bluuebunny/crossref_metadata_2025 huggingface dataset:
Equipment for in situ measurement of machining defects of large aperture optical elements
Authors: Tie Guipeng , Zhou Haifeng , Shi Feng , Chen Jian , Qiao Shuo , Tian Ye , Song Ci
Published: June 2022

A set of in situ measurement equipment of large aperture strong light element based on the principle of laser scattering is established. The size and distribution of defects (damage points) can be judged by the laser scattering signal. The maximum scanning range is 700 mm*1000 mm. The type and size of defects are directly obtained by scanning the quartz sample with a diameter of 100 mm. The types of defects are pitting and scratches, and the width of the scratches and the diameter of the pitting are mostly in the range of 0–10μm. The processing time could reach 31.06s. The device can realize the on‐line in situ measurement of large aperture optical elements, and has the advantages of fast response speed and high measurement accuracy.
Connecting the dots: social networks in the classroom and white matter connections in the brain
Authors: Mulder Rosa H. , López‐Vicente Mónica , Cortes Hidalgo Andrea P. , Steenkamp Lisa R. , Güroğlu Berna , Tiemeier Henning , Muetzel Ryan L.
Published: June 2022

Background

Peer connections in school classrooms play an important role in social–emotional development and mental health. However, research on the association between children's peer relationships and white matter connections in the brain is scarce. We studied associations between peer relationships in the classroom and white matter structural connectivity in a pediatric population‐based sample.

Methods

Bullying and victimization, as well as rejection and acceptance, were assessed in classrooms in 634 children at age 7. White matter microstructure (fractional anisotropy (FA), mean diffusivity (MD)) was measured with diffusion tensor imaging at age 10. We examined global metrics of white matter microstructure and used Tract‐Based Spatial Statistics (TBSS) for voxel‐wise associations.

Results

Peer victimization was associated with higher global FA and lower global MD and peer rejection was associated with lower global MD; however, these associations did not remain after multiple testing correction. Voxel‐wise TBSS results for peer victimization and rejection were in line with global metrics both in terms of direction and spatial extent of the associations, with associated voxels (pFWE <.05) observed throughout the brain (including corpus callosum, corona radiata, sagittal stratum and superior longitudinal fasciculi).

Conclusions

Although based only on cross‐sectional data, the findings could indicate accelerated white matter microstructure maturation in certain brain areas of children who are victimized or rejected more often. However, repeated measurements are essential to unravel this complex interplay of peer connections, maturation and brain development over time.
Emerging from the shadows: Digital stories of self‐advocates with intellectual disabilities
Authors: Ellem Kathy , Harris Paul , Strnadová Iva
Published: June 2022

People with intellectual disabilities tend to be subjugated to social roles which make them feel invisible and misunderstood. This study examines the digital stories of self‐advocates with intellectual disabilities and explores their experiences of becoming leaders. The digital stories of self‐advocates show how people made themselves visible and heard to others through their individual questioning, forming important alliances and collective achievements. Their stories, articulated through the digital platform, were analysed using constructivist grounded theory. These digital stories demonstrated how individual self‐advocates overcame adversity and found ways to have their voices heard and personal problems addressed. Each self‐advocate possessed the insight to question unfair treatment and discrimination, and in turn was strengthened in their efforts to make change by becoming involved in a self‐advocacy group. Self‐advocacy can nurture both individual leadership capacities in people with intellectual disabilities and facilitate a safe space for people to come together, support one another and make positive change. Digital stories can illustrate how people with intellectual disabilities become self‐advocates. The use of this technology has the potential to strengthen advocacy efforts.
Surprising partners: Teachers' contribution to school bullying
Authors: Zioni‐Koren Vered , Gumpel Thomas P. , Bekerman Zvi
Published: June 2022

Participant role theory describes the designation of social roles and the use of contextually appropriate social scripts and provides a context for the interpretation of a range of social and interpersonal issues, including bullying in the school setting. This study uses participant role theory to analyze interpersonal engagements in a 10th grade class in a high school in central Israel. Data were drawn from ethnographic observations conducted by the first author of the cohort over the course of a school year, together with in‐depth semi‐structured interviews with the students and teachers. The findings suggest that students apply “role switching” (the flexible presentation of multiple social roles, depending on context) to negotiate the challenge of bullying in the school setting. The study also assesses the influence of individual teachers on role switching, positing that a teacher's relationship with individual students can serve as a catalyst for role‐switching in three specific circumstances: where the teacher–student relationship instigates bullying against a specific child; where the teacher is a bully; and where a supportive relationship enables positive role‐switching on the part of specific classroom actors. These findings have theoretical and applied significance in both pre‐ and in‐service training for teachers and school administrative staff.
A Novel Energy Storage System Based on Carbon Dioxide Unique Thermodynamic Properties
Authors: Astolfi Marco , Rizzi Dario , Macchi Ennio , Spadacini Claudio
Published: June 2022

This paper focuses on the thermodynamic performance and techno-economic assessment of a novel electrical energy storage technology using carbon dioxide as a working fluid. This technology, named CO2 battery and recently patented by Energy Dome SpA., addresses an energy market which has a great need for energy storage solutions able to handle the increasing share of nondispatchable renewable energy sources like photovoltaic and wind energy. After a brief introduction, the present study presents the concept of CO2 batteries and their operation. Then the detailed numerical model developed for the accurate calculation of system round trip efficiency is presented with the adopted assumptions and the optimization routine description. Results on the reference case and following sensitivity analysis confirm a round trip efficiency of around 77% (±2%) which makes CO2 batteries a very promising technology with respect to other energy storage systems based on thermodynamic cycles like compressed air and liquid air energy storage thanks to the high performance and the easiness of installation. Finally, calculation of system footprint, capital investment cost and levelized cost of storage are discussed.
One new genus and two new species of eriophyoid mites (Acari: Eriophyoidea) from South China
Authors: Qin Fengping , Yang Juan , Wang Guoquan
Published: June 2022

One new genus and two new species of eriophyoid mites from South China are described and illustrated: Epicecidophyes cinnamomi sp. nov. infesting Cinnamomum camphora (L.) J. Presl (Lauraceae) belongs to the subfamily Cecidophyinae and Fairina dimocarpi gen. nov. & sp. nov. infesting Dimocarpus longan Lour. (Sapindaceae) belongs to the subfamily Phyllocoptinae. Both new species are vagrants causing no apparent damage to their host plants.
Coactivation of antagonistic genes stabilizes polarity patterning during shoot organogenesis
Authors: Guan Chunmei , Qiao Lingxia , Xiong Yuanyuan , Zhang Lei , Jiao Yuling
Published: June 2022

Spatiotemporal patterns of gene expression are instrumental to morphogenesis. A stable pattern interface, often between reciprocal-inhibiting morphogens, must be robustly maintained after initial patterning cues diminish, organ growth, or organ geometry changes. In plants, floral and leaf primordia obtain the adaxial-abaxial pattern at the shoot apical meristem periphery. However, it is unknown how the pattern is maintained after primordia have left the shoot apex. Here, through a combination of computational simulations, time-lapse imaging, and genetic analysis, we propose a model in which auxin simultaneously promotes both adaxial and abaxial domains of expression. Furthermore, we identified multilevel feedback regulation of auxin signaling to refine the spatiotemporal patterns. Our results demonstrate that coactivation by auxin determines and stabilizes antagonistic adaxial-abaxial patterning during aerial organ formation.
Prospective Study of the Detection of Bacterial Pathogens in Pediatric Clinical Specimens Using the Melting Temperature Mapping Method
Authors: Uejima Yoji , Suganuma Eisuke , Ohnishi Takuma , Takei Haruka , Furuichi Mihoko , Sato Satoshi , Kawano Yutaka , Kitajima Isao , Niimi Hideki
Published: June 2022

This study provides novel insights regarding the use of the melting temperature (

T
m

) mapping method to identify the dominant bacteria in samples collected from pediatric patients. We designed a new set of primers for commercial use and developed a database of different bacteria that can be identified using these primers.
Host Age Prediction from Fecal Microbiota Composition in Male C57BL/6J Mice
Authors: Low Adrian , Soh Melissa , Miyake Sou , Seedorf Henning
Published: June 2022

The gut microbiome of a host changes with age. Cross-sectional studies demonstrate that microbiota of different age groups are distinct but do not demonstrate the temporal change that a longitudinal study is able to show. Here, we performed a longitudinal study of adult mice for over 2 years.
Comparison of biodegradable and durable polymer drug-eluting stents in acute coronary syndrome: a meta-analysis
Authors: Yuan Haoyong , Wu Zhongshi , Lu Ting , Wei Tingting , Zeng Yifan , Liu Yalin , Huang Can
Published: June 2022

Objective

To compare the safety and effectiveness between biodegradable polymer drug-eluting stents (BP-DES) and durable polymer drug-eluting stents (DP-DES) in patients with acute coronary syndrome (ACS).

Design

Meta-analysis of randomised controlled trials (RCTs).

Primary and secondary outcome measures

Major adverse cardiovascular events (MACEs) were considered the primary endpoint. Efficacy endpoints included target vessel revascularisation (TVR) and target lesion revascularisation (TLR). Safety endpoints included all-cause death, cardiac death, target vessel myocardial infarction and stent thrombosis (ST).

Methods

We searched PubMed, Medline, Embase and the Cochrane Controlled Register of Trials for comparative studies of BP-DES and DP-DES in patients with ACS from January 2000 to July 2021. Statistical pooling was performed to estimate incidence using a random-effects model with generic inverse-variance weighting. Risk estimates were computed with 95% CIs.

Results

Eight articles with seven RCTs that compared BP-DES and DP-DES in patients with ACS were identified and included in the qualitative and quantitative analyses. There was no difference in the baseline characteristics, except for the number of smoking patients (OR: 1.13, 95% CI 1.03 to 1.24; p=0.008, I2=29%), which was significantly lower in the BP-DES group. The meta-analysis demonstrated that MACEs, efficacy endpoints and safety endpoints were similar between the groups at 1 year. However, the incidence of total ST was signiﬁcantly different between the BP-DES and DP-DES groups in the follow-up period (p=0.0001). Further analysis showed a statistically significant difference in MACEs (OR: 0.71, 95% CI 0.57 to 0.88; p=0.002, I2=0 %), TLR (OR: 0.71, 95% CI 0.51 to 1.01; p=0.05, I2=0%), TVR (OR: 0.70, 95% CI 0.52 to 0.94; p=0.002, I2=15%), total ST incidence (OR: 0.59, 95% CI 0.46 to 0.77; p=0.0001, I2=48%) and ST incidence (OR: 0.63, 95% CI 0.47 to 0.85; p=0.002, I2=0%) over 2 years.

Conclusion

This meta-analysis revealed that both stent types demonstrated excellent safety and efficacy profiles at 12 months. However, a slight increase in MACEs, TLR, TVR and ST incidence was observed in the DP-DES group over the 2-year follow-up period, suggesting that BP-DES may be more favourable when treating patients with ACS.

Trial registration number

NCT00389220.
Effect of non-pharmacological interventions for overweight/obese women with polycystic ovary syndrome on ovulation and pregnancy outcomes: a protocol for a systematic review and network meta-analysis
Authors: Yang Han , Xiao Yan-qun , Liu Jia-jia , Xu Gui-xing , Li Juan , Xiao Zhi-yong , Zhou Jun , Zheng Xiao-yan , Liu Li-ying , Yu Zheng , Yang Jie , Liang Fan-rong
Published: June 2022

Introduction

Most overweight/obese women with polycystic ovary syndrome (PCOS) have infertility issues which are difficult to treat. Non-pharmacological interventions used for the management of infertility include lifestyle interventions, acupuncture therapies and nutritional supplements. These interventions have been reported to be beneficial in alleviating infertility among overweight women with PCOS. However, effect and safety of these non-pharmacological interventions vary, and there is no standard method of clinical application. Therefore, it is necessary to conduct a systematic review and network meta-analysis (NMA) to rank these non-pharmacological interventions in terms of effect and determine which one is more effective for clinical application.

Methods and analysis

We will retrieve eight databases including Cochrane Library, Medline, Embase, PsycINFO, Chinese National Knowledge Infrastructure, WanFang Data, the Chongqing VIP Database and China Biology Medicine disc from their inceptions onwards. In addition, four clinical trial registries and the related references will be manually retrieved. The primary outcome will be clinical pregnancy. Live birth, ovulation, pregnancy loss, multiple pregnancy and adverse events related to interventions will be considered as the secondary outcomes. STATA software V.15.0 and Aggregate Data Drug Information System V.1.16.8 will be used to conduct pairwise meta-analysis and NMA. The Grading of Recommendations Assessment, Development and Evaluation system will be adopted to evaluate the certainty of evidence.

Ethics and dissemination

Ethical approval will not be required because the study will not include the original information of participants. The results will be published in a peer-reviewed journal or disseminated in relevant conferences.

PROSPERO registration number

CRD42021283110.
What are the gaps in cardiovascular risk assessment and management in primary care for Māori and Pacific people in Aotearoa New Zealand? Protocol for a systematic review
Authors: Brewer Karen Marie , Grey Corina , Paynter Janine , Winter-Smith Julie , Hanchard Sandra , Selak Vanessa , Ameratunga Shanthi , Harwood Matire
Published: June 2022

Introduction

In New Zealand, significant inequities exist between Māori and Pacific peoples compared with non-Māori, non-Pacific peoples in cardiovascular disease (CVD) risk factors, hospitalisations and management rates. This review will quantify and qualify already-reported gaps in CVD risk assessment and management in primary care for Māori and Pacific peoples compared with non-Māori/non-Pacific peoples in New Zealand.

Methods and analysis

We will conduct a systematic search of the following electronic databases and websites from 1 January 2000 to 31 December 2021: MEDLINE (OVID), EMBASE, Scopus, CINAHL Plus, NZresearch.org, National Library Catalogue (Te Puna), Index New Zealand (INNZ), Australia/New Zealand Reference Centre. In addition, we will search relevant websites such as the Ministry of Health and research organisations. Data sources will include published peer reviewed articles, reports and theses employing qualitative, quantitative and mixed methods.

Two reviewers will independently screen the titles and abstracts of the citations and grade each as eligible, not eligible or might be eligible. Two reviewers will read each full report, with one medically qualified reviewer reading all reports and two other reviewers reading half each. The final list of included citations will be compiled from the results of the full report reading and agreed on by three reviewers. Data abstracted will include authors, title, year, study characteristics and participant characteristics. Data analysis and interpretation will involve critical inquiry and a strength-based approach that is inclusive of Māori and Pacific values. This means that critical appraisal includes an assessment of quality from an Indigenous perspective.

Ethics and dissemination

Ethical approval is not required. The findings will be published in a peer-reviewed journal and shared with stakeholders. This review contributes to a larger project which creates a Quality-Improvement Equity Roadmap to reduce barriers to Māori and Pacific peoples accessing evidence-based CVD care.
Particle detection in rare gas solid crystals: a feasibility experimental study—exploring new ways for dark matter searches
Authors: Guarise Marco
Published: June 2022

This article reviews the experimental activity that has been carried out within the INFN DEMIURGOS research and development (R &D) project. This R &D concerns the study of possible innovative experimental approaches for the detection of low-energy-releases of feeble interacting particles within the matter. Possible applications could be the direct investigation of Dark Matter candidates. The idea behind the proposed scheme is to exploit rare gas solid crystals both pure and doped, combined with the in-vacuum single electron detection technology. In pure materials, the signal can be the charge produced directly during the ionization. Laser-assisted processes can instead be used to probe low-energy-releases in doped materials. Both these mechanisms should lead to a detectable electronic signal triggered by the incoming particle. In such a way, energy threshold ranging from meV to tens of eV could in principle be reached, opening-up the possibility to probe theoretically, well-motivated regions of unexplored electroweak parameter-space and thus test the existence of light Dark Matter candidates. The activity presented here has been performed to understand the mechanisms at the basis of the proposed detection scheme and possible showstopper. The experimental investigations refer to the research and development phases about: the crystal growing techniques and the corresponding set-up, the electrons’ extraction from rare gas crystals to the vacuum environment, and finally the spectroscopic studies on atomic species embedded into rare gas matrices.
Algorithm for Swimmers’ Starting Posture Correction Based on Kinect
Authors: Chang Zheng , Zhao Yu
Published: June 2022

Effective identification and correction of swimmers’ improper postures can significantly improve athletes’ weekday swimming training quality. The human body’s affine deformation is prone to occur during swimming movements when performing posture recognition and correction, resulting in the creation of low-brightness action feature locations. The inability of coaches to identify and correct athletes’ improper posture in real time is a result of a lack of detection and correction. Additionally, the human skeleton motion data from the depth camera Kinect contains a high amount of noise and fewer skeleton nodes, and the data level of detail is low. To overcome this issue, this research proposes a network for enhancing Kinect skeleton motion data. The network is composed of six bidirectional cyclic autoencoder stacks. The stacking structure improves the smoothness and naturalness of the data, and the training phase includes hidden variable limitations to ensure that the bone motion data preserve a genuine bone shape when the degree of detail is raised. The trials demonstrate that the optimized data from the network have a better degree of smoothness and can keep a more realistic bone structure, enabling the goal of obtaining high-precision motion capture data with low-precision Kinect equipment to be met.
Dance Fitness Action Recognition Method Based on Contour Image Spatial Frequency Domain Features and Few-Shot Learning
Authors: Chi Qinglong , Li Lifeng
Published: June 2022

In recent years, the research work of artificial intelligence technology has progressed rapidly, and various classic Few-Shot learning models have achieved unprecedented success in many artificial intelligence application fields. These include face recognition, object classification detection and tracking, speech recognition, and natural language processing, which greatly facilitate our lives. This paper aims to identify dance fitness movements based on contour image spatial frequency domain features and Few-Shot learning technology. This paper proposes a Few-Shot learning method based on contrastive average loss for Few-Shot learning. This method makes the learned model more representative by improving the loss function and performing a normalization process, and it proposes a feature extraction algorithm that combines improved LBP and HOG for action recognition technology. The experimental results show that the recognition accuracy of the algorithm in this paper is 93.10%, 90.30%, and 92.70% for walking, opening hands, and running, respectively. This illustrates the effectiveness of the fusion feature algorithm.
Evaluating A’s of Big Data for Transformation of Smart Cities
Authors: Zhang Jun , Nazir Shah
Published: June 2022

Smart devices and things are widely increasing with the passage of time and with the developments of industrial technology. Various smarts devices such as sensors and actuators are interacting with each other for diverse purposes and specific goals. The role of automation can drastically revolutionize to adopt the things, to automate and accurately access, with cost-efficient resources, and save human time and effort. Data plays a vital role in industries and is the fundamental part of organizations. An efficient system is the dire need of the modern industry to efficiently and accurately assess the A’s of big data for transformation of smart cities. The existing literature was searched for finding the associated materials and to represent them. The current study considers the A’s of big data and with the support of analytic network process (ANP), the same has been evaluated. The approach of ANP works in situation of complexity where decision-making is difficult and challenging. The approach adopted the network hierarchy of goal, criteria, and alternatives for assessing the A’s of big data. Various calculations of the process have been carried out for experiments, and the experimental results show the effectiveness of the proposed research in terms of evaluation of A’s of big data.
Behavior Recognition and Exhibition Tour Scene Classification Using In-Depth Learning
Authors: Ren Xinlu
Published: June 2022

The rapid development of exhibition tourism has led to a sharp increase in the amount of data in the tourism and exhibition industry. Through in-depth mining and application of exhibition tourism data, it can intuitively show its potential relevance and produce much valuable knowledge. The huge value of exhibition tourism data can better meet social needs. Through the analysis of exhibition tourism data, it has certain use-value and significance for the development of the industry. Scene classification in the field of computer vision is a research hotspot. However, there are far few research-related algorithms on mice tourism scene classification. Therefore, based on in-depth learning, this paper studies behavior recognition, and mice tourism scene classification, applies computer vision technology to mice tourism scene classification, collects many visual data, and speeds up the rapid development of the field of vision. In this paper, the scene classification algorithm based on a self-attention generation countermeasure network is constructed to deal with the problem of convention and exhibition tourism. The test results show that the accuracy of the classification results of this algorithm is as high as 99.12%, which is the highest compared with the classification results of other models, which fully proves that this algorithm can accurately classify conventional and exhibition tourism scenes.
Significance of a Tumor Mutation Burden Gene Signature with Prognosis and Immune Feature of Gastric Cancer Patients
Authors: Xiang Li , Lan Chuan
Published: June 2022

Gastric cancer (GC) is a common digestive tumor which ranks the fourth most common malignancy worldwide. Immunotherapy is a promising treatment for GC, especially for advanced gastric cancer (AGC). However, in clinical practice, not all patients are sensitive to immunotherapy. Recent studies showed that tumor mutation burden (TMB) is closely correlated with the response of immunotherapy. The current study identified a TMB-related genes’ signature to predict the prognosis and immune feature of GC patients. Firstly, we acquired the TMB data and expression data from The Cancer Genome Atlas (TCGA) and the National Center for Biotechnology Information (NCBI) GEO databases. Then, we extracted TMB-related genes from the expression data of TCGA and two GEO cohorts. By using univariate Cox analysis, we identified that the 429 genes were correlated to GC patients’ overall survival. Subsequently, an immune prognostic signature was constructed by using the least absolute shrinkage and selection operator analysis (LASSO) and multivariate Cox regression analysis. The signature could be utilized to predict the prognosis of GC patients. In addition, the signature showed a closed correlation with immune feature of GC patients. In conclusion, our risk signature could offer hints for the prognosis of GC patients and might provide insights to formulate new immunotherapy strategies for GC patients.
Novel Analysis of Fuzzy Fractional Emden-Fowler Equations within New Iterative Transform Method
Authors: Al-Sawalha M. Mossa , Amir Naila , Shah Rasool , Yar Muhammad
Published: June 2022

The analytical behavior of fractional differential equations is often puzzling and difficult to predict under uncertainty. It is crucial to develop a robust, extensive, and extremely successful theory to address these problems. An application of fuzzy fractional differential equations can be found in applied mathematics and engineering. Using the iterative transform technique, the study determines the analytic solution of fractional fuzzy Emden-Fowler equation in the sense of the Caputo operator, which is applied to evaluate the physical model range in several scientific and engineering disciplines. The derived solutions to the fractional fuzzy Emden-Fowler equations are more generic and applicable to a broader range of problems. Through the translation of fractional fuzzy differential equations into equivalent crisp systems of fractional differential equations, we obtain a parametric description of the solutions. The graphical and numerical representation demonstrates the symmetry among the upper and lower fuzzy solution representations in their simplest form, which may aid in the comprehension of artificial intelligence, control system models, computer science, image processing, quantum optics, medical science, physics, measure theory, stochastic optimization theory, biology, mathematical finance, and other domains, as well as nonfinancial evaluation.
Research on High-Satisfaction Evaluation of Health-Care Product Design Based on Genetic Optimization Algorithm
Authors: Zhao Yanyun , Xue Yujia
Published: June 2022

This paper proposes a high-satisfaction evaluation method for health-care product design based on the genetic optimization algorithm in order to deeply understand consumers' satisfaction with forest health-care products. This article builds a consumer demand index system for the service content of forest health-care bases from the four levels of environmental conditions, service items, supporting facilities, and service levels. According to the questionnaire survey results of 1000 randomly selected forest health-care consumers, based on the genetic optimization algorithm, the overall design takes the four levels of satisfaction evaluation into account, resulting in a more reasonable evaluation of health-care products. Experiments show that the method proposed in this paper outperforms the traditional method for evaluating health-care products.
The Unmasking Effect: Propofol-Induced Brugada Pattern in a Critically Ill Patient
Authors: Akhigbe Esiemoghie , Ezeh Ebubechukwu , Dao Benjamin , Okoro Kelechukwu , Okhumale Paul
Published: June 2022

Brugada syndrome is a known cause of dysrhythmias and sudden cardiac death. It is linked to mutations in myocardial sodium channel leading to hyperexcitable cardiac myocytes. The use of this sedative has been linked to the development of inducible Brugada via blockade of sodium currents in cardiac myocytes. Although propofol is usually avoided in patients with known Brugada syndrome, some patients might have undiagnosed Brugada syndrome and thus are at risk for complications. We present a case of propofol induced Brugada in a critically ill patient.
Muscle-targetedinterleukin-12gene therapy of orthotopic hepatocellular carcinoma in mice usingin vivoelectrosonoporation
Authors: Yamashita Yo-ichi , Shimada Mitsuo , Minagawa Ryosuke , Tsujita Eiji , Harimoto Norifumi , Tanaka Shinji , Shirabe Ken , Miyazaki Jun-ichi , Maehara Yoshihiko
Published: June 2022

We developed a new potent nonviral gene transfer method into mouse muscles in vivo named “electrosonoporation.” We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-γ and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.
Modulation of p53 in 7,12-dimethylbenz[a]anthracene–induced skin tumors by diallyl sulfide in Swiss albino mice
Authors: Arora Annu , Siddiqui Imtiaz A. , Shukla Yogeshwer
Published: June 2022

Allium vegetables have been shown to have beneficial health effects against several chronic diseases including cancer. Diallyl sulfide (DAS), an organosulfur compound present in garlic, is well known for its chemopreventive properties in several tumor models. The pharmacologic role of DAS in prevention and treatment of cancer is well documented in the literature, but its molecular mechanism of action is not yet well defined. In the present study, modulation in p53 expression by topical application of DAS was recorded in 7,12-dimethylbenz[a]anthracene (DMBA)–induced skin tumors in Swiss albino mice. Western blot analysis and immunohistochemical protein detection, combined with multivariable flow cytometry, show that DAS application induces the expression of the wild-type (wt) p53 and down-regulates the expression of mutant (mut) p53. Immunoblotting analysis of tumors showed significant increase in levels of wtp53 by DAS application, whereas for mutp53 the DMBA-induced levels of protein were found to reduce to near normal levels with DAS application. The quantitative analysis of immunostained skin/tumor sections using image analysis and quantitative stereology showed 66.6% and 54.2% increases in wtp53 levels and 53.4% and 44.3% decreases in mutp53 levels in animals where DAS was applied 1 hour prior to or 1 hour after DMBA application, respectively. Flow cytometric analysis further confirmed modulation of wtp53 and mutp53 protein in DAS-supplemented tumors. The increase in the expression of wt tumor suppressor gene protein p53 was accompanied by elevation of the levels of cyclin-dependent kinase inhibitor p21/waf1. The percentage increase in the levels of p21/waf1 was found to be 72.9% and 61.3%, respectively, in DAS-supplemented groups before and after administration. These results thus show that DAS is a potential chemopreventive agent capable of modulating and regulating the tumor suppressor p53 along with its downstream effective molecule, p21/waf1. Thus, DAS can be a potential chemopreventive agent against skin tumor development.
A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy
Authors: Stein Rhona , Goldenberg David M.
Published: June 2022

A variety of observations have shown that carcinoembryonic antigen (CEA) is associated with growth and metastasis of cancers, including correlation of CEA serum levels with poor clinical outcome, mediation of cell-cell adhesion by CEA, and involvement of CEA in the immune recognition of tumors and apoptotic pathways. The purpose of this study was to investigate the effect that an anti-CEA monoclonal antibody (MAb) may have on the growth of medullary thyroid cancer (MTC), a CEA-expressing tumor, alone and in combination with chemotherapy. Antitumor effects were evaluated in a nude mouse-human MTC xenograft model. Using the TT MTC cell line grown s.c., we compared tumor growth in untreated mice with that of mice given the humanized anti-CEA MAb labetuzumab or an isotype-matched control MAb. The effects of time of administration post-tumor injection, MAb dose response, specificity of response, and combination with dacarbazine (DTIC) chemotherapy were studied. The humanized anti-CEA MAb, labetuzumab, has direct, specific, antitumor effects in this model, without conjugation to a cytotoxic agent. In addition, labetuzumab sensitizes these tumor cells to chemotherapy with an effective drug in this model, DTIC, without increased toxicity. Significant delays in tumor growth were caused by the MAb therapy or chemotherapy alone; however, the combination of these agents was significantly more effective than either agent given as a monotherapy or use of an irrelevant MAb in this model. The superiority of the combined modality treatment argues for the integration of CEA MAb therapy into chemotherapeutic regimens for MTC management and possibly other CEA-expressing neoplasms.
A therapeutic model for advanced endometrial cancer: Systemic progestin in combination with local adenoviral-mediated progesterone receptor expression
Authors: Dai Donghai , Albitar Lina , Nguyen Tan , Laidler Laura L. , Singh Meenakshi , Leslie Kimberly K.
Published: June 2022

Cancer of the uterine endometrium is a frequent gynecologic malignant disease for which few therapeutic options are available for advanced disease. Progesterone is the normal female hormone that limits growth and proliferation of endometrial cancers; however, progesterone receptors are frequently down-regulated, leading to treatment failures. The current studies explored the effectiveness of adenoviral-mediated progesterone receptor gene transduction in combination with progestin therapy in mouse xenograft models. Pretreatment of cells with progesterone receptor–encoding adenovirus and progestin inhibited the development of s.c. tumors in athymic mice. In the i.p. xenograft model, replacement of both isoforms of progesterone receptor, PRA and PRB, in combination with progestin treatment resulted in a significant 2.6-fold increase in overall survival time compared with control animals. These studies indicate that when progesterone receptor levels are maintained, progestin therapy is effective in limiting tumor growth. Future therapeutic regimens targeted at enhancing progesterone receptor expression have the potential to improve outcomes in women with endometrial cancer.
AG490 inhibits G1-S traverse in BALB/c-3T3 cells following either mitogenic stimulation or exogenous expression of E2F-1
Authors: Savell Jason , Ma Yihong , Morrow Kristin S. , Jove Richard , Olashaw Nancy , Moseley Pope L. , Cress W. Douglas , Wharton Walker
Published: June 2022

AG490, a member of the tryphostin family of protein kinase inhibitors, repressed G0-G1 traverse in BALB/c-3T3 cells. While the early induction of STAT activity was repressed by AG490, extracellular signal-regulated kinase (ERK) activation was unaffected and a pattern of gene expression suggested that cells exited G0 in the presence of the inhibitor. Although AG490 did not alter the induction of cyclin D1 protein, neither cyclin D1- nor cyclin D3-associated kinase activity was observed in growth-inhibited cells. Surprisingly, p130 was partially phosphorylated, and E2F3A protein was expressed in mitogen-stimulated AG490-treated cells despite the lack of cyclin D-associated kinase activity. These data suggest that AG490 inhibits a cellular pathway required for mid-G0-G1 traverse that is located after the induction of early processes potentially mediated by E2F (although independent of cyclin D-associated kinase activity) but before the late G1 increase in E2F-dependent transcription. Infection of AG490-treated cells with an E2F-1 adenovirus caused the induction of cyclin A, but could not overcome the drug-induced cell cycle arrest that was coincident with the repression of cyclin-dependent kinase 2 (cdk2)-associated kinase activation. We conclude that cdk2-associated kinase activity is modulated by a cellular process repressed by AG490. Furthermore, this cdk2-associated kinase activity is required for G0-G1 traverse in some role other than the regulation of E2F-dependent transcription.
The nuclear factor κB inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)–induced apoptosis in antiestrogen-resistant breast cancer cells
Authors: Riggins Rebecca B. , Zwart Alan , Nehra Ruchi , Clarke Robert
Published: June 2022

The molecular mechanisms underlying the acquisition of resistance to the antiestrogen Faslodex are poorly understood, although enhanced expression and activity of nuclear factor κB (NFκB) have been implicated as a critical element of this phenotype. The purpose of this study was to elucidate the mechanism by which NFκB up-regulation contributes to Faslodex resistance and to determine whether pharmacologic inhibition of NFκB by the small molecule parthenolide could restore Faslodex-mediated suppression of cell growth. Basal expression of multiple NFκB-related molecules in MCF7-derived LCC1 (antiestrogen-sensitive) and LCC9 (antiestrogen-resistant) breast cancer cells was determined, and cells were treated with Faslodex or parthenolide. The effect of these drugs either singly or in combination was assessed by cell proliferation, estrogen receptor (ER)–dependent transcriptional activation, cell cycle analysis, and apoptosis assays. Expression of the p65 NFκB subunit and the upstream NFκB regulator IκB kinase γ/NFκB essential modulator were increased in the resistant MCF7/LCC9 cells (P = 0.001 and 0.04, respectively). Whereas MCF7/LCC9 cells were unresponsive to Faslodex alone, parthenolide effectively inhibited MCF7/LCC9 cell proliferation and the combination of Faslodex and parthenolide resulted in a 4-fold synergistic reduction in cell growth (P = 0.03). This corresponded to a restoration of Faslodex-induced apoptosis (P = 0.001), with no observable changes in ER-dependent transcription or cell cycle phase distribution. Because parthenolide has shown safety in Phase I clinical trials, these findings have direct clinical relevance and provide support for the design of clinical studies combining antiestrogens and parthenolide in ER-positive breast cancer.
Development of a high-throughput screen for inhibitors of replication protein A and its role in nucleotide excision repair
Authors: Andrews Brooke J. , Turchi John J.
Published: June 2022

The heterotrimeric protein, replication protein A (RPA), is essential for DNA repair and replication. RPA is a viable target in the treatment of cancer as many chemotherapeutic agents act by blocking DNA replication. Furthermore, inhibition of RPA could prove useful in treating cancers that have acquired resistance to DNA damaging agents through enhanced DNA repair mechanisms as has been observed with certain platinum-resistant carcinomas. In an effort to identify inhibitors of RPA, we employed a novel fluorescent reporter and established a homogeneous high-throughput screening assay to measure RPA's DNA binding activity. Using this assay, we have screened a collection of small molecules and determined the effect they have on the RPA-DNA interaction. Of the 2000 compounds screened, 79 scored positive for inhibition of RPA binding activity. Secondary screenings were performed using an electrophoretic mobility shift assay; of the 79 compounds, 9 scored positive and were further characterized in titration experiments to determine the most potent inhibitor, resulting in several compounds showing an IC50 in the low micromolar range. Fluorescence polarization analyses were also performed to determine the mechanism of inhibition for each compound. Validation of the inhibitory activity of selected compounds was verified using in vitro nucleotide excision repair (NER) catalyzed excision of a single cisplatin lesion in a duplex DNA. The identification and use of RPA inhibitors may aid in inhibiting NER activity that could potentially circumvent resistance to certain chemotherapeutic agents as well as be useful in the characterization of RPA and its interaction with DNA.
Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins
Authors: Danam Rebecca P. , Howell Sherie R. , Brent Thomas P. , Harris Linda C.
Published: June 2022

Transcriptional silencing of the DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT) in a proportion of transformed cell lines is associated with methylated CpG hotspots in the MGMT 5′ flank. The goal of the study was to evaluate the mechanism by which CpG methylation of theMGMT promoter region influenced silencing of the gene. Analysis of histone acetylation status in two regions of the promoter using chromatin immunoprecipitation assay showed that a higher level of histone acetylation was associated with expression in three MGMT-expressing cell lines (HeLa CCL2, HT29, and Raji) compared with three MGMT-silenced cell lines (HeLa S3, BE, and TK6). To determine how the modulation of CpG methylation and histone acetylation influenced MGMT expression, we exposed the cells to 5-aza-2′deoxycytidine (5-Aza-dC), inhibitor of DNA methylation, which strongly up-regulated MGMT expression in three MGMT-silenced cell lines whereas trichostatin A, inhibitor of histone deacetylase, weakly induced MGMT. However, combined treatment with 5-Aza-dC and trichostatin A significantly up-regulated MGMT RNA expression to a greater extent than in cells treated with either agent alone suggesting that histone deacetylation plays a role in MGMT silencing but that CpG methylation has a dominant effect. Consistent with enhanced MGMT expression, 5-Aza-dC increased the association of acetylated histone H3 and H4 bound to the MGMT promoter. Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.
Involvement of base excision repair in response to therapy targeted at thymidylate synthase
Authors: Li Li , Berger Sondra H. , Wyatt Michael D.
Published: June 2022

Thymidylate synthase (TS) is an important target of several classes of chemotherapeutic agents. Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure, uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation. Base excision repair (BER) plays a primary role in removing damaged or modified bases from the genome, including uracil. Because of uracil misincorporation, BER is hypothesized to play a role in the cellular response to thymidylate deprivation. In this study, we used murine embryo fibroblasts wild-type or homozygous null for DNA polymerase β (β-pol), which plays a central role in BER. We found that, compared with wild-type, β-pol null cells were resistant to the toxic effects of raltitrexed (Tomudex, ZD1694), a folate inhibitor of TS. There was little difference in TS levels or in TS-ligand complex formation between the cell lines. Furthermore, cells deficient in XRCC1, a scaffold protein for the final steps of BER, were also modestly resistant to raltitrexed compared with XRCC1-proficient cells. Cell cycle analysis revealed that the responses of the wild-type and β-pol null cells were similar during drug exposure. However, following drug removal, the β-pol null cells appeared to resume cell cycle progression more rapidly than the wild-type cells. The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors, and that this role occurs during recovery from TS inhibition.
p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas
Authors: Qin Jian-Zhong , Stennett Lawrence , Bacon Patricia , Bodner Barbara , Hendrix Mary J.C. , Seftor Richard E.B. , Seftor Elisabeth A. , Margaryan Naira V. , Pollock Pamela M. , Curtis Amy , Trent Jeffrey M. , Bennett Frank , Miele Lucio , Nickoloff Brian J.
Published: June 2022

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a γ-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.