bluuebunny/crossref_metadata_2025 huggingface dataset:
Antinociceptive Effects of Shenling Baizhu through PI3K‐Akt‐mTOR Signaling Pathway in a Mouse Model of Bone Metastasis with Small‐Cell Lung Cancer
Authors: Feng Zhe , Feng Ziyi , Han Jie , Cheng Weimin , Su Bo , Mo Jian , Feng XinJian , Feng Sitan , Chen GuoJian , Huang Peng , Huang Long , Cui Zhenwei
Published: June 2020

Shenling Baizhu additive powder (SLBZ‐AP), a formulation of a variety of natural medicinal plants, has clinical efficacy in treating cancers in previous studies. We explored the effect of SLBZ‐AP in bone metastasis of lung cancer (BMLC) mice, and the possible mechanism involved was further investigated in the present study. Mice model of BMLC was made and treated with SLBZ‐AP. Pain behavioral tests were performed to explore the effect on BMLC‐induced pain in mice. TUNEL staining was used to investigate apoptosis. The mRNA expression of markers in the PI3K/Akt/mTOR pathway was measured by qPCR, and protein expression was detected by western blotting and immunohistochemistry analysis. SLBZ‐AP relieved BMLC‐induced pain and prolonged animals’ survival, promoted cell apoptosis in the marrow from the tibia of BMLC mice, and inhibited mRNA and protein expression of AKT, mTOR, P70S6, and VEGF, as well as protein expression of p‐AKT, p‐mTOR, p‐P70S6, and VEGF upregulation in the marrow of tibia induced by BMLC, an effect which was similar to rapamycin. Our results suggested that SLBZ‐AP may have antinociceptive effect and prolong survival of BMLC mice at least partially by inhibiting cell proliferation and promoting apoptosis through the PI3K/Akt/mTOR signaling pathway. SLBZ‐AP may be a potential candidate for BMLC therapy.
Investigating the Impact of Big Data Analytics on Perceived Sales Performance: The Mediating Role of Customer Relationship Management Capabilities
Authors: Shahbaz Muhammad , Gao Changyuan , Zhai Lili , Shahzad Fakhar , Abbas Adnan , Zahid Rimsha
Published: June 2020

A persistent question for information technology researchers and practitioners is how big data analytics (BDA) can improve sales performance. Therefore, this study proposed a research model to investigate the impact of BDA on perceived sales performance in accordance with the resource-based view (RBV) and dynamic capability theory. The 416 valid responses collected from the employees of pharmaceutical organizations were analyzed using structural equation modelling to test the proposed research model. Results indicated that the BDA and customer relationship management (CRM) capabilities shared a strong positive impact on perceived sales performance. BDA, as organizational resources, creates organizational dynamic capabilities, such as CRM capabilities. BDA and CRM capabilities can influence perceived sales performance. Furthermore, CRM capabilities have a significant mediating impact on the relationships between BDA and perceived sales performance. This study also highlighted the practical and theoretical implications of the proposed model, the research limitations, and the future research directions.
Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway
Authors: Chen Meng , Yan Xue-Tao , Ye Li , Tang Jun-Jiao , Zhang Zong-Ze , He Xiang-Hu
Published: June 2020

Intestinal ischemia/reperfusion (I/R) is a clinical emergency, which often causes lung injury with high morbidity and mortality. Although dexmedetomidine has been identified to have a protective effect on lung injury caused by intestinal I/R, its specific mechanism is still elucidated. In recent years, the cannabinoid (CB2) receptor pathway has been found to be involved in I/R injury of some organs. In the current study, we investigated whether the CB2receptor pathway contributes to the protective effect of dexmedetomidine on the intestinal I/R-induced lung injury in rats. Dexmedetomidine treatment upregulated the expression of CB2receptor and suppressed the I/R-induced increases in lung injury scores, inflammatory cell infiltration, lung wet/dry ratio, MPO activity, MDA level, inflammatory cytokines, and caspase-3 expression while augmenting SOD activity and Bcl-2 expression, indicating attenuation of lung injury. Dexmedetomidine treatment also increased the expression of Akt. The protective effects of dexmedetomidine treatment were reversed by the CB2receptor antagonist AM630 or the PI3K inhibitor wortmannin. And the CB2receptor antagonist AM630 also downregulated the expression of Akt. Thus, our findings suggest that treatment with dexmedetomidine provides a protective role against lung injury caused by intestinal I/R in rats, possibly due to the upregulation of the CB2receptor, followed by the activation of the PI3K/Akt pathway.
Characterization and Comparative Analysis of Two Rheum Complete Chloroplast Genomes
Authors: Zhao Kaihui , Li Lianqiang , Lu Yazhou , Yang Junbo , Zhang Zhirong , Zhao Fangyu , Quan Hong , Ma Xiaojing , Liao Zhihua , Lan Xiaozhong
Published: June 2020

Rheum species present a significant economic value. Traditional Chinese medicine rhubarb is an important medicinal material in China. It has a long history of use, with a record of use as early as two thousand years ago. Here, we determined the complete chloroplast genome sequences of Rheum nobile and Rheum acuminatum and comprehensively compared them to two other available Rheum cp genomes at the genome scale. The results revealed cp genomes ranging in size from 159,051 to 161,707 bp with a similar typical quadripartite and circular structure. The genome organization, gene numbers, gene order, and GC contents of these four Rheum cp genomes were similar to those of many angiosperm cp genomes. Repeats and microsatellites were detected in the R. nobile and R. acuminatum cp genomes. The Mauve alignment revealed that there were no rearrangements in the cp genomes of the four Rheum species. Thirteen mutational hotspots for genome divergence were identified, which could be utilized as potential markers for phylogenetic studies and the identification of Rheum species. The phylogenetic relationships of the four species showed that the members of Rheum cluster into a single clade, indicating their close relationships. Our study provides valuable information for the taxonomic, phylogenetic, and evolutionary analysis of Rheum.
Prediction and Potential Preventions for the Development of Posttraumatic Osteoarthritis after the Terrible Triad Injury: A Multicenter Risk Factors Study
Authors: Li Jingjing , Lu Di , Lin Wenxiao , Li Qinglong , Hu Jing , Xu Ding , Zhao Youming , Guo Weijun
Published: June 2020

Objective. A multicenter study to evaluate risk factors for the development of moderate or severe posttraumatic osteoarthritis (PTOA) and to find potential preventions. Methods. We conducted a retrospective multicenter study including the terrible triad injury (TTI) patients with surgical treatment from January 2007 to November 2014. Demographics, injury information, and treatment history were obtained retrospectively. According to the Broberg and Morrey criterion, 198 included patients were sorted into two groups: the mild or no PTOA and moderate or severe PTOA. Uni‐ and multivariate logistic regression analyses were used to identify risk factors for moderate or severe PTOA. Results. Moderate or severe PTOA was present in 64 patients (32.3%). Significant risk factors were Mason III radial head fracture (OR 4.049, 95% CI 1.877‐8.736, p < 0.001), medial collateral ligament injury (OR 5.120, 95% CI 1.261‐20.790, p = 0.022), and heavy use of elbow (OR 2.333, 95% CI 1.060‐5.136, p = 0.035). Besides, patients suffered subluxation (p = 0.007) and those with more risk factors had a higher risk to develop moderate or severe PTOA. Conclusions. Moderate or severe PTOA was common after the TTI. Patients need to be counseled about avoiding heavy use of the elbow, especially for those with Mason III radial head fractures. Surgeons should be aware of the recurrent instability of the elbow.
Climate Regionalization of Asphalt Pavement Based on the K‐Means Clustering Algorithm
Authors: Yang Yanhai , Qian Baitong , Xu Qicheng , Yang Ye
Published: June 2020

The climate regionalization of asphalt pavement plays an active role in ensuring the good performance and service life of asphalt pavement. In order to better adapt to the climate characteristics of a region, this study developed a multi‐index method of climate regionalization of asphalt pavement. First, meteorological data from the research region were statistically analyzed and the major climate variables were identified. Then, a principal component analysis (PCA) was used to eliminate any correlation between the major climate variables. Three principal components were extracted by the PCA as cluster factors, namely, the temperature factor, precipitation factor, and radiation factor. The research region was divided into the following four asphalt pavement climate zones via the K‐means clustering algorithm. Those zones are affected by the climate comprehensively: an inland zone with high temperatures, little rainfall, and radiation, a coastal zone with high temperatures, and a rainy mountainous zone. The results of the climate regionalization were compared with the results of on‐site investigations. The pavement degradation in each climatic zone was related to the climate characteristics of the region. Probabilistic neural network (PNN) and support vector machine (SVM) climate regionalization predictive models were established with MATLAB. The clustering factors were used as the input data to identify the climate zones, and the identification accuracy rate was determined to be over 90%. The climate regionalization of pavement can provide reference and guidance for the selection of reasonable technical measures, parameters, and building materials in highway projects with similar climatic conditions.
Local Discontinuous Galerkin Method for Nonlinear Time-Space Fractional Subdiffusion/Superdiffusion Equations
Authors: Qiu Meilan , Li Dewang , Wu Yanyun
Published: June 2020

Fractional partial differential equations with time-space fractional derivatives describe some important physical phenomena. For example, the subdiffusion equation (time order 0<α<1) is more suitable to describe the phenomena of charge carrier transport in amorphous semiconductors, nuclear magnetic resonance (NMR) diffusometry in percolative, Rouse, or reptation dynamics in polymeric systems, the diffusion of a scalar tracer in an array of convection rolls, or the dynamics of a bead in a polymeric network, and so on. However, the superdiffusion case (1<α<2) is more accurate to depict the special domains of rotating flows, collective slip diffusion on solid surfaces, layered velocity fields, Richardson turbulent diffusion, bulk-surface exchange controlled dynamics in porous glasses, the transport in micelle systems and heterogeneous rocks, quantum optics, single molecule spectroscopy, the transport in turbulent plasma, bacterial motion, and even for the flight of an albatross (for more physical applications of fractional sub-super diffusion equations, one can see Metzler and Klafter in 2000). In this work, we establish two fully discrete numerical schemes for solving a class of nonlinear time-space fractional subdiffusion/superdiffusion equations by using backward Euler difference 1<α<2 or second-order central difference 1<α<2/local discontinuous Galerkin finite element mixed method. By introducing the mathematical induction method, we show the concrete analysis for the stability and the convergence rate under the L2 norm of the two LDG schemes. In the end, we adopt several numerical experiments to validate the proposed model and demonstrate the features of the two numerical schemes, such as the optimal convergence rate in space direction is close to Ohk+1. The convergence rate in time direction can arrive at Oτ2−α when the fractional derivative is 0<α<1. If the fractional derivative parameter is 1<α<2 and we choose the relationship as h=C′τ (h denotes the space step size, C′ is a constant, and τ is the time step size), then the time convergence rate can reach to Oτ3−α. The experiment results illustrate that the proposed method is effective in solving nonlinear time-space fractional subdiffusion/superdiffusion equations.
Missing Value Estimation Methods Research for Arrhythmia Classification Using the Modified Kernel Difference‐Weighted KNN Algorithms
Authors: Yang Fei , Du Jiazhi , Lang Jiying , Lu Weigang , Liu Lei , Jin Changlong , Kang Qinma
Published: June 2020

Electrocardiogram (ECG) signal is critical to the classification of cardiac arrhythmia using some machine learning methods. In practice, the ECG datasets are usually with multiple missing values due to faults or distortion. Unfortunately, many established algorithms for classification require a fully complete matrix as input. Thus it is necessary to impute the missing data to increase the effectiveness of classification for datasets with a few missing values. In this paper, we compare the main methods for estimating the missing values in electrocardiogram data, e.g., the “Zero method”, “Mean method”, “PCA‐based method”, and “RPCA‐based method” and then propose a novel KNN‐based classification algorithm, i.e., a modified kernel Difference‐Weighted KNN classifier (MKDF‐WKNN), which is fit for the classification of imbalance datasets. The experimental results on the UCI database indicate that the “RPCA‐based method” can successfully handle missing values in arrhythmia dataset no matter how many values in it are missing and our proposed classification algorithm, MKDF‐WKNN, is superior to other state‐of‐the‐art algorithms like KNN, DS‐WKNN, DF‐WKNN, and KDF‐WKNN for uneven datasets which impacts the accuracy of classification.
Extension Mechanism of the Proximal Interphalangeal Joint of the Human Phalanx: A Cadaveric Biomechanical Study
Authors: Park Junho , Lee Chang-Hun , Choi Youngjin , Joo Il-Han , Lee Kwang-Hyun , Kim Sung Jae
Published: June 2020

Our purpose was to compare the contributions of these two systems to assess PIP joint extension in fresh cadaver models. Nine middle fingers of fresh cadavers were used. The PIP joint angle was measured while an extension load was applied on the extensor tendons. Specimens on which extension load was applied on the extrinsic extensors were classified as the extrinsic group, and those on which extension load was applied on the intrinsic extensors were classified as the intrinsic group. Linear regression analyses were performed to obtain regression equation and the extension load‐PIP joint angle curve. The mean of slope of the curve was compared between the two groups using paired t‐test. The same experiments were done for the metacarpophalangeal (MP) joint in 0° and 60° flexion to evaluate the effect of MP joint flexion on PIP joint extension. The mean slope of the extension load‐PIP joint angle curve of the extrinsic group was significantly greater than that of the intrinsic group. With the MP joint in 0° flexion, the mean slope of the extrinsic and intrinsic groups was ‐0.148 and ‐0.117, respectively (greater absolute value means greater slope, p = 0.01). With the MP joint in 60° flexion, the mean slopes were ‐0.147 and ‐0.104, respectively (p = 0.015). The contribution of the intrinsic extensor for PIP joint extension shows decreasing trends with MP joint flexion. The extrinsic extensors have greater contribution for PIP joint extension compared with the intrinsic extensors.
Analysis of Terpolymerization Systems for the Development of Carbon Fiber Precursors of PAN
Authors: Alcalá-Sánchez Daniel , Tapia-Picazo Juan-Carlos , Bonilla-Petriciolet Adrian , Luna-Bárcenas Gabriel , López-Romero J. M. , Álvarez-Castillo Alberto
Published: June 2020

The thermal stabilization of polyacrylonitrile fibers (FPAN) is one of the most important steps in the production of carbon fibers (CFs). In this paper, new precursor polymers from PAN have been synthesized with different chemical characteristics using a solution polymerization, and FPAN was obtained using an unconventional wet spinning system in the drying and collapsing steps. The effect of different operation conditions, comonomers, and termonomers on the properties of precursor polymers, polymerization reactions, mechanical properties, structural characteristics, and stabilization of the FPAN was studied and analyzed. FTIR and optical microscopy were used to analyze structural changes of FPAN in the thermal stabilization. The impact of the chemical composition of the precursor polymers on the physicochemical characteristics of FPAN and their behavior in the thermal stabilization process were evaluated. In particular, itaconic acid termonomer improved the tensile strength of the fibers from 8.07 to 16.87 cN/dtex, and the extent stabilization increased from 1.81 to 4.6. FTIR indicated that the reaction of stabilization of the terpolymer developed was initiated at a lower temperature compared to that of a commercial precursor polymer.
Safety Assessment of High‐ and Low‐Molecular‐Weight Hyaluronans (Profhilo®) as Derived from Worldwide Postmarketing Data
Authors: Cassuto Daniel , Delledonne Mara , Zaccaria Giovanna , Illiano Immacolata , Giori Andrea Maria , Bellia Gilberto
Published: June 2020

Background. At present, dermal fillers based on hyaluronic acid (HA) represent the most popular intervention of dermoesthetic medicine for the treatment of skin aging. Recent studies have shown that the combination of HA chains of different lengths and molecular weights improves tissue repair and regeneration through a synergistic mechanism. Profhilo® is a product available that has been on the market since 2015 and is based on stable, hybrid, and cooperative complexes (HyCoCos) produced by means of NAHYCO® Hybrid Technology, which is an innovative thermal process that rules out the use of any chemical reagents. The result is a filler with high biocompatibility and low viscosity that favors optimal diffusion at the tissue level to obtain the target bioremodeling of the facial contour. The objective of this review is to provide data from the overall postmarketing experience after 3 years of use and more than 40,000 patients treated with the medical device. Methods. All spontaneous postmarketing adverse event (AE) reports received from physicians and healthcare professionals worldwide between February 9, 2015, and February 8, 2018, associated with the use of the studied medical device and sent to the IBSA global safety database were analyzed. Results. In total, 12 adverse event reports were logged in the global database, and none were considered serious. Early‐onset injection site reactions, i.e., swelling, edema, redness, ecchymosis, and erythema, were the most frequently observed. Late‐onset local reactions (e.g., swelling, nodules) followed. The genesis of these reactions was considered, both by the reporting physician and IBSA, as being local reactions of hypersensitivity and/or due to inappropriate injection techniques. In no case was the product held liable for direct damage. All events resolved without any complications according to the treatment guidelines. Two late‐onset reactions were collected. Conclusions. Although underreporting of minor events cannot be ruled out, the overall number of reports is very low, thereby supporting the high tolerability and safety of the product. After 3 years of postmarketing experience, the safety profile of the studied medical device is favorable and consistent with the product information.
Diagnostic and Prognostic Value of IL-6 and sTREM-1 in SIRS and Sepsis in Children
Authors: Smok Beata , Domagalski Krzysztof , Pawłowska Małgorzata
Published: June 2020

Purpose. The aim of this study was to evaluate the diagnostic and prognostic value of IL-6 and sTREM-1 in the course of SIRS and sepsis in children with reference to routinely used CRP and PCT. Methods. A prospective study included 180 patients at the ages from 2 months to 18 years hospitalized due to fever from November 2015 to January 2017. Forty-nine children without fever hospitalized due to noninfectious causes formed the control group. IL-6 and sTREM-1 serum concentrations were assessed with the enzyme-linked immunosorbent assay method. Results. The mean serum concentrations of all the analyzed biomarkers were statistically significantly higher in the study group compared to the control group. Mean IL-6, sTREM-1, and PCT serum concentrations were statistically significantly higher in the group of patients with SIRS/sepsis compared to the group of feverish patients without diagnosed SIRS (N-SIRS). Based on the ROC curve analysis, it was shown that of all the biomarkers tested, only two—IL-6 and procalcitonin—had potential usefulness in the diagnosis of SIRS/sepsis in children with fever. Conclusion. Elevated levels of IL-6 and PCT are important risk factors for the development of SIRS/sepsis in children with fever. It seems that elevated IL-6 baseline serum level may predict a more severe course of febrile illness in children, because based on the ROC curve analysis, it was found that IL-6 is a statistically significant prognostic marker of prolonged fever≥3 days and prolonged hospitalization>10 days. The assessment of the usefulness of sTREM-1 in the diagnosis of SIRS/sepsis in feverish children requires further research.
Evaluation and Selection of Manufacturing Suppliers in B2B E-Commerce Environment
Authors: Zhang Quan , Guo Zhen , Man Feiyu , Ma Jiyun
Published: June 2020

The evaluation and selection of manufacturing suppliers in B2B e-commerce environment is summed up as a multiple-attribute decision-making problem. In B2B E-commerce environment, some performance indicators of manufacturing suppliers present uncertainty and could not be expressed with precise numeric values. Linguistic terms, preference orderings, or interval numbers are commonly used to express the performances of the suppliers accurately instead of crisp values when the available information is uncertain or incomplete. This paper proposes an approach to the selection of manufacturing suppliers in B2B E-commerce environment, where the attribute values in decision matrix are expressed with linguistic terms, preference orderings, and interval numbers. Firstly, the hybrid decision matrix is normalized by calculating the grey correlation coefficients of attribute values with the ideal values of attributes. Secondly, a deviation maximization model is proposed to determine the attribute weights, which is combined with those derived from the entropy method. Thirdly, the overall values of suppliers are calculated and their rankings are obtained. Finally, an example is used to illustrate the proposed approach.
Aflatoxin M1 in Milk Worldwide from 1988 to 2020: A Systematic Review and Meta-Analysis
Authors: Salari Nader , Kazeminia Mohsen , Vaisi-Raygani Aliakbar , Jalali Rostam , Mohammadi Masoud
Published: June 2020

Background. Aflatoxins are found in various types of food and animal feed. Food contamination with aflatoxin toxin is of particular importance today. Various studies have reported different prevalence of aflatoxin M1 in animal milk. Therefore, due to the importance of this toxin, its role in health, and lack of general statistics about it worldwide, the present study aimed to determine the prevalence of aflatoxin M1 in milk worldwide with a systematic review and meta-analysis study. Methods. In this review study, national and international databases were extracted from SID, MagIran, IranMedex, IranDoc, Embase, ScienceDirect, Scopus, PubMed, and Web of Science (ISI) between January 1988 and February 2020. A random effects model was used for analysis, and heterogeneity of studies with an I2 index was investigated. Data were analyzed using Comprehensive Meta-Analysis (version 2). Results. The prevalence of aflatoxin M1 in milk worldwide from January 1988 to February 2020 in 122 articles with a sample size of 18921 was 79.1% (95% CI: 75.5–82.3%). Regarding the heterogeneity based on metaregression, there was a significant difference between the effect of the year of study (p≤0.001) and sample size (p≤0.001) with the prevalence of aflatoxin M1 in animal milk. Conclusion. The results of this study show that the prevalence of aflatoxin M1 in milk is high worldwide. Therefore, considering the importance of the milk group and its products, special measures should be taken to protect the ration from aflatoxin molds and milk quality.
Measurement Invariance and Psychometric Analysis of Oxford Happiness Inventory Scale across Gender and Marital Status
Authors: Mousavi Amin , Sharafi Zahra , Mahmoudi Abdolreza , Shahraki Hadi Raeisi
Published: June 2020

Background. The Oxford Happiness Inventory (OHI) is a self‐report tool to measure happiness. A brief review of previous studies on OHI showed the lack of evaluation of OHI fairness/equivalence in measuring happiness among identified groups. Methods. To examine the psychometric properties and measurement invariance of the OHI, responses of 500 university students were analyzed using item response theory and ordinal logistic regression (OLR). Relevant measures of effect size were utilized to interpret the results. Differential test functioning was also evaluated to determine whether there is an overall bias at the test level. Results. OLR analysis detected four items across gender and two items across marital status to function differentially. An assessment of effect sizes implied negligible differences for practical considerations. Conclusions. This study was a significant step towards providing theoretical and practical information regarding the assessment of happiness by presenting adequate evidence regarding the psychometric properties of OHI.
Relationship between Prolactin, Chronic Kidney Disease, and Cardiovascular Risk
Authors: Dourado Marclébio , Cavalcanti Frederico , Vilar Lucio , Cantilino Amaury
Published: June 2020

CKD has a high prevalence worldwide, mainly due to its main etiologies—diabetes and hypertension. It has high cardiovascular morbidity and mortality, with traditional risk factors such as atherosclerosis, hypertension, diabetes, smoking, and left ventricular hypertrophy being common. Nontraditional cardiovascular risk factors, such as anemia, hyperparathyroidism, chronic inflammation, and microalbuminuria, are also well studied. Prolactin is a hormone not only related to lactation but also being considered a uremic toxin by some authors. It accumulates with loss of renal function, and it is associated with cardiovascular outcomes in both normal renal function population and CKD population. The purpose of this narrative review is to raise the main common aspects of CKD, prolactinemia, and cardiovascular risk.
ciRS‐7 Promotes the Proliferation and Migration of Papillary Thyroid Cancer by Negatively Regulating the miR‐7/Epidermal Growth Factor Receptor Axis
Authors: Han Jun-ya , Guo Si , Wei Na , Xue Rui , Li Wencai , Dong Gang , Li Jianhua , Tian Xiangyu , Chen Chao , Qiu Sen , Wang Tong , Xiao Qiankun , Liu Chenguang , Xu Jingjing , Chen Kui-sheng
Published: June 2020

Purpose. The incidence of papillary thyroid cancer (PTC) is increasing, and traditional diagnostic methods are unsatisfactory. Therefore, identifying novel prognostic markers is very important. ciRS‐7 has been found to play an important role in many cancers, but its role in PTC has not been reported. This study was performed to evaluate the biological role and mechanism of ciRS‐7 in PTC. Material and Methods. The expression of ciRS‐7 in PTC tissues and the matched adjacent tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT‐PCR). The PTC cell lines (TPC‐1 and BCPAP) were used to evaluate the role of ciRS‐7. ciRS‐7‐siRNA and overexpression plasmid were constructed and transfected into PTC cells. A CCK‐8 assay and colony formation assay were performed to explore the effects of ciRS‐7 on cell proliferation. Annexin V/PI staining and FACS detection were used to detect cell apoptosis. Wound healing assay was performed to detect cell migration. A transwell assay was conducted to explore the effects of ciRS‐7 on invasion and migration. Western blotting was performed to evaluate protein expression. The luciferase reporter system was used to determine the underlying mechanism of miR‐7. Result. ciRS‐7 was highly expressed in PTC tissues and cell lines compared with the corresponding controls. In vitro study showed that ciRS‐7 silencing suppressed proliferation, migration, and invasion of TPC‐1 and BCPAP. Mechanistically, the effects of ciRS‐7 on invasion and migration may be related to epithelial‐mesenchymal transition (EMT). ciRS‐7 silencing could attenuate effects on PTC cells induced by miR‐7 knockdown. Epidermal growth factor receptor (EGFR), which was demonstrated to be a target of miR‐7, decreased significantly in ciRS‐7‐siRNA PTC cells. Overexpression of EGFR also attenuated effects of PTC cells induced by silencing ciRS‐7. Conclusion. ciRS‐7 was significantly upregulated in PTC tissues, and it promoted the progression of PTC by regulating the miR‐7/EGFR axis. ciRS‐7 is a promising prognostic biomarker and therapeutic target in PTC.
Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor
Authors: Xu Yibin , Bankhead Armand , Tian Xiaoli , Tang Jianming , Ljungman Mats , Neamati Nouri
Published: June 2020

GST omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we have validated GSTO1 as an impactful target in oncology. Transcriptional profiling coupled with proteomics uncovered novel pharmacodynamic markers and cellular pathways regulated by GSTO1. CRISPR/Cas9 GSTO1 knockout (KO) cell lines failed to form tumors or displayed growth delay in vivo; they also formed smaller 3D spheroids in vitro. Multiomics analysis in GSTO1 KO cells found a strong positive correlation with cell adhesion molecules and IFN response pathways and a strong negative correlation with Myc transcriptional signature. In addition, several clinically used drugs showed significant synthetic lethality with loss or inhibition of GSTO1. Transcription and protein expression of tissue factor (gene name, F3) were downregulated in response to GSTO1 KO. F3 is associated with poor patient survival and promotion of tumor progression in multiple cancers and is a known risk factor for metastasis. Transcription of F3 was regulated by IL1β, whose secretion decreased upon inhibition of GSTO1, suggesting that IL1β links GSTO1 expression and F3 transcription. In summary, our results implicate GSTO1 as a potential therapeutic target in cancer and offer new mechanistic insights into its significant role in cancer progression.

Significance:

These findings validate GSTO1 as a therapeutic target in cancer and implicate GSTO1 in the modulation of tumor growth, immune responses, and expression of F3.
Improving the Clinical Significance of Preclinical Immunotherapy Studies through Incorporating Tumor Microenvironment–like Conditions
Authors: Maggs Luke , Ferrone Soldano
Published: June 2020

Frequently, the results generated when testing novel antitumor immunotherapies in vitro do not correlate with data collected in in vivo models and/or in clinical settings. It is our hypothesis that this discrepancy is caused by the use of in vitro conditions, such as normoxia, a two-dimensional surface, optimal growth media, and lack of cell complexity and heterogeneity. These conditions do not accurately reflect the tumor microenvironment (TME) that the tested immunotherapeutic strategies experience in vivo. While there are many variables which can have an impact upon the antitumor efficacy of an immunotherapy, the immunosuppressive TME is one in which several of the conditions commonly found in vivo can be mimicked in vitro. These conditions, which include hypoxia, low pH, low glucose, presence of adenosine, cell complexity and heterogeneity, as well as the three-dimensional structure of TME, can all affect immune cell–tumor cell interactions. Here, we discuss the impact that these conditions, either individually or in combination, can have on these interactions. Furthermore, we propose that performing in vitro assays under TME-like conditions improves the clinical relevance of the yielded results. This, in turn, contributes to accelerate the speed, reduce the cost, and increase efficiency of screening novel immunotherapies and eventually the development of prospective clinical trials.
Identification of Somatically AcquiredBRCA1/2Mutations by cfDNA Analysis in Patients with Metastatic Breast Cancer
Authors: Vidula Neelima , Dubash Taronish , Lawrence Michael S. , Simoneau Antoine , Niemierko Andrzej , Blouch Erica , Nagy Becky , Roh Whijae , Chirn Brian , Reeves Brittany A. , Malvarosa Giuliana , Lennerz Jochen , Isakoff Steven J. , Juric Dejan , Micalizzi Douglas , Wander Seth , Spring Laura , Moy Beverly , Shannon Kristen , Younger Jerry , Lanman Richard , Toner Mehmet , Iafrate A. John , Getz Gad , Zou Lee , Ellisen Leif W. , Maheswaran Shyamala , Haber Daniel A. , Bardia Aditya
Published: June 2020

Purpose:

Plasma genotyping may identify mutations in potentially “actionable” cancer genes, such as BRCA1/2, but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired BRCA1/2 mutations in patients with metastatic breast cancer (MBC).

Experimental Design:

Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic BRCA1/2 mutations were classified as known germline pathogenic mutations or novel variants, and linked to clinicopathologic characteristics. The effect of the PARP inhibitor, olaparib, was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation.

Results:

Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA BRCA1/2 mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic BRCA1/2 mutations were common in younger patients (P = 0.008), those with triple-negative disease (P = 0.022), and they were more likely to be protein-truncating alterations and be associated with TP53 mutations. Functional analysis of a CTC culture harboring a somatic BRCA1 mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the “BRCA” mutational signature (COSMIC Signature 3) were present in BRCA1/2-mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC.

Conclusions:

Somatic BRCA1/2 mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.
Population-based Screening for BRAFV600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis
Authors: Chu Jenny E. , Johnson Benny , Kugathasan Laveniya , Morris Van K. , Raghav Kanwal , Swanson Lucas , Lim Howard J. , Renouf Daniel J. , Gill Sharlene , Wolber Robert , Karsan Aly , Kopetz Scott , Schaeffer David F. , Loree Jonathan M.
Published: June 2020

Purpose:

BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing.

Experimental Design:

We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAFV600E testing. Outcomes among IHC-detected BRAFV600E mCRC (BRAFIHC) were compared with patients with next-generation sequencing (NGS)–identified BRAFV600E-mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004 to 2018.

Results:

All-stage population prevalence of BRAFV600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAFIHC had worse median overall survival (mOS) than BRAFNGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89–4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAFV600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96–2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.

Conclusions:

Patients with BRAFV600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.
Skin- and Nipple-Areola-Sparing Mastectomy with Immediate Breast Reconstruction Using Transverse Rectus Abdominis Myocutaneous Flap and Silicone Implants in Breast Carcinoma Patients
Authors: Li Xueyang , Wang Yanli 
Published: June 2020

Background: We aimed to assess patient satisfaction and aesthetic outcome in breast cancer patients undergoing nipple-sparing mastectomy (NSM) and immediate breast reconstruction. Materials and Methods: The study population comprised 215 patients with histopathologically diagnosed breast cancer. The inclusion criteria were as follows: a diagnosis of breast cancer, a tumor of any size, any stage of nodal metastasis, and a tumor margin >2.0 cm from the margin of the nipple-areola complex. To measure the aesthetic outcome, the Lowery scale was used. After mastectomy, immediate breast reconstruction was performed using the transverse rectus abdominis myocutaneous (TRAM) flap, and by pacing the silicone implant. Results: Most of the patients were aged between 40 and 51 years. Lymphadenopathy was positive in 87 out of 215 subjects; among these 87 subjects, 61 showed macrometastasis and 26 micrometastasis. A lateral incision was performed for mastectomy in all cases, and immediate breast reconstruction was performed using autologous grafts: the latissimus dorsi myocutaneous (TRAM) flap in 83% of cases, and silicone implants in 17% of cases were used for reconstruction. An excellent aesthetic outcome was seen in 70% of the cases, and 22% showed a good outcome. Conclusions: NSM is a very safe and technically feasible procedure that provides a high level of patient satisfaction and an excellent aesthetic outcome.
The Many Faces of Endometriosis-Related Neoplasms in the Same Patient: A Brief Report
Authors: Santoro Angela , Angelico Giuseppe , Inzani Frediano , Spadola Saveria , Arciuolo Damiano , Valente Michele , Fiorentino Vincenzo , Mulè Antonino , Scambia Giovanni , Zannoni Gian Franco
Published: June 2020

Introduction: Endometriosis is a common benign gynecological condition that can be associated with a slightly increased risk of developing a wide range of malignancies. Case Presentation: We herein report a singular case of a 62-year-old woman with a history of pelvic endometriosis, referred to our institution for chronic pelvic pain and uterine bleeding, with clinical and radiological evidence of left ovarian mass of 18 cm in largest diameter and multiple nodular mural lesions of the uterine cavity. The patient underwent exploratory laparotomy followed by hysterectomy, bilateral salpingo-oophorectomy, and omentectomy with pelvic lymph-node sampling. The histological examination of the ovarian mass revealed a clear-cell ovarian carcinoma arising from an endometriotic cyst. The microscopic examination of the uterine cavity showed multiple conventional leiomyomas, diffuse foci of adenomyosis, and a 1.5-cm yellow nodule diagnosed as low-grade endometrial stromal sarcoma associated with glandular atypical differentiation and with extension into parametrial and omental tissues. Following the diagnosis, the patient was treated with chemotherapy, radiation therapy, and hormonal therapy and after 9 months of follow-up is alive without local recurrences and distant metastases. Discussion/Conclusions: To the best of our knowledge, the present case represents the first evidence of the simultaneous occurrence of clear-cell carcinoma and low-grade endometrial stromal sarcoma arising within ovarian and uterine endometriotic foci, respectively.
Does Internal Mammary Node Irradiation for Breast Cancer Make a Significant Difference to the Diameter of the Internal Mammary Artery? Correlation with Computed Tomography
Authors: Durhan Gamze , Erdemir Ahmet Gürkan , Yuce Sari Sezin , Gultekin Melis , Karakaya Jale , Akpınar Meltem Gülsün , Özyiğit Gökhan , Yildiz Ferah , Demirkazık Figen
Published: June 2020

Objective: Lymphatic irradiation in breast cancer improves locoregional control and has been shown to decrease distant metastasis. However, irradiation also accelerates the formation of atherosclerosis and can cause stenosis, not only in the coronary arteries but also in the internal mammary artery (IMA). The aim of this study was to investigate the effects of radiation on IMAs via computed tomography (CT). Methods: We reviewed the data of 3,612 patients with breast cancer treated with radiotherapy (RT) between January 2010 and December 2016. We included 239 patients with appropriate imaging and nodal irradiation in the study. All patients were treated with lymphatic irradiation of 46–50 Gy, and a boost dose (6–10 Gy) to the involved internal mammary nodes (IMNs) when imaging studies demonstrated pathological enlargement. Bilateral IMA diameter and the presence of calcification were assessed via thin contrast-enhanced CT and those of ipsilateral irradiated IMAs were compared with those of contralateral nonirradiated IMAs. Results: The mean diameter ofirradiated IMAs was significantly shorter than that of nonirradiated IMAs, regardless of laterality. All vascular calcifications were determined on the irradiated side. A boost dose of radiation to the IMNs and radiation technique did not significantly affect the IMA diameter or the presence of calcification. Conclusions: The diameter of the IMA is decreased due to RT regardless of laterality, radiation technique, and administration of a boost dose. Evaluation of vessels on CT before coronary artery bypass graft or flap reconstruction can help the surgeon select the most appropriate vessel.
Prognosis and Staging of AL Amyloidosis
Authors: Dittrich Tobias , Kimmich Christoph , Hegenbart Ute , Schönland Stefan O.
Published: June 2020

The treatment options for systemic light chain amyloidosis (AL) are currently widening in an unprecedented way, brought about by an expanding arsenal of anti-myeloma therapy as well as by novel approaches to target toxic light chains and, most recently, deposited amyloid directly. In this context, accurate estimates of prognosis in AL, which allow for reliable patient advice and for example comparison of different therapies, are particularly important to clinicians. Some biomarkers and especially the genetic background of the underlying clonal disease as evaluated by interphase fluorescence in situ hybridization even have predictive value, enabling an appropriate treatment selection. Derived from the most frequently involved organs in AL, heart and kidney, this review focuses on overall survival and renal survival. A comprehensive overview and summary of reported prognostic factors and biomarkers in AL is given and the most important and validated factors are highlighted. Finally, established staging systems in AL as well as validated and perspective response criteria are presented.
Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model
Authors: Luengas-Martinez Andrea , Hardman-Smart Jonathan , Rutkowski David , Purba Talveen S. , Paus Ralf , Young Helen S.
Published: June 2020

Background/Aims: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, plays a key role in physiological processes and is a major contributor to several diseases including cancer and psoriasis. Anti-VEGF therapies are widely used as cancer and ophthalmological treatments. There is some evidence that VEGF blockade may have utility in the management of psoriasis, although their potential has been largely unexplored. We hypothesized that a human skin organ culture could provide a stable ex vivo model in which the cutaneous microvascular network could be studied and experimentally manipulated. Methods: Punch biopsies (3 mm) of skin, donated by healthy individuals (39–72 years old, n = 5), were incubated with monoclonal antibody (mAb) to human VEGF (bevacizumab) at doses based on data from animal and clinical studies. After 3-day culture, cell death and proliferation as well as vascular endothelial cell changes were assessed using quantitative immunohistomorphometry. Results: Anti-VEGF mAb at 0.8 mg/mL induced a significant increase in cleaved caspase-3 expression in CD31+ cells (p < 0.05). None of the doses tested increased TUNEL or decreased Ki-67 expression in the basal layer of the epidermis, confirming the model’s viability. In addition, the lactate dehydrogenase (LDH) assay showed no increase in LDH activity in treated samples compared to untreated control. The highest anti-VEGF mAb dose (0.8 mg/mL) induced an increase in TUNEL expression in the upper epidermis, which did not correlate with caspase-3 immunoreactivity. Further investigation revealed that anti-VEGF mAb did not change the expression of markers of terminal differentiation such as keratin 10, filaggrin, and involucrin, suggesting that VEGF depletion does not affect keratinocyte terminal differentiation. In contrast to the control group, levels of VEGF protein were undetectable in the culture supernatant of samples treated with 0.8 mg/mL of anti-VEGF mAb, suggesting sufficient dose. Conclusion: Our pilot study provides the first evidence that anti-VEGF therapy promotes endothelial cell apoptosis in human skin ex vivo. Our pragmatic human skin organ culture assay offers a valuable tool for future preclinical endothelial cell and translational microvascular network/anti-angiogenesis research in human skin.
A Rare Case of an Osteoid Osteoma of the Cervical Spine
Authors: Silva Gomes Francisco , Alves Cristina , Cardoso Pedro Sa , Ling Tah Pu
Published: June 2020

Osteoid osteoma (OO) is a benign bone tumor rarely affecting the cervical spine. OO, currently diagnosed by X-ray, computed tomography (CT), bone scan, and magnetic resonance imaging, is difficult to identify when located in the cervical spine based on spine radiographs due to their usually small size and the complex anatomy of the cervical spine. CT scans successfully diagnose 20–30% of the small osteolytic lesions with dense sclerotic rings and central calcifications and the anatomic location of the nidus. CT-guided radiofrequency ablation is a noninvasive treatment option widely used. However, in specific cases, surgical resection of the nidus is recommended. We present a rare clinical case of cervical spine OO of a 16-year-old female patient. The lesion was located on the left lamina of C7, and once the diagnosis was established by physical examination and imaging, laminectomy and cervical arthrodesis (C6-T1) were performed. Twelve months after the surgical intervention, the patient showed complete remission of the symptoms and no disabilities.