bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2, ACE2 expression, and systemic organ invasion
Authors: Ashraf Usman M. , Abokor Ahmed A. , Edwards Jonnelle M. , Waigi Emily W. , Royfman Rachel S. , Hasan Syed Abdul-Moiz , Smedlund Kathryn B. , Hardy Ana Maria Gregio , Chakravarti Ritu , Koch Lauren Gerard
Published: December 2020

A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a “spike” protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outcomes of COVID-19. This perspective review based on the current literature was prompted to show how disruption of ACE2 by SARS-CoV-2 can affect different organ systems.
COVID-19 Modelling: The Effects of Social Distancing
Authors: Bendtsen Cano Oliva , Cano Morales Sabrina , Bendtsen Claus
Published: December 2020

The purpose of this article is to reach all those who find it difficult to become well informed about the steps that have been implemented to tackle the COVID-19 pandemic and to spark discussion and thought. Here, we use simple stochastic simulations to evaluate different approaches taken to manage the crisis. We then compare these results with updated data of what really happened in the UK and in South Africa. The initial simulations aligned well with how the pandemic has evolved throughout five months following lockdown. The models are, as expected, not fully accurate, but exact enough to be used as a guideline to the evolution of the disease in both high- and middle-income countries. This is shown through simulations formed by an open source code, which allows evaluation of the outcomes from different intervention scenarios or conditions.
ABCG1 Attenuates Oxidative Stress Induced by H2O2 through the Inhibition of NADPH Oxidase and the Upregulation of Nrf2-Mediated Antioxidant Defense in Endothelial Cells
Authors: Xue Jiahong , Fan Jiali , Li Yuan , Wu Wenhuan , Yan Qing , Zheng Qiangsun
Published: December 2020

Summary. Oxidative stress is an important factor that is related to endothelial dysfunction. ATP-binding cassette transporter G1 (ABCG1), a regulator of intracellular cholesterol efflux, has been found to prevent endothelial activation in vessel walls. To explore the role of ABCG1 in oxidative stress production in endothelial cells, HUAECs were exposed to H2O2 and transfected with the specific ABCG1 siRNA or ABCG1 overexpression plasmid. The results showed that overexpression of ABCG1 by ABCG1 plasmid or liver X receptor (LXR) agonist T0901317 treatment inhibited ROS production and MDA content induced by H2O2 in HUAECs. Furthermore, ABCG1 upregulation blunted the activity of prooxidant NADPH oxidase and the expression of Nox4, one of the NADPH oxidase subunits. Moreover, the increased migration of Nrf2 from the cytoplasm to the nucleus and antioxidant HO-1 expression were detected in HUAECs with upregulation of ABCG1. Conversely, ABCG1 downregulation by ABCG1 siRNA increased NADPH oxidase activity and Nox4 expression and abrogated the increase at Nrf2 nuclear protein levels. In addition, intracellular cholesterol load interfered with the balance between NADPH oxidase activity and HO-1 expression. It was suggested that ABCG1 attenuated oxidative stress induced by H2O2 in endothelial cells, which might be involved in the balance between decreased NADPH oxidase activity and increased Nrf2/OH-1 antioxidant defense signaling via its regulation for intracellular cholesterol accumulation.
Cloning and Functional Determination of Ammonium Transporter PpeAMT3;4 in Peach
Authors: You Shuanghong , Wang Yuqing , Li Yanju , Li Yuhe , Tan Ping , Wu Zheng , Shi Wenjing , Song Zhizhong
Published: December 2020

Ammonium (NH4+) plays key roles in plant growth, development, fruit quality, and yield. In plants, NH4+ uptake and transport are facilitated by NH4+ transporters (AMT). However, molecular mechanisms and physiological functions of type‐II AMT (AMT2) transporters in fruit trees are still unclear, especially in peach. In this study, we cloned and characterized an AMT2 family gene from peach, PpeAMT3;4, and determined its function in yeast mutant. Expression analysis showed that PpeAMT3;4 was majorly expressed in peach roots and significantly decreased by NH4+ excess but had no response to NH4+ deficiency. Functional determination and 15nitrogen‐labeled NH4+ uptake assay in yeast cells implied that PpeAMT3;4 was a typical high‐affinity transporter, with a Km value of 86.3 μM, that can uptake external NH4+ in yeast cells. This study provides gene resources to uncover the biological function of AMT2 transporters and reveals molecular basis for NH4+ uptake and nitrogen (N) nutrition mechanisms in fruit trees.
Investigation of Cytotoxicity, Oxidative Stress, and Inflammatory Responses of Tantalum Nanoparticles in THP-1-Derived Macrophages
Authors: Zhang Li , Haddouti El-Mustapha , Beckert Hannes , Biehl Ralf , Pariyar Shyam , Rüwald Julian M. , Li Xian , Jaenisch Max , Burger Christof , Wirtz Dieter C. , Kabir Koroush , Schildberg Frank A.
Published: December 2020

Tantalum (Ta) is gaining attention as a biomaterial in bone tissue engineering. Although the clinical advantage of Ta-based implants for primary and revision total joint replacement (TJA) has been well documented, few studies investigated the effect of wear products of Ta implants on peri-implant cells, and their potential contribution to aseptic implant loosening. This study is aimed at examining the cytotoxicity, oxidative stress, and proinflammatory potential of Ta and TiO2 nanoparticles (NPs) on macrophages in vitro. NPs were characterized using scanning electron microscopy, dynamic light scattering, and energy-dispersive X-ray. To test the NP-mediated cellular response in macrophages, THP-1-derived macrophages were challenged with both NPs, and cytotoxicity was analyzed using CCK-8 and LDH assays. Flow cytometry was used to investigate particle uptake and their internalization routes. NP-mediated oxidative stress was investigated by measuring the production of reactive oxygen species, and their proinflammatory potential was determined by quantifying the production of TNFα and IL-1β in cell culture supernatants using ELISA. We found that both Ta and TiO2 NPs were taken up through actin-dependent phagocytosis, although TiO2 NPs did also show some involvement of macropinocytosis and clathrin-mediated endocytosis. Ta NPs caused no apparent toxicity, while TiO2 NPs demonstrated significant cytotoxicity at a concentration of over 100μg/mL at 24 h. Ta NPs induced negligible ROS generation and proinflammatory cytokines (TNFα, IL-1β) in macrophages. In contrast, TiO2 NPs markedly induced these effects in a dose-dependent manner. Our findings indicate that Ta NPs are inert, nontoxic, and noninflammatory. Therefore, Ta could be considered an excellent biomaterial in primary and revision joint arthroplasty implants.
Equilibrative Nucleoside Transporter 2: Properties and Physiological Roles
Authors: Naes Safaa M. , Ab-Rahim Sharaniza , Mazlan Musalmah , Abdul Rahman Amirah
Published: December 2020

Equilibrative nucleoside transporter 2 (ENT2) is a bidirectional transporter embedded in the biological membrane and is ubiquitously found in most tissue and cell types. ENT2 mediates the uptake of purine and pyrimidine nucleosides and nucleobase besides transporting a variety of nucleoside‐derived drugs, mostly in anticancer therapy. Since high expression of ENT2 has been correlated with advanced stages of different types of cancers, consequently, this has gained significant interest in the role of ENT2 as a potential therapeutic target. Furthermore, ENT2 plays critical roles in signaling pathway and cell cycle progression. Therefore, elucidating the physiological roles of ENT2 and its properties may contribute to a better understanding of ENT2 roles beyond their transportation mechanism. This review is aimed at highlighting the main roles of ENT2 and at providing a brief update on the recent research.
A Hybrid Prediction Method for Stock Price Using LSTM and Ensemble EMD
Authors: Yujun Yang , Yimei Yang , Jianhua Xiao
Published: December 2020

The stock market is a chaotic, complex, and dynamic financial market. The prediction of future stock prices is a concern and controversial research issue for researchers. More and more analysis and prediction methods are proposed by researchers. We proposed a hybrid method for the prediction of future stock prices using LSTM and ensemble EMD in this paper. We use comprehensive EMD to decompose the complex original stock price time series into several subsequences which are smoother, more regular and stable than the original time series. Then, we use the LSTM method to train and predict each subsequence. Finally, we obtained the prediction values of the original stock price time series by fused the prediction values of several subsequences. In the experiment, we selected five data to fully test the performance of the method. The comparison results with the other four prediction methods show that the predicted values show higher accuracy. The hybrid prediction method we proposed is effective and accurate in future stock price prediction. Hence, the hybrid prediction method has practical application and reference value.
Clinicopathological Features and Prognostic Implication of Gastric Carcinoma with Lymphoid Stroma
Authors: Pyo Jung-Soo , Kim Nae Yu , Son Byoung Kwan , Lee Hyo Young , Oh Il Hwan , Chung Kwang Hyun
Published: December 2020

Background/Objective. Gastric carcinoma with lymphoid stroma (GCLS) has been referred to as lymphoepithelioma-like carcinoma and medullary carcinoma. The present study aims at elucidating the clinicopathologic features and prognostic implications of GCLS through a meta-analysis. Methods. This study included 34 eligible studies and 1757 GCLSs. The clinicopathologic characteristics of GCLS were investigated from eligible studies, and the meta-analysis was performed. In addition, we compared the survival rates between GCLS and non-GCLS. Results. The estimated rate of GCLS was 0.062 (95% confidence interval (CI) 0.040-0.097). GCLS was significantly correlated with the diffuse type of Lauren’s classification, proximal tumor location, less-frequent lymphatic invasion, and lower pTNM stage. However, there was no significant difference in age, sex, tumor differentiation, vascular invasion, perineural invasion, pT stage, lymph node metastasis, and distant metastasis between GCLS and non-GCLS patients. EBV positive rates in GCLS and non-GCLS patients were 0.723 (95% CI 0.643-0.791) and 0.064 (95% CI 0.039-0.103), respectively. HER2 expression in GCLS was significantly lower than that in non-GCLS. GCLS patients had a more favorable prognosis than that of non-GCLS patients (hazard ratio 0.500, 95% CI 0.305-0.821). Conclusion. GCLS comprised 6.2% of overall GC and more frequent in the proximal portion of the stomach. Since GCLS was associated with better prognosis, the histologic finding can be useful for predicting the patient’s prognosis.
Forecasting Oil Price by Hierarchical Shrinkage in Dynamic Parameter Models
Authors: Liu Yuntong , Wei Yu , Liu Yi , Li Wenjuan
Published: December 2020

The aim of this paper is to forecast monthly crude oil price with a hierarchical shrinkage approach, which utilizes not only LASSO for predictor selection, but a hierarchical Bayesian method to determine whether constant coefficient (CC) or time-varying parameter (TVP) predictive regression should be employed in each out-of-sample forecasting step. This newly developed method has the advantages of both model shrinkage and automatic switch between CC and TVP forecasting models; thus, this may produce more accurate predictions of crude oil prices. The empirical results show that this hierarchical shrinkage model can outperform many commonly used forecasting benchmark methods, such as AR, unobserved components stochastic volatility (UCSV), and multivariate regression models in forecasting crude oil price on various forecasting horizons.
A Robust Authentication Algorithm for Medical Images Based on Fractal Brownian Model and Visual Cryptography
Authors: Tiankai Sun , Xingyuan Wang , Daihong Jiang , Da Lin , Bin Ding , Dan Li
Published: December 2020

In this paper, we aimed to discuss the security authentication requirements of medical images in the medical network, and a security authentication method is designed based on fractal and visual cryptography. Based on the discrete fractal Brownian random field model, the gray-level statistical information and spatial structure information of medical images is fully mined. The gray distribution of medical images is expressed in the form of fractal features. By using the spatial data mining methods, the data of fractal structure space is analyzed, and by using the stability of the energy structure, the authentication features are formed. Using the visual cryptography (VC), the robustness of the authentication method is further enhanced. Through the centralized test of common medical images and the comparison analysis with existing methods, it is further verified that the method is effective against common attacks such as JPEG compression, scaling, rotation operation, clipping, added noise, filtering, and blurring.
An Analytical Solution for the Frost Heaving Force considering the Freeze‐Thaw Damage and Transversely Isotropic Characteristics of the Surrounding Rock in Cold‐Region Tunnels
Authors: Zhang Jiabing , Zhang Xiaohu , Fu Helin , Wu Yimin , Huang Zhen , Chen Deyue
Published: December 2020

Frost damage is a frequent occurrence in cold regions and can threaten the normal use and structural stability of tunnel engineering projects. To accurately determine the frost heaving force and effectively evaluate the frost damage in cold‐region tunnels, an analytical solution for the frost heaving force considering the freeze‐thaw (F‐T) damage and transversely isotropic characteristics of surrounding rock is presented based on complex variable theory and the power series method. The calculation results indicate that the frost heaving force acts on the lining considering that the transversely isotropic characteristics of surrounding rock are significantly greater than those when assuming the surrounding rock is homogeneous isotropic media. This demonstrates that the transversely isotropic characteristics of surrounding rock have a considerable impact on the frost heaving force and should be considered. The frost heaving force continuously increases as the bedding angle increases from 0° to 90°, and the maximum frost heaving force in the Guanjiao tunnel (the rock mass bedding angle is 30°) of the Xining‐Geermu Railway in China is approximately 1.04 MPa. In addition, the influence of F‐T cycles on the frost heaving force in cold‐region tunnels is investigated based on the analytical solution of the frost heaving force proposed in this paper. The frost heaving force acting on the lining decreases with an increasing number of F‐T cycles due to the deterioration of the mechanical parameters of the surrounding rock.
Phytochemical Analysis, Cytotoxic, Antioxidant, and Antibacterial Activities of Lichens
Authors: Aoussar Noura , Laasri Fatima Ezzahra , Bourhia Mohammed , Manoljovic Nedeljko , Mhand Rajaa Ait , Rhallabi Naima , Ullah Riaz , Shahat Abdelaaty A. , Noman Omar M. , Nasr Fahd A , Almarfadi Omer M. , El Mzibri Mohammed , Vasiljević Perica , Benbacer Laila , Mellouki Fouad
Published: December 2020

Background. Lichens present a complex symbiotic relationship between a filamentous fungus, photoautotrophic partner (algae or cyanobacteria), and bacterial community. The Objective of the Study. This study aimed at investigating the chemical composition and cytotoxic, antioxidant, and antimicrobial activities of acetone extracts of Moroccan Evernia prunastri (E. prunastri), Ramalina farinacea (R. farinacea), and Pseudevernia furfuracea (P. furfuracea). Materials and Methods. The phytochemical analysis was carried out by HPLC‐UV. The cytotoxic effect was assessed on human prostate cancer (22RV1), human colon carcinoma (HT‐29), human hepatocellular carcinoma (Hep‐G2), and Hamster ovarian cancer (CHO) cells lines by WST1 assay. The antioxidant power was assessed by DPPH and FRAP assays. The antibacterial effect was obtained using the broth microdilution method. Results. The findings of phytochemical analysis showed that the lichens studied possess interesting bioactive molecules such as physodalic acid, evernic acid, and usnic acid, as well as protocetraric acid. According to the American National Cancer Institute guidelines, the WST‐1 test showed that all crude extracts did not show significant cytotoxic effects against all concerous cell lines, and IC50 values ranged from 42.30 to 140.24 µg/mL. Regarding the antioxidant activity, P. furfuracea extract showed the highest free‐radical‐scavenging ability (IC50 = 498.40 µg/mL). The most potent antibacterial extract was recorded for P. furfuracea extract with a minimum inhibitory concentration (MIC) ranging from 0.039 to 0.31 mg/mL. Conclusion. In this research work, we report that the studied lichen extracts exhibit an important biological effect, supporting that lichens represent a hopeful source of original natural products for the research of new bioactive molecules having a pharmaceutical interest.
Effect of Traditional Chinese Medicine Poge Heart‐Saving Decoction on Cardiac Function in Heart Failure Rat Model
Authors: Liu Lei , Mo Yanfei , Wu Bingying , Yu Zongliang , Sun Bugao
Published: December 2020

Background. Poge heart‐saving decoction (PHSD) has been used as a medicine treating heart failure in China for many years. The study aimed to explore the effect of PHSD on cardiac function in heart failure conditions and its underlying mechanism. Methods. Adriamycin was used to induce the model of heart failure (HF) in rats. Sixty rats were randomly divided into six groups: blank control group, sham group, 9.33 g/kg group (low‐PHSD, test group), 13.995 g/kg group (moderate‐PHSD, test group), 18.66 g/kg group (high‐PHSD, test group), and fosinopril group (4.67 mg/kg, comparison test group). Cardiac ultrasound was used to evaluate the cardiac function of the rats, and radioimmunoassay was used to measure aldosterone (ALD) and angiotensin II (AngII) levels in the serum. Results. Compared with the blank control group, the left ventricular end‐diastolic dimension (LVEDd) and left ventricular end‐systolic dimension (LVEDs) in the sham group were increased (1.04 ± 0.12 vs. 0.67 ± 0.13 cm; 0.75 ± 0.13 vs. 0.28 ± 0.10 cm; P < 0.05), and the left ventricular ejection fraction was decreased (36.65 ± 5.74 vs. 76.09 ± 4.23%; P < 0.05). The ejection fraction of HF rats was increased in 9.33 g/kg group, 13.995 g/kg group, and 18.66 g/kg group compared with those of the sham group (57.13 ± 1.63, 58.43 ± 1.98, and 59.21 ± 1.37 vs. 36.65 ± 5.74%; P < 0.05). PHSD also improved cardiac function by reducing the LVEDd and LVEDs (0.88 ± 0.11, 0.75 ± 0.13, and 0.72 ± 0.18 vs. 1.04 ± 0.12 cm; 0.62 ± 0.10, 0.63 ± 0.17, and 0.45 ± 0.11 vs. 0.75 ± 0.13 cm; P < 0.05). The levels of ALD and AngII in the serum of rats in the sham group were significantly higher than those in the blank control group (371.58 ± 39.25 vs. 237.12 ± 17.35 μg/L; 232.18 ± 16.33 vs. 159.44 ± 18.42 pg/L; P < 0.05). The ALD and AngII of the rats in all of the three PHSD groups and the fosinopril group were decreased (276.81 ± 25.63, 277.18 ± 21.35, 268.19 ± 19.28, and 271.47 ± 28.96 vs. 371.58 ± 39.25 μg/L; 169.41 ± 27.53, 168.81 ± 19.78, 164.23 ± 21.34, and 174.27 ± 22.84 vs. 232.18 ± 16.33 pg/L; P < 0.05). The histopathological changes of the myocardium in the sham group showed the disorganized fiber, shaded staining, fracture, and zonation. The fracture of the myocardium was relieved in all groups except the sham group and the blank control group. Conclusion. Therefore, PHSD could shorten LVEDd and LVEDs of rats and reverse ventricular remodeling. The mechanism might be related to the inhibition of the activation level of renin‐angiotensin‐aldosterone system (especially ALD and AngII) and decreasing the postload of the heart.
Microseismic Monitoring, Positioning Principle, and Sensor Layout Strategy of Rock Mass Engineering
Authors: Ma Tianhui , Lin Daoyuan , Tang Chun’an , Yadav Kedar Prasad , Feng Zhiqiang , Ma Ke
Published: December 2020

Microseismic monitoring technology can start from the most initial stage of rock deformation and track and monitor the progressive failure process of rock mass from the fracture of rock blocks to the instability of rock mass. Thus, the scientific nature of monitoring work is greatly promoted, and the accuracy and advance of the prediction of engineering and geological disasters are improved. In this paper, the fracture and instability of rock can be analyzed by analyzing the microseismic signals produced by rock failure; The location of microseismic source can be determined by multipoint synchronous data acquisition to determine the time when each sensor (at least 5) receives microseismic signals; Combined with practical engineering experience for underground engineering in growth, heading tunnel, put forward only sensor arrangement to take mobile, follow the semienclosed layout network. We hope to give some reference to the researchers who are concerned with microseismic monitoring technology.
A Study on Differences between Simplified and Traditional Chinese Based on Complex Network Analysis of the Word Co-Occurrence Networks
Authors: Jiang Zhongqiang , Zhao Dongmei , Zheng Jiangbin , Chen Yidong
Published: December 2020

Currently, most work on comparing differences between simplified and traditional Chinese only focuses on the character or lexical level, without taking the global differences into consideration. In order to solve this problem, this paper proposes to use complex network analysis of word co-occurrence networks, which have been successfully applied to the language analysis research and can tackle global characters and explore the differences between simplified and traditional Chinese. Specially, we first constructed a word co-occurrence network for simplified and traditional Chinese using selected news corpora. Then, the complex network analysis methods were performed, including network statistics analysis, kernel lexicon comparison, and motif analysis, to gain a global understanding of these networks. After that, the networks were compared based on the properties obtained. Through comparison, we can obtain three interesting results: first, the co-occurrence networks of simplified Chinese and traditional Chinese are both small-world and scale-free networks. However, given the same corpus size, the co-occurrence networks of traditional Chinese tend to have more nodes, which may be due to a large number of one-to-many character/word mappings from simplified Chinese to traditional Chinese; second, since traditional Chinese retains more ancient Chinese words and uses fewer weak verbs, the traditional Chinese kernel lexicons have more entries than the simplified Chinese kernel lexicons; third, motif analysis shows that there is no difference between the simplified Chinese network and the corresponding traditional Chinese network, which means that simplified and traditional Chinese are semantically consistent.
An Efficient Skewed Line Segmentation Technique for Cursive Script OCR
Authors: Malik Saud , Sajid Ahthasham , Ahmad Arshad , Almogren Ahmad , Hayat Bashir , Awais Muhammad , Kim Kyong Hoon
Published: December 2020

Segmentation of cursive text remains the challenging phase in the recognition of text. In OCR systems, the recognition accuracy of text is directly dependent on the quality of segmentation. In cursive text OCR systems, the segmentation of handwritten Urdu language text is a complex task because of the context sensitivity and diagonality of the text. This paper presents a line segmentation algorithm for Urdu handwritten and printed text and subsequently to ligatures. In the proposed technique, the counting pixel approach is employed for modified header and baseline detection, in which the system first removes the skewness of the text page, and then the page is converted into lines and ligatures. The algorithm is evaluated on manually generated Urdu printed and handwritten dataset. The proposed algorithm is tested separately on handwritten and printed text, showing 96.7% and 98.3% line accuracy, respectively. Furthermore, the proposed line segmentation algorithm correctly extracts the lines when tested on Arabic text.
Leishmania mexicana: Novel Insights of Immune Modulation through Amastigote Exosomes
Authors: Soto-Serna Laura Enedina , Diupotex Mariana , Zamora-Chimal Jaime , Ruiz-Remigio Adriana , Delgado-Domínguez José , Cervantes-Sarabia Rocely Buenaventura , Méndez-Bernal Adriana , Escalona-Montaño Alma Reyna , Aguirre-García María Magdalena , Becker Ingeborg
Published: December 2020

Exosomes are extracellular microvesicles of endosomal origin (multivesicular bodies, MVBs) constitutively released by eukaryotic cells by fusion of MVBs to the plasma membrane. The exosomes from Leishmania parasites contain an array of parasite molecules such as virulence factors and survival messengers, capable of modulating the host immune response and thereby favoring the infection of the host. We here show that exosomes of L. mexicana amastigotes (aExo) contain the virulence proteins gp63 and PP2C. The incubation of aExo with bone marrow-derived macrophages (BMMs) infected with L. mexicana led to their internalization and were found to colocalize with the cellular tetraspanin CD63. Furthermore, aExo inhibited nitric oxide production of infected BMMs, permitting enhanced intracellular parasite survival. Expressions of antigen-presenting (major histocompatibility complex class I, MHC-I, and CD1d) and costimulatory (CD86 and PD-L1) molecules were modulated in a dose-dependent fashion. Whereas MHC-I, CD86 and PD-L1 expressions were diminished by exosomes, CD1d was enhanced. We conclude that aExo of L. mexicana are capable of decreasing microbicidal mechanisms of infected macrophages by inhibiting nitric oxide production, thereby enabling parasite survival. They also hamper the cellular immune response by diminishing MHC-I and CD86 on an important antigen-presenting cell, which potentially interferes with CD8 T cell activation. The enhanced CD1d expression in combination with reduction of PD-L1 on BMMs point to a potential shift of the activation route towards lipid presentations, yet the effectivity of this immune activation is not evident, since in the absence of costimulatory molecules, cellular anergy and tolerance would be expected.
Chemical Composition of Essential Oils Obtained from Heteromorpha arborescens (Spreng.) Cham. and Schltdl Leaves Using Two Extraction Methods
Authors: Abifarin Taiwo Oluwafunmilola , Otunola Gloria Aderonke , Afolayan Anthony Jide
Published: December 2020

This study was aimed at comparing the essential oils obtained from Heteromorpha arborescens leaves by Solvent-Free Microwave Extraction (SFME) and Hydrodistillation (HD) methods in terms of their chemical compositions, yield, CO2 emission, and energy consumption. The solvent-free microwave extraction method indicated a higher oil yield of 0.7 mL/200 g (0.35%) as compared to 0.59 mL/200 g (0.295%) obtained through hydrodistillation. GC-MS analysis of the oils revealed a total of 52 chemical components from both methods with the presence of 35 (96.52%) and 30 (71.15%) chemical constituents for HD and SFME, respectively. The major constituents observed in the essential oil extracted by SFME methods include α-pinene (6%), D-limonene (11.27%), β-ocimene (9.09%), β-phellandrene (6.33%), β-mycene (8.49%), caryophyllene (5.96%), and camphene (4.28%). However, in the hydrodistillation method, the oil was majorly composed of a-pinene (4.41%), β-pinene (10.68%), β-ocimene (6.30%), germacrene-D (5.09%), humulene (5.55%), and α-elemene (6.18%). The SFME method was better in terms of saving energy (0.25 kWh against 4.2 kWh of energy consumed), reduced CO2 emission (200 g against 3360 g of CO2), a higher yield, and better quality of essential oil due to the presence of higher valuable oxygenated compounds (8.52%) against that of the hydrodistillation method (2.96%). The SFME method is, therefore, a good alternative for extracting the oils of H. arborescens leaves since the essential oil yield is higher with more oxygenated compounds, considerable energy savings, lower cost, and reduced environmental burden at substantially reduced extraction time (30 min as opposed to 180 min).
Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy
Authors: Lee Geun Taek , Nagaya Naoya , Desantis Jenny , Madura Kiran , Sabaawy Hatem E. , Kim Wun-Jae , Vaz Roy J. , Cruciani Gabriele , Kim Isaac Yi
Published: December 2020

Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel–Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents—abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.
Outlook for New CAR-Based Therapies with a Focus on CAR NK Cells: What Lies Beyond CAR-Engineered T Cells in the Race against Cancer
Authors: Daher May , Rezvani Katayoun
Published: December 2020

Chimeric antigen receptor (CAR) engineering of T cells has revolutionized the field of cellular therapy for the treatment of cancer. Despite this success, autologous CAR-T cells have recognized limitations that have led to the investigation of other immune effector cells as candidates for CAR modification. Recently, natural killer (NK) cells have emerged as safe and effective platforms for CAR engineering. In this article, we review the advantages, challenges, and preclinical and clinical research advances in CAR NK cell engineering for cancer immunotherapy. We also briefly consider the feasibility and potential benefits of applying other immune effector cells as vehicles for CAR expression.

Significance:

CAR engineering can redirect the specificity of immune effector cells, converting them to a much more potent weapon to combat cancer cells. Expanding this strategy to immune effectors beyond conventional T lymphocytes could overcome some of the limitations of CAR T cells, paving the way for safer and more effective off-the-shelf cellular therapy products.
Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells
Authors: Drijvers Jefte M. , Gillis Jacob E. , Muijlwijk Tara , Nguyen Thao H. , Gaudiano Emily F. , Harris Isaac S. , LaFleur Martin W. , Ringel Alison E. , Yao Cong-Hui , Kurmi Kiran , Juneja Vikram R. , Trombley Justin D. , Haigis Marcia C. , Sharpe Arlene H.
Published: December 2020

Metabolic constraints in the tumor microenvironment constitute a barrier to effective antitumor immunity and similarities in the metabolic properties of T cells and cancer cells impede the specific therapeutic targeting of metabolism in either population. To identify distinct metabolic vulnerabilities of CD8+ T cells and cancer cells, we developed a high-throughput in vitro pharmacologic screening platform and used it to measure the cell type–specific sensitivities of activated CD8+ T cells and B16 melanoma cells to a wide array of metabolic perturbations during antigen-specific killing of cancer cells by CD8+ T cells. We illustrated the applicability of this screening platform by showing that CD8+ T cells were more sensitive to ferroptosis induction by inhibitors of glutathione peroxidase 4 (GPX4) than B16 and MC38 cancer cells. Overexpression of ferroptosis suppressor protein 1 (FSP1) or cytosolic GPX4 yielded ferroptosis-resistant CD8+ T cells without compromising their function, while genetic deletion of the ferroptosis sensitivity–promoting enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) protected CD8+ T cells from ferroptosis but impaired antitumor CD8+ T-cell responses. Our screen also revealed high T cell–specific vulnerabilities for compounds targeting NAD+ metabolism or autophagy and endoplasmic reticulum (ER) stress pathways. We focused the current screening effort on metabolic agents. However, this in vitro screening platform may also be valuable for rapid testing of other types of compounds to identify regulators of antitumor CD8+ T-cell function and potential therapeutic targets.
Elevated Expression of T-Cell Immunoglobulin and Mucin Domain 3 on T Cells from Peripheral Blood in Patients with Cervical Carcinoma
Authors: Li Juan , Sun Xiao-fei , Shen Ying , Yang Qing , Dai Shu-yan
Published: December 2020

Objective: To investigate the expression of T-cell immunoglobulin and mucin domain 3 (TIM-3) on peripheral T cells of cervical carcinoma patients. Methods: Peripheral blood samples from 15 high-grade cervical squamous intraepithelial lesion (HSIL) patients, 24 cervical carcinoma patients, and 21 healthy controls were collected. TIM-3 expressions on the surface of peripheral CD4+ T cells and CD8+ T cells were analyzed with flow cytometry. Results: There was significantly lower expression of CD4+ T cells and CD8+ T cells in HSIL patients and cervical carcinoma patients compared with healthy controls. We also found that TIM-3 expression on peripheral CD4+ T and CD8+ T cells of both HSIL patients and cervical carcinoma patients was significantly increased compared to the control group. Further analyses revealed that the expression of TIM-3 on peripheral CD4+ T and CD8+ T cells significantly increased in stage III–IV cervical carcinoma patients compared to stages I–II. Conclusion: The increased expression of TIM-3 on CD4+ T cells and CD8+ T cells of patients with cervical carcinoma and HSIL suggests the potential role of TIM-3 in the development and progression of cervical carcinoma, which may be a novel therapy target for cervical carcinoma.
White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease
Authors: Hannawi Yousef , Yanek Lisa R. , Kral Brian G. , Becker Lewis C. , Vaidya Dhananjay , Haughey Norman J. , Becker Diane M. , Nyquist Paul A.
Published: December 2020

Introduction: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. Methods: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. Results: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = −0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = −0.03, p = 0.003, C20: β = −0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = −0.0103, p = 0.027). Conclusions: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.
Extracorporeal Ammonia Clearance for Hyperammonemia in Critically Ill Patients: A Scoping Review
Authors: Naorungroj Thummaporn , Yanase Fumitaka , Eastwood Glenn M. , Baldwin Ian , Bellomo Rinaldo
Published: December 2020

Introduction: Hyperammonemia is a life-threatening condition. However, clearance of ammonia via extracorporeal treatment has not been systematically evaluated. Methods: We searched EMBASE and MEDLINE databases. We included all publications reporting ammonia clearance by extracorporeal treatment in adult and pediatric patients with clearance estimated by direct dialysate ammonia measurement or calculated by formula. Two reviewers screened and extracted data independently. Results: We found 1,770 articles with 312 appropriate for assessment and 28 studies meeting eligibility criteria. Most of the studies were case reports. Hyperammonemia was typically secondary to inborn errors of metabolisms in children and to liver failure in adult patients. Ammonia clearance was most commonly reported during continuous renal replacement therapy (CRRT) and appeared to vary markedly from <5 mL/min/m2 to >250 mL/min/m2. When measured during intermittent hemodialysis (IHD), clearance was highest and correlated with blood flow rate (R2 = 0.853; p < 0.001). When measured during CRRT, ammonia clearance could be substantial and correlated with effluent flow rate (EFR; R2 = 0.584; p < 0.001). Neither correlated with ammonia reduction. Peritoneal dialysis (PD) achieved minimal clearance, and other extracorporeal techniques were rarely studied. Conclusions: Extracorporeal ammonia clearance varies widely with sometimes implausible values. Treatment modality, blood flow, and EFR, however, appear to affect such clearance with IHD achieving the highest values, PD achieving minimal values, and CRRT achieving substantial values especially at high EFRs. The role of other techniques remains unclear. These findings can help inform practice and future studies.
A Rare Case of Hairy Cell Leukemia with Unusual Loss of CD123 Associated with COVID-19 at the Time of Presentation
Authors: Kohla Samah , Ibrahim Feryal A. , Aldapt Mahmood B. , ELSabah Hesham , Mohamed Shehab , Youssef Reda
Published: December 2020

Coronavirus disease 2019 (COVID-19) pandemic has been a serious threat and has been reported with different presentations and complications. Older age, along with comorbidities such as diabetes, hypertension, or cardiac disease, increases the risk factors for COVID-19 severity and death [N Engl J Med. 2020;382(18):1708–20 and Lancet Respir Med. 2020 05;8(5):475–81]. It is proposed that cancer patients have a significantly higher incidence of severe incidents including admission to the intensive care unit, the necessity for assisted ventilation, and even death after catching the virus compared with non-cancer patients [Lancet Oncol. 2020;21(3):335–7]. It is also described that cancer patients appear to be twice as likely to contract infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [JAMA Oncol. 2020;6(7):1108–10]. Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder, with patients typically presenting with cytopenias, marked splenomegaly in 80–90% of patients, circulating leukemia cells, bone marrow infiltration and the presence of BRAF V600E somatic mutation [Indian J Hematol Blood Transfus. 2014;30(Suppl 1):413–7]. Leukemic cells classically have central nuclei and abundant cytoplasm with hairy-like projections and express CD11c, CD25, CD103, and CD123 [Indian J Hematol Blood Transfus. 2014;30(Suppl 1):413–7]. Loss of CD123 in HCL has been rarely reported in the literature [Am J Hematol. 2019;94(12):1413–22]. We describe a unique case of a COVID-19-positive male who presented with severe respiratory symptoms, deteriorated quickly, and was intubated. Workup of severe progressive pancytopenia and bone marrow examination revealed HCL without splenomegaly and with atypical unusual loss of CD123. To our knowledge, this is the first case of CD123-negative HCL without splenomegaly associated with COVID-19 infection as the initial presentation.
Ovarialkarzinomrezidiv: Sollte operiert werden oder reicht die medikamentöse Therapie?
Authors: Pölcher Martin
Published: December 2020

Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010–2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59–0.97, p = 0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54–0.82, p < 0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 mos in favor of the surgery arm (HR 0.65, 95%CI 0.52–0.81, p < 0.001). An analysis according to treatment showed an OS benefit exceeding 12 mos for pts with complete resection (CR) compared to pts without surgery (median 60.7 vs. 46.2 mos); pts with surgery and incomplete resection even did worse (median 28.8 mos). 60 d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparotomies were performed in 3.7% of operated pts. Further grade 3/4 adverse events did not differ significantly between arms. Conclusions: This is the first surgical study demonstrating a meaningful survival benefit in OC: Surgery in pts with first relapse and TFIp of 6+ mos and selected by a positive AGO-Score resulted in a significant increase of OS, PFS and TFST with acceptable morbidity and, therefore, should be offered to suitable pts. The benefit was exclusively seen in pts with CR indicating the importance of both the optimal selection of pts (eg. by AGO score) and of centres with expertise and a high chance of achieving a CR. Clinical trial information: NCT01166737.
Cytokine Profiles and the Effect of Intravitreal Aflibercept Treatment on Experimental Choroidal Neovascularization
Authors: Wang Chen , Zhang Rongrong , Zhang Qi , Jin Huixiang , Wei Chenghua , Wu Changfan , Mei Lixin , Liu Yinping , Zhang Pengfei
Published: December 2020

Purpose: The purpose of our study was to investigate the profiles of inflammatory cytokines and the macrophage polarization gene in a choroidal neovascularization (CNV) mouse model before and after intravitreal aflibercept treatment. Methods: The CNV mouse model was conducted by laser photocoagulation. A total of 58 cytokines were measured by the multiplex mouse cytokine antibody array. The macrophage polarization genes were tested by reverse transcription polymerase chain reaction. The relationship between the cytokines and the CNV lesion area was analyzed by correlation. Results: MIP-1a on day 3 after laser photocoagulation, MCP-5 and Fas-L on day 7, and IL-15 and IL-7 on day 14 were significantly upregulated (p < 0.001, fold change >10.0). After the intravitreal aflibercept treatment, GM-CSF and MCP-1 on day 3 and TIMP-1 on days 7 and 14 were the most significantly upregulated cytokines (p < 0.001, fold change >10.0). MIP-1 on day 3, IL-13 and Fas-L on day 7, and Fas-L on day 14 were the most significantly downregulated cytokines after intravitreal aflibercept treatment (p < 0.001, fold change >5.0). M2 polarization and VEGFA genes were significantly increased in the CNV formation, whereas aflibercept suppressed M2 polarization and VEGFA genes. IL-7 was negatively related to the CNV lesion area on day 14 after intravitreal aflibercept treatment (r = −0.938, p = 0.006). Conclusion: The inflammatory cytokines and the M1/M2 macrophage genes significantly changed in the CNV mouse model. This result suggests that inflammatory cytokines and macrophages play a critical role in the physiopathology of CNV.