bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Data Approach for Short-Term Electricity Demand Forecasting
Authors: Shah Ismail , Jan Faheem , Ali Sajid
Published: June 2022

In today’s liberalized electricity markets, modeling and forecasting electricity demand data are highly important for the effective management of the power system. However, electricity demand forecasting is a challenging task due to the specific features it exhibits. These features include the presence of extreme values, spikes or jumps, multiple periodicities, long trend, and bank holiday effect. In addition, the forecasts are required for a complete day as electricity demand is decided a day before the physical delivery. Therefore, this study aimed to investigate the forecasting performance of models based on functional data analysis, a relatively less explored area in energy research. To this end, the demand time series is first treated for the extreme values. The filtered series is then divided into deterministic and stochastic components. The generalized additive modeling technique is used to model the deterministic component, whereas functional autoregressive (FAR), FAR with exogenous variable (FARX), and classical univariate AR models are used to model and forecast the stochastic component. Data from the Nord Pool electricity market are used, and the one-day-ahead out-of-sample forecast obtained for a whole year is evaluated using different forecasting accuracy measures. The results indicate that the functional modeling approach produces superior forecasting results, while FARX outperforms FAR and classical AR models. More specifically, for the NP electricity demand, FARX produces a MAPE value of 2.74, whereas 6.27 and 9.73 values of MAPE are obtained for FAR and AR models, respectively.
Investigating the Supply and Demand Bias between Media and Audience in the Information Technology Era: Evidence from Data Analysis of Chinese Outreach
Authors: Yang Guoping
Published: June 2022

As an integral part of discourse system, external publicity frequently functions as a useful tool of information release and also an indispensable part effective communication. The existing studies on external publicity concentrate more on the information release of bilateral side, namely, on the side of information issuer, than on the side of information receiver, not to say, the perspective of the supply and demand deviation between media and audience. Based on the questionnaire and in-depth interviews, this paper has investigated the deviations between the information supply of Chinese Media and the information demand of the foreign residents in China, as well as the deviations of the information channels between Chinese Media and foreign residents in China. It is revealed that the factors of age, nationality, occupation, and the length of stay in China have exerted a significant influence on the preference of information needs and also the mode of their access to the information issued by Chinese media. Despite the fact that the current Chinese external publicity could meet the general needs of foreign residents, the awareness of targeted supply of information should be continuously improved. The influence of Chinese media on foreign residents is still limited, even though they undertake the responsibility of information dissemination in China and function as a bridge between China and western world. For this reason, there is still much room for the improvement in the scope of communication concept, communication methods, the media topics, as well as the effect of external publicity.
Random Matrix-Based Multivariate Statistical Analysis of Enterprises in a Distributed Environment Human Resource Management
Authors: Xu Chunbo
Published: June 2022

This paper addresses the design of an enterprise human resource management system due to multivariate statistical analysis computation in a random matrix recommendation algorithm in a distributed scenario. This paper defines multivariate statistical analysis human resource practice (DI-RP). It determines the composition of DI-HRP based on the nature of multivariate statistical analysis and enterprise human resource practice. In addition, the role of DI-HRP in influencing employees’ innovative behaviors is explored based on the theoretical basis of resource conservation theory. This paper mainly develops according to the software development process typical to software engineering, organizes the current business logic of the company, understands the relevant content of the company’s human resource management, conducts requirement research on the human resource department, analyzes the feasibility of system implementation from different perspectives, and finally designs a human resource management system based on B/S architecture on the result of requirement analysis. The technology and tools used in the system were decided on the existing technical architecture of the company. The system design was divided into five modules: personal information management module, work management module, attendance management module, reimbursement management module, and entry/exit management module according to the requirements and finishing process, and each functional module of the system was coded and implemented, respectively. The development tool is PyCharm, and some front-end pages are edited and modified by Visual Studio Code. The Permission model of Django is used to add corresponding permissions for various types of users to ensure the security of the system when running.
Learner Autonomy: Algerian EFL Teachers’ Beliefs
Authors: Boudouaia Azzeddine , Cheriet Henen , Khattala Asma , Hamli Salsabila , Belmamoune Souheila , Ntorukiri Timothy Bariu , Dou Abdelbasset , AL-Qadri Abdo Hasan
Published: June 2022

Learner autonomy represents a consumed subject in the realm of English as a foreign language instruction. Nonetheless, the Algerian literature demonstrates a dearth of research on teachers’ beliefs about learner autonomy in the Algerian Middle school setting. This paper, therefore, examines the beliefs of English as a Foreign Language (EFL) teachers about learner autonomy in Algeria. To this end, quantitative and qualitative data were collected from a sample of 129 Algerian middle school teachers of English as a foreign language. The study deployed a questionnaire in conjunction with an interview for data collection. The questionnaires’ data were numerically analysed using Statistical Package for the Social Sciences (SPPS), while the interviews’ data were analysed qualitatively using coding and theme generation. Findings reveal that teachers often view learner autonomy from psychological and technical orientations, implying that it encompasses the concepts of independence, choice, and collaboration. Additionally, the findings indicate a strong belief in teachers’ roles in promoting learner autonomy as well as in the latter’s role in enhancing the learning process. Furthermore, the findings indicated teachers’ desirability to involve learners in decision-making and assist them in developing skills for learning how to learn outweighs their feasibility. The investigation concluded with some suggestions.
An Enhanced Moth-Flame Optimization with Multiple Flame Guidance Mechanism for Parameter Extraction of Photovoltaic Models
Authors: Wang Zhenyu , Cao Zijian , Liu Chen , Jia Haowen , Tian Feng , Liu Fuxi
Published: June 2022

How to accurately and efficiently extract photovoltaic (PV) model parameters is the primary problem of photovoltaic system optimization. To accurately and efficiently extract the parameters of PV models, an enhanced moth-flame optimization (EMFO) with multiple flame guidance mechanism is proposed in this study. In EMFO, an adaptive flame number updating mechanism is used to adaptively control the flame number, which enhances the local and global exploration capabilities of MFO. Meanwhile, a multiple flame guidance mechanism is designed for the full use of the position information of flames, which enhances the global diversity of the population. The EMFO is evaluated with other variants of the MFO on 25 benchmark functions of CEC2005, 28 functions of CEC2017, and 5 photovoltaic model parameter extraction problems. Experimental results show that the EMFO has obtained a better performance than other compared algorithms, which proves the effectiveness of the proposed EMFO. The method proposed in this study provides MFO researchers with ideas for adaptive research and making full use of flame population information.
Effect of CDCA5 on Proliferation and Metastasis of Triple Negative Breast Cancer Cells under shRNA Interference Technology
Authors: Li Yilin , Peng Wei , Deng Yunfang , Heng Jianfu , Yang Yang , Jin Xia , Li Jigang , Li Ting
Published: June 2022

Objective. It was to explore the effect of cell division cycle associated 5 (CDCA5) under shRNA interference on proliferation and metastasis of triple negative breast cancer (TNBC) cells. Methods. MDA-ME-231 and BT549 cells were selected as the research objects. According to the different interference methods and CDCA5 interference sequences, they were divided into the interference group 1MDA-ME-231, the interference group 2MDA-ME-231, the interference group 1BT549, the interference group 2BT549 (using shRNA technology), the control group MDA-ME-231, and the control group BT549 (breast cancer cells under normal culture conditions). MCF10A cells were routinely cultured as the negative control group to analyze the effect of CDCA5 expression on the proliferation and migration of cancer cells. Results. The expression of CDCA5 protein in MDA-ME-231 and BT549 cells in control group was significantly higher than that in negative control group (

P
<
0.05

). Compared with the control group, the inhibition rates of CDCA5 expression in 1MDA-ME-231, 2MDA-ME-231, 1BT549, and 2BT549 cells in the interference group were 39.01%, 42.98%, 49.57%, and 60.98%, respectively (

P
<
0.05

). From 12 h, the proliferation level of TNBC cells at different culture time was lower than that of the control group (

P
<
0.05

). Compared with the number of staining cells in the control group, the positive staining cells in 1MDA-ME-231 (61.42%), 2MDA-ME-231 (72.06%), 1BT549 (52.53%), and 2BT549 (59.65%) in the interference group were significantly decreased (

P
<
0.05

). Conclusion. The results show that the expression of CDCA5 in TNBC is increased, which plays an important role in the proliferation and migration of cancer cells. shRNA interference technology can knock down the expression of CDCA5 and inhibit its “promoting cancer” effect.
Integrated Bioinformatics Analysis for Identifying the Significant Genes as Poor Prognostic Markers in Gastric Adenocarcinoma
Authors: Li Yamei , Luo Yan , Tian Qiang , Lai Yu , Xu Lei , Yun Hailong , Liang Yang , Liao Dandan , Gu Rui , Liu Liye , Yuan Mu , Li Yijiao , Li Yufan , Lu Mingze , Yong Xin , Zhang Hua
Published: June 2022

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer and imposes a considerable health burden globally. The purpose of this study was to identify significant genes and key pathways participated in the initiation and progression of GAC. Four datasets (GSE13911, GSE19826, GSE54129, and GSE79973) including 171 GAC and 77 normal tissues from Gene Expression Omnibus (GEO) database were collected and analyzed. Through integrated bioinformatics analysis, we obtained 69 commonly differentially expressed genes (DEGs) among the four datasets, including 20 upregulated and 49 downregulated genes. The prime module in protein-protein interaction network of DEGs, including ADAMTS2, COL10A1, COL1A1, COL1A2, COL8A1, BGN, and SPP1, was enriched in protein digestion and absorption, ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and amoebiasis. Furthermore, expression and survival analysis found that all seven hub genes were highly expressed in GAC tissues and 6 of them (except for SPP1) were able to predict poor prognosis of GAC. Finally, we verified the 6 high-expressed hub genes in GAC tissues via immunohistochemistry, Western blot, and RNA quantification analysis. Altogether, we identified six significantly upregulated DEGs as poor prognostic markers in GAC based on integrated bioinformatical methods, which could be potential molecular markers and therapeutic targets for GAC patients.
Study on the Color Genesis of South Red Agate and the Geological Characteristics of the Siliceous Gravel Layer
Authors: Li Kongliang , Yuan Ye
Published: June 2022

The aim of the study was to explore the gem mineralogical characteristics of southern red agate and then analyze its structural characteristics and color causes. The mineral composition, structure, and chromogenic minerals of Nanhong agate were tested by a conventional gemmological test and observed under the microscope, infrared spectrum, and microlaser Raman spectrum. It is found that the color of southern red agate samples is mainly dark red or orange red, and colorless, white or yellow bands can be seen in some samples; the relative density is in the range of 2.59∼2.65. The matrix structure of the sample is mainly long fiber and short fiber, and some of them are fine-grained and crystalline plasmid. There are concentric ring-banded structures, and some horizontal banded and vein structures can also be seen. The analysis and test results show that the south red agate has a typical radial fiber structure, and the main chemical component is SiO2; Under the orthogonal polarizing microscope, a large number of round reddish brown mineral inclusions with banded distribution can be seen, the spot-colored mineral is iron oxide hematite, and calcite of the late hydrothermal origin can be seen in the cracks. In addition, the study shows that the formation of south red agate is multistage and the formation of hematite inclusions is also multistage.
Application of Industrial Communication Device-Based Mobile Learning in Ideological and Political Education
Authors: Peng Haoyan , Cao Junmei
Published: June 2022

Mobile learning theory and the demand analysis of mobile learning systems for ideological and political education at universities are presented in this study. The study analyses the use of mobile learning based on industrial communication devices (ICDs) in ideological and political education by doing research on mobile development technology and mobile learning systems. ICD-based mobile learning platforms can be used for ideological and political education by conducting a questionnaire. The main advantage of using this ICD-based mobile learning platform is the teaching and learning process will be continued under any circumstances. Even if the teacher and the students are in distant location, secured access privileges can be provided for effective communication for the processes. For ideological and political education, a remote supervision algorithm was developed to evaluate the performance of industrial communication devices. The proposed algorithm generated 90% more accuracy than the current technique.
Enterprise Management Performance Evaluation Model Using Improved Fuzzy Clustering Algorithm in IoT Networks
Authors: Li Jia , Ma Liangliang
Published: June 2022

Enterprise core competence is closely related to enterprise management performance, and it is important to evaluate enterprise management performance. However, the current enterprise management performance evaluation model has the problems of high eigenvalues of sample data, low cumulative contribution and correlation, high error rate in the calculation of business management performance evaluation index weights, low evaluation accuracy, and long evaluation time. Therefore, the enterprise management performance evaluation model using improved fuzzy clustering algorithm in Internet of things (IoT) networks is proposed. First, in the IoT architecture, the enterprise management performance evaluation index system is established by using the balanced scorecard theory. Second, the evaluation index system is reduced in dimensionality by combining principal component analysis and kernel-independent component analysis, the fuzzy C-mean clustering algorithm based on the objective function is designed, and finally, the improved fuzzy clustering algorithm is obtained to establish the enterprise management performance evaluation model, the reduced evaluation index system is input, and the evaluation results are output. The results show that the sample data eigenvalue of this model is low. The maximum error rate of weight calculation is 2.3%, the accuracy is always more than 95%, and the average value of evaluation time is 0.57 s, which effectively realize enterprise management performance evaluation in IoT networks.
Rural Planning Evaluation Based on Artificial Neural Network
Authors: Liu Yumei , Huang Xuezhou
Published: June 2022

The continuation of human civilization is inseparable from the development and construction of rural areas, and infrastructure is the core of rural development. China has been building large-scale rural infrastructure in recent years. Rural infrastructure building, for example, is huge in both quantity and scope, but it is beset by challenges in its current construction and development, and it urgently requires suitable leadership. Planning assessment, as a technical method, can identify problems in regional development and is a powerful tool for evaluating the impact of planning and construction and promoting the development of complete new areas. This paper is aimed at the planning evaluation of rural construction and the evaluation of rural construction and guides the planning and implementation of the next step of rural construction, to assist China’s supervision and inspection of rural construction effect and promote rural construction and development into a good track. In view of the low accuracy and efficiency of the current evaluation model of rural planning and the problem that a single neural network easily produces local extreme value, the neural network method is improved, and the application of LM-BP neural network in the evaluation model of rural planning is proposed. Input sample elements are five factors affecting rural construction, including industrial construction, population distribution, and utilization rate of large-scale facilities, construction of public facilities, and promotion effect of supporting policies. Output sample is the evaluation result. On this foundation, the LM-BP neural network was used to convert the training into a least square problem, and the LM method was used to redefine the number of hidden layer nodes, resulting in the construction of a rural planning evaluation model based on the LM-BP neural network. This approach is used to determine the outcomes of rural planning evaluations. The experimental results show that the designed evaluation model has a small evaluation error, has the advantage of high accuracy compared with similar models, and is a reliable evaluation model for rural planning.
Increased Heparanase Expression Is Caused by Promoter Hypomethylation and Up-Regulation of Transcriptional Factor Early Growth Response-1 in Human Prostate Cancer
Authors: Ogishima Tatsuya , Shiina Hiroaki , Breault Julia E. , Tabatabai Laura , Bassett William W. , Enokida Hideki , Li Long-Cheng , Kawakami Toshifumi , Urakami Shinji , Ribeiro-Filho Leopoldo A. , Terashima Masaharu , Fujime Makoto , Igawa Mikio , Dahiya Rajvir
Published: June 2022

Purpose: Heparanase degrades heparan sulfate and has been implicated in tumor invasion and metastasis. The transcription factor, early growth response 1 (EGR1), is associated with the inducible transcription of the heparanase gene. We hypothesize that CpG hypomethylation in the heparanase promoter coupled with up-regulation of EGR1 levels may induce heparanase expression in human prostate cancer.

Experimental Design: Cultured prostate cancer cell lines (Du145, DuPro, LNCaP, and PC-3) with and without 5′-aza-2-deoxycytidine treatment, 177 prostate cancer samples, and 69 benign prostatic hyperplasia (BPH) samples were used. The frequency and level of heparanase promoter methylation were analyzed by methylation-specific primers which covered the core binding motif of EGR1 (GGCG) or SP1 (GGGCGG) or both.

Results: In cultured Du145, DuPro, LNCaP, and PC-3 cell lines, mRNA transcripts of heparanase were significantly increased after 5′-aza-2-deoxycytidine treatment, suggesting that promoter methylation was involved in the regulation of heparanase mRNA transcript. Significantly higher methylation was found in BPH samples than in prostate cancer samples (P < 0.0001), whereas mRNA transcripts of the heparanase gene were inversely lower in BPH samples than in prostate cancer samples (P < 0.01). EGR1 expression in prostate cancer tissues was significantly higher than in BPH tissues (P < 0.001) and correlated with heparanase expression (P < 0.0001). Moreover, multiple regression analysis revealed that up-regulation of EGR1 contributed significantly more to heparanase expression than did promoter CpG hypomethylation in prostate cancer samples (P < 0.0001).

Conclusions: To our knowledge this is the first comprehensive study demonstrating that increased heparanase expression in prostate cancer tissues is due to promoter hypomethylation and up-regulation of transcription factor EGR1.
Patterns of Cyclin E, Retinoblastoma Protein, and p21Cip1/WAF1 Immunostaining in the Oncogenesis of Papillary Thyroid Carcinoma
Authors: Brzeziński Jan , Migodziński Adam , Toczek Aleksandra , Tazbir Józef , Dedecjus Marek
Published: June 2022

Purpose: Uncontrolled cell proliferation, a hallmark of cancer, may result from an increased expression of cell cycle up-regulators, and/or from a reduced expression of cell cycle down-regulators. In the present study, we analyzed, by immunohistochemistry, the expression of a panel of three proteins: cyclin E and two cell cycle inhibitors, p21Cip1/WAF1 and retinoblastoma protein (pRb) product, in different stages of papillary thyroid carcinomas (PTC).

Experimental Design: We investigated immunostaining patterns of the proteins in question in 51 resected PTC in pathologic stages, ranging from pT1a to pT4, taking into consideration their relation to clinicohistopathologic factors.

Results: We observed a significant, progressive loss of expression of p21Cip1/WAF1 with advancing tumor grade. The differences reached values of significance between pT1a [papillary thyroid microcarcinomas (PMC)] and pT2 and between PMC and pT4 stages of PTC. pRb presented a similar immunostaining pattern to that of p21Cip1/WAF1 and the differences reached values of significance between pT1a and pT2, and between PMC and pT4 stages of PTC. The results of cyclin E immunostaining corresponded to our recently published result, and a negative correlation was observed between the immunostaining index of cyclin E and pRb.

Conclusions: The results of the present study suggest that cyclin E expression and suppression of pRb and p21Cip1/WAF1 may be characteristic patterns of immunostaining for PTC with a tendency to early metastasizing. If our results are confirmed in a larger study, the diagnostic panel, constructed of the antibodies against these proteins, may become a valuable tool in predicting the metastatic potential in PTC.
Macrophage Migration Inhibitory Factor Promotes Tumor Invasion and Metastasis via the Rho-Dependent Pathway
Authors: Sun Bailong , Nishihira Jun , Yoshiki Takashi , Kondo Masao , Sato Yuji , Sasaki Fumiaki , Todo Satoru
Published: June 2022

Purpose: Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system but also in tumorigenesis. In this study, we investigated the potential role of MIF in association with tumor invasion and metastasis.

Methods: To assess the function of MIF, we knocked down the MIF mRNA using small interfering RNA (siRNA). Twenty-one base siRNA specific for the mRNA sequence of mouse MIF was introduced to a murine colon cancer cell line, colon 26. Tumor cell invasion was evaluated using a transwell method (8-μm pores) coated with Matrigel on the upperside membrane and with fibronectin on the underside membrane. Moreover, we investigated the signal transduction of lysophosphatidic acid (LPA) relevant to the Rho-dependent pathway and further examined the effect of MIF siRNA on this signal transduction system. In vivo, the tumor cells were pretreated with MIF siRNA and injected into the portal vein, and the effects on metastasis to the liver were evaluated.

Results: We found that MIF siRNA markedly reduced the invasion of the cells from the upperside to lowerside membranes. We revealed that the Rho-dependent pathway activated by LPA was suppressed by MIF siRNA. Next, we found that the tyrosine-phosphorylation of focal adhesion kinase and LPA-induced expressions of integrin β1 were significantly suppressed by MIF siRNA. In vivo, metastasis to the liver was significantly inhibited by pretreatment of the cells with MIF siRNA.

Conclusion: Taken together, these results suggest that MIF promotes tumor invasion and metastasis via the Rho-dependent pathway.
Polymorphisms in ER-α Gene Interact with Estrogen Receptor Status in Breast Cancer Survival
Authors: Boyapati Sonia M. , Shu Xiao Ou , Ruan Zhi Xian , Cai Qiuyin , Smith Jeffrey R. , Wen Wanqing , Gao Yu-Tang , Zheng Wei
Published: June 2022

Purpose: The effects of estrogens are mediated primarily through estrogen receptor (ER) in breast tissue, and polymorphisms in the ER genes may alter the functions of these receptors. Polymorphisms in the ER-α gene have been reported to be associated with breast cancer risk. However, to our knowledge, no study has been published on the relation between ER-α gene polymorphisms and breast cancer survival.

Experimental Design: To determine whether three common polymorphisms in the ER-α gene, PvuII, XbaI, and GT dinucleotide repeats are associated with breast cancer survival, we evaluated data from a cohort of 1,069 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. The median follow-up time for this cohort of women was 5.2 years.

Results: No overall association was observed between ER gene polymorphisms and breast cancer survival. The genotype associations, however, were modified by ER status in breast cancer tissues. Comparing those with the PP genotype to the pp genotype of the PvuII polymorphism, the hazard ratios (HR) of dying were 3.30 [95% confidence interval (95% CI), 1.42-7.69] and 0.54 (95% CI, 0.24-1.23), respectively, for participants with ER-negative breast cancer and ER-positive breast cancer. Similarly, compared with those with no (GT)23 alleles, carrying one or two (GT)23 alleles of the GT repeat polymorphism was related to a HR of 1.48 (95% CI, 0.77-2.87) for ER-negative breast cancer and a HR of 0.25 (95% CI, 0.09-0.69) for ER-positive cancer. The effect of ER on breast cancer survival was also modified by genotypes of ER-α gene. Tests for multiplicative interaction were highly significant.

Conclusions: These data suggest that the ER-α gene polymorphisms and ER status may have an interactive effect on breast cancer survival.
Plasma Protein Profiling for Diagnosis of Pancreatic Cancer Reveals the Presence of Host Response Proteins
Authors: Koomen John M. , Shih Lichen Nancy , Coombes Kevin R. , Li Donghui , Xiao Lian-chun , Fidler Isaiah J. , Abbruzzese James L. , Kobayashi Ryuji
Published: June 2022

Plasma protein profiling using separations coupled to matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) has great potential in translational research; it can be used for biomarker discovery and contribute to disease diagnosis and therapy. Previously reported biomarker searches have been done solely by MS protein profiling followed by bioinformatics analysis of the data. To add to current methods, we tested an alternative strategy for plasma protein profiling using pancreatic cancer as the model. First, offline solid-phase extraction is done with 96-well plates to fractionate and partially purify the proteins. Then, multiple profiling and identification experiments can be conducted on the same protein fractions because only 5% of the fractions are used for MALDI MS profiling. After MALDI MS analysis, the mass spectra are normalized and subjected to a peak detection algorithm. Over three sets of mass spectra acquired using different instrument variables, ∼400 unique ion signals were detected. Classification schemes employing as many as eight individual peaks were developed using a training set with 123 members (82 cancer patients) and a blinded validation set with 125 members (57 cancer patients). The sensitivity of the study was 88%, but the specificity was significantly lower, 75%. The reason for the low specificity becomes apparent upon protein identification of the ion signals used for the classification. The identifications reveal only common serum proteins and components of the acute phase response, including serum amyloid A, α-1-antitrypsin, α-1-antichymotrypsin, and inter-α-trypsin inhibitor.
The Expression of Hypoxia-Inducible Factor 1α Is a Favorable Independent Prognostic Factor in Renal Cell Carcinoma
Authors: Lidgren Anders , Hedberg Ylva , Grankvist Kjell , Rasmuson Torgny , Vasko Janos , Ljungberg Börje
Published: June 2022

Purpose: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional RCCs are, in contrast to the other RCC types, characterized by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation. The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1α (HIF-1α) expression. The pVHL is the physiologic regulator of the activity of HIF-1α by targeting it to the proteasome for degradation under normoxia. Both pVHL and HIF-1α target other genes that are important for cancer survival and proliferation. Expression of HIF-1α has been linked to poor prognosis in different malignancies, although few studies have been done on the relation between HIF-1α and clinical variables in RCC.

Experimental Design: HIF-1α protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1α was quantified by Western blot relative to a positive control.

Results: The HIF-1α protein was expressed as two bands which strongly correlated (r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association between HIF-1α and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1α expression compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1α was an independent prognostic factor.

Conclusion: HIF-1α levels varied significantly between the different RCC types. In conventional RCC, HIF-1α was an independent prognostic factor. These data indicate that HIF-1α is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target gene products and correlation to angiogenesis seems warranted.
Preclinical Evaluation of New and Highly Potent Analogues of Octreotide for Predictive Imaging and Targeted Radiotherapy
Authors: Ginj Mihaela , Chen Jianhua , Walter Martin A. , Eltschinger Veronique , Reubi Jean Claude , Maecke Helmut R.
Published: June 2022

Purpose: Molecular imaging and targeted radiotherapy are emerging fields in nuclear oncology. Five human somatostatin receptors (hsstr1-hsstr5) are known to be overexpressed to some degree on various tumors, sstr2 being the most important one. Clinically used somatostatin based radiopeptides target exclusively sstr2. The aim of this study was to develop novel analogues with a broader sstr profile for diagnostic (positron emission tomography and single-photon emission computed tomography) and radiotherapeutic applications.

Experimental Design: The following promising structures emerged from a parallel synthetic approach: [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA0),1-Nal3,Thr8]-octreotide (1, DOTA-NOC-ATE) and [DOTA0,BzThi3,Thr8]-octreotide (2, DOTA-BOC-ATE). The conjugates were labeled with cold and radioactive 111In. Pharmacologic properties were compared with [111In-DOTA,Tyr3]-octreotide ([111In-DOTA]-TOC).

Results: The receptor affinity profile showed high affinity of both peptides to hsstr2, hsstr3, and hsstr5 and some intermediate affinity to hsstr4, whereas [111In-DOTA]-TOC shows affinity only to sstr2. The internalization is fast in sstr2 expressing AR4-2J and in transfected sstr3 expressing human embryonic kidney 293 cells. Both radiopeptides internalize much more efficiently than [111In-DOTA]-TOC. Animal biodistribution studies showed very high and specific uptake of [111In]-1 and [111In]-2 in s.c. implanted AR4-2J tumors (Lewis rats) and in somatostatin receptor expressing normal tissues. The uptake was at least 2-fold higher in these tissues and in the tumor compared with [111In-DOTA]-TOC. In addition, the kidney uptake was significantly lower for both radiopeptides.

Conclusions: These data suggest that the novel radiopeptides are superior to [111In/90Y-DOTA]-TOC and show great promise for the clinical application in the imaging of somatostatin receptor–positive tumors and their targeted radiotherapy.
Transcriptional Profiles in Peripheral Blood Mononuclear Cells Prognostic of Clinical Outcomes in Patients with Advanced Renal Cell Carcinoma
Authors: Burczynski Michael E. , Twine Natalie C. , Dukart Gary , Marshall Bonnie , Hidalgo Manuel , Stadler Walter M. , Logan Theodore , Dutcher Janice , Hudes Gary , Trepicchio William L. , Strahs Andrew , Immermann Fred , Slonim Donna K. , Dorner Andrew J.
Published: June 2022

Purpose: Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations.

Experimental Design: In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes.

Results: Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively.

Conclusions: The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.
Identification of Epigenetic Aberrant Promoter Methylation in Serum DNA Is Useful for Early Detection of Lung Cancer
Authors: Fujiwara Keiichi , Fujimoto Nobukazu , Tabata Masahiro , Nishii Kenji , Matsuo Keitaro , Hotta Katsuyuki , Kozuki Toshiyuki , Aoe Motoi , Kiura Katsuyuki , Ueoka Hiroshi , Tanimoto Mitsune
Published: June 2022

Purpose: The purpose of this study is to evaluate the usefulness of serum DNA methylation of five tumor suppressor genes for early detection of lung cancer.

Experimental Design: Methylation status in serum DNA from 200 patients undergoing bronchofiberscopic examination for abnormal findings on chest radiograph detected by lung cancer screening or surveillance was examined using methylation-specific PCR.

Results: Ninety-one patients were given a pathologic diagnosis of lung cancer, 9 other malignant diseases, and 100 nonmalignant pulmonary diseases. In patients with lung cancer, methylation was detected in 18.7% for MGMT, 15.4% for p16INK4a, 12.1% for RASSF1A, 11.0% for DAPK, and 6.6% for RAR-β, which was higher compared with that in patients with nonmalignant diseases. Age and smoking status seemed to associate with methylation status. Sensitivity, specificity, and predictive value of methylation in at least one gene for diagnosis of lung cancer were 49.5%, 85.0%, and 75.0%, respectively. Adjusted odds ratio (95% confidence interval) for having lung cancer was 5.28 (2.39-11.7) for patients with methylation in one gene and 5.89 (1.53-22.7) for those with methylation in two or more genes. It is of note that methylation was identified in 50.9% of stage I lung cancer patients, whereas serum protein tumor markers were positive in 11.3% of them.

Conclusions: These results suggest that identification of promoter methylation of tumor suppressor genes in serum DNA could be useful for early detection of lung cancer.
UGT1A7 and UGT1A9 Polymorphisms Predict Response and Toxicity in Colorectal Cancer Patients Treated with Capecitabine/Irinotecan
Authors: Carlini Leslie E. , Meropol Neal J. , Bever John , Andria Michael L. , Hill Todd , Gold Philip , Rogatko Andre , Wang Hao , Blanchard Rebecca L.
Published: June 2022

Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11).

Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies.

Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 −118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response.

Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.
Visualization of Endogenous p53-Mediated Transcription In vivo Using Sodium Iodide Symporter
Authors: Kim Kwang Il , Chung June-Key , Kang Joo Hyun , Lee Yong Jin , Shin Jae Hoon , Oh Hyun Jeong , Jeong Jae Min , Lee Dong Soo , Lee Myung Chul
Published: June 2022

Purpose: To develop a gamma camera imaging method for the determination of endogenous gene expression, we evaluated the expression of endogenous p53 gene using human sodium iodide symporter (hNIS) gene as reporter.

Experimental Design: We constructed cis-p53RE-hNIS reporter vector placed under control of an artificial enhancer (p53RE). Moreover, we transfected it into human hepatoma cell line SK-Hep1 by liposome. Geneticin was used for the selection of stable transfectant (SK-Hep1p53NIS). To evaluate the function of hNIS, the inhibition study was examined with 1 mmol/L potassium perchlorate. After treatment of Adriamycin with serial dose for 24 hours, we measured the uptake of 125I and did Western blot analysis to evaluate expression of p53 protein. Tumor xenografts were produced in nude mice by s.c. injection of SK-Hep1p53NIS cells. After 7 days, scintigraphic images of nude mice before and after Adriamycin treatment were obtained using [99mTc]-pertechnetate.

Results: In the SK-Hep1p53NIS cells, Adriamycin-treated cells accumulated up to three times higher than did nontreated cells. Potassium perchlorate inhibited completely the uptake of 125I. As Adriamycin dose increased, radioiodide uptake was significantly correlated with activated p53 as well as total p53 protein level. When Adriamycin (2 mg/kg) was treated in the same mice, a significantly higher uptake of [99mTc]-pertechnetate was observed in SK-Hep1p53NIS xenografts compared with nontreated xenografts (P < 0.05, unpaired t test).

Conclusions: These results suggest that p53 expression level can be monitored by NIS gene expression using cis-p53RE-hNIS system in vitro and in vivo.
Different Effect of Paclitaxel on Primary Tumor Mass, Tumor Cell Contents, and Metastases for Four Experimental Human Prostate Tumors Expressing Luciferase
Authors: El Hilali Nadia , Rubio Nuria , Blanco Jerónimo
Published: June 2022

Purpose: Primary tumor growth is usually assesed by measuring tumor mass or volume, under the assumption that such variables correlate with the contents of tumor cells. However, tumors are complex interacting mixtures of tumor cells and host components. The different sensitivity of such components to cytostatic agents should be taken into consideration when evaluating the effectiveness of antineoplastic agents. We evaluate the effect of the antineoplastic agent paclitaxel on primary tumors expressing luciferase and their metastases using a sensitive luminescence-based procedure to directly asses the number tumor cells, in comparison with traditionally used tumor mass measurement.

Experimental Design: Nude mice bearing human prostate tumors expressing the luciferase gene, LNCaP.Sluc, DU 145.Sluc, and PC-3.Sluc, i.m. inoculated, and PC-3M.Sluc, orthotopically inoculated, were subjected to a 10-day treatment with either 10 mg/kg/d paclitaxel or saline solution. At the end of the treatment period, primary tumors as well as metastasis target organs were harvested, weighed, and homogenized. The presence of tumor cells in the tissue homogenates was evaluated using a luminometer, following the addition of luciferin. Tumor cell equivalent is defined as the amount of light produced by a single tumor cell in culture.

Results: Paclitaxel had a different effect on the primary tumor mass and the contents of tumor cells for each tumor type. Whereas LNCaP.Sluc, PC-3.Sluc, and PC-3M.Sluc primary tumor masses were significantly reduced by the action of paclitaxel, their contents in tumor cell equivalents were not significantly affected. In contrast, paclitaxel only reduced significantly the number of tumor cell equivalents in DU 145 primary tumors. In the lymph nodes, paclitaxel reduced the number of DU 145.Sluc metastases significantly, by a factor of 103, but had no significant effect on the rest of tumor cells. However, in lungs and muscle, paclitaxel treatment reduced significantly the number of metastatic PC-3.Sluc and PC-3M.Sluc tumor cell equivalents. In the bones, no tumor cell type was significantly affected by paclitaxel.

Conclusions: Some components of tumor stroma seem to be more sensitive to antineoplastic agents than the tumor cells themselves and may also contribute to modulate the response to therapy. Our results caution against the use of a single general variable, such as tumor mass, to evaluate the effectiveness of antineoplastic agents and emphasize the effect of the tumor cell environment in their sensitivity to treatment.
Therapy of Hematogenous Melanoma Brain Metastases with Endostatin
Authors: Kirsch Matthias , Weigel Patrick , Pinzer Thomas , Carroll Rona S. , Black Peter McL. , Schackert Hans-Konrad , Schackert Gabriele
Published: June 2022

Purpose: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases.

Experimental Design: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed.

Results: In vitro secretion of endostatin by 2.5 × 105 cells within 24 hours was 0.12 ± 0.03 ng, 4.35 ± 0.4, and 1.18 ± 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 ± 2.6 versus 13.3 ± 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 × 105 wild-type cells killed the mice within 24 ± 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals.

Conclusion: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.
Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor
Authors: Tuccillo Concetta , Romano Marco , Troiani Teresa , Martinelli Erika , Morgillo Floriana , De Vita Ferdinando , Bianco Roberto , Fontanini Gabriella , Bianco Raffaele A. , Tortora Giampaolo , Ciardiello Fortunato
Published: June 2022

Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions.

Experimental Design: The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway.

Results: The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor–bearing mice and in 4 of 10 A549 tumor–bearing mice.

Conclusions: This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.