bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction Method of Graphene Defect Modification Based on Neural Network
Authors: Feng Meili , Yao Wenjun , An Jingjing , Huang Zhipeng , Yuan Yongrang , Yao Yuze
Published: June 2022

Because of its excellent thermal, mechanical, and electrical properties, graphene has been used in a variety of functional coatings. Noncovalent bond functionalization and covalent bond functionalization are the most common graphene surface functionalization methods. Polymer modification, for example, can be used to give graphene and its derivatives new structure, morphology, and properties. The basic structure and predictive control principle of neural networks are discussed in this study, and a high thermal resistance porous graphene structure is reversely designed using machine learning. The effect of a graphene defect modification prediction model based on a GA (genetic algorithm) and improved BPNN (BP neural network) algorithm is investigated. The RMSE predicted by submodels 1–4 decreases by 13.26%, 3.86%, 11.71%, and 19.63%, respectively, according to the simulation results. The BPNN graphene defect modification prediction model optimized by GA has a better training and prediction effect than before optimization.
Mathematical Modeling and Numerical Simulation for the Outbreak of COVID-19 Involving Loss of Immunity and Quarantined Class
Authors: Arif Faiza , Majeed Zain , Rahman Jamshaid Ul , Iqbal Naveed , Kafle Jeevan
Published: June 2022

For the analysis of the recent deadly pandemic Sars-Cov-2, we constructed the mathematical model containing the whole population, partitioned into five different compartments, represented by SEIQR model. This current model especially contains the quarantined class and the factor of loss of immunity. Further, we discussed the stability of the SEIQR model (constructed on the basis of system of coupled differential equations). The basic reproduction that indicates the behavior of the disease is also estimated by the use of next-generation matrix method. Numerical simulation of this model is provided, the results are analyzed by theoretically strong numerical methods, and computationally known tool MATLAB Simulink is also used for visualization of the results. Validation of results by Simulink software and numerical methods shows that our model and adopted methodology are appropriate and accurate and could be used for further predictions on COVID-19. Our results suggest that the isolation of the active cases and strong immunization of patients or individuals play a major role to fight against the deadly Sars-Cov-2.
Analysis of Bearing Performance of Monopile and Single Suction Bucket Foundation for Offshore Wind Power under Horizontal Load
Authors: Wang Bin , Qin Tianqing , Yuan Changfeng , Li Liang , Yuan Minghui , Li Ying
Published: June 2022

In conjunction with the geological conditions of the East China Sea, the bearing performance of monopile and single-suction bucket foundations is compared and analyzed in shallow and deep-sea conditions under static horizontal loads. Furthermore, the statistical data of wind and wave from 2010 to 2020 in the East China Sea were tabulated into amplitude curves applied to the two foundations in the form of dynamic loads, and the bearing performances of the two foundations under dynamic loads were analyzed. The results show that the typical suction bucket foundation for a wind turbine currently designed in the shallow sea is destabilized under static horizontal loads, while the pile foundation is more stable; both foundations are stable in the deep-sea area. However, the suction bucket foundation displacement is less than the pile foundation. Under dynamic loading, the maximum displacement of monopile in the shallow sea was 127 mm. The maximum displacement of the suction bucket foundation was 434 mm, and the foundation was unstable. Both foundations are stable in deep-sea conditions, and the maximum displacement of the pile foundation is 1.4 times the maximum displacement of the suction bucket. Considering the difficulty construction in the deep sea, it is recommended to use suction bucket foundations.
AdvU-Net: Generating Adversarial Example Based on Medical Image and Targeting U-Net Model
Authors: Kwon Hyun , Jeong Jongwook
Published: June 2022

Deep neural networks (DNNs) provide excellent performance in image recognition, speech recognition, video recognition, and pattern analysis. These neural networks are often applied in the medical field to predict or classify patients’ illnesses. One such network, the U-Net model, has shown good performance in data segmentation and is an important technology in medical imaging. However, deep neural networks such as those applied in medicine are vulnerable to attack by adversarial examples. Adversarial examples are samples created by adding a small amount of noise to an original data sample that is difficult for a human to see but that induces misclassification by the targeted model. In this paper, we propose AdvU-Net, a method for generating an adversarial example targeting the U-Net model used in segmentation. Performance was analyzed according to epsilon, using the fast gradient sign method (FGSM) for generating adversarial examples. We used ISBI 2012 as the dataset and TensorFlow as the machine learning library. In the experiment, when an adversarial example was generated using an epsilon value of 0.3, the pixel error was 3.54 or greater while the pixel error of the original sample was maintained at 0.15 or less.
Design and Analysis of a Provable Secure Two-Factor Authentication Protocol for Internet of Things
Authors: Chen Chien-Ming , Liu Shuangshuang , Li Xuanang , Kumari Saru , Li Long
Published: June 2022

Because sensor nodes are deployed in public areas, these sensors are easy to capture by adversaries. Once a sensor is stolen, the sensitive information stored in it is likely to be exposed. Accordingly, designing a secure authentication protocol should consider this issue. Sadri et al. recently proposed a two-factor authentication protocol with anonymity for wireless sensor networks. Unfortunately, we found that their protocol had a design flaw in the user and sensor authentication phase. Besides, their protocol can not resist stolen smart card attacks, sensor capture attacks, and user impersonation attacks. In addition, their protocol does not provide perfect forward security. This paper proposes a provably secure authentication to overcome these weaknesses and flaws. By comparing the security and performance of the proposed protocol with other related protocols, we find that our work has reasonable computation overhead and better security.
Electrochemical Preparation of Recycled Self-Compacting Concrete Composite Beams and Their Application in Prefabricated Buildings
Authors: Yuan Yuan , Zhu Yongchao
Published: June 2022

In order to solve the problems of electrochemical preparation of recycled self-compacting concrete composite beams and their application in prefabricated buildings, we need to meet the requirements of national housing industrialization and green buildings, make up for the low development capacity of prefabricated buildings, and improve the speed of housing construction and the rapid development of the construction industry. Now the prefabricated building has entered a period of rapid growth. However, the research on the construction technology of the prefabricated building is still in its infancy, and there are many difficulties and challenges in the construction. The deformation and internal force of a prefabricated residential laminated floor slab in the construction process of prestressed PK slab transportation, stacking, hoisting, and the laminated cast-in-situ layer will affect the normal use of the building. However, at present, there is less mechanical analysis of its construction process, so there is blindness in the formulation, implementation, and inspection of the construction scheme. Through the social survey of 200 people, 179 people believe that prefabricated buildings will be better than traditional buildings. Therefore, by participating in the practice of prefabricated housing engineering, the key mechanical problems in the construction of the composite floor slab of prefabricated housing are explored and found.
Use of an Improved Car-Following Model to Explain the Influence of Traffic Composition on Saturation Headway at Signalized Intersections
Authors: Wang Yi , Rong Jian , Luo Wei , Gao Yacong
Published: June 2022

Previous studies mainly used statistical methods to analyze the impact of traffic composition on saturation flow rate from the mesolevel, and there is insufficient research on how traffic composition affects driving behavior. Thus, the purpose of this paper is to establish a more accurate car-following model, establish the relationship between microbehavior and mesostatistical regularity, and explain the influence of vehicle composition on saturation headway. In this paper, an improved full velocity difference (FVD) model is proposed, which abstracts the driver characteristics of a heterogeneous flow into four scenarios: car-car, car-bus, bus-car, and bus-bus. The measured data are used to calibrate and verify the basic FVD and the improved FVD models. The performance of the improved model is significantly improved. The RMSE and RMSPE are reduced by 15.29% and 22.32%, respectively. Finally, through numerical simulation experiments, the variation of saturation headway with different proportions of buses is analyzed. The saturation headway increases with the increase of the proportion of heavy vehicles. Moreover, another important finding is that the saturation headway is not significantly influenced by the position of the buses but only by the proportion of the buses. The research results could provide theoretical support for the control and management of fleets composed of different vehicles at intersections.
Establishment of Emergency Teaching Model and Optimization of Discrete Dynamic Calculation in Complex Virtual Simulation Environment
Authors: Li He , Sun Yuansong , Song Kai , Yin Chunlin
Published: June 2022

Virtual surgery is a typical application of virtual reality technology in the medical field, which can help improve the success rate of surgery and reduce medical costs in various aspects such as medical training, surgery planning, and intraoperative navigation, and is becoming a hot research topic and a frontier subject in the medical field. The establishment of virtual surgery simulation system involves the intersection and penetration of various disciplines, and the research is difficult, and many functional modules are still not perfect. This study focuses on the key technologies in the virtual surgery simulation system, focusing on two core modules, the soft tissue modeling method and the collision detection algorithm, to improve the accuracy of the soft tissue model deformation under the condition of meeting the real-time system. The biomechanical properties of soft tissues are studied, the viscoelastic properties are analyzed, and the viscoelastic theory is used as the basis for soft tissue modeling; the geometric model is established by using a complementary method of surface model and tetrahedral mesh cells, with the surface model covering the outer surface for visual rendering and the tetrahedral mesh cells for skeleton support of the physical model, so that the model has a better visual effect and deformation effect, which enhances the model fidelity that is enhanced by the better visual effect and deformation effect; the soft tissue physical modeling method is summarized and summarized to lay the foundation for soft tissue model optimization. The experimental results show that the bilateral teleoperation system under analog control can give the operator a better haptic sensation (smaller value of input impedance felt by the operator when doing free motion from the robot) while ensuring good positional tracking and force tracking effects. This method solves the problems of collapse distortion and lack of viscoelastic properties of the traditional mass-spring model, and improves the accuracy of model deformation. Based on the improved algorithm, the viscoelastic hybrid filled sphere model of the liver organ is successfully established, which proves that the modeling method is feasible and effective.
[Retracted] Efficacy and Safety of rCCK96‐104PE38 Targeted Drug in the General Surgical Treatment of Colon Cancer
Authors: Cao Wenbin , Zhang Bo , Liu Yang
Published: June 2022

To evaluate the clinical efficacy and safety of the rCCK96-104PE38 targeted drug in patients with colon cancer in general surgery, data of 80 patients with colon cancer who were admitted to the hospital from April 2019 to July 2021 were selected and randomly divided into the treatment group and the control group, with 40 cases in each group. Patients in the treatment group were treated with the rCCK96-104PE38 targeted drug, and those in the control group were treated with oxaliplatin. The treatment efficiency and incidence of adverse reactions were compared between the two groups. The inverse cholecystokinin (CCK96-104) was fused with pseudomonas aeruginosa exotoxin (PE38 toxin) through the gene amplification technique to construct a prokaryotic expression vector. Then, the rCCK96-104PE38 was purified by Ni‐nitrilotriacetate (Ni‐NTA) affinity chromatography, and the antitumor activity of rCCK96-104PE38 was verified. The results showed that the amplified rCCK96-104PE38 sequence was correct and the pET‐28a prokaryotic expression system was adopted to successfully achieve active expression. The purified recombinant protein could induce the apoptosis of colon cancer cells in vitro and inhibit tumor growth in vivo. The total effective rate in the treatment group (80%, 32/40) was higher than that in the control group (60%, 24/40) (P < 0.05). To sum up, the recombinant toxin rCCK96-104PE38 could not only specifically adsorb the colon cancer cells with high expression of CCK2R but also effectively inhibit tumor tissue growth and proliferation. Besides, the rCCK96-104PE38 protein had a good anticancer effect that helped effectively reduce the incidence of adverse reactions in patients, which was worthy of promoting.
HD-RMPC: A Hierarchical Distributed and Robust Model Predictive Control Framework for Urban Traffic Signal Timing
Authors: Ren Yilong , Jiang Han , Zhang Le , Liu Runkun , Yu Haiyang
Published: June 2022

Due to the nonlinearity and dynamics of transportation systems, traffic signal control (TSC) in urban traffic networks has always been an important challenge. In recent years, model predictive control (MPC) has shown extraordinary potential in TSC due to its outstanding ability to model dynamic systems. However, the relatively complex online computing, lack of reasonable setpoints for target solving, and uncertainty of traffic network hinder MPC from being further applied. To address these problems, we propose a hierarchical, distributed, and robust model predictive control (HD-RMPC) framework for urban TSC. At the slow-update layer, the road network is dynamically divided into several subareas according to regional attributes and real-time traffic demand. Meanwhile, the volume is coordinated in a robust way for the purpose of traffic equilibrium and overflow prevention. Then, the set-point matrix of each subarea is calculated to equalize the flow in the subarea. This distributed framework guarantees the real-time performance of MPC in urban traffic networks. At the fast-update layer, we adopt an improved prediction model by explicit modeling of the disturbance and reduce the prediction error. Finally, the objective function is reconstructed and solved at the control layer to obtain the optimal control law. Through continuous and asynchronous optimization of the set point and prediction model, the framework significantly improves the control effect. Simulation evaluation based on a real-world road network demonstrates that the proposed HD-RMPC method outperforms all baselines and maintains excellent real-time performance.
Study on Control of Risks Existing in the Construction of Information Management System in Public Hospitals
Authors: Xu Feifei , Guan Qingya
Published: June 2022

In terms of the medical information management system, it can effectively increase the resource utilization rate of medical and health institutions, optimize the management process, and provide relevant, efficient management approaches, all of which help medical and health institutions meet their internal and external demands to the greatest possible extent. However, the projects related to the information management system in hospitals or other medical institutions are characterized by high system complexity, multiple related links, and uncertainty of project demands due to their own professional and industrial characteristics, which are frequently manifested as many limiting factors in the construction process. It is essential to determine the kind of risk and evaluation methods to explore the risk evaluation indicators and formulate corresponding countermeasures for ongoing medical institution information systems projects. In such a background, this study establishes a perfect risk identification and evaluation system by taking the risk management of projects related to medical institution information system in R hospital as the research object and proposes the corresponding countermeasures as the reference for the establishment of the information management system.
Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis
Authors: Attia Hala , Albekairi Norah , Albdeirat Layal , Soliman Arwa , Rajab Reem , Alotaibi Hend , Ali Rehab , Badr Amira
Published: June 2022

Aim. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and if untreated, it may propagate into end-stage liver disease. The classical arm of the renin-angiotensin system (RAS) has a fundamental role in triggering oxidative stress and inflammation, which play potential roles in the pathogenesis of NAFLD. However, the nonclassical alternative axis of RAS, angiotensin- (Ang-) converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor, opposes the actions of the classical arm, mitigates the metabolic dysfunction, and improves hepatic lipid metabolism rendering it a promising protective target against NAFLD. The current study is aimed at investigating the impact of chrysin, a well-known antioxidant flavonoid, on this defensive RAS axis in NAFLD. Methods. Rats were randomly distributed and treated daily for eight weeks as follows: the normal control, chrysin control (50 mg/kg, p.o), NAFLD group (received 20% fructose in drinking water), and treated groups (25 and 50 mg/kg chrysin given orally and concomitantly with fructose). Diminazene aceturate (DIZE) (15 mg/kg, s.c.) was used as a reference ACE2 activator. Key Findings. High fructose induced significant weight gain, hepatocyte degeneration with fat accumulation, and inflammatory cell infiltration (as examined by H&E staining). This was accompanied by a substantial increase in liver enzymes, glucose, circulating and hepatic triglycerides, lipid peroxides, inflammatory cytokines, and Ang II (the main component of classical RAS). At the same time, protein levels of ACE2, Ang (1-7), and Mas receptors were markedly reduced. Chrysin (25 and 50 mg/kg) significantly ameliorated these abnormalities, with a prominent effect of the dose of 50 mg/kg over DIZE and the lower dose in improving ACE2, Ang (1-7), and Mas. Significance. Chrysin is a promising efficient protective remedy against NAFLD; mechanisms include the activation of ACE2/Ang (1-7)/Mas axis.
The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines
Authors: Hamdouchi Chafiq , Keyser Heather , Collins Elizabeth , Jaramillo Carlos , De Diego Jose Eugenio , Spencer Charles D. , Dempsey Jack Alan , Anderson Bryan D. , Leggett Tillie , Stamm Nancy B. , Schultz Richard M. , Watkins Scott A. , Cocke Kim , Lemke Stephanie , Burke Teresa F. , Beckmann Richard P. , Dixon Jeffrey T. , Gurganus Thomas M. , Rankl Nancy B. , Houck Keith A. , Zhang Faming , Vieth Michal , Espinosa Juan , Timm David E. , Campbell Robert M. , Patel Bharvin K. R. , Brooks Harold B.
Published: June 2022

The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.
Roscovitine-induced up-regulation of p53AIP1 protein precedes the onset of apoptosis in human MCF-7 breast cancer cells
Authors: Węsierska-Gądek Józefa , Gueorguieva Marieta , Horky Marcel
Published: June 2022

We reported recently that roscovitine arrested human MCF-7 cancer cells at G2-M phase of the cell cycle and concomitantly induced apoptosis. After roscovitine treatment, the level of wild-type p53 protein strongly increased and p53 was accumulated in the nucleus. Here, we raised the question of which pathway would be involved in roscovitine-induced apoptosis in MCF-7 cells, which are known to be caspase-3-deficient, and whether roscovitine-mediated activation of p53 protein might positively affect the execution of cell death. Roscovitine induced a depolarization of mitochondrial potential beginning at 6 hours posttreatment as evidenced by changes in J-aggregate formation and release of the mitochondrial proteins cytochrome c and apoptosis-inducing factor. Interestingly, roscovitine stimulated a site-specific phosphorylation of wild-type p53 protein in a time-dependent manner. p53 protein was specifically phosphorylated at Ser46. P-Ser46-activated wild-type p53 tumor suppressor up-regulated p53AIP1 protein, its downstream target known to mediate the depolarization of mitochondria. The onset of phosphorylation of p53 at Ser46 preceded the up-regulation of p53AIP1 protein and the depolarization of mitochondrial potential. We compared the kinetics of roscovitine-mediated p53 activation between caspase-3-deficient parental MCF-7 cells and cells reconstituted with caspase-3. The kinetics and the extent of p53 protein activation in caspase-3-proficient cells differed from those observed in caspase-3-deficient parental cells. Remarkably, roscovitine failed to induce phosphorylation at Ser46 in caspase-3-reconstituted MCF-7 cells. Our results indicate that, depending on the status of caspase-3 in MCF-7 cells, different apoptotic pathways were initialized.
BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors
Authors: Fukazawa Hidesuke , Noguchi Kohji , Masumi Atsuko , Murakami Yuko , Uehara Yoshimasa
Published: June 2022

Loss of contact with substratum triggers apoptosis in many normal cell types, a phenomenon termed anoikis. We reported previously that mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors induced apoptosis in nonanchored MDA-MB231 and HBC4 human breast cancer cells, whereas anchored cells remained viable. Here, we report that activation of the BH3-only protein BimEL is the major mechanism for induction of anoikis sensitivity by MEK inhibitors in MDA-MB231 and HBC4 cells. On treatment with MEK inhibitors, BimEL in MDA-MB231 and HBC4 cells rapidly increased, irrespective of the state of anchorage. However, it translocated to mitochondria only in nonanchored cells, explaining why attached cells remain viable. MDA-MB231 and HBC4 cells had exceedingly low basal levels of BimEL compared with other breast cancer cells, suggesting that maintenance of low BimEL amount is important for survival of these cells. MEK inhibitors also induced the electrophoretic mobility shift of BimEL, indicative of reduced phosphorylation. In vitro, BimEL was phosphorylated by extracellular signal-regulated kinase on Ser69, which resides in the BimEL-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of Ser69 promotes ubiquitination of BimEL. We conclude that MEK inhibitors sensitize MDA-MB231 and HBC4 cells to anoikis by blocking phosphorylation and hence degradation of BimEL, a mechanism that these cells depend on to escape anoikis.
Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-XL [(−)-gossypol] against diffuse large cell lymphoma
Authors: Mohammad Ramzi M. , Wang Shaomeng , Aboukameel Amro , Chen Ben , Wu Xihan , Chen Jianyong , Al-Katib Ayad
Published: June 2022

Overexpression of Bcl-2/Bcl-XL protein has been observed in more than 80% of B-cell lymphomas. Diffuse large cell lymphoma (DLCL) is the most common subtype of non-Hodgkin's lymphoma. (−)-Gossypol, a natural product isolated from cottonseeds, was discovered as a potent small-molecule inhibitor of Bcl-2 and Bcl-XL proteins, with a Ki value in the nanomole per liter range for both. In vitro, (−)-gossypol showed significant growth inhibition effect against WSU-DLCL2 lymphoma cell line and fresh cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. As expected (−)-gossypol induced complete cytochrome c release from mitochondria, increased caspases-3 and -9 activity, and caused apoptotic death without affecting protein levels of Bcl-2, Bcl-XL, Bax, and Bak. The addition of cyclophosphamide-Adriamycin-vincristine-prednisolone (CHOP) regimen to lymphoma cells preexposed to (−)-gossypol enhanced killing significantly. The maximum tolerated dose of (−)-gossypol in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg × 3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the tumor growth inhibition, the tumor growth delay, and the log10 kill of mice treated with (−)-gossypol + CHOP were better than CHOP or (−)-gossypol alone. We conclude that adding Bcl-2/Bcl-XL small-molecule inhibitor to standard chemotherapy may prove an effective strategy in lymphoma therapy.
Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity
Authors: Kasibhatla Shailaja , Gourdeau Henriette , Meerovitch Karen , Drewe John , Reddy Sanjeeva , Qiu Ling , Zhang Hong , Bergeron Frederick , Bouffard David , Yang Quan , Herich John , Lamothe Serge , Cai Sui Xiong , Tseng Ben
Published: June 2022

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.
Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines
Authors: El-Rayes Basil F. , Ali Shadan , Sarkar Fazlul H. , Philip Philip A.
Published: June 2022

Cyclooxygenase-2 (COX-2) is involved in inhibition of apoptosis, potentiation of cell growth, and angiogenesis and as such is a target for drug development. The COX-2 enzyme is frequently overexpressed in pancreatic cancer. The aim of this study was to determine the effects of celecoxib on the growth inhibition and induction of apoptosis by gemcitabine in pancreatic cancer cell lines. Baseline expression of COX-2 enzyme was determined by Western blot analysis in five human pancreatic cancer cell lines. Cells were treated with gemcitabine (100 nmol/L), celecoxib (1, 10, and 50 μmol/L), and the combination. No potentiation in growth inhibition was observed in MIAPaCa cells (low COX-2 expression). However, growth inhibition and apoptosis were significantly increased with celecoxib in the BxPC-3 cells that have a high COX-2 expression. Significant down-regulation of nuclear factor-κB activation was observed in BxPC-3 cells treated with celecoxib and gemcitabine. Moreover, down-regulation of COX-2 mRNA and protein expression was also observed in the BxPC-3 cells treated with the combination as compared with the untreated and the celecoxib-treated and gemcitabine-treated cell lines. We conclude that celecoxib potentiates gemcitabine-induced growth inhibition and apoptosis in pancreatic cell lines. In addition to inhibition of the COX-2 enzyme, the celecoxib and gemcitabine combination down-regulated nuclear factor-κB activation, which in turn may have contributed to the induction of apoptosis and the down-regulation of transcription of the COX-2 enzyme.
(−)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer
Authors: Xu Liang , Yang Dajun , Wang Shaomeng , Tang Wenhua , Liu Meilan , Davis Mary , Chen Jianyong , Rae James M. , Lawrence Theodore , Lippman Marc E.
Published: June 2022

Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves antiapoptotic signal transduction pathways that prevent radiation-induced cell death. The majority of human prostate cancers overexpress the important antiapoptotic proteins Bcl-2 and/or Bcl-xL, which render tumors resistant to radiation therapy. (−)-Gossypol, a natural polyphenol product from cottonseed, has recently been identified as a potent small molecule inhibitor of both Bcl-2 and Bcl-xL. In the current study, we investigated the antitumor activity of (−)-gossypol in prostate cancer and tested our hypothesis that (−)-gossypol may improve prostate cancer's response to radiation by potentiating radiation-induced apoptosis and thus making cancer cells more sensitive to ionizing radiation. Our data show that (−)-gossypol potently enhanced radiation-induced apoptosis and growth inhibition of human prostate cancer PC-3 cells, which have a high level of Bcl-2/Bcl-xL proteins. Our in vivo studies using PC-3 xenograft models in nude mice show that orally given (−)-gossypol significantly enhanced the antitumor activity of X-ray irradiation, leading to tumor regression in the combination therapy. In situ terminal deoxynucleotidyl transferase–mediated nick end labeling staining showed that significantly more apoptotic cells were induced in the tumors treated with (−)-gossypol plus radiation than either treatment alone. Anti-CD31 immunohistochemical staining indicates that (−)-gossypol plus radiation significantly inhibited tumor angiogenesis. Our results show that the natural polyphenol inhibitor of Bcl-2/Bcl-xL, (−)-gossypol, can radiosensitize prostate cancer in vitro and in vivo without augmenting toxicity. (−)-Gossypol may improve the outcome of current prostate cancer radiotherapy and represents a promising novel anticancer regime for molecular targeted therapy of hormone-refractory prostate cancer with Bcl-2/Bcl-xL overexpression.
The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells
Authors: Wu Tong , Leng Jing , Han Chang , Demetris Anthony Jake
Published: June 2022

The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho-Akt (Thr 308), a protein kinase activated by COX-2-mediated prostaglandins, in human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time-dependent reduction of cell viability. Fluorescence microscopy, Western blot, and caspase activity assays demonstrated that celecoxib induced morphological features of apoptosis, activation of caspase-9 and caspase-3, and release of cytochrome c. The celecoxib-induced cell death was significantly blocked by N-benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax were not altered. Inhibition of Akt activation by LY294002 significantly decreased the viability of human cholangiocarcinoma cells. These findings suggest that celecoxib inhibits cholangiocarcinoma growth partly through induction of apoptosis and inhibition of Akt phosphorylation.
Apoptotic killing of B-chronic lymphocytic leukemia tumor cells by allicin generated in situ using a rituximab-alliinase conjugate
Authors: Arditti Fabian D. , Rabinkov Aharon , Miron Talia , Reisner Yair , Berrebi Alain , Wilchek Meir , Mirelman David
Published: June 2022

Allicin, a highly active component from freshly crushed garlic, is produced upon the reaction of the small molecular weight molecule alliin, with the enzyme alliinase (EC 4.4.1.4). Because allicin was shown to be toxic to various mammalian cells in vitro, we devised a novel approach for the therapy of B-cell malignancies based on site-directed generation of allicin. Alliinase was conjugated to the monoclonal antibody rituximab, which recognizes the CD20 antigen, and the resulting conjugate was targeted to CD20+ B chronic lymphocytic leukemia (B-CLL) and other B-cell lymphomas. Upon addition of alliin, allicin was formed in situ, killing the CD20+ tumor B cells via apoptosis. Following a 72-hour treatment, an 85% and 96% reduction was observed in the number of viable B-CLL and EBV-transformed B cells, respectively. Using the human/mouse radiation chimera for the evaluation of allicin targeting in a preclinical animal model, we showed a significant reduction in the number of recovered B-CLL, mantle cell lymphoma, or EBV-transformed B cells. We conclude that our system offers a new powerful and less toxic therapy for B-CLL and other B-cell malignancies. Furthermore, combining alliinase with the appropriate monoclonal antibody may extend the application of this approach to other conditions in which the elimination of a specific cell population is desired.
Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis
Authors: Raynaud Florence I. , Fischer Peter M. , Nutley Bernard P. , Goddard Phyllis M. , Lane David P. , Workman Paul
Published: June 2022

Determination of pharmacokinetic properties in the intact animal remains a major bottleneck in drug discovery. Cassette dosing involves administration of a cocktail of drugs to individual animals. Here we describe the cassette dosing properties of a 107-membered library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 (CDK2) inhibitors. A three-step parallel synthesis approach produced compounds with purity ranging from 63% to 100%. Cassette dosing was validated by comparing the pharmacokinetic parameters obtained following i.v. administration of a mixture of olomoucine, R-roscovitine (CYC202), and bohemine, each at 16.6 mg/kg, with results for administration of single agents at 50 mg/kg. No significant difference was observed between the pharmacokinetic parameters of agents when dosed in combination compared with those of individual compounds. CYC202 showed the highest area under the curve (AUC) and the longest elimination half-life (t1/2). Further cassettes evaluated the library of trisubstituted purines with CYC202 and purvalanol A included as pharmacokinetic standards in a validated limited sampling strategy. The ratios of pharmacokinetic parameters to that of CYC202 [AUC, maximum concentration (Cmax), and t1/2] remained similar when compounds were tested in two different cassettes or as individual compounds. Following dosing of the same cassette on three different days, there was less than 20% variation in pharmacokinetic parameters between days. The structure-pharmacokinetics relationship showed that the favored purine substituents are benzylamine and veratrylamine at position 6, amino-2 propanol at position 2, and methylpropyl or hydroxyethyl at position 9. Without cassette dosing, this study would have used 3 times as many animals and would have taken 4 times longer, illustrating the power of this method in lead optimization.
Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription
Authors: Cho Sung Dae , Jiang Cheng , Malewicz Barbara , Dong Yan , Young Charles Y.F. , Kang Kyung-Sun , Lee Yong-Soon , Ip Clement , Lü Junxuan
Published: June 2022

Prostate-specific antigen (PSA) is widely used clinically for prostate cancer diagnostics and as an indicator of therapeutic efficacy and recurrence. Several human chemoprevention trials are being conducted to validate the prostate cancer prevention efficacy of selenium and PSA is used in these trials as a biomarker of response. A better understanding of the effects of selenium metabolites on the kinetics of PSA turnover and secretion in prostate cancer cells treated with selenium at concentrations which are achievable physiologically will be important for interpreting the results of these trials. This study addresses whether the putative active anticancer selenium metabolite methylselenol or its precursor methylseleninic acid (MSeA) specifically inhibits PSA expression in the androgen-responsive LNCaP prostate cancer cell model. The results show that exposure to sub-apoptotic concentrations of MSeA and methylselenol inhibited PSA protein expression and secretion, whereas sodium selenite and selenomethionine lacked inhibitory effect. The inhibition was detectable at 3 h of exposure and required a threshold level of MSeA to sustain. Turnover experiments showed that MSeA caused rapid PSA degradation, which was partially blocked by lysosomal inhibitors, but not by a proteasomal inhibitor. Furthermore, MSeA treatment reduced PSA mRNA level, down-regulated androgen receptor protein expression, and inhibited androgen-stimulated PSA promoter transcription. In summary, methylselenol or MSeA specifically and rapidly inhibited PSA expression through two mechanisms of action: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. These findings may have important mechanistic implications for the prostate specific cancer chemopreventive action of selenium.
Covalent binding of antitumor benzoacronycines to double-stranded DNA induces helix opening and the formation of single-stranded DNA: Unique consequences of a novel DNA-bonding mechanism
Authors: David-Cordonnier Marie-Hélène , Laine William , Lansiaux Amélie , Rosu Frédéric , Colson Pierre , de Pauw Edwin , Michel Sylvie , Tillequin Francois , Koch Michel , Hickman John A. , Pierré Alain , Bailly Christian
Published: June 2022

The majority of DNA-binding small molecules known thus far stabilize duplex DNA against heat denaturation. A high, drug-induced increase in the melting temperature (Tm) of DNA is generally viewed as a good criterion to select DNA ligands and is a common feature of several anticancer drugs such as intercalators (e.g., anthracyclines) and alkylators (e.g., ecteinascidin 743). The reverse situation (destabilization of DNA to facilitate its denaturation) may be an attractive option for the identification of therapeutic agents acting on the DNA structure. We have identified the tumor-active benzoacronycine derivative S23906-1 [(±)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2]acridin-7-one] as a potent DNA alkylating agent endowed with a helicase-like activity. Using complementary molecular approaches, we show that covalent binding to DNA of the diacetate compound S23906-1 and its monoacetate analogue S28687-1 induces a marked destabilization of the double helix with the formation of alkylated ssDNA. The DNA-bonding properties and effects on DNA structure of a series of benzoacronycine derivatives, including the dicarbamate analogue S29385-1, were studied using complementary biochemical (electromobility shift assay, nuclease S1 mapping) and spectroscopic (fluorescence and Tm measurements) approaches. Alkylation of guanines in DNA by S28687-1 leads to a local denaturation of DNA, which becomes susceptible to cleavage by nuclease S1 and significantly decreases the Tm of DNA. The drug also directly alkylates single-strand DNA, but mass spectrometry experiments indicate that guanines in duplexes are largely preferred over single-stranded structures. This molecular study expands the repertoire of DNA-binding mechanisms and provides a new dimension for DNA recognition by small molecules.
Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling
Authors: Ihle Nathan T. , Williams Ryan , Chow Sherry , Chew Wade , Berggren Margareta I. , Paine-Murrieta Gillian , Minion Daniel J. , Halter Robert J. , Wipf Peter , Abraham Robert , Kirkpatrick Lynn , Powis Garth
Published: June 2022

We have developed biologically stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compound was PX-866 (acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester), which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 hours after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 minutes and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metabolism with sequential N-deallylation. Synthetic standards of the N-deallylated metabolites of PX-866 inhibited PtdIns-3-kinase at low nanomolar per liter concentrations. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodefficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biologically stable broad-spectrum PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment.
Curcumin sensitizes prostate cancer cells to tumor necrosis factor–related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-κB through suppression of IκBα phosphorylation
Authors: Deeb Dorrah , Jiang Hao , Gao Xiaohua , Hafner Mikehl S. , Wong Henry , Divine George , Chapman Robert A. , Dulchavsky Scott A. , Gautam Subhash C.
Published: June 2022

Epidemiologic studies suggest that diet rich in plant-derived foods plays an important role in the prevention of prostate cancer. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and growth inhibitory activities against multiple tumor cell lines. We have shown previously that curcumin and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)/Apo2L interact to induce cytotoxicity in the LNCaP prostate cancer cell line. In this study, we investigated the mechanism by which curcumin augments TRAIL-induced cytotoxicity in LNCaP cells. Subtoxic concentrations of the curcumin-TRAIL combination induced strong apoptotic response in LNCaP cells as demonstrated by the binding of Annexin V-FITC and cleavage of procaspase-3. Furthermore, LNCaP cells express constitutively active nuclear factor-κB (NF-κB), which is inhibited by curcumin. Because NF-κB has been shown to mediate resistance to TRAIL-induced apoptosis in tumor cells, we investigated whether there is a relationship between NF-κB activation and resistance to TRAIL in LNCaP prostate cancer cells. Pretreatment with curcumin inhibited the activation of NF-κB and sensitized LNCaP cells to TRAIL. A similar increase in the sensitivity of LNCaP cells to TRAIL-induced apoptosis was observed following inhibition of NF-κB by dominant negative mutant IκBα, an inhibitor of NF-κB. Finally, curcumin was found to inhibit NF-κB by blocking phosphorylation of IκBα. We conclude that NF-κB mediates resistance of LNCaP cells to TRAIL and that curcumin enhances the sensitivity of these tumor cells to TRAIL by inhibiting NF-κB activation by blocking phosphorylation of IκBα and its degradation.