bluuebunny/crossref_metadata_2025 huggingface dataset:
A Study on Mobile Resources for Language Education of Preschool Children Based on Wireless Network Technology in Artificial Intelligence Context
Authors: Li QiuMing
Published: June 2022

Preschool language education is a requirement of basic education reform as well as a requirement for children’s growth in all aspects of body and mind. It is extremely important and valuable in encouraging the entire growth of preschool education as well as children’s general harmonious development. The degree of informatization is changing day by day, and many information technology concepts and tools have entered the preschool education field. The Internet, electronic school bags, ECE whiteboards, terminal devices, and rich digital resources and tools have been introduced into kindergarten classrooms. The continuous advancement and application of information technology have provided the feasibility of building a smart learning environment for kindergartens. To this end, this paper starts from the core concepts and theoretical foundations of preschool education and sorts out the concepts of learning resources, smart learning, and smart learning environments. Learning theory, teaching theory, and activity theory provide the theoretical foundation for the creation of language learning tools in preschool education. The technologies of campus network, Internet of Things, artificial intelligence, and rich media are examined under the role and inspiration of smart learning environment to provide theoretical support for scientific design of smart language learning environment in preschool education.
Design of Machine Learning Algorithm for Tourism Demand Prediction
Authors: Yu Nan , Chen Jiaping
Published: June 2022

Unused hotel rooms, unused event tickets, and unsold items are all examples of wasted expenses and earnings. Governments require accurate tourism demand forecasting in order to make informed decisions on topics such as infrastructure development and lodging site planning; therefore, accurate tourism demand forecasting becomes vital. Artificial intelligence (AI) models such as neural networks and security violation report (SVR) have been used effectively in tourist demand forecasting as a result of the fast advancement of AI. This paper constructs a tourism demand forecasting model based on machine learning on the basis of the existing forecasting model research. The completed work is as follows: (1) It introduces a large number of domestic and foreign literatures on tourism volume forecasting and proposes the research content of this paper. (2) It is proposed to stack the long short-term memory- (LSTM-) based autoencoders deeply, by adopting a hierarchical greedy pretraining method to replace the random weight initialization method used in the deep network and combining this pretraining stage and fine-tuning network together to form the SAE-LSTM prediction model for improving the performance of deep learning models. (3) This paper uses the monthly search engine strength data of city A’s monthly tourist volume and its related influencing factors as the data set; processes the data set to make the model adapt to the data input; uses mean absolute error (MAE), root mean square error (RMSE), MAPE, and other model evaluation indicators; and uses LSTM and the constructed SAE-LSTM model to conduct comparative experiments to predict the number of tourist arrivals in four years. The prediction results of the models proposed in this paper are better than those of the LSTM model. According to the experimental results, the superiority of the proposed LSTM-based unsupervised pretraining method is demonstrated.
Identification of Effective and Nonpromiscuous Antidiabetic Drug Molecules from Penicillium Species
Authors: Saleem Shahzad , Bibi Shabana , Yousafi Qudsia , Hassan Tehzeem , Khan Muhammad Saad , Hasan Mohammad Mehedi , Chopra Hitesh , Moustafa Mahmoud , Al-Shehri Mohammed , Khalid Mohammad , Kabra Atul
Published: June 2022

Diabetes mellitus (DM) is a very common metabolic disorder/disease. The deterioration of β-cells by autoimmune system is the hallmark of this disease. Thioredoxin-Interacting Protein (TXNIP) is responsible for β-cells degradation by T-cells in the pancreas. This protein had been declared a good drug target for controlling DM. Lots of side effects have been reported as a result of long-time consumption of conventional antidiabetic drugs. The development of new and effective drugs with the minimal side effects needs time. TXNIP was selected as a target for Computer-Aided Drug Design. The antidiabetic fungal metabolite compounds were selected from the literature. The compounds were screened for their drug-likeness properties by DruLiTo and DataWarior tools. Twenty-two drug-like fungal compounds were subjected to Quantitative Structure-Activity Relationship (QSAR) analysis by using CheS-Mapper 2.0. The lowest (0.01) activity cliff was found for three compounds: Pinazaphilone A, Pinazaphilone B, and Chermesinone A. The highest value for apol (81.76) was shown by Asperphenamate, while Albonoursin and Sterenin L showed highest score (40.66) for bpol. The lowest value (0.46) for fractional molecular frame (FMF) was calculated for Pinazaphilone A and Pinazaphilone B. TPSA for Pinazaphilone A and Pinazaphilone B was 130.51 Å2.

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was observed for all the twenty-two compounds. Molecular docking of fungal compounds with TXNIP was done by AutoDock Vina. The binding energy for complexes ranged between −9.2 and −4.6 kcal/mol. Four complexes, TXNIP-Pinazaphilone A, TXNIP-Pinazaphilone B, TXNIP-Asperphenamate, and TXNIP-Sterenin L, were selected for MD simulation to find out the best lead molecule. Only one complex, TXNIP-Pinazaphilone B, showed a stable conformation throughout the 80 ns run of MD simulation. Pinazaphilone B derived from the Penicillium species fungi was selected as the lead molecule for development of antidiabetic drug having the least side effects.
Blockchain‐Based IoT‐Enabled System for Secure and Efficient Logistics Management in the Era of IR 4.0
Authors: Ugochukwu Nwosu Anthony , Goyal S. B. , Arumugam Sampathkumar
Published: June 2022

As the global logistics business expands as a result of the industrial 4.0 revolution, logistics operations continue to evolve as new technologies such as IoT, cloud, and big data are deployed. These IoT devices improve the logistics function by boosting real‐time product tracking, improved data collection, smart storage of logistics data, etc. Some of these new technologies present an avenue for cyberattacks on these logistics systems due to their centralized database structure. Logistics operations entail the exchange of private consumer information (name, address, phone number, and bank account information) as well as product information amongst logistics stakeholders (manufacturers, suppliers, transporters, and customers). And the engagement of so many logistics stakeholders creates privacy and security issues for the private information because customer information, as well as product details, are transferred and shared across different logistical stakeholders during the logistics process. It faces unwanted access, which could lead to fraud or the creation of counterfeit products by a bad actor in the system. All of these challenges are significant because logistics data integrity is important for customer satisfaction. The deployment of Blockchain innovation will address these challenges with the application of its special feature such as immutability, efficient cryptography, and distributed decentralized storage system. In this paper, we highlighted the technology that enables smart logistics and reviewed smart logistics, Blockchain, and IoT in logistics; we present the significance of integrating Blockchain and IoT in logistics. We proposed a Blockchain‐based IoT‐enabled system framework for secure and efficient logistics management where logistics data can be captured with the use of IoT sensors, and we also designed and describe the sequence diagram for secured communication between the logistics stakeholder through a smart contract. In conclusion, Blockchain can provide security to logistics data and enhance operational efficiency with its key features.
Finite Element Study on Temperature Field of Underwater Dredging Devices via the Artificial Ground Freezing Method
Authors: Wu Yuwei , Zeng Hui , Hu Jun , Ren Xingyue , Xue Xiang
Published: June 2022

Increased urbanization has led to undesirable increases in the discharge of refuse waste and pollutants in urban and rural rivers. Blockages and river pollution adversely affect navigation and aquatic ecosystems and cause flooding during the flood season. Regular riverbed dredging is essential to protect local ecosystems and maintain waterways’ health. However, the current dredging methods cause secondary pollution during dredging. This study examined a new river dredging method with a parametric analysis of its reliability for different construction environments. ADINA software solved the temperature field model using the finite element method to build a three-dimensional transient heat conduction model. The analysis determined the distribution and development of the temperature field during the freezing process and the effective dredging range of the frozen device. We compared thermal conductivities, specific heat capacities, freezing device sizes, initial ground temperatures, and brine cooling plans to examine the effect of the soil’s thermophysical properties and construction environment on the dredging area of the freezing device.
A Decisive Metaheuristic Attribute Selector Enabled Combined Unsupervised-Supervised Model for Chronic Disease Risk Assessment
Authors: Mishra Sushruta , Thakkar Hiren Kumar , Singh Priyanka , Sharma Gajendra
Published: June 2022

Advanced predictive analytics coupled with an effective attribute selection method plays a pivotal role in the precise assessment of chronic disorder risks in patients. Traditional attribute selection approaches suffer from premature convergence, high complexity, and computational cost. On the contrary, heuristic-based optimization to supervised methods minimizes the computational cost by eliminating outlier attributes. In this study, a novel buffer-enabled heuristic, a memory-based metaheuristic attribute selection (MMAS) model, is proposed, which performs a local neighborhood search for optimizing chronic disorders data. It is further filtered with unsupervised K-means clustering to remove outliers. The resultant data are input to the Naive Bayes classifier to determine chronic disease risks’ presence. Heart disease, breast cancer, diabetes, and hepatitis are the datasets used in the research. Upon implementation of the model, a mean accuracy of 94.5% using MMAS was recorded and it dropped to 93.5% if clustering was not used. The average precision, recall, and F-score metric computed were 96.05%, 94.07%, and 95.06%, respectively. The model also has a least latency of 0.8 sec. Thus, it is demonstrated that chronic disease diagnosis can be significantly improved by heuristic-based attribute selection coupled with clustering followed by classification. It can be used to develop a decision support system to assist medical experts in the effective analysis of chronic diseases in a cost-effective manner.
Seismic Response and Nonlinear Mechanical Characteristics of Bridge Pile Foundation in Yushu Permafrost Area
Authors: Liu Hongwei
Published: June 2022

In order to analyze the application effect of bridge pile foundation in Yushu permafrost area, this paper uses the research methods of theoretical analysis, model testing, and numerical simulation to collect soil samples in the Yushu area, study various indicators of frozen soil, simulate different frozen soil foundations in the Yushu area, and study different seismic waves under the influence of different temperatures. The seismic response mechanism of bridge pile foundations in the Yushu permafrost region under the influence of loading mode, soil material, and single pile in different permafrost regions is analyzed, and the dynamic response and mechanical nonlinear characteristics of displacement and deformation under different seismic forces are obtained. The simulation results show that under the influence of different temperatures, different seismic wave loading methods, and different soil quality single piles, the bridge pile foundation in the Yushu permafrost area has obvious seismic response laws and obvious mechanical nonlinear characteristics. Under the influence of permafrost material, most single piles have response coefficients of between 0 and 1.
Regional Financial Economic Data Processing Based on Distributed Decoding Technology
Authors: Zhang HuiLi
Published: June 2022

To improve the effect of regional financial and economic data processing, this study combines the distributed decoding technology to construct the regional financial data processing system. Furthermore, this study combines the technical characteristics of cooperative communication and unitary space-time codes to design a non-differential distributed space-time code based on cyclic unitary matrix groups. In addition, this study uses the particularity of trigonometric functions to design a non-differential distributed space-time code based on trigonometric functions. Finally, according to the characteristics of the distributed space-time code of trigonometric functions, this study obtains a decoding algorithm with low decoding complexity and uses MATLAB to conduct simulation experiments to verify the financial data processing and economic analysis effect of the system in this study. The experimental analysis results show that the regional financial and economic data processing system based on distributed decoding technology proposed in this study can play an important role in the analysis of financial and economic data.
Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity
Authors: Jansen Aaron P. , Camalier Corinne E. , Stark Cristi , Colburn Nancy H.
Published: June 2022

Programmed cell death 4 (Pdcd4), originally identified as an inhibitor of murine cellular transformation, inhibits protein synthesis by directly interacting with eukaryotic initiation factor 4A (eIF4A) of the translation initiation complex. The relevance of Pdcd4 to a broad range of human cancers derived from multiple tissue sites is unknown. Protein expression patterns from the National Cancer Institute drug-screening panel of 60 human cancer cells (NCI60) were analyzed by Western blot methods and revealed frequent reduction of Pdcd4 protein levels in renal-, lung-, and glia-derived tumors. Greater than mean Pdcd4 protein levels correlated with the antitumor activity of geldanamycin and tamoxifen. Stable expression of antisense PDCD4 significantly reduced the sensitivity of MCF-7 breast cancer cells to geldanamycin and to tamoxifen. Sensitivity to geldanamycin significantly increased in UO-31 renal cancer cells expressing sense PDCD4 cDNA. Increased geldanamycin sensitivity was accompanied by enhanced cell cycle arrest and apoptosis. One primary mode of inactivation of Pdcd4 in human cancers appears to involve down-regulated expression, and this down-regulation causes a decreased sensitivity to geldanamycin cytotoxicity. Thus, up-regulating Pdcd4 expression may be promising for geldanamycin-based combination therapy.
Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts
Authors: Bani Maria Rosa , Nicoletti Maria Ines , Alkharouf Nawal W. , Ghilardi Carmen , Petersen David , Erba Eugenio , Sausville Edward A. , Liu Edison T. , Giavazzi Raffaella
Published: June 2022

We have investigated gene expression profiles of human ovarian carcinomas in vivo during Taxol® (paclitaxel) treatment and observed a difference in expression. Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg/kg of paclitaxel. Therapeutic efficacy was achieved for 1A9, while 1A9PTX22 did not respond. Tumor tissues harvested 4 and 24 h after treatment were evaluated by cDNA microarray against untreated tumors. Paclitaxel caused the modulation of more genes in 1A9 than in 1A9PTX22 tumors, in accordance to their therapeutic response. Most gene expression alterations were detected 24 h after paclitaxel administration and affected genes involved in various biological functions including cell cycle regulation and cell proliferation (CDC2, CDKN1A, PLAB, and TOP2A), apoptosis (BNIP3 and PIG8), signal transduction and transcriptional regulation (ARF1, ATF2, FOS, GNA11, HDAC3, MADH2, SLUG, and SPRY4), fatty acid biosynthesis and sterol metabolism (FDPS, IDI1, LIPA, and SC5D), and IFN-mediated signaling (G1P3, IFI16, IFI27, IFITM1, and ISG15). The modulation of two representative genes, CDKN1A and TOP2A, was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel. We found that the changes in expression level of these genes was strictly associated with the responsiveness to paclitaxel. Our study shows the feasibility of obtaining gene expression profiles of xenografted tumor models as a result of drug exposure. This in turn might provide insights related to the drugs' action in vivo that will anticipate the response to treatment manifested by tumors and could be the basis for novel approaches to molecular pharmacodynamics.
Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo
Authors: Laurent Nathalie , de Boüard Sophie , Guillamo Jean-Sébastien , Christov Christo , Zini Roland , Jouault Hélène , Andre Patrice , Lotteau Vincent , Peschanski Marc
Published: June 2022

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
Novel peptide ligands for integrin α4β1 overexpressed in cancer cells
Authors: Mikawa Masahito , Wang Henry , Guo Linlang , Liu Ruiwu , Marik Jan , Takada Yoshikazu , Lam Kit , Lau Derick
Published: June 2022

Using the “one-bead one-peptide” combinatorial technology, a library of random cyclic octapeptides and nonapeptides, consisting of natural and unnatural amino acids, was synthesized on polystyrene beads. This library was used to screen for peptides that promoted attachment and proliferation of bronchioloalveolar carcinoma cells (H1650), employing a “cell growth on bead” assay. Consensus peptide sequences of cNleDXXXXc and cXNleDXXXXc (where Nle is norleucine) were identified. With alanine scanning and site-directed deletion, a typical ligand consisted of a motif of -NleDI/V/Nle- with two flanking cysteines. These peptide ligands were specific for promoting cell attachment of the H1650 cells and the cells of lymphoid cancers (Jurkat and Raji) but not other selected human cell lines of lung cancer and fibroblast. In an antibody blocking assay, integrin α4β1, which was overexpressed in H1650, Jurkat, and Raji, was identified as a putative receptor for these peptide ligands. Using Chinese hamster ovary cells transfected with either wild-type or mutant integrin α4, a critical binding site for these peptides was localized to the glycine residue at position 190 of integrin α4.
Caspase-mediated apoptosis and caspase-independent cell death induced by irofulven in prostate cancer cells
Authors: Liang Huiyun , Salinas Richard A. , Leal Belinda Z. , Kosakowska-Cholody Teresa , Michejda Christopher J. , Waters Stephen J. , Herman Terence S. , Woynarowski Jan M. , Woynarowska Barbara A.
Published: June 2022

Irofulven (hydroxymethylacylfulvene) is a novel antitumor drug, which acts by alkylating cellular macromolecular targets. The drug is a potent inducer of apoptosis in various types of tumor cells, whereas it is nonapoptotic in normal cells. This study defined molecular responses to irofulven involving mitochondrial dysfunction and leading to death of prostate tumor LNCaP-Pro5 cells. Irofulven caused early (2–5 hours) translocation of the proapoptotic Bax from cytosol to mitochondria followed by the dissipation of mitochondrial membrane potential and cytochrome c release at 4 to 12 hours. These effects preceded caspase activation and during the first 6 hours were not affected by caspase inhibitors. Processing of caspase-9 initiated the caspase cascade at ∼6 hours and progressed over time. The activation of the caspase cascade provided a positive feedback loop that enhanced Bcl-2-independent translocation and cytochrome c release. General and specific caspase inhibitors abrogated irofulven-induced apoptotic DNA fragmentation with the following order of potency: pan-caspase ≥ caspase-9 > caspase-8/6 > caspase-2 > caspase-3/7 > caspase-1/4. Abrogation of caspase-mediated DNA fragmentation failed to salvage irofulven-treated cells from growth inhibition and loss of viability, demonstrating a substantial contribution of a caspase-independent cell death. Monobromobimane, an inhibitor of alternative caspase-independent apoptotic pathway that is mediated by mitochondrial permeability transition, antagonized both apoptosis, measured as phosphatidylserine externalization, and cytotoxicity of irofulven. Collectively, the results indicate that irofulven-induced signaling is integrated at the level of mitochondrial dysfunction. The induction of both caspase-dependent and caspase-independent death pathways is consistent with pleiotropic effects of irofulven, which include targeting of cellular DNA and proteins.
Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro
Authors: Green Shane K. , Francia Giulio , Isidoro Ciro , Kerbel Robert S.
Published: June 2022

Multicellular resistance, a subtype of therapeutic resistance manifested in cancer cells grown as three-dimensional multicellular masses, such as spheroids in vitro and solid tumors in vivo, occurs with respect to a variety of anticancer treatment strategies including chemotherapy, ionizing radiation, and even host-mediated antibody-dependent cellular cytotoxicity. Previous studies from our laboratory have shown that multicellular resistance to chemotherapy demonstrated by aggregates of EMT-6 murine mammary carcinoma cells can be overcome by using hyaluronidase to disrupt intercellular adhesive interactions and associated patterns of protein expression. In this proof of principle study, we explored the concept of antiadhesive chemosensitization in the context of human cancer cells by using a monoclonal antibody to disrupt E-cadherin-mediated cell-cell interactions in multicellular spheroids of HT29 human colorectal adenocarcinoma. In so doing, we found that disruption of E-cadherin-mediated adhesion sensitizes multicellular spheroids of HT29 in vitro to treatment with 5-fluorouracil, paclitaxel, vinblastine, and etoposide but not cisplatin. Furthermore, we have found that antibody-mediated blockage of E-cadherin function leads to decreased expression and activity of protein kinase C α and β1, both of which have previously been implicated in chemoresistance exhibited by HT29 cells; however, we have found that the chemosensitization effects of the anti-E-cadherin antibody are independent of its influence on protein kinase C β1.
Regulation of Vinca alkaloid-induced apoptosis by NF-κB/IκB pathway in human tumor cells
Authors: Huang Yi , Fang Yong , Wu Jinmin , Dziadyk Jennifer M. , Zhu Xueming , Sui Meihua , Fan Weimin
Published: June 2022

Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere with the dynamics of microtubules and have shown significant cell killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In this study, we found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis without affecting G2-M arrest in human breast cancer BCap37 cells and human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis may occur via a pathway independent of cell cycle arrest. Further analyses indicated that Vinca alkaloids cause significant degradation of IκBα, which in turn results in nuclear factor-κB (NF-κB) activation. Transfection of antisense IκBα in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IκB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IκBα, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-κB activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-κB/IκB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells.
The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo
Authors: Kamat Ashish M. , Karashima Takashi , Davis Darren W. , Lashinger Laura , Bar-Eli Menashe , Millikan Randall , Shen Yu , Dinney Colin P. N. , McConkey David J.
Published: June 2022

Bortezomib (PS-341, Velcade) is a dipeptidyl boronic acid inhibitor of the 20S proteasome that was developed as a therapeutic agent for cancer. Here, we investigated the effects of bortezomib on the growth of human 253JB-V bladder cancer cells. Although the drug did not stimulate significant increases in levels of apoptosis, it inhibited cell growth in a concentration-dependent fashion and augmented the growth inhibitory effects of gemcitabine in vitro. These effects were associated with accumulation of p53 and p21 and suppression of cyclin-dependent kinase 2 activity. Bortezomib also inhibited secretion of the proangiogenic factors matrix metalloproteinase-9, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF). In vivo studies with 253JB-V tumors growing in nude mice demonstrated that bortezomib (1 mg/kg) did not inhibit tumor growth when it was delivered as a single agent, although it reduced tumor microvessel density and inhibited expression of VEGF and IL-8. However, combination therapy with bortezomib plus gemcitabine produced synergistic tumor growth inhibition associated with strong suppression of tumor cell proliferation. Together, our results demonstrate that bortezomib has significant antiproliferative activity in aggressive bladder cancer cells, which is best exploited within the context of combination chemotherapy.
Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
Authors: Ikeda Takashi , Nakata Yukiko , Kimura Fumihiko , Sato Ken , Anderson Kenneth , Motoyoshi Kazuo , Sporn Michael , Kufe Donald
Published: June 2022

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-l-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.
Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy
Authors: Dowlati Afshin , Nethery David , Kern Jeffrey A.
Published: June 2022

Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.
Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma
Authors: Ozvaran Mustafa K. , Cao Xiaobo X. , Miller Steven D. , Monia Brett A. , Hong Waun Ki , Smythe W. Roy
Published: June 2022

Objective: Malignant pleural mesothelioma (MPM) is resistant to both conventional chemotherapy and apoptosis. The bcl-2 family proteins are major determinants of apoptotic homeostasis. MPM lines and tumors routinely overexpress the anti-apoptotic protein BCL-XL. We have previously shown that antisense inhibition of BCL-XL in MPM cells leads to apoptosis. We sought to determine whether antisense oligonucleotides directed at the bcl-xl gene product would augment response to a conventional chemotherapeutic agent in human mesothelioma cell lines.

Methods: The human MPM cell lines REN and I-45 were exposed to two bcl-xl antisense oligonucleotides (15999, 16009) and one sense oligonucleotide (113529) construct at varying doses, followed by IC50 cisplatin. Cellular viability was assessed by a calorimetric assay, and apoptosis was evaluated by Hoechst staining, Annexin V staining, and sub-G1 fluorescence-activated cell sorter analysis. Western blot analysis of BCL-2 family proteins was performed following single agent and combined treatment. Isobologram mathematical analysis was used to determine whether or not combination therapies were additive or synergistic.

Results: Cell viability was most affected with the 15999 antisense oligonucleotides plus IC50 cisplatin combination (70% of I-45 and 90% of REN cells killed), and apoptosis was markedly increased with this combination by all measures. Western blot demonstrated 15999 antisense oligonucleotides construct down-regulation of BCL-XL, but no further effect on expression of BCL-2 proteins with cisplatin. Isobologram analysis demonstrated 15999 + cisplatin synergistic effect.

Conclusions: Exposure of human MPM cells to bcl-xl antisense oligonucleotides sensitizes human mesothelioma cells to the conventional chemotherapeutic agent cisplatin. Similar approaches using a combination of molecular and conventional treatment may have clinical utility for this tumor.
Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen
Authors: Lupold Shawn E. , Rodriguez Ronald
Published: June 2022

The prostate-specific membrane antigen (PSMA) is a well-characterized surface antigen, overexpressed in the most advanced, androgen-resistant human prostate cancer cells. We sought to exploit PSMA cell surface properties as a target for short peptides that will potentially guide protein-based therapeutics, such as viral vectors, to prostate cancer cells. Two separate phage display peptide strategies were applied, in parallel, to purified PSMA protein bound to two separate substrates. We reasoned that peptide sequences common to both substrate selections would be specific binders of PSMA. Additionally, the design allowed for stringent cross-selections, where phage populations from one selection condition could be applied to the alternative substrate. These strategies resulted in a series of phage displayed peptides able to bind to PSMA by ELISA and direct binding assays, both with purified protein and in prostate cancer cells. Cell binding is competitively inhibited by purified PSMA. The synthesized peptides are capable of enhancing PSMA carboxypeptidase enzymatic activity, suggesting protein folding stabilization. The discovery of these peptides provides the foundation for subsequent development of peptide targeted therapeutics against prostate cancer.
Hypoxia inducible factor-1α as a cancer drug target
Authors: Powis Garth , Kirkpatrick Lynn
Published: June 2022

The hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is an important regulator of the growing tumor's response to hypoxia. HIF-1 activity in tumors depends on the availability of the HIF-1α subunit, the levels of which increase under hypoxic conditions and through the activation of oncogenes and/or inactivation of tumor suppressor genes. HIF-1 activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Increased tumor HIF-1α has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1α as a cancer drug target. A number of anticancer agents have been reported to decrease HIF-1α or HIF-1 transactivating activity in cells in culture. However, more relevant to the agents' antitumor activity is whether HIF-1 is inhibited in tumors in vivo. This has been demonstrated for only a few of the reported HIF-1 inhibitors. Some of the agents are moving toward clinical trial where it will be important to demonstrate that the agents inhibit HIF-1α in patient tumors or, failing this, the downstream consequences of HIF-1 inhibition such as decreased vascular endothelial growth factor formation, and relate this inhibition to antitumor activity. Only in this way will it be possible to determine if HIF-1α is a valid cancer drug target in humans.
Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition
Authors: Wang Dong , Luo Meihua , Kelley Mark R.
Published: June 2022

Osteosarcoma is the most common highly malignant bone tumor with primary appearance during the second and third decade of life. It is associated with a high risk of relapse, possibly resulting from a developed resistance to chemotherapy agents. As a means to overcome osteosarcoma tumor cell resistance and/or to sensitize tumor cells to currently used chemotherapeutic treatments, we examined the role of human apurinic endonuclease 1 (APE1) in osteosarcoma tumor cell resistance and prognosis. Sixty human samples of archived conventional (intramedullary) osteosarcoma were analyzed. APE1 protein was elevated in 72% of these tissues and among those with a known clinical outcome, there was a significant correlation between high APE1 expression levels and reduced survival times. The remaining 28% of samples showed low expression of APE1. Given that APE1 was overexpressed in osteosarcoma, we decreased APE1 levels using silencing RNA (siRNA) targeting technology in the osteosarcoma cell line, human osteogenic sarcoma (HOS), to enhance chemo- and radiation sensitivity. Using siRNA targeted technology of APE1, protein levels were reduced by more than 90% within 24 hours, remained low for 72 hours, and returned to normal levels at 96 hours. There was also a clear loss of APE1 endonuclease activity following APE1-siRNA treatment. A decrease in APE1 levels in siRNA-treated human osteogenic sarcoma cells led to enhanced cell sensitization to the DNA damaging agents: methyl methanesulfonate, H2O2, ionizing radiation, and chemotherapeutic agents. The findings presented here have both prognostic and therapeutic implications for treating osteosarcoma. The APE1-siRNA results demonstrate the feasibility for the therapeutic modulation of APE1 using a variety of molecules and approaches.
SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility
Authors: Hjelmeland Mark D. , Hjelmeland Anita B. , Sathornsumetee Sith , Reese Elizabeth D. , Herbstreith Michael H. , Laping Nicholas J. , Friedman Henry S. , Bigner Darell D. , Wang Xiao-Fan , Rich Jeremy N.
Published: June 2022

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-β2 ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-β in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-β receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-β signaling, with decreased TGF-β–mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-β-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-β–mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-β receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.
Preclinical validation of anti-TMEFF2-auristatin E–conjugated antibodies in the treatment of prostate cancer
Authors: Afar Daniel E.H. , Bhaskar Vinay , Ibsen Eric , Breinberg Danna , Henshall Susan M. , Kench James G. , Drobnjak Marija , Powers Rick , Wong Melanie , Evangelista Ferdinand , O'Hara Chris , Powers David , DuBridge Robert B. , Caras Ingrid , Winter Ruth , Anderson Terri , Solvason Nanette , Stricker Phillip D. , Cordon-Cardo Carlos , Scher Howard I. , Grygiel John J. , Sutherland Robert L. , Murray Richard , Ramakrishnan Vanitha , Law Debbie A.
Published: June 2022

Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor–like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B–sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
Use of Freeze-dried Watercress for Detoxification of Carcinogens and Toxicants in Smokers: Implications of the Findings and Potential Opportunities
Authors: El-Bayoumy Karam , Stoner Gary
Published: June 2022

Bonorden and colleagues designed a clinical trial to test the hypothesis that daily consumption of freeze-dried watercress, a rich source of the chemopreventive agent phenethyl isothiocyanate, can enhance the detoxification of well-known tobacco and environmental carcinogens and toxicants. Initial results have validated subject compliance and a positive outcome of this study would further support the use of watercress as a whole food-based approach to cancer chemoprevention. On the basis of the design of the clinical trial and the various biological samples to be collected, we discuss potential opportunities to test future hypotheses.

See related article, p. 143
Accuracy and Reproducibility of Myocardial Blood Flow Quantification by Single Photon Emission Computed Tomography Imaging in Patients With Known or Suspected Coronary Artery Disease
Authors: de Souza Ana Carolina do A.H. , Harms Hendrik J. , Martell Laurel , Bibbo Courtney , Harrington Meagan , Sullivan Kyle , Hainer Jon , Dorbala Sharmila , Blankstein Ron , Taqueti Viviany R. , Foley Kijewski Marie , Park Mi-Ae , Meretta Alejandro , Breault Christopher , Roth Nathaniel , Poitrasson-Rivière Alexis , Soman Prem , Gullberg Grant T. , Di Carli Marcelo F.
Published: June 2022

Background:

Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate
99m
Tc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with
13
N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique.

Methods:

Accuracy was assessed in 34 participants who underwent dynamic
99m
Tc-sestamibi SPECT and
13
N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2
99m
Tc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model‚ and MFR was derived as the stress/rest MBF ratio.

Results:

SPECT global MBF with splines showed good correlation with
13
N-ammonia positron emission tomography (r=0.81,
P
<0.001) and MFR estimates (r=0.74,
P
<0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61,
P
<0.001 and r=0.34,
P
=0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77,
P
<0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68,
P
<0.001) and MFR correlations (r=0.33,
P
=0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm (
P
>0.05 for all).

Conclusions:

MBF and MFR quantification using
99m
Tc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with
13
N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.
Endothelial Natriuretic Peptide Receptor 1 Play Crucial Role for Acute and Chronic Blood Pressure Regulation by Atrial Natriuretic Peptide
Authors: Tokudome Takeshi , Otani Kentaro , Mao Yuanjie , Jensen Lars Jørn , Arai Yuji , Miyazaki Takahiro , Sonobe Takashi , Pearson James T. , Osaki Tsukasa , Minamino Naoto , Ishida Junji , Fukamizu Akiyoshi , Kawakami Hayato , Onozuka Daisuke , Nishimura Kunihiro , Miyazato Mikiya , Nishimura Hirohito
Published: June 2022

Background:

ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP.

Methods and Results:

Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specific
Npr1
–knockout mice but not in endothelial cell–specific
Npr1
–knockout mice. Moreover, ANP significantly lowered systolic blood pressure in
Nos3
-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca
2+
concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased
Rgs2
mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in
Rgs2
-knockout mice. Endothelial cell–specific
Npr1
-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography.

Conclusions:

Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.