bluuebunny/crossref_metadata_2025 huggingface dataset:
Steering-by-example for Progressive Visual Analytics
Authors: Hogräfer Marius , Angelini Marco , Santucci Giuseppe , Schulz Hans-Jörg
Published: June 2022

Progressive visual analytics allows users to interact with early, partial results of long-running computations on large datasets. In this context, computational steering is often brought up as a means to prioritize the progressive computation. This is meant to focus computational resources on data subspaces of interest so as to ensure their computation is completed before all others. Yet, current approaches to select a region of the view space and then to prioritize its corresponding data subspace either require a one-to-one mapping between view and data space, or they need to establish and maintain computationally costly index structures to trace complex mappings between view and data space. We present steering-by-example, a novel interactive steering approach for progressive visual analytics, which allows prioritizing data subspaces for the progression by generating a relaxed query from a set of selected data items. Our approach works independently of the particular visualization technique and without additional index structures. First benchmark results show that steering-by-example considerably improves Precision and Recall for prioritizing unprocessed data for a selected view region, clearly outperforming random uniform sampling.
Advanced Sensing Performance towards Simultaneous Determination of Binary Mixture of Antihypertensives Using PANI–Cerium Oxide Nanoparticles as Modifier in Carbon Paste Incorporating Graphite and Silicon-Oil
Authors: Sharma Swati , Jain Rajeev , Pandey Annu
Published: June 2022

Present paper reports multianalyte electroanalysis of hypertensive having amlodipine and nebivolol molecules in a single dose. Amlodipine and Nebivolol exhibited oxidation peaks at 0.70 and 0.90 V respectively on the Graphite/Polyaniline-Cerium Oxide/Carbon paste electrode. The linearity range was 0.1 to 1.6μg ml−1in Britton Robinson buffer (pH 8.0). The limit of detection was 20.0 ng ml−1for Amlodipine and 30.0 ng ml−1for Nebivolol and the limit of quantification was 80.0 ng ml−1for Amlodipine and 100 ng ml−1for Nebivolol respectively. These analytes were also determined in pharmaceutical formulation and human serum and good recovery was obtained for the developed method.
Fabrication of Polyaniline (PANI) through Parallel Nanopores: Charge Transport Properties of PANI@SiO2Nanopore Molecular Junctions
Authors: Sun Xiaonan , Ullah Wahid , Lacroix Jean-Christophe , Walcarius Alain , Herzog Grégoire , Vilà Neus
Published: June 2022

Aniline is electropolymerized through mesoporous silica nanopores (100 nm-long, 3 nm in diameter) orthogonally oriented on indium-tin oxide (ITO). Only a few polyaniline (PANI) wires are accommodated in the nanochannels and their growth is electrochemically controlled. The electronic transport properties of PANI@SiO2are studied by Conductive Atomic Force Microscopy (C-AFM), using a Pt-coated C-AFM tip. Three different behaviors are observed. First, linear I/V curves are obtained when PANI is deposited in the nanopores with material spilling over the silica membrane; electron transport occurs through many PANI@SiO2channels and the overall conductance is high. Second, flat I/V curves are recorded, indicating “insulator” behavior when the SiO2nanopores are not fully filled by PANI wires. Thirdly, non-linear I/V curves, which are quantitatively highly reproducible and independent of the point probed, are obtained. These are attributed to the formation of molecular junctions where the C-AFM tip in contact with the nanopores acts as the top electrode and vertical PANI wires just fill the SiO2channels. The size of the top electrode and the reproducilility of the I/V suggest that the C-AFM is seeing about 5 nanopores each filled with one or two PANI wires.
Proteoglycans in Toll-like receptor responses and innate immunity
Authors: Garantziotis Stavros , Savani Rashmin C.
Published: June 2022

The extracellular matrix (ECM) is an active and dynamic feature of tissues that not only provides gross structure but also plays key roles in cellular responses. The ever-changing microenvironment responds dynamically to cellular and external signals, and in turn influences cell fate, tissue development, and response to environmental injury or microbial invasion. It is therefore paramount to understand how the ECM components interact with each other, the environment and cells, and how they mediate their effects. Among the ECM components that have recently garnered increased attention, proteoglycans (PGs) deserve special note. Recent evidence strongly suggests that they play a crucial role both in health maintenance and disease development. In particular, proteoglycans dictate whether homeostasis or cell death will result from a given injury, by triggering and modulating activation of the innate immune system, via a conserved array of receptors that recognize exogenous (infectious) or endogenous (tissue damage) molecular patterns. Innate immune activation by proteoglycans has important implications for the understanding of cell-matrix interactions in health and disease. In this review, we will summarize the current state of knowledge of innate immune signaling by proteoglycans, discuss the implications, and explore future directions to define progress in this area of extracellular matrix biology.
Optimized Multiscale Entropy Model Based on Resting-State fMRI for Appraising Cognitive Performance in Healthy Elderly
Authors: Yang Fan , Zhang Fuyi , Belkacem Abdelkader Nasreddine , Xie Chong , Wang Ying , Chen Shenghua , Yang Zekun , Song Zibo , Ge Manling , Chen Chao
Published: June 2022

Many studies have indicated that an entropy model can capture the dynamic characteristics of resting-state functional magnetic resonance imaging (rfMRI) signals. However, there are problems of subjectivity and lack of uniform standards in the selection of model parameters relying on experience when using the entropy model to analyze rfMRI. To address this issue, an optimized multiscale entropy (MSE) model was proposed to confirm the parameters objectively. All healthy elderly volunteers were divided into two groups, namely, excellent and poor, by the scores estimated through traditional scale tests before the rfMRI scan. The parameters of the MSE model were optimized with the help of sensitivity parameters such as receiver operating characteristic (ROC) and area under the ROC curve (AUC) in a comparison study between the two groups. The brain regions with significant differences in entropy values were considered biomarkers. Their entropy values were regarded as feature vectors to use as input for the probabilistic neural network in the classification of cognitive scores. Classification accuracy of 80.05% was obtained using machine learning. These results show that the optimized MSE model can accurately select the brain regions sensitive to cognitive performance and objectively select fixed parameters for MSE. This work was expected to provide the basis for entropy to test the cognitive scores of the healthy elderly.
Effect of Bairui Granule on Inflammatory Mediators in Induced Sputum, Leukotriene C4, and EOS in Peripheral Blood of Children with Cough Variant Asthma
Authors: Shen Yi , Lu Min , Xu Qiuyan , Liu Lu , Cheng Zhi
Published: June 2022

Objective. To study the effect of Hanchuan Zupa granule combined with conventional western medicine in the treatment of children with bronchial asthma. Methods. 98 cases in Fengrun District People’s Hospital of Tangshan City from June 2018 to February 2021 were selected. The control group was given oxygen therapy, antibiotics, and aerosol inhalation of quick acting β 2 receptor agonist, glucocorticoid, and other conventional western medicine treatment, while the observation group was treated with Bairui granule on the basis of the control group. The course of treatment of the two groups was 1 week. Results. After treatment, the levels of sputum IL-4, IL-17, neu, and ECP in the two groups decreased, and the observation group was lower than the control group (

P
<
0.05

). The levels of EOS, CXCR4, LTB4, and SDF-1 in peripheral blood of the two groups were lower than those in the control group (

P
<
0.05

). The daytime cough, night cough, and TCM syndrome scores of the two groups were decreased, and the observation group was lower than the control group (

P
<
0.05

). Conclusion. Bairui granule combined with conventional western medicine in the treatment of children with bronchial asthma, the curative effect is worthy of affirmation, can effectively improve cough symptoms, reduce EOS, CXCR, LTB4, SDF-1 levels, inhibit airway inflammation, and has good clinical application value.
Fault Location Approach for Distribution Network with Dynamic Environment
Authors: Yu Yang , Li Mengshi , Ji Tianyao , Wu Qinghua
Published: June 2022

This paper proposes a continuous tracing framework for fault location in distribution network, which is divided into two stages: parameter correction and fault location. On the stage of parameter correction, it is capable of correcting line parameters based on data in the steady state. On the stage of fault location, it can locate the fault according to the one cycle signal after it occurs based on the corrected parameters in the former stage. The stage of parameter correction is beneficial to the fault location process. The core algorithm of the framework is parameter adaptive group search optimizer (PAGSO), which is a kind of improved metaheuristic optimization algorithm. The adjustment strategy and regulatory mechanism are introduced in exploitation, whereas the adaptive mechanism based on reinforcement learning (RL) is introduced in exploration. Improvements could enhance search capability and help the algorithm converge faster. The proposed framework is tested in IEEE 34-bus model. Other meta-heuristic algorithms are adopted for comparison, including genetic algorithms (GA), particle swarm optimization (PSO), grey wolf optimization (GWO), and the standard group search optimizer (GSO). For fault location, PAGSO has been verified under three cases, including ideal condition, noisy condition, and the system with renewable penetration. For line parameters, experiments are designed to prove the algorithm feasibility and verify the necessity of the correction.
Efficacy of Cabbage Leaf versus Cooling Gel Pad or Diclofenac Gel for Patients with Knee Osteoarthritis: A Randomized Open-Labeled Controlled Clinical Trial
Authors: Chobpenthai Thanapon , Arunwatthanangkul Patcharapol , Mahikul Wiriya
Published: June 2022

Background. Osteoarthritis (OA) is one of the most common joint degeneration ailments adversely affecting the elderly population by impairing their physical movements and quality of life. This study aimed to establish the efficacy of cabbage leaf application in alleviating pain-related distress and positively improving OA conditions. Materials and Methods. Patients with moderate to severe (grades 3-4) OA by the Kellgren and Lawrence grading system with a poor to good Oxford Knee Score were selected for enrollment in this clinical trial. The participants were divided into three intervention groups: the cooling gel pad group for 20 minutes duration once a day (n = 20), the diclofenac gel group for 4 times a day (n = 20) as the control group (total n = 40), and the cabbage leaf group for 1-hour duration once a day (n = 20) as the experimental group (total n = 20). All trial participants were trained to record their Numerical Rating Scale (NRS) pain score and Oxford Knee Score and were advised to undergo weekly follow-ups and assessment of the outcome at 4 weeks. Data were analyzed by the paired t-test and analysis of variance (ANOVA). Results. The cabbage leaf group and cooling gel pad group showed a significant difference in both the Oxford Knee Score (

p
<
0.001

in both groups) and NRS score (

p
<
0.001

in both groups) before and after the intervention, by using the paired t-test. The three study procedures were found to be significantly different with respect to both the Oxford Knee Score (

p
=
0.012

) and NRS score (

p
<
0.001

), by using ANOVA. Conclusion. This study clinically demonstrated that cabbage leaf application and cooling gel pad application showed similar improvements in reducing OA symptoms in terms of the overall NRS score and Oxford Knee Score. Their therapeutic effectiveness was better than that of diclofenac gel.
Performance, Emission, and Study of DI Diesel Engine Running on Pumpkin Seed Oil Methyl Ester with the Effect of Copper Oxide Nanoparticles as an Additive
Authors: Surendrababu K. , Muthurajan K. G. , Prabhahar M. , Prakash S. , Saravana Kumar M. , Jayakumar Mani
Published: June 2022

The usage of petroleum fuels in IC engines is hazardous to humans, plants, and agriculture since they exhaust poisonous pollutants into the environment. Substantial research is now being conducted to identify an alternative to petroleum fuel and to enhance its quality. Nanoparticles are a relatively new technology that may be used to improve the properties of fuel. Engine tests were performed on conventional CI engines using a diesel and biodiesel blend under different running circumstances. The purpose of this study is to investigate the performance, emissions, and combustion characteristics of a pumpkin seed oil methyl ester diesel blend (PSOME20) in a diesel engine with the help of a copper oxide nanoparticle. CuO nanoparticles in varying concentrations (50 and 100 ppm) were dispersed in the PSOME20 fuel. The results showed that the BTE of the PSOME20CuO100 fuel is 2.3% higher than that of the PSOME20 fuel, but the reduction in BSFC is 6.4%. Engine HC, CO, and smoke emissions were being significantly minimized when CuO nanoparticles were mixed with PSOME20. The addition of CuO nanoparticles to PSOME20 enhanced combustion behaviors such as HRR and cylinder pressure.
Nonlinear Integrated Fuzzy Modeling to Predict Dynamic Occupant Environment Comfort for Optimized Sustainability
Authors: Syed Ahmad Sharifah Sakinah , Yung Soh Meng , Kausar Nasreen , Karaca Yeliz , Pamucar Dragan , Al Din Ide Nasr
Published: June 2022

In the ever-evolving vibrant landscape of our times, it is crucial that a peaceful environment is ensured taking into account all the likely ecological parameters along with humidity and temperature while conserving energy. Thus, besides mechanical and electric control systems, it has become vital to ensure that artificial intelligence (AI) is assimilated and deployed into the systems so as to raise the well-being of the environment. By disseminating intelligence across the building by utilizing the new internet of things (IoT) technology, along with control formats, local open standard data, AI algorithms, and cloud-based predictive analytics, the heating, ventilation, and air conditioning (HVAC) mechanism renders the capability to acclimatize to use patterns, alterations in use patterns, and equipment breakdown. By tracing human activity coupled with analysis of noise, energy, and temperature in the building, its occupants and facility managers can obtain vital insights for planning, optimum use of space, and behavioral changes, in turn ensuring more content and safer inhabitants and considerably more efficient structures. Moreover, fuzzy modeling shows its applicability factor with the execution of human rationale and reasoning with if-then rules as attained from the system’s input-output info for model setup and training. Additionally, it presents advantages pertaining to predictive functions for tackling nonlinearity and uncertainty as well as studying the capability of the models recommended. Thus, the multi-dimensional model recommended in this study outlines a system architecture as an implementation methodology and how it harmonizes prevailing systems while offering comprehensive knowledge to HVAC systems for the accomplishment of lower energy consumption and inhabitant safety and well-being on the basis of the fuzzy modeling. With tolerance for CO2 discharges moving towards zero, the recommended multi-dimensional model provides substantial advantages for the HVAC sector for meeting the essential objectives while taking into account enhanced sustainability in vibrant and nonlinear environments for enhancing the accuracy and fairness of the assessment outcomes.
Clinical Characteristics and Outcomes of Patients Hospitalized with COVID-19 at Case Hospital, Uganda
Authors: Apiyo Mirriam , Olum Ronald , Kabuye Amina , Khainza Betty , Amate Anne M. , Byabashaija Vittal , Nomujuni Derrick , Sebbaale Kato , Senfuka Peter , Kazibwe Simon , Sharma Gurav , Davidson Lindsay , Bongomin Felix
Published: June 2022

Data on clinical outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19) in private health facilities in Uganda is scarce. We conducted a retrospective cohort study of patients hospitalized with COVID-19 at Case Hospital, Kampala, Uganda, between June 2020 and September 2021. Data of 160 participants (median age 45 years (interquartile range [IQR]: 37–57) and 63.5% male) was analyzed. Seventy-seven (48.1%) participants had non-severe, 18 (11.3%) severe, and 83 (51.9%) critical COVID-19 illness. In 62 participants with chest computed tomography findings, 54 (87%) had bilateral disease, with 22 (35%) having ground-glass opacities. The median duration of hospitalization was 5 days (IQR: 3–9 days). Overall, 18 (11.3%) participants died. Survival at 14 and 28 days was 89% and 72%, respectively. Factors strongly associated with all-cause mortality were as follows: age >50 years (odds ratio [OR]: 8.6, 95% confidence interval [CI]: 1.1–69.2, and

p
=
0.042

), having at least 1 comorbidity (OR: 3.2, 95% CI: 1.1–8.9, and

p
=
0.029

), hypertension (OR: 3.2, 95% CI: 1.2–8.6, and

p
=
0.024

), diabetes mellitus (OR: 2.9, 95% CI: 1.0–8.5, and

p
=
0.056

), and oxygen saturation <92% (OR: 5.1, 95% CI: 1.8–14.4, and

p
=
0.002

). In this private health facility, mortality was about 1 in 10 patients, and more people presented with critical illness in the second wave of the pandemic, and most deaths occurred after 2 weeks of hospitalization.
Automatic Recommendation of Online Music Tracks Based on Deep Learning
Authors: Gao Hong
Published: June 2022

It is one of the main goals of personalized music recommendation system that how to accurately recommend the songs in line with users’ interests in the huge music library. In view of the above problems, this study proposes a personalized music recommendation method based on convolutional neural network. First, this study defines a training set containing potential musical characteristics and, combined with the depth of the belief network, design a music information prediction model and the research in the music-type classification method with different dimensions. Based on selecting four different kinds of music information better describing the underlying characteristics of 40D feature vector to every song music composition, the music feature set is constructed. Then, the CNN (convolutional neural network), which is widely used in audio field, is used as the music information prediction model, and its structural parameters are redesigned to complete the multidimensional music information prediction, which solves the cold start problem to some extent.
Patchouli Alcohol Inhibits D-Gal Induced Oxidative Stress and Ameliorates the Quality of Aging Cartilage via Activating the Nrf2/HO-1 Pathway in Mice
Authors: Chen Ming , Wen Haiyan , Zhou Siqi , Yan Xinxin , Li Haohuan
Published: June 2022

Chondrocytes play an essential role in maintaining the structure and function of articular cartilage. Oxidative stress occurred in chondrocytes accelerates cell senescence and death, which contributes to the development of osteoarthritis (OA). Patchouli alcohol (PA), a kind of sesquiterpene in Pogostemon cablin, processes multiple bioactivities in treatment of many diseases. However, its effects of antisenescence and antioxidation on chondrocytes in a D-gal-induced aging mice model are still obscure. In this study, we found that PA treatment could ameliorate the degradation of cartilage extracellular matrix (ECM) in a D-gal-induced aging mice model. Further analyses through the immunofluorescent staining and western blot revealed that PA inhibited D-gal-induced chondrocyte senescence via the activation of antioxidative system. Besides, the damage caused by D-gal could not be recovered with PA treatment in Nrf2-silencing chondrocytes. In addition, molecular docking analysis between PA and Keap1 further suggested that the mechanism of PA’s antisenescence and antioxidation was attributed to the activation of Nrf2/HO-1 pathway. Therefore, our results demonstrated that PA was a promising candidate for preventing the quality loss of aging cartilage through inhibiting oxidative stress-mediated senescence in chondrocytes.
Study on the Grammar System of Teaching Chinese as a Foreign Language in the Background of Information Technology
Authors: Fang Yu , Shen Li
Published: June 2022

In order to improve the convenience and reliability of teaching Chinese as a foreign language, this study applies information technology to the intelligent system of teaching Chinese as a foreign language and the picture semantic recognition of teaching Chinese as a foreign language. Moreover, this paper proposes a sparse neural network SRSCNN, which shortens the training time without affecting the reconstruction effect and calculation speed, and improves the intelligent processing of teaching resources in the teaching process. When designing the overall framework of the system, a hierarchical and modular design method is adopted to make the logical structure of the whole system reasonable and the process clear. The study of the test results shows that teaching Chinese as a foreign language system based on information technology proposed in this paper has a good teaching effect and can effectively promote the reform of teaching Chinese as a foreign language.
Application of Digital Technology in Intangible Cultural Heritage Protection
Authors: Liu Ying
Published: June 2022

Intangible cultural heritage itself is fragile, so it needs human protection. The existence of everything is a dynamic process, and its emergence, growth, continuation, and demise are objective existences, including “intangible cultural heritage.” With the continuous deepening and development of science and technology, the development of digital acquisition technology, storage technology, remote sensing technology, and spatial modeling technology provides a corresponding realistic basis and platform for the protection of different types of intangible cultural heritage. This paper mainly discusses the application of a variety of modern information technologies in the protection of intangible cultural heritage, deeply discusses the problems existing in digital protection of intangible cultural heritage, analyzes the characteristics of digital protection of intangible cultural heritage, discusses how to better establish the protection platform and management mechanism, and puts forward the application prospect of computer digital technology in the protection of intangible cultural heritage, so as to realize relatively comprehensive digital protection of intangible cultural heritage.
Myricetin Inhibited Fear and Anxiety-Like Behaviors by HPA Axis Regulation and Activation of the BDNF-ERK Signaling Pathway in Posttraumatic Stress Disorder Rats
Authors: Sur Bongjun , Lee Bombi
Published: June 2022

Posttraumatic stress disorder (PTSD) is a stress-related psychiatric or mental disorder characterized by experiencing a traumatic stress. The cause of such PTSD is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and imbalance of monoamines. Myricetin (MYR) is a common natural flavonoid that has various pharmacological activities. We investigated the effects of MYR on fear, depression, and anxiety following monoamine imbalance and hyperactivation of HPA axis in rats exposed to a single prolonged stress (SPS). Male rats were dosed with MYR (10 and 20 mg/kg, i.p.) once daily for 14 days after exposure to SPS. Administration of MYR reduced freezing responses to extinction recall, depression, and anxiety-like behaviors and decreased increase of plasma corticosterone and adrenocorticotropic hormone levels. Also, administration of MYR restored decreased serotonin and increased norepinephrine in the fear circuit regions, medial prefrontal cortex, and hippocampus. It also increased the reduction in the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B mRNA expression and the ratio of p-ERK/extracellular signal-regulated kinase (ERK) in the hippocampus. Thus, MYR exerted antidepressant and anxiolytic effects by regulation of HPA axis and activation of the BDNF-ERK signaling pathway. Finally, we suggest that MYR could be a useful therapeutic agent to prevent traumatic stress such as PTSD.
Research on Complex Multiconstraint Path Planning Based on ACA Hybrid Algorithm
Authors: Wang Hongyun , Gao Min , Gao Weiwei , Li Wenzhao
Published: June 2022

Aiming at the multiconstraint complex problem of path planning, a hybrid algorithm with fast convergence and fast obstacle avoidance is proposed. According to the actual aircraft, a multiconstrained path cost model with seven components is constructed and defined the parameters and penalty factors of each part. To improve the sensitivity of each part of the trace planning cost function, according to the inconsistency of the cost index unit and measurement range, the expert scoring method is used to configure and normalize the index with weight. Make full advantage of the ACO algorithm and the artificial potential field algorithm to form the ACA hybrid algorithm, a pheromone heuristic function improvement method is proposed, and a control factor is introduced. The proposed model and planning algorithm are simulated based on the MATLAB platform environment, and it is shown by simulations that the hybrid algorithm has obvious advantages in terms of motion trajectory smoothness, number of iterations, and minimum path cost .It well solved the practical application problem of fast path planning convergence and fast avoiding obstacles in the complex environment.
Evaluation of Annexins Family as Potential Biomarker for Predicting Progression and Prognosis in Clear Renal Cell Carcinoma
Authors: Zhao Jiyu , Chang Luchen , Tu Jianping , Sun Bei , Wei Xi
Published: June 2022

Background. Annexins family (ANXAs), as a Ca2+-dependent phospholipid-binding protein superfamily, participates in a wide variety of biological activities and has been reported to be dysregulated in numerous types of human cancers. Evidence from cell lines and human tissues indicates that ANAXs are involved in kidney clear renal cell carcinoma (KIRC) tumorigenesis. However, their prognostic value and expression pattern associated with KIRC remain to be elucidated. Methods. We visited public databases, including ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier plotter, cBioPortal, and GeneMANIA, to conduct comprehensive bioinformatics analysis and tried to detect basic relationships between each Annexins family member and KIRC. Results. We found that the expression level of ANXA1/2/4/5/6/7/8/13 in clear renal cell carcinoma tissue was higher than that in the kidney tissue, while the expression level of ANXA3/9/11 in the former was lower than that in the latter. The expression level of ANXA7/8/13 is related to the stage of the tumour. Survival analysis using the Kaplan–Meier plotter database showed that a high transcription level of ANXA2/5/8/10 is related to a low overall survival rate (OS) in predicting KIRC patients. In contrast, high ANXA3/4/7/9/11/13 levels are associated with a high OS in these patients. Conclusions. Our study implies that ANXA4/8/13 are potential targets of precision therapy for patients with KIRC and that ANXA2/5/8/10 are new biomarkers for the prognosis of KIRC.
Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines
Authors: Barton Beverly E. , Karras James G. , Murphy Thomas F. , Barton Arnold , Huang Hosea F-S.
Published: June 2022

Signal transducers and activators of transcription (STAT) were originally discovered as components of cytokine signal transduction pathways. Persistent activation of one STAT, STAT3, is a common feature of prostate cancer. Activated STAT3 was found in pathology specimens obtained from prostatectomy in the cancerous areas but not in the normal margins. Because the activation of STAT3 is mediated by the action of an upstream Janus kinase (JAK) kinase, usually JAK1 or JAK2, the activation step for STAT3 might itself be a target for therapy in prostate cancer. However, the redundancy of upstream kinases may make this strategy unreliable for therapy. To develop molecular targets for prostate cancer treatment, JAK kinase and STAT3 inhibition of two prostate cancer lines were compared. DU145 and NRP-154 cells were treated with JAK kinase inhibitors, analyzed for onset of apoptosis, and measured by annexin V binding and propidium iodide uptake. Activation of caspases in the cells was determined by measuring cleaved caspase-3 following treatment. For determining the effect on mitochondrial membrane depolarization that accompanies apoptosis, the fluorescent dye JC-1 was used. STAT3 was specifically inhibited by transfecting either a dominant-negative (DN) STAT3 plasmid or antisense STAT3 oligonucleotides into the cells. To look for reduction in STAT3 levels within cells, fixed and permeabilized prostate cancer cells were stained with antibody to STAT3. We found that more than one JAK kinase is involved in STAT3 activation in prostate cancer lines. AG490 (JAK2 specific) induced apoptosis in DU145 but not in NRP-154 prostate cancer lines, whereas piceatannol (JAK1 specific) induced apoptosis in NRP-154 but not in DU145 cells. Next, we demonstrated efficacy of specific STAT3 inhibitors in prostate cancer lines. Both induction of apoptosis and reduction in intracellular STAT3 protein were observed following treatment with antisense STAT3 oligonucleotides, while transfection of a DN-STAT3 plasmid into both prostate cancer cell lines resulted in loss of viability and onset of apoptosis. We conclude that STAT3-specific inhibitors, rather than JAK kinase-specific inhibitors, should be more useful therapeutically in treating androgen-resistant prostate cancer and that STAT3 is an appropriate target in the treatment of prostate cancer.
Chemoinducible gene therapy: A strategy to enhance doxorubicin antitumor activity
Authors: Lopez Carlos A. , Kimchi Eric T. , Mauceri Helena J. , Park James O. , Mehta Neil , Murphy Kevin T. , Beckett Michael A. , Hellman Samuel , Posner Mitchell C. , Kufe Donald W. , Weichselbaum Ralph R.
Published: June 2022

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-α. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-α by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.
Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase
Authors: Barvaux Vincent A. , Lorigan Paul , Ranson Malcolm , Gillum Amanda M. , McElhinney R. Stanley , McMurry T. Brian H. , Margison Geoffrey P.
Published: June 2022

Temozolomide is an alkylating agent that mediates its cytotoxic effects via O6-methylguanine (O6-meG) adducts in DNA. O6-alkylguanine-DNA-alkyltransferase (MGMT) can repair such adducts and therefore constitutes a major resistance mechanism to the drug. MGMT activity can be attenuated in vitro and in vivo by the pseudosubstrate O6-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib), which in clinical trials is in combination with temozolomide. Resistance to cytotoxic agents can also be mediated by the Bcl-2 protein, which inhibits apoptosis and is frequently up-regulated in tumor cells. Attenuation of Bcl-2 expression can be affected by treatment of cells with the antisense oligonucleotide, oblimersen sodium (Genasense), currently in phase III clinical trials in combination with the methylating agent dacarbazine. Using a human ovarian cancer cell line (A2780) that expresses both Bcl-2 and MGMT, we show that cells treated with active dose levels of either oblimersen (but not control reverse sequence or mismatch oligonucleotides) or PaTrin-2 are substantially sensitized to temozolomide. Furthermore, the exposure of oblimersen-pretreated cells to PaTrin-2 leads to an even greater sensitization of these cells to temozolomide. Thus, growth of cells treated only with temozolomide (5 μg/mL) was 91% of control growth, whereas additional exposure to PaTrin-2 alone (10 μmol/L) or oblimersen alone (33 nmol/L) reduced this to 81% and 66%, respectively, and the combination of PaTrin-2 (10 μmol/L) and oblimersen (33 nmol/L) reduced growth to 25% of control. These results suggest that targeting both Bcl-2 with oblimersen and MGMT with PaTrin-2 would markedly enhance the antitumor activity of temozolomide and merits testing in clinical trials.
Peroxisome proliferator-activated receptor γ and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias
Authors: Konopleva Marina , Elstner Elena , McQueen Teresa J. , Tsao Twee , Sudarikov Andrey , Hu Wei , Schober Wendy D. , Wang Rui-Yu , Chism David , Kornblau Steven M. , Younes Anas , Collins Steven J. , Koeffler H. Phillip , Andreeff Michael
Published: June 2022

The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPARγ receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPARγ ligands including BRL49653 (rosiglitazone), 15-deoxy-Δ12,14-prostaglandin J2, and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPARγ ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin's cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPARγ ligands induced the differentiation of myeloid leukemic cells. A combination of PPARγ ligands with a retinoid X receptor agonist (i.e., LG100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPARγ ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid–induced apoptosis. These results suggest that PPARγ ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias.
The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells
Authors: Doi Seiji , Soda Hiroshi , Oka Mikio , Tsurutani Junji , Kitazaki Takeshi , Nakamura Yoichi , Fukuda Minoru , Yamada Yasuaki , Kamihira Shimeru , Kohno Shigeru
Published: June 2022

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.
Synergistic antitumor effect of combined use of adenoviral-mediatedp53gene transfer and antisense oligodeoxynucleotide targetingclusteringene in an androgen-independent human prostate cancer model
Authors: Yamanaka Kazuki , Gleave Martin E. , Hara Isao , Muramaki Mototsugu , Miyake Hideaki
Published: June 2022

Our recent studies showed that antisense oligodeoxynucleotide targeting antiapoptotic gene, clusterin, enhanced apoptosis induced by conventional therapeutic modalities using several prostate cancer models. In this study, to establish a more effective therapeutic strategy against prostate cancer, we investigated the effect of combined treatment with antisense clusterin oligodeoxynucleotide and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) in an androgen-independent human prostate PC3 tumor model. Treatment of PC3 cells with 500 nmol/L antisense clusterin oligodeoxynucleotide decreased clusterin mRNA by >80% compared with that with 500 nmol/L mismatch control oligodeoxynucleotide. Clusterin mRNA expression in PC3 cells was highly up-regulated by Ad5CMV-p53 treatment; however, antisense clusterin oligodeoxynucleotide treatment further suppressed clusterin expression in PC3 cells after Ad5CMV-p53 treatment. Antisense clusterin oligodeoxynucleotide treatment significantly enhanced the sensitivity of Ad5CMV-p53 in a dose-dependent manner, reducing the IC50 of Ad5CMV-p53 by 75%. Apoptotic cell death was detected after combined treatment but not after treatment with either agent alone. In vivo administration of antisense clusterin oligodeoxynucleotide and Ad5CMV-p53 resulted in a significant inhibition of s.c. PC3 tumor growth as well as lymph node metastases from orthotopic PC3 tumors compared with administration of either agent alone. Furthermore, combined treatment with antisense clusterin oligodeoxynucleotide, Ad5CMV-p53, and mitoxantrone completely eradicated s.c. PC3 tumors and lymph node metastases from orthotopic PC3 tumors in 60% and 100% of mice, respectively. These findings suggest that combined treatment with antisense clusterin oligodeoxynucleotide and Ad5CMV-p53 could be a novel strategy to inhibit progression of hormone-refractory prostate cancer and that further addition of chemotherapeutic agents may help to enhance the efficacy of this combined regimen.
H-RAS V12–induced radioresistance in HCT116 colon carcinoma cells is heregulin dependent
Authors: Carón Rubén W. , Yacoub Adly , Zhu Xiaoyu , Mitchell Clint , Han Song Iy , Sasazuki Takehiko , Shirasawa Senji , Hagan Michael P. , Grant Steven , Dent Paul
Published: June 2022

The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways following exposure to ionizing radiation is unknown. Loss of K-RAS D13 expression in HCT116 colorectal carcinoma cells blunted basal extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and c-Jun NH2-terminal kinase 1/2 activity. Deletion of the allele to express K-RAS D13 also enhanced expression of ERBB1, ERBB3, and heregulin but nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells but did not restore or alter basal c-jun NH2-terminal kinase 1/2 activity. In parental cells, radiation caused stronger ERK1/2 pathway activation compared with that of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which correlated with constitutive translocation of Raf-1 into the plasma membrane of parental cells. Inhibition of mitogen-activated protein kinase/ERK1/2, but not PI3K, radiosensitized parental cells. In H-RAS V12 cells, radiation caused stronger PI3K/AKT pathway activation compared with that of the ERK1/2 pathway, which correlated with H-RAS V12–dependent translocation of PI3K into the plasma membrane. Inhibition of PI3K, but not mitogen-activated protein kinase/ERK1/2, radiosensitized H-RAS V12 cells. Radiation-induced activation of the PI3K/AKT pathway in H-RAS V12 cells 2 to 24 hours after exposure was dependent on heregulin-stimulated ERBB3 association with membrane-localized PI3K. Neutralization of heregulin function abolished radiation-induced AKT activation and reverted the radiosensitivity of H-RAS V12 cells to those levels found in cells lacking expression of any active RAS protein. These findings show that H-RAS V12 and K-RAS D13 differentially regulate radiation-induced signaling pathway function. In HCT116 cells expressing H-RAS V12, PI3K-dependent radioresistance is mediated by both H-RAS-dependent translocation of PI3K into the plasma membrane and heregulin-induced activation of membrane-localized PI3K via ERBB3.
Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members
Authors: DeFeo-Jones Deborah , Barnett Stanley F. , Fu Sheng , Hancock Paula J. , Haskell Kathleen M. , Leander Karen R. , McAvoy Elizabeth , Robinson Ronald G. , Duggan Mark E. , Lindsley Craig W. , Zhao Zhijian , Huber Hans E. , Jones Raymond E.
Published: June 2022

Recent studies indicate that dysregulation of the Akt/PKB family of serine/threonine kinases is a prominent feature of many human cancers. The Akt/PKB family is composed of three members termed Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ. It is currently not known to what extent there is functional overlap between these family members. We have recently identified small molecule inhibitors of Akt. These compounds have pleckstrin homology domain-dependent, isozyme-specific activity. In this report, we present data showing the relative contribution that inhibition of the different isozymes has on the apoptotic response of tumor cells to a variety of chemotherapies. In multiple cell backgrounds, maximal induction of caspase-3 activity is achieved when both Akt1 and Akt2 are inhibited. This induction is not reversed by overexpression of functionally active Akt3. The level of caspase-3 activation achieved under these conditions is equivalent to that observed with the phosphatidylinositol-3-kinase inhibitor LY294002. We also show that in different tumor cell backgrounds inhibition of mammalian target of rapamycin, a downstream substrate of Akt, is less effective in inducing caspase-3 activity than inhibition of Akt1 and Akt2. This shows that the survival phenotype conferred by Akt can be mediated by signaling pathways independent of mammalian target of rapamycin in some tumor cell backgrounds. Finally, we show that inhibition of both Akt1 and Akt2 selectively sensitizes tumor cells, but not normal cells, to apoptotic stimuli.
Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells
Authors: Ko Ching-Huai , Shen Shing-Chuan , Lee Tony J.F. , Chen Yen-Chou
Published: June 2022

Colorectal carcinoma is a leading cause of human mortality due to its high metastatic ability. Because the activation of matrix metalloproteinases (MMP) is a key factor in the metastatic process, agents with the ability to inhibit MMP activity have potential in the treatment of colorectal carcinoma. In the present study, among 36 flavonoids examined, myricetin was found to be the most potent inhibitor of MMP-2 enzyme activity in COLO 205 cells (IC50 = 7.82 μmol/L). Myricetin inhibition of MMP-2 enzyme activity was also found in the human colorectal carcinoma cell lines COLO 320HSR, COLO 320DM, HT 29, and COLO 205-X (IC50 = 11.18, 11.56, 13.25, and 23.51 μmol/L, respectively). In contrast, no inhibitory effect of MMP-2 protein expression or enzyme activity was observed in myricitrin (myricetin-3-rhamnoside)-treated cells. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated COLO 205 cells, an increase in MMP-2 protein expression and enzyme activity, as well as of protein kinase C (PKC) α protein translocation, extracellular signal-regulated kinase (ERK) 1/2 protein phosphorylation, and c-Jun protein expression was observed. ERK inhibitor (PD98059) and PKC inhibitors (GF-109203X and H-7), but not p38 inhibitor (SB203580) or c-jun-NH2-kinase inhibitor (SP600125), significantly inhibited TPA-induced MMP-2 protein expression, with reduced ERK phosphorylation and c-Jun protein expression. Addition of myricetin but not myricitrin suppressed TPA-induced MMP-2 protein expression in COLO 205 cells by blocking the TPA-induced events, including translocation of PKCα from cytosol to membrane, phosphorylation of ERK1/2 protein, and induction of c-Jun protein expression. Addition of PD98059 or GF-109203X significantly enhanced the inhibitory effect of myricetin on MMP-2 enzyme activity induced by TPA. Furthermore, myricetin, but not myricitrin, suppressed TPA-induced invasion of COLO 205 cells in an in vitro invasion assay using Engelbreth-Holm-Swarm sarcoma tumor extract Matrigel–coated Transwells. Results of the present study indicate that myricetin significantly blocked both endogenous and TPA-induced MMP-2 enzyme activity by inhibiting its protein expression and enzyme activity. The blockade involved suppression of PKC translocation, ERK phosphorylation, and c-Jun protein expression.