bluuebunny/crossref_metadata_2025 huggingface dataset:
CORPORATE VENTURE CAPITAL DIVERSIFICATION, PARENT COMPANY VALUE SPILLOVERS AND VALUE CREATION OF START-UPS
Authors: WANG LEI , YANG YE , AN YUNBI
Published: February 2021

Corporate venture capital (CVC) not only promotes value creation for CVC parent companies but also brings rich entrepreneurial resources to invested start-ups. This paper explores the mechanisms through which CVC portfolio diversification promotes value creation for both parent companies as well as the invested start-ups. Focusing on 142 start-ups in China from 2003 to 2015, invested in by 49 companies listed on the Shanghai and Shenzhen Main Boards, we find that CVC portfolio diversification has a positive impact on the value of invested start-ups and CVC parent company value spillovers play a mediating role in this effect. In addition, CVC portfolio diversification has a nonlinear U-shaped relationship with the value of parent companies. Finally, geographical proximity between parent companies and their invested start-ups renders a significant reciprocal positive moderating effect on the relationship between CVC diversification and the value of parent companies, as well as the relationship between the value of parent companies and the value of invested start-ups.
From weak interaction to gravity
Authors: Novello M. , Hartmann A. E. S.
Published: February 2021

We follow an old suggestion made by Stueckelberg that there exists an intimate connection between weak interaction and gravity, symbolized by the relationship between the Fermi and Newton’s constants. We analyze the hypothesis that the effect of matter upon the metric that represents gravitational interaction in general relativity is an effective one. This leads us to consider gravitation to be the result of the interaction of two neutral spinorial fields ([Formula: see text]-neutrinos) [Formula: see text] and [Formula: see text] with all kinds of matter and energy. We present three examples with only one [Formula: see text]-neutrino: two static and spherically symmetric configurations and a cosmological framework for an isotropic dynamical universe. Without self-interaction, the associated effective geometry is precisely the Schwarzschild metric. On the other hand, a self-interacting [Formula: see text]-neutrino generates a new gravitational black hole.
Xilinx Zynq FPGA for Hardware Implementation of a Chaos-Based Cryptosystem for Real-Time Image Protection
Authors: Gafsi Mohamed , Abbassi Nessrine , Hajjaji Mohammed Ali , Malek Jihene , Mtibaa Abdellatif
Published: February 2021

This paper proposes a well-optimized FPGA implementation of a chaos-based cryptosystem for real-time image encryption and decryption. A highly sensitive Pseudo-Random Number Generator (PRNG) based on the Lorenz chaotic system is designed to generate pseudo-random numbers. A high-quality encryption key is acquired by encrypting the numbers of a 128-bit counter using the PRNG. For image encryption, the image is first decomposed into 128-bit blocks. Then, the blocks are encrypted by XORing pixels with the key stream. [Formula: see text] cycles of encryption can be achieved to increase complexity. Finally, the blocks are concatenated to form an encrypted image. The algorithm is designed, implemented, and validated on the Xilinx Zynq FPGA platform using the Vivado/System Generator tool. The hardware design is well optimized for pipeline processing and low resource utilization. The experimental synthesis indicates that the provided architecture achieves high performance in terms of frequency and throughput. The encryption scheme is evaluated and analyzed by several tools and tests using different images. The experimental simulation results demonstrate that the hardware implementation is faster than a software implementation while maintaining the technique’s effectiveness. The proposed hardware implementation is extremely adopted for secret image encryption and decryption that can be used in real-time applications.
Improved Design Method for Nearly Linear-Phase IIR Filters Using Constrained Optimization
Authors: Omar Abdussalam , Shpak Dale , Agathoklis Panajotis
Published: February 2021

In this paper, the design of nearly linear-phase recursive digital filters using a constrained optimization method is investigated. The method is based on existing constrained optimization techniques for nearly linear-phase IIR digital filters, and it is expected to be useful in applications where both magnitude and phase response specifications are required to be satisfied. Starting from an initial filter, the proposed method minimizes the group delay deviation under a set of linear constraints in terms of the magnitude response and filter stability. Improved sampling functions are introduced to the optimization problem, which are used to control the sampling points that are used for approximating the group delay and the rest of the constraints in various frequency bands. By using the proposed sampling functions we get an improved IIR filter response.
THE FIRST PRINCIPLE STUDY OF COMPARISON OF DIVALENT AND TRIVALENT IMPURITY IN RRAM DEVICES USING GGA+U
Authors: KHERA EJAZ AHMAD , ULLAH HAFEEZ , IMRAN MUHAMMAD , ALGADI HASSAN , HUSSAIN FAYYAZ , KHALIL RANA MUHAMMAD ARIF
Published: February 2021

Resistive switching (RS) performances had prodigious attention due to their auspicious potential for data storage. Oxide-based devices with metal insulator metal (MIM) structure are more valuable for RS applications. In this study, we have studied the effect of divalent (nickel) as well as trivalent (aluminum) dopant without and with oxygen vacancy ([Formula: see text] in hafnia ([Formula: see text]-based resistive random-access memory (RRAM) devices. All calculations are carried out within the full potential linearized augmented plane-wave (FP-LAPW) method based on the WIEN2k code by using generalized gradient approximation (GGA) and generalized gradient approximation with U Hubbard parameters (GGA+U) approach. The studies of the band structure, density of states and charge density reveal that HfNiO2+Vo are more appropriate dopant to enhance the conductivity for RRAM devices.
Serrin’s type problems in warped product manifolds
Authors: Farina Alberto , Roncoroni Alberto
Published: February 2021

In this paper, we consider Serrin’s overdetermined problems in warped product manifolds and we prove Serrin’s type rigidity results by using the [Formula: see text]-function approach introduced by Weinberger.
Uprolling unrolled quantum groups
Authors: Creutzig Thomas , Rupert Matthew
Published: February 2021

We construct families of commutative (super) algebra objects in the category of weight modules for the unrolled restricted quantum group [Formula: see text] of a simple Lie algebra [Formula: see text] at roots of unity, and study their categories of local modules. We determine their simple modules and derive conditions for these categories being finite, non-degenerate, and ribbon. Motivated by numerous examples in the [Formula: see text] case, we expect some of these categories to compare nicely to categories of modules for vertex operator algebras. We focus in particular on examples expected to correspond to the higher rank triplet vertex algebra [Formula: see text] of Feigin and Tipunin and the [Formula: see text] algebras.
Higher dimensional elliptic fibrations and Zariski decompositions
Authors: Grassi Antonella , Wen David
Published: February 2021

We study the existence and properties of birationally equivalent models for elliptically fibered varieties. In particular these have either the structure of Mori fiber spaces or, assuming some standard conjectures, minimal models with a Zariski decomposition compatible with the elliptic fibration. We prove relations between the birational invariants of the elliptically fibered variety, the base of the fibration and of its Jacobian.
On S-1-absorbing prime submodules
Authors: Farzalipour Farkhonde , Ghiasvand Peyman
Published: February 2021

Let [Formula: see text] be a commutative ring with non-zero identity, [Formula: see text] a multiplicatively closed subset of [Formula: see text] and [Formula: see text] a unital [Formula: see text]-module. In this paper, we introduce and study the concept of [Formula: see text]-1-absorbing prime submodules. A submodule [Formula: see text] of [Formula: see text] with [Formula: see text] is said to be [Formula: see text]-1-absorbing prime, if there exists an [Formula: see text] whenever [Formula: see text] for some non-unit elements [Formula: see text] and [Formula: see text], then [Formula: see text] or [Formula: see text]. Some examples, characterizations and properties of [Formula: see text]-1-absorbing prime submodules are given. Moreover, we give some characterizations of [Formula: see text]-1-absorbing prime submodules in multiplication modules.
Subgroups, hyperbolicity and cohomological dimension for totally disconnected locally compact groups
Authors: Arora S. , Castellano I. , Cook G. Corob , Martínez-Pedroza E.
Published: February 2021

This paper is part of the program of studying large-scale geometric properties of totally disconnected locally compact groups, TDLC-groups, by analogy with the theory for discrete groups. We provide a characterization of hyperbolic TDLC-groups, in terms of homological isoperimetric inequalities. This characterization is used to prove the main result of this paper: for hyperbolic TDLC-groups with rational discrete cohomological dimension [Formula: see text], hyperbolicity is inherited by compactly presented closed subgroups. As a consequence, every compactly presented closed subgroup of the automorphism group [Formula: see text] of a negatively curved locally finite [Formula: see text]-dimensional building [Formula: see text] is a hyperbolic TDLC-group, whenever [Formula: see text] acts with finitely many orbits on [Formula: see text]. Examples where this result applies include hyperbolic Bourdon’s buildings.

We revisit the construction of small cancellation quotients of amalgamated free products, and verify that it provides examples of hyperbolic TDLC-groups of rational discrete cohomological dimension [Formula: see text] when applied to amalgamated products of profinite groups over open subgroups.

We raise the question of whether our main result can be extended to locally compact hyperbolic groups if rational discrete cohomological dimension is replaced by asymptotic dimension. We prove that this is the case for discrete groups and sketch an argument for TDLC-groups.
Prediction of mechanical and thermal properties of particle reinforced hydrogel composites using the structural genome approach
Authors: Han Lingzhi , Lei Jincheng , Liu Zishun , Lee Heow Pueh
Published: February 2021

In this paper, the structural genome approach is used for multiscale analyses to predict the mechanical and thermal properties of particle reinforced hydrogel composites. First, the structure genome model of particle reinforced hydrogel composites is created by the random sequential adsorption algorithm. Then the mechanical properties and equivalent thermal conductivity of hydrogel composites are numerically studied by the structural genome approach. The effects of particles with different volume fractions and material properties on their mechanical and thermal properties are investigated. From the simulation results, it can be found that within a certain range of volume fraction, the mechanical properties and equivalent thermal conductivity of hydrogel composites are positively correlated with the volume fractions of particles. We also find that with the increase of the mechanical properties and thermal conductivity of particles, the properties of hydrogel can be improved and eventually reach stabilization. The structural genome approach shows excellent efficiency in multiscale structure analysis. It is a convenient method for the simulation of complex soft material composites.
Symbiotic Relationship Between Machine Learning and Industry 4.0: A Review
Authors: Azeem Mohd , Haleem Abid , Javaid Mohd
Published: February 2021

Industry 4.0 though launched less than a decade ago, has revolutionized the way technologies are being used. It has found its application in almost every field of manufacturing, cybersecurity, health, banking, and other services. Industry 4.0 is heavily dependent on interconnectivity and data. Machine learning (ML) acts as a foundation for building industry 4.0 applications. In this paper, we have provided a broad view of how ML is necessary to accomplish the benefits of industry 4.0. The paper includes ML usage in companies and the limitations of ML, which need to be mitigated. There are also some instances of the failure of ML algorithms and their repercussions. Though industry 4.0 requires a lot more inputs and capital than normal processes, the long-run benefits outweigh the initial costs. ML is gaining popularity, and extensive research is happening to exploit its potential and develop full smart applications.
Determinants of the Malaysian Cars Brand Loyalty: Mediating Effect of Brand Satisfaction
Authors: Alfakih Khaled Ali Ahmed , Saraih Ummi Naiemah , Al-Shammari Serhan A. , Abdulrab Mohammed , ur Rehman Anis , Al-Mamary Yaser Hasan S.
Published: February 2021

The objective of this study is to investigate the associations among brand price, brand advertisement, brand image, brand trust and brand loyalty of the Malaysian car. In addition, the objective of this study is to determine the mediating effect of brand satisfaction on those associations. Questionnaire is used to collect data. 319 usable responses were received from respondents in the Northern Region of Malaysia (Kedah, Perlis and Penang). Partial Least Squares Structural Equation Modeling (PLS-SEM) is employed in the data analysis. The findings reveal significant associations among brand advertisement, brand image, brand trust and brand loyalty. However, this study does not find any significant associations among brand price and brand loyalty. This study observes that brand satisfaction mediates the effects of brand price, brand image, brand trust toward brand loyalty. However, brand satisfaction does not mediate the associations between brand advertisement and brand loyalty. The study conducted for the locally operating car manufacturers this is why the findings are not general for other car manufacturers and certain international brands. The research contributes in the research work available for automobile market and is significant for automobile manufacturing firms, automobile sellers, consumers and government in emerging economies, like Malaysia, for market expansion strategic plans. This research revealed that loyalty toward the locally operating Malaysian car brands based on various determinants, with some directly attributed to brand satisfaction. The significance of this study can be seen in the incorporation of brand satisfaction as the mediating variable to explain the associations among brand price, brand image, brand trust and brand loyalty.
Using Big Data Fuzzy K‐Means Clustering and Information Fusion Algorithm in English Teaching Ability Evaluation
Authors: Zhen Chen
Published: February 2021

Aiming at the problem of inaccurate classification of big data information in traditional English teaching ability evaluation algorithms, an English teaching ability evaluation algorithm based on big data fuzzy K‐means clustering and information fusion is proposed. Firstly, the author uses the idea of K‐means clustering to analyze the collected original error data, such as teacher level, teaching facility investment, and policy relevance level, removes the data that the algorithm considers unreliable, uses the remaining valid data to calculate the weighting factor of the modified fuzzy logic algorithm, and evaluates the weighted average with the node measurement data and gets the final fusion value. Secondly, the author integrates the big data information fusion and K‐means clustering algorithm, realizes the clustering and integration of the index parameters of English teaching ability, compiles the corresponding English teaching resource allocation plan, and realizes the evaluation of English teaching ability. Finally, the results show that using this method to evaluate English teaching ability has better information fusion analysis ability, which improves the accuracy of teaching ability evaluation and the efficiency of teaching resources application.
Application of Cloud Model and Bayesian Network to Piracy Risk Assessment
Authors: Liu Kefeng , Yang Lizhi , Li Ming
Published: February 2021

Piracy is a major threat to maritime safety. Assessing piracy risk is crucial to ship safety, travel security, and emergency plan preparation. In the absence of a thorough understanding of the factors and mechanisms that influence piracy, no perfect mathematical equation can be set up for such risk assessment. Therefore, the major factors that influence piracy were identified to construct an indicator system for assessment. These factors were analyzed, keeping in view the overall hazard, vulnerability, and antirisk properties, and then the Bayesian network was introduced into the risk assessment model to fuse multiresource information. For some indicators, which have only qualitative information or fragmentary statistical data, the cloud model theory was adopted to realize prior probability settings of the Bayesian network and thus made up for the deficiency in parameter settings. Finally, the inherent hazard of the South China Sea was assessed, as an example for the model, and two real piracy cases were studied to validate the proposed model. The assessment model constructed here can be applied to all cases, similar to the ones studied here.
FPGA Implementation of Improved Security Approach for Medical Image Encryption and Decryption
Authors: Hafsa Amal , Gafsi Mohamed , Malek Jihene , Machhout Mohsen
Published: February 2021

Securing medical images is a great challenge to protect medical privacy. An image encryption model founded on a complex chaos-based Pseudorandom Number Generator (PRNG) and Modified Advanced Encryption Standard (MAES) is put forward in this paper. Our work consists of the following three main points. First, we propose the use of a complex PRNG based on two different chaotic systems which are the 2D Logistic map in a complex set and Henon’s system in the key generation procedure. Second, in the MAES 128 bits, the subbytes’ operation is performed using four different S-boxes for more complexity. Third, both shift-rows’ and mix-columns’ transformations are eliminated and replaced with a random permutation method which increases the complexity. More importantly, only four rounds of encryption are performed in a loop that reduces significantly the execution time. The overall system is implemented on the Altera Cyclone III board, which is completed with an SD card interface for medical image storage and a VGA interface for image display. The HPS software runs on μClinux and is used to control the FPGA encryption-decryption algorithm and image transmission. Experimental findings prove that the propounded map used has a keyspace sufficiently large and the proposed image encryption algorithm augments the entropy of the ciphered image compared to the AES standard and reduces the complexity time by 97%. The power consumption of the system is 136.87 mw and the throughput is 1.34 Gbit/s. The proposed technique is compared to recent image cryptosystems including hardware performances and different security analysis properties, such as randomness, sensitivity, and correlation of the encrypted images and results prove that our cryptographic algorithm is faster, more efficient, and can resist any kind of attacks.
Ovine Progressive Pneumonia: Diagnosis and Seroprevalence in the South of Sonora, Mexico
Authors: Borquez Cuevas Mercedes Yannin , Hernández Chávez Juan Francisco , Armenta Leyva Betsy , Cedillo Cobián Jesús Raymundo , Molina Barrios Ramón Miguel
Published: February 2021

Ovine progressive pneumonia (OPP) is the most severe presentation of small ruminant lentivirus (SRLV) infection known as Maedi-Visna. Serological evidence in Mexico of the presence of this lentivirus was published in 1986. After that, studies revealed that SRLVs have a broad distribution in Mexico by detecting antibodies or/and molecular tests; however, a descriptive case of the disease has not been published. This work’s objective was to describe the diagnosis of a case of OPP through lesion description, serology, and molecular test. The histopathological study showed that lymph follicular hyperplasia, interstitial pneumonia, and smooth muscle hyperplasia were presented. The serological test demonstrated specific antibodies against the Maedi-Visna virus, and PCR analysis demonstrated a positive outcome. These results include the criteria for the diagnosis of OPP. The serological prevalence of this disease is presented, contributing to the knowledge of the ecology of this disease in the world. This work is the first case report of ovine progressive pneumonia in Mexico and evidence of seroprevalence in sheep herds from Sonora, Mexico.
Uncertain Random Data Envelopment Analysis: Efficiency Estimation of Returns to Scale
Authors: Jiang Bao , Feng Shuang , Gao Jinwu , Li Jian
Published: February 2021

Evaluating efficiency according to the different states of returns to scale (RTS) is crucial to resource allocation and scientific decision for decision-making units (DMUs), but this kind of evaluation will become very difficult when the DMUs are in an uncertain random environment. In this paper, we attempt to explore the uncertain random data envelopment analysis approach so as to solve the problem that the inputs and outputs of DMUs are uncertain random variables. Chance theory is applied to handling the uncertain random variables, and hence, two evaluating models, one for increasing returns to scale (IRS) and the other for decreasing returns to scale (DRS), are proposed, respectively. Along with converting the two uncertain random models into corresponding equivalent forms, we also provide a numerical example to illustrate the evaluation results of these models.
Preparation of Biocomposite Material with Superhydrophobic Surface by Reinforcing Waste Polypropylene with Sisal (Agave sisalana) Fibers
Authors: Abebayehu Seyoum Getaneh , Engida Adam Mekonnen
Published: February 2021

Nowadays, eco-friendly, renewable, and biodegradable biocomposites are among the most intensely sought materials of choice. Biocomposites have been widely used as substitutes for plastics due to their biodegradability. However, biocomposite materials absorb water and ultimately loss mechanical properties that affect service life. In this work, a biocomposite material with superhydrophobic surface was prepared by reinforcing waste polypropylene with sisal (Agave sisalana) fibers. The biocomposite was prepared by mixing waste polypropylene and sisal fiber with 5%, 10%, 15%, and 20% fiber loading. Based on characterization results, the composite with 15% fiber content is considered as optimum ratio. Physicochemical properties of composites were evaluated using standard American Society of Testing Materials including biodegradability test and chemical resistance test. The biodegradability of the composite before surface modification was determined by calculating weight loss and found to be 0.11%, 4.62%, 7.15%, and 10.97% for 0%, 5%, 10%, and 15% fiber loadings, and their tensile strength was

10.25
±
0.05

,

14.47
±
0.02

,

14.48
±
0.02

, and

19.90
±
0.09
 
MPa

for 0%, 5%, 10%, and 15% fiber content, respectively. The surface of the composite was modified for hydrophobicity by etching the surface with chromic acid followed by treating with stearic acid. The FTIR and the SEM images of unmodified and modified (superhydrophobic) surface of composites clearly state the significant difference in chemical composition and surface structure, respectively. The superhydrophobicity of the surface-modified biocomposite was defined by its self-cleaning and low wet ability properties.
Spontaneously Regressing Neonatal Oral Aphthous Ulceration of the Palate
Authors: Madurapperuma Sandara Wayangi , Jayaweera Andra Hennadige Heshan Malinga , Jayasinghe Ruwan Duminda
Published: February 2021

Background. Neonatal oral aphthous ulceration of the palate also known as Bednar’s aphthae is not an uncommon presentation. They clinically present as spontaneously regressing, shallow, and symmetrical ulcers on the posterior palate of newborns from 2 days up to 6 weeks of age. Case Presentation. We, herein, report a case of a one-month-old baby girl who presented with an ulcer in the posterior palate and intermittent mild fever. The patient was admitted and monitored in the ward. Haematologic investigations disclosed features of ongoing infection. Nasogastric feeding was commenced to avoid any irritation of the ulcer, and glycerine was applied on the ulcer. Antibiotic therapy was continued because of the intermittent mild fever. The lesion healed spontaneously within one week, and fever subsided afterwards. Currently, the patient is faring healthily without any complications. Conclusion. Although Bednar’s aphthae is not a rare presentation, clinicians are often met with a diagnostic dilemma due to the alarming clinical presentation of this condition. Therefore, it leads to overinvestigation and overtreatment. With this case report, we would like to highlight the importance of being aware of this condition to provide the patients with the appropriate treatment.
A Novel Hyperchaotic Image Encryption System Based on Particle Swarm Optimization Algorithm and Cellular Automata
Authors: Zeng Jie , Wang Chunhua
Published: February 2021

In this paper, we propose a hyperchaotic image encryption system based on particle swarm optimization algorithm (PSO) and cellular automata (CA). Firstly, to improve the ability to resist plaintext attacks, the initial conditions of the hyperchaotic system are generated by the hash function value which is closely related to the plaintext image to be encrypted. In addition, the fitness of PSO is the correlation coefficient between adjacent pixels of the image. Moreover, On the basis of hyperchaotic system, cellular automata technology is adopted, which can enhance the randomness of population distribution and increase the complexity and diversity of the population so that the security of the encryption system can be improved and avoid falling into local optimum. The simulation results and security analysis of the proposed encryption system demonstrate that the hyperchaotic image encryption system has high resistance against plaintext attack and statistical attack.
The Effectiveness and Safety of Cinobufotalin Injection as an Adjunctive Treatment for Lung Cancer: A Meta-Analysis of Randomized Controlled Trials
Authors: Li Lin-Lu , Su Yi-Xin , Mao Yun , Jiang Peng-Yuan , Chu Xue-Lei , Xue Peng , Jia Bo-Hui , Zhu Shi-Jie
Published: February 2021

Cinobufotalin injection is a water-soluble preparation extracted from the skin secretion of Bufo bufo gargarizans Cantor or B. melanotictus Schneider, which has been widely used as an adjuvant treatment in lung cancer patients. This study aimed to evaluate the clinical efficacy and safety of cinobufotalin (PubChem CID: 259776) injection as an adjunctive treatment for lung cancer. We designed a meta-analysis that performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We aim to include randomized controlled trials by systematically searching the PubMed, EMBASE, CNKI, Wanfang database, VIP, CBM, the Cochrane Central Register of Controlled Trials, and Chinese Clinical Trial Registry from inception to Mar 1, 2020, comparing the difference between the use of cinobufotalin injection as an adjunctive treatment and a control group without cinobufotalin injection. The objective response rate (ORR) and quality of life (QOL) will be defined as the primary outcomes, and the disease control rate (DCR) and adverse events will be defined as the secondary outcomes. We included 21 articles with 1735 cases of lung cancer patients. Comparison results show that combining with cinobufotalin injection can improve ORR (OR = 1.77, 95% CI [1.43, 2.21],

P

 < 0.001), with low heterogeneity (

P

 = 0.94, I2 = 0%); DCR (OR = 2.20, 95% CI [1.70, 2.85],

P

 < 0.001), with low heterogeneity (

P

 = 0.60, I2 = 0%); KPS score (OR = 3.10, 95% CI [2.23, 4.32],

P

 < 0.001), with low heterogeneity (

P

 = 0.85, I2 = 0%); and the effect of pain relief (OR = 2.68, 95% CI [1.30, 5.55],

P

 = 0.008), with low heterogeneity (

P

 = 0.72, I2 = 0%). Low-to-moderate evidence shows that cinobufotalin injection combined with chemotherapy can significantly increase ORR, DCR, QOL, and the effect of pain relief. Meanwhile, cinobufotalin injection did not bring additional adverse events such as hematological toxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, and nephrotoxicity; however, multicenter, large-sample, high-quality clinical research results are still needed to reveal the therapeutic effect of cinobufotalin injection in small-cell lung cancer (PROSPERO registration number: CRD42020170052).
Secretagogin Mediates the Regulatory Effect of Electroacupuncture on Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Surgical Trauma
Authors: Zhang Mizhen , Sun Jingxian , Wang Yu , Tian Zhanzhuang
Published: February 2021

Electroacupuncture (EA) improves hypothalamic-pituitary-adrenal (HPA) axis disorder by reducing corticotropin-releasing hormone (CRH) synthesis and release in the paraventricular nucleus (PVN). However, the potential mechanism underlying CRH regulation remains unclear. Secretagogin (SCGN) is closely related to stress and is involved in regulating the release of CRH. We hypothesized that SCGN in the PVN might trigger the HPA system and be involved in EA-mediated modulation of HPA dysfunction caused by surgical trauma. Serum CRH and adrenocorticotropic hormone (ACTH) and plasma corticosterone (CORT) levels at 6 h and 24 h after hepatectomy were determined by radioimmunoassay. CRH and SCGN protein levels in the PVN were detected by western blot and immunofluorescence, and CRH and SCGN mRNA levels in the PVN were determined by means of real-time polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Our studies showed that serum CRH, ACTH, and CORT levels and PVN CRH expression were significantly increased at 6 h and 24 h after hepatectomy in the hepatectomy group compared with the control group, and those in the EA+hepatectomy group were decreased compared with those in the hepatectomy group. The protein and mRNA levels of SCGN in the PVN were also increased after hepatectomy, and their expression in the EA+hepatectomy group was decreased compared with that in the hepatectomy group. When SCGN expression in the PVN was functionally knocked down by a constructed CsCI virus, we found that SCGN knockdown decreased the serum CRH, ACTH, and CORT levels in the SCGN shRNA+hepatectomy group compared with the hepatectomy group, and it also attenuated CRH expression in the PVN. In summary, our findings illustrated that EA normalized HPA axis dysfunction after surgical trauma by decreasing the transcription and synthesis of SCGN.
Based on Network Pharmacology Tools to Investigate the Molecular Mechanism of Cordyceps sinensis on the Treatment of Diabetic Nephropathy
Authors: Li Yan , Wang Lei , Xu Bojun , Zhao Liangbin , Li Li , Xu Keyang , Tang Anqi , Zhou Shasha , Song Lu , Zhang Xiao , Zhan Huakui
Published: February 2021

Background. Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus and is a major cause of end-stage kidney disease. Cordyceps sinensis (Cordyceps, Dong Chong Xia Cao) is a widely applied ingredient for treating patients with DN in China, while the molecular mechanisms remain unclear. This study is aimed at revealing the therapeutic mechanisms of Cordyceps in DN by undertaking a network pharmacology analysis. Materials and Methods. In this study, active ingredients and associated target proteins of Cordyceps sinensis were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Swiss Target Prediction platform, then reconfirmed by using PubChem databases. The collection of DN-related target genes was based on DisGeNET and GeneCards databases. A DN-Cordyceps common target interaction network was carried out via the STRING database, and the results were integrated and visualized by utilizing Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to determine the molecular mechanisms and therapeutic effects of Cordyceps on the treatment of DN. Results. Seven active ingredients were screened from Cordyceps, 293 putative target genes were identified, and 85 overlapping targets matched with DN were considered potential therapeutic targets, such as TNF, MAPK1, EGFR, ACE, and CASP3. The results of GO and KEGG analyses revealed that hub targets mainly participated in the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, PI3K-Akt signaling pathway, and IL-17 signaling pathway. These targets were correlated with inflammatory response, apoptosis, oxidative stress, insulin resistance, and other biological processes. Conclusions. Our study showed that Cordyceps is characterized as multicomponent, multitarget, and multichannel. Cordyceps may play a crucial role in the treatment of DN by targeting TNF, MAPK1, EGFR, ACE, and CASP3 signaling and involved in the inflammatory response, apoptosis, oxidative stress, and insulin resistance.
Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response
Authors: Zhang Ping , Kitchen-Smith Isaac , Xiong Lingyun , Stracquadanio Giovanni , Brown Katherine , Richter Philipp H. , Wallace Marsha D. , Bond Elisabeth , Sahgal Natasha , Moore Samantha , Nornes Svanhild , De Val Sarah , Surakhy Mirvat , Sims David , Wang Xuting , Bell Douglas A. , Zeron-Medina Jorge , Jiang Yanyan , Ryan Anderson J. , Selfe Joanna L. , Shipley Janet , Kar Siddhartha , Pharoah Paul D. , Loveday Chey , Jansen Rick , Grochola Lukasz F. , Palles Claire , Protheroe Andrew , Millar Val , Ebner Daniel V. , Pagadala Meghana , Blagden Sarah P. , Maughan Timothy S. , Domingo Enric , Tomlinson Ian , Turnbull Clare , Carter Hannah , Bond Gareth L.
Published: February 2021

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.

Significance:

These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.
Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation
Authors: Henrich Ian C. , Jain Kanika , Young Robert , Quick Laura , Lindsay Jarrett M. , Park Daniel H. , Oliveira Andre M. , Blobel Gerd A. , Chou Margaret M.
Published: February 2021

Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a “hot” tumor microenvironment in immunotherapy.

Significance:

This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.
An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer
Authors: Li Ning , Bu Hualei , Liu Jihong , Zhu Jianqing , Zhou Qi , Wang Li , Yin Rutie , Wu Xiaohua , Yao Shuzhong , Gu Kangsheng , Zhang Hui , Li Guiling , Pan Hongming , Wu Qiang , An Ruifang , Yang Xinfeng , Zhu Yaping , Wan Xiaoping , Duan Wei , Xiong Jianping , Guo Hongyan , Lou Ge , Wang Jing , Hu Wenjing , Zhang Xin , Meng Yuanguang , Zhang Ben , Wang Yuting , Wang Quanren , Wu Lingying
Published: February 2021

Purpose:

Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer.

Patients and Methods:

This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1.

Results:

A total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5–18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6–78.2] and 70.8% (95% CI, 61.5–79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3–13.9) and 10.3 months (95% CI, 9.2–12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2–96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred.

Conclusions:

Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, fluzoparib might be a novel treatment option for this population.
Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms
Authors: Tukachinsky Hanna , Madison Russell W. , Chung Jon H. , Gjoerup Ole V. , Severson Eric A. , Dennis Lucas , Fendler Bernard J. , Morley Samantha , Zhong Lei , Graf Ryon P. , Ross Jeffrey S. , Alexander Brian M. , Abida Wassim , Chowdhury Simon , Ryan Charles J. , Fizazi Karim , Golsorkhi Tony , Watkins Simon P. , Simmons Andrew , Loehr Andrea , Venstrom Jeffrey M. , Oxnard Geoffrey R.
Published: February 2021

Purpose:

Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care.

Experimental Design:

Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP.

Results:

A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.

Conclusions:

Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.

See related commentary by Hawkey and Armstrong, p. 2961
Clinical Implications of the “Brush Sign” in Susceptibility-Weighted Imaging for Moyamoya Disease
Authors: Lu Junlin , Zhao Yahui , Li Mingtao , Ma Li , Chen Yu , Wang Rong , Ye Xun , Wang Hao , Chen Xiaolin , Zhao Yuanli
Published: February 2021

Objective: Infarction is one of the most common postoperative complications after surgical revascularization for moyamoya disease (MMD). Increased conspicuity of deep medullary veins (DMVs) on susceptibility-weighted imaging (SWI), known as “brush sign,” could predict the severity of MMD. This study aimed to reveal the features of the “brush sign” in preoperative SWI and to verify its relationship to postoperative infarction. Methods: Consecutive patients with MMD who had undergone cerebral revascularization surgery were included. Routine preoperative SWI was performed. The “brush sign” was defined according to the number of the conspicuous DMVs > 5 detected on SWI. Postoperative infarctions were defined as the high-intensity signal on postoperative DWI images, with or without neurologic deficits. The modified Rankin scale (mRS) was applied to evaluate the prognosis of patients. Results: In the enrolled 100 hemispheres, 35 were presented with the “brush sign.” Patients with ischemic onset manifestation and previous infarction history tended to present with the “brush sign.” Multivariate analysis showed that the “brush sign” (OR 13.669; 95% CI, 1.747–106.967, p = 0.013) and decreased rCBF (OR 6.050; 95% CI, 1.052–34.799, p = 0.044) were independent risk factors of postoperative infarction. Besides, the “brush sign” showed a significant correlation with a higher mRS score at discharge (p = 0.047). Conclusion: The findings strongly suggest that the presence of the “brush sign” preoperatively can be a predictor of infarction after surgical revascularization for ischemic MMD. It may contribute to an improved surgical result through focused perioperative management based on appropriate surgical risk stratification.
Thirty Years (and More) of Hair Research Societies
Authors: Westgate Gill , Bergfeld Wilma F. , Ceh Victoria , Hordinsky Maria , Sinclair Rodney , Piraccini Bianca Maria , Kang Hoon , Ohyama Manabu
Published: February 2021

The contributions of the core hair research societies and their members over the past 30 years have advanced the field of hair research and the understanding and treatment of hair disorders and normal hair growth.
Hyperglycemia Induces Generation of Reactive Oxygen Species and Accelerates Apoptotic Cell Death in Salivary Gland Cells
Authors: Matsumoto Naoyuki , Omagari Daisuke , Ushikoshi-Nakayama Ryoko , Yamazaki Tomoe , Inoue Hiroko , Saito Ichiro
Published: February 2021

Introduction: Type-2 diabetes mellitus (T2DM) is associated with several systemic vascular symptoms and xerostomia. It is considered that hyperglycemia-induced polyuria and dehydration cause decreased body-water volume, leading to decreased saliva secretion and, ultimately, xerostomia. In T2DM, increased production of reactive oxygen species (ROS) causes tissue damage to vascular endothelial cells as well as epithelial tissue, including pancreas and cornea. Hence, a similar phenomenon may occur in other tissues and glands in a hyperglycemic environment. Methods: Salivary gland tissue injury was examined, using T2DM model mouse (db/db). Transferase‐mediated dUTP nick‐end labeling (TUNEL) was conducted to evaluate tissue injury. The levels of malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine, Bax/Bcl-2 ratio were measured as indicator of oxidative stress. Moreover, in vitro ROS production and cell injury was evaluated by mouse salivary gland-derived normal cells under high-glucose condition culture. Results: In vivo and in vitro analysis showed a higher percentage of TUNEL-positive cells and higher levels of MDA and 8-hydroxy-2′-deoxyguanosine in salivary gland tissue of db/db mice. This suggests damage of saliva secretion-associated lipids and DNA by hyperglycemic-induced oxidative stress. To analyze the mechanism by which hyperglycemia promotes ROS production, mouse salivary gland-derived cells were isolated. The cell culture with high-glucose medium enhanced ROS production and promotes apoptotic and necrotic cell death. Conclusion: These findings suggest a novel mechanism whereby hyperglycemic-induced ROS production promotes salivary gland injury, resulting in hyposalivation.