AAPS Open最新文献

{"title":"Pre-analytical stability of ocrelizumab in serum after delayed centrifugation of whole blood","authors":"Jeongsup Shim, Montserrat Carrasco-Triguero, Saloumeh K. Fischer","doi":"10.1186/s41120-024-00098-9","DOIUrl":"https://doi.org/10.1186/s41120-024-00098-9","url":null,"abstract":"<p>Ocrelizumab, an anti-CD20 antibody that depletes B cells (Hauser et al. 2017; Montalban et al. 2017; Carlson et al. 2024), is approved for treating various forms of multiple sclerosis (MS) in adults, including relapsing multiple sclerosis (RMS), active secondary progressive disease, and primary progressive multiple sclerosis (PPMS). Since its approval in 2017, this groundbreaking treatment has continued to expand its reach with ongoing clinical studies such as investigating its efficacy in pediatric MS (Bibinoglu Amirov et al. 2023) and testing subcutaneous injections as a way to enhance and expedite drug delivery in patients (Xu et al. 2023). This exploration into the subcutaneous route of administration highlights the continued efforts to maximize patient-centered therapy.</p><p>Accurate and precise pharmacokinetic (PK) measurements are crucial in the clinical development of therapeutic drugs, including ocrelizumab (Gibiansky et al. 2021) in order to evaluate drug exposure and the PK/PD (pharmacodynamics) relationship (Danhof et al. 2008), to inform the optimal dose for patients, the frequency of administration, and the duration of the therapy (Tang and Cao 2021).</p><p>During clinical trials, samples from patients are collected for drug measurements and PK characterization. This necessitates for patients to travel to clinical sites to have a phlebotomist collect blood samples which are processed within 30 min -1 h to generate serum/plasma used for drug measurements (Tuck et al. 2009). For some individuals living with debilitating diseases like multiple sclerosis (MS) making routine clinic visits can be challenging. A patient-centric approach would be to collect blood samples at patient’s home, so patients can undergo necessary tests without the burden of traveling to medical facilities. In addition to convenience, this approach promotes patient adherence to treatment and monitoring regimens and reducing patients’ risk of exposure to infections. However, prior to enabling in-home sample collection by nurses, the impact of collection logistics and processing must be evaluated. Therefore, for ocrelizumab, this necessitated a study to evaluate the impact of whole blood delayed centrifugation on serum drug concentration measurements.</p><p>Numerous investigations have assessed the influence of whole blood delayed centrifugation on the stability of endogenous proteins such as metabolites in serum or plasma (Debik et al. 2022; Qundos et al. 2013; Zhang et al. 1998; Salvagno et al. 2009). Amongst those studies, stability was tested and demonstrated for total protein (immunoglobulins represent ~ 40%) for up to 1 week at room temperature (Hedayati et al. 2020), for IgA, IgG and IgM for up to 10 h (Henriksen et al. 2014) and for IgE for up to 48 h (Ostergaard and Sandfeld-Paulsen 2023). However, to the authors knowledge, there is a lack of information on delayed centrifugation impact on the stability of antibody therapeutics.</p><p>Here, we demonstrat","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"197 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization, stability, and skin application of astaxanthin particulates","authors":"Miyu Ai, Risa Kanai, Hiroaki Todo, Junki Tomita, Takashi Tanikawa, Yutaka Inoue","doi":"10.1186/s41120-024-00099-8","DOIUrl":"https://doi.org/10.1186/s41120-024-00099-8","url":null,"abstract":"Astaxanthin (AX), commonly used for dermal applications, exhibits anti-inflammatory and antioxidant activities; however, it has poor water solubility. In this study, we investigated the physicochemical properties of AX-containing particulates formulated using the amphiphilic graft copolymer Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: Sol) and polyethylene glycol-2000 (PEG 2000); in addition, the stability and skin applications of AX particulates were investigated. AX, Sol, and PEG were mixed by weight to prepare AX particles using the hydration method. The prepared particles were subjected to stability evaluations including particle size distribution, zeta potential estimation, and fluorescence spectroscopy as well as physical evaluations including 1H-1H NOESY NMR spectral measurement, powder X-ray diffraction, and differential scanning calorimetry. Functional evaluations included singlet oxygen scavenging, skin permeation test, and fluorescence microscopy. Relatively stable particles of Sol/AX and Sol/PEG 2000/AX, approximately 100 nm and 125 nm in size, respectively, were formed at a mixed weight ratio (9/1) of 0.1 M Ascorbic Acid solution (0.1 M ASC) and a mixed weight ratio (8/1/1) of 0.1 M ASC, respectively, at 25 °C after storage for 14 days under light-shielded condition. Stability evaluations revealed a decrease in fluorescence intensity and color fading for Sol/AX = 9/1 and Sol/PEG 2000/AX = 8/1/1 (dispersion medium: distilled water); however, no change in fluorescence intensity of AX was observed immediately after preparation in Sol/AX = 9/1 and Sol/PEG 2000/AX = 8/1/1 (dispersion medium: 0.1 M ASC). The fluorescence intensity of AX did not fluctuate significantly immediately after adjustment, and the particles remained stable, showing a bright orange color with time. NMR spectra of Sol/AX = 9/1 and Sol/PEG 2000/AX (dispersion medium: 0.1 M ASC) showed the interactions between the CH3 group e from Sol (1.8 ~ 2.0 ppm) and the CH groups H-15,11 from AX (6.7 ~ 6.8 ppm), 8’,12’ (6.4 ~ 6.5 ppm), H-10,14 (6.4 ~ 6.5 ppm), and 7,7’ (6.2 ~ 6.3 ppm), indicating the disappearance of cross peaks. Furthermore, new cross peaks were identified for the CH3 group e of Sol (1.8 ~ 2.0 ppm), the 7-membered ring z of Sol (1.5 ~ 1.8 ppm), the 5-membered ring S of ASC (3.5 ~ 3.6 ppm), the CH group T (3.8 ~ 3.9 ppm), and the CH group U (4.7 ppm). Fluorescence microscopy observations of microparticles formulated with Sol/PEG 2000/AX showed a slight improvement in skin penetration. New AX particulates were formed using Sol/PEG 2000/AX = 8/1/1, suggesting that Sol/PEG 2000/AX maintained the stability and improved the skin penetration of AX.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A controlled vocabulary and taxonomy for the submission of quality attributes for therapeutic proteins","authors":"Joel T. Welch, Steven Kozlowski, Bazarragchaa Damdinsuren, Brian A. Roelofs","doi":"10.1186/s41120-024-00096-x","DOIUrl":"https://doi.org/10.1186/s41120-024-00096-x","url":null,"abstract":"Structured product quality data offer tremendous promise to revolutionize the submission of drug applications. However, the quality attributes for biological products do not have a systematic naming taxonomy, and consequently this limit poses a critical challenge in the development of systems for structured regulatory submissions. Here, we describe the creation of a controlled vocabulary with a structured taxonomical naming approach for quality attributes of therapeutic proteins. Additionally, we endeavor to make the case for why such systematic harmonized naming is required to support the successful implementation of structured data systems. We also describe the key principles of our structured naming approach, including a top-down view of the product and protein structure and a distinction between a quality attribute and the test to evaluate the attribute. Finally, we describe how this approach can accommodate emerging product types, advanced manufacturing technologies, and be used across the variety of submission sections in a regulatory dossier that discusses quality attributes.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"359 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An in-silico approach towards multivariate acceptable ranges in biopharmaceutical manufacturing","authors":"Marco Kunzelmann, Judith Thoma, Sabrina Laibacher, Joey M. Studts, Beate Presser, Julia Spitz","doi":"10.1186/s41120-024-00095-y","DOIUrl":"https://doi.org/10.1186/s41120-024-00095-y","url":null,"abstract":"Multivariate interactions between process parameters can heavily impact product quality and process performance in biopharmaceutical manufacturing processes. Thus, multivariate interactions should be identified and appropriately controlled. This article describes an in-silico approach to establish multivariate acceptable ranges; these ranges help to illustrate the combined impact of multiple input variables on product quality and process performance. Additionally, this article includes a case study for a monoclonal antibody polishing application. Proven acceptable ranges are set by changing only one input parameter at a time while keeping all others constant to understand the impact of process variability on product quality or process performance, but the impact of synergistic variables are not evaluated. Within multivariate acceptable ranges, any combination of input parameters of a unit operation yields the desired product quality and process performance. The layered approach applied in this article is based on risk assessment and statistical models to leverage prior knowledge and existing data. The risk assessment is specific for a manufacturing facility but is applicable to multiple products manufactured in the same facility. No additional wet-lab experiments are required for building the statistical models when development and process characterization are executed using a design of experiments approach, compared to a univariate evaluation of data. The established multivariate acceptable range justifies revised normal operating ranges to ensure process control. Further, the determination of multivariate acceptable ranges adds to overall process knowledge, ultimately supporting the implementation of a more effective control strategy.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer","authors":"Jiayi Shen, Liping Chen, Yulan Song, Sheng Chen, Wei Guo, Yongdong Li","doi":"10.1186/s41120-024-00094-z","DOIUrl":"https://doi.org/10.1186/s41120-024-00094-z","url":null,"abstract":"Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Falsified and problematic methandienone products available online: active pharmaceutical ingredient identification by portable Raman spectrometers and quantification by ultra-high-performance liquid chromatography–Fourier transform mass spectrometry","authors":"Robin Schreiber, Manami Hori, Chisato Takahashi, Mohammad Sofiqur Rahman, Ayane Nakao, Shu Zhu, Feiyu Zhu, Naoko Yoshida, Keiko Maekawa, Kazuko Kimura","doi":"10.1186/s41120-024-00093-0","DOIUrl":"https://doi.org/10.1186/s41120-024-00093-0","url":null,"abstract":"This study aimed on the one hand to clarify the quality, authenticity, safety, and other issues related to products of the anabolic-androgenic steroid methandienone advertised on the Internet and personally imported to Japan and on the other hand to evaluate the use of two portable Raman spectrometers in identifying the active pharmaceutical ingredient (API). The study found that all n = 15 samples purchased from 14 websites were problematic regarding their package, labeling, and/or content. Specifically, one sample (6.7%) was confirmed falsified, twelve samples (80%) were found either to be falsified or unlicensed as pharmaceutical product, and two samples (13.3%) were received without information on the manufacturers’ physical address or country of origin, with one sample (6.7%) having no labeling or other accompanying information at all. Both Raman spectrometers were able to identify the API in all samples as confirmed and quantified by ultra-high-performance liquid chromatography–Fourier transform mass spectrometry. Twelve samples contained on average less than 90% of the declared API content. By contacting national regulatory authorities in 44 countries, methandienone products were found to be approved in 1 country and not approved in 21 countries. To prevent health hazards and abuse, measures against the acquisition of anabolic-androgenic steroids from unknown sources are required. Portable Raman spectrometers may be suitable for the non-destructive and quick identification of methandienone in tablets. ","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141252816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of chemical penetration enhancers on the transdermal delivery of olanzapine in human skin in vitro","authors":"Amitkumar Virani, Nirali Dholaria, Hana Mohd, Nubul Albayati, Bozena Michniak-Kohn","doi":"10.1186/s41120-024-00092-1","DOIUrl":"https://doi.org/10.1186/s41120-024-00092-1","url":null,"abstract":"This research study involves the development of an olanzapine (OLZ) formulation using various chemical penetration enhancers (CPEs) for transdermal delivery. The aim of this study was to obtain the initial data needed about the effects of various CPEs on the skin permeation of OLZ. The effects of the selected CPEs were examined by studying the permeation profiles of OLZ from formulations applied to human cadaver skin samples. A control formulation of OLZ in propylene glycol (PG) was prepared and compared against formulations containing chemical penetration enhancers. Five different CPEs (oleic acid (OA), cineole (Cin), isopropyl alcohol (IPA), Tween 80 (T80), and N-methyl pyrrolidone (NMP)) at 5% w/w were individually added to the formulation containing OLZ in PG. The in vitro permeation study was carried out using vertical Franz diffusion cells mounted with human cadaver skin. Samples from the receptor compartment of the cell were collected at 2 h, 4 h, 8 h, 12 h, and 24 h at room temperature. The amount (µg/cm2) of permeated drug (OLZ) was measured using a validated HPLC method, and the percentage (%) of OLZ permeated was calculated. Based on the data obtained, different CPEs were found to have a significant impact on OLZ permeability compared to the control formulation. The most effective chemical penetration enhancer was shown to be 5% w/w OA with a 3.3-fold increase in enhancement ratio (ER). The rank of order for the highest concentration of OLZ permeated from each of CPE containing formulation was as follows: OA > Cin > IPA > T80 > NMP. The most effective chemical penetration enhancer was OA but the cytotoxic study using human fibroblast cells suggests that OA may not be safe due to its cytotoxic effects.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140829677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissolution profile evaluation of selected brands of amoxicillin-clavulanate potassium 625 mg tablets retailed in Hawassa town, Sidama Regional State, Ethiopia","authors":"Eyob Endashaw, Ramanjireddy Tatiparthi, Tesfaye Mohammed, Henok Teshome, Markos Duguma, Yesuneh Tefera","doi":"10.1186/s41120-024-00091-2","DOIUrl":"https://doi.org/10.1186/s41120-024-00091-2","url":null,"abstract":"Poor quality amoxicillin-clavulanate potassium tablets have been recently discovered in generic drugs related to Augmentin-like medicines containing amoxicillin and clavulanic acid, as well as its derivatives containing falsified active ingredients. One of the most important dosage form characteristics are a detailed active pharmaceutical ingredients dissolution release profile evaluation obtained through dissolution testing. The dissolution test is used in the development of both brand-name and generic drugs. Prior to beginning bioequivalence studies, it is critical to compare the dissolution profiles of various pharmaceutical products. As a result, dissolution is a critical quality control parameter for drugs because it has a direct impact on absorption of pharmaceutical products. Dissolution profile evaluation of seven brands of amoxicillin-clavulanate potassium tablets is retailed in Hawassa town, Sidama Regional State, Ethiopia. The seven brands of amoxicillin-clavulanate potassium tablets were collected from Hawassa town, Sidama Regional State, Ethiopia. The dissolution study was conducted as per USP40-NF35. Then, the dissolution profile test results were compared by one-way ANOVA Dunnett’s test, model independent, and model dependent method. All of the included brand tablets complied with a single-point dissolution study specification. All brand tablets had similar dissolution profiles (p > 0.05), difference factor (f1) < 15%, and dissolution efficiency $$(le 10varvec{%}$$ ). However, the f2 (similarity factor) value justifies that all brand tablets were not within USFDA specification ( $$ge$$ 50%). The evaluated brands followed the Korsemeyer-Peppas followed by the Weibull curve models. All brand tablets passed the single point USP dissolution specification and the USFDA therapeutic interchangeability guideline. The similarity factor (f2), on the other hand, confirmed that none of the tested brand tablets were interchangeable with the innovator product. Therefore, researchers, national medicine regulatory bodies, and the manufacturer should conduct a properly designed dissolution test as proof of an in vitro bioequivalence study supported by in vivo bioavailability data. Dissolution profile evaluation of seven brands of amoxicillin-clavulanate potassium tablets retailed in Hawassa town, Sidama Regional State, Ethiopia. Why was the study done? Ever since a medicine must dissolve before it can be absorbed. Because the rate at which a drug dissolves from a dosage form generally influences the rate and amount of absorption. The Food and Drug Administration (FDA) should recommend that amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Augmentin with no significant difference in absorption after oral administration. When given orally, drugs with slow dissolution rates have intermittent and inadequate absorption, resulting in limited bioavailability. Aside from that, when a signif","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140575805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acceleration of new medicines–CMC lessons learned from emergency use authorizations","authors":"James Bernstein, Kim Huynh-Ba, Patrick Lynch, Thomas Oliver, Reza Oliyai, Scott W. Roberts, Andrea Schirmer, David Schwinke, Kin Tang, Jessica Ursin","doi":"10.1186/s41120-023-00089-2","DOIUrl":"https://doi.org/10.1186/s41120-023-00089-2","url":null,"abstract":"The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on July 15, 2022, to provide a forum to discuss industry and regulator CMC challenges associated with emergency use authorizations.","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"2012 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140025773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Observation of antitumor mechanism of GE11-modified paclitaxel and curcumin liposomes based on cellular morphology changes","authors":"Hailing Tang, Lijuan Li, Baoshan Wang","doi":"10.1186/s41120-023-00090-9","DOIUrl":"https://doi.org/10.1186/s41120-023-00090-9","url":null,"abstract":"Curcumin and paclitaxel are widely used as anti-tumor hydrophobic model drugs for the designation of smart tumor-targeting nanocarriers and the study of the correlation between structural characteristics of nanoparticles and in vivo therapeutic efficacy. Various signaling pathways on cell growth and proliferation have been comprehensively studied in vitro and in vivo under the action of curcumin and paclitaxel nanoparticles. In this paper, we prepared EGFR-targeted GE11 peptide-modified curcumin and paclitaxel compound liposomes (CUR-PTX@GE11-L). The tumor suppression mechanism of CUR-PTX@GE11-L is observed from the aspects of drug release behavior, changes of cell morphology, liver retention, and tumor-targeting efficiency. We hope it can provide a new vision for the rational construction of smart nanoscale drug delivery system through the observation of cytotoxic effects of CUR-PTX@GE11-L, especially on the cellular morphology change. ","PeriodicalId":453,"journal":{"name":"AAPS Open","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139758158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}