Rebecca L. , May Sarah C. , Reho John J. , Grobe Justin L. , Gantner Benjamin , Sahoo Daisy , Sorci-Thomas Mary G.
Published: September 2021

Objective:

To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)–mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage.

Approach and Results:

Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI– mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI–mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI–mediated HDL-C uptake is unknown. Differentiated cells from
Ldlr
−/−
/
Pcpe2
−/−
(Pcpe2
−/−
) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to
Ldlr
−/−
(control) adipose tissue. SR-BI–mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans.

Conclusions:

Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

Graphic Abstract:

A graphic abstract is available for this article.