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Hai-Feng Liu, Yang Lu, Qing Wang, Yu-Jie Lu, Wei Xing Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, 213000, People’s Republic of ChinaCorrespondence: Wei Xing, Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou City, Jiangsu Province, People’s Republic of China, Email suzhxingwei@suda.edu.cnPurpose: To develop and compare various machine learning (ML) classifiers that employ radiomics extracted from contrast-enhanced magnetic resonance imaging (CEMRI) for diagnosing pathological differentiation of hepatocellular carcinoma (HCC), and validate the performance of the best model.Methods: A total of 251 patients with HCCs (n = 262) were assigned to a training (n = 200) cohort and a validation (n = 62) cohort. A collection of 5502 radiomics signatures were extracted from the CEMRI images for each HCC nodule. To reduce redundancy and dimensionality, Spearman rank correlation, minimum redundancy maximum relevance (mRMR), and the least absolute shrinkage and selection operator (LASSO) approach were employed. Eight ML classifiers were trained to obtain the best radiomics model. The performance of each model was evaluated based on the area under the receiver operating characteristic curve (AUC). The radiomics model was integrated with liver imaging reporting and data system (LI-RADS) features to design a combined model.Results: The eXtreme Gradient Boosting (XGBoost)-based radiomics model outperformed other ML classifiers in evaluating pHCC, achieving an AUC of 1.00 and accuracy of 1.00 in the training cohort. The LI-RADS model demonstrated an AUC value of 0.77 and 0.82 in the training and validation cohorts. The combined model exhibited best performance in both the training and validation cohorts, with AUCs of 1.00 and 0.86 for evaluating HCC differentiation, respectively.Conclusion: CEMRI radiomics integrating LI-RADS features demonstrated excellent performance in evaluating HCC differentiation, suggesting an optimal clinical decision tool for individualized diagnosis of HCC differentiation.Keywords: machine learning, radiomics, LI-RADS, differentiation, hepatocellular carcinoma, HCC

Ming-Ying Lan,1,2 Yen-Bin Hsu,1,2 Ming-Chin Lan,3,4 Jyh-Ping Chen,5– 8 Yu-Jen Lu9 1Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; 2School of Medicine, National Yang-Ming University, Taipei, Taiwan; 3Department of Otolaryngology-Head and Neck Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 4School of Medicine, Tzu Chi University, Hualien, Taiwan; 5Department of Chemical and Materials Engineering, Chang Gung University, Taoyuan, Taiwan; 6Department of Plastic and Reconstructive Surgery and Craniofacial Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 7Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; 8Department of Materials Engineering, Ming Chi University of Technology, Taipei, Taiwan; 9Department of Neurosurgery, Chang Gung Memorial Hospital Linkuo Medical Center and College of Medicine, Chang Gung University, Taoyuan, TaiwanCorrespondence: Yu-Jen LuDepartment of Neurosurgery, Chang Gung Memorial Hospital Linkuo Medical Center and College of Medicine, Chang Gung University, Taoyuan, TaiwanEmail alexlu0416@gmail.comJyh-Ping ChenDepartment of Chemical and Materials Engineering, Chang Gung University, Taoyuan, TaiwanEmail jpchen@mail.cgu.edu.twIntroduction: Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Taiwan, and radiation therapy combined with or without chemotherapy is its mainstay treatment. Although it is highly sensitive to radiotherapy, local recurrence and distant metastasis remain difficult unsolved problems. In recent years, graphene oxide (GO) has been found to be a promising novel anticancer drug carrier. Here, we present our designed functionalized GO, polyethylene glycol-coated GO (GO-PEG), as a drug carrier, which was loaded with erlotinib and showed promising anticancer effects on NPC cells.Methods: The effects of GO-PEG-erlotinib on the proliferation, migration, and invasion of NPC cells were investigated by WST-8 assay, wound healing assay, and invasion assay, respectively. RNA sequencing was conducted and analyzed to determine the molecular mechanisms by which GO-PEG-erlotinib affects NPC cells.Results: Our results showed that GO-PEG-erlotinib reduced NPC cell viability in a dose-dependent manner and also inhibited the migration and invasion of NPC cells. The RNA sequencing revealed several related molecular mechanisms.Conclusion: GO-PEG-erlotinib effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. GO-PEG-erlotinib may be a potential therapeutic agent for treating NPC in the future.Keywords: nasopharyngeal carcinoma, anti-cancer, graphene oxide, erlotinib, drug carrier

Hsin-Ying Wu,1,* Kun-Ju Lin,2,* Ping-Yen Wang,1 Chi-Wen Lin,3 Hong-Wei Yang,3 Chen-Chi M Ma,3 Yu-Jen Lu,4 Tong-Rong Jan1 1Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan; 2Animal Molecular Imaging Center and Department of Nuclear Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan; 3Department of Chemical Engineering, National Tsing Hua University, Hsin-Chu, Taiwan; 4Department of Neurosurgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan *These authors contributed equally to this work Background: Graphene oxide (GO) is a promising nanomaterial for potential application in the versatile field of biomedicine. Graphene-based nanomaterials have been reported to modulate the functionality of immune cells in culture and to induce pulmonary inflammation in mice. Evidence pertaining to the interaction between graphene-based nanomaterials and the immune system in vivo remains scarce. The present study investigated the effect of polyethylene glycol-coated GO (PEG-GO) on antigen-specific immunity in vivo. Methods: BALB/c mice were intravenously administered with a single dose of PEG-GO (0.5 or 1 mg/kg) 1 hour before ovalbumin (OVA) sensitization, and antigen-specific antibody production and splenocyte reactivity were measured 7 days later. Results: Exposure to PEG-GO significantly attenuated the serum level of OVA-specific immunoglobulin E. The production of interferon-γ and interleukin-4 by splenocytes restimulated with OVA in culture was enhanced by treatment with PEG-GO. In addition, PEG-GO augmented the metabolic activity of splenocytes restimulated with OVA but not with the T-cell mitogen concanavalin A. Conclusion: Collectively, these results demonstrate that systemic exposure to PEG-GO modulates several aspects of antigen-specific immune responses, including the serum production of immunoglobulin E and T-cell functionality. Keywords: graphene oxide, T-cell, antigen-specific, immune, ovalbumin

Jyh-Ping Chen,1 Pei-Ching Yang,1 Yunn-Hwa Ma,2 Su-Ju Tu,3 Yu-Jen Lu1,41Department of Chemical and Materials Engineering, 2Department of Physiology and Pharmacology, 3Department of Medical Imaging and Radiological Sciences, Chang Gung University, Kwei-San, Taoyuan, Taiwan, Republic of China; 4Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan, Republic of ChinaBackground and methods: Silica-coated magnetic nanoparticle (SiO2-MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO2 surface, which provides abundant —NH2 functional groups for conjugating with tPA.Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO2-MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO2-MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO2-MNP (SiO2-MNP-tPA) did not alter blood component concentrations. After conjugating to SiO2-MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO2-MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO2-MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis.Conclusion: Biocompatible SiO2-MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.Keywords: magnetic nanoparticles, drug delivery, thrombolysis, tissue plasminogen activator, silica

Yu-Jen Lu1,2,#, Hung-Wei Yang1,#, Sheng-Che Hung3, Chiung-Yin Huang2, Shin-Ming Li4, Chen-Chi M Ma4, Pin-Yuan Chen2, Hong-Chieh Tsai2, Kuo-Chen Wei2, Jyh-Ping Chen1 1Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan, Taiwan; 2Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan; 3Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan#These authors contributed equally to this workBackground: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life.Methods: Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA–GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA–GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA–GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug.Results: Single layer PAA–GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA–GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 µg BCNU/mg PAA–GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA–GO–BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC50 value toward GL261 compared with the same dosage of free drug.Conclusion: Nanosized PAA–GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.Keywords: graphene oxide, BCNU, glioma cells, drug delivery, thermal stability

Objective: To verify the reliability and feasibility of Hoffmann method in establishing pediatric reference intervals (RI) of erythrocyte count., Methods: Three hundreds and ninty-two thousands of hospital-based data for erythrocyte count of children aged in 1 to 17, measured by the Sysmex Xs-800i, was collected from Beijing Children's Hospital during January to December 2014. Outliers were removed using the Dixon method, then Hoffmann method was conducted to establish the gender and age stratified pediatric RIs of erythrocyte count. The erythrocyte count of 2 217 healthy children, recruited from Beijing Children's Hospital and Liaocheng Children's Hospital in Shandong province, was conducted as normal reference to verify the reliability of Hoffmann method in establishing RIs and to compare with existing RIs., Results: In 4 subgroups as following, male aging 1 to 12 years, male aging 13 to 17 years, female aging 1 to 12 years, female aging 13 to 17 years, the RIs of erythrocyte count established using Hoffmann method were (4.1-5.4)×10(12)/L, (4.4-5.7)×10(12)/L, (4.0-5.3)×10(12)/L, (4.0-5.3)×10(12)/L, respectively. The verification results in 2 217 healthy children showed that the proportions of out of range in four subgroups were 6.17%, 8.81%, 6.22%, 7.78%, respectively., Conclusion: Hoffmann method produce reliable RIs according with the actual situation in healthy children, which is also convenient and is worth popularizing in clinical practice.

In the title complex, [Cu(4)Cl(4)(C(58)H(52)N(2)P(4))](n), four Cu(II) atoms are held together via two doubly bridging and two triply bridging chlorides, forming a stair-like Cu(4)Cl(4) core having crystallographically imposed inversion symmetry, while the benzene-1,4-diamine ligand (with a crystallographic inversion center at the centroid) acts in a tetra-dentate coordination mode, bridging two adjacent Cu(4)Cl(4) cores, resulting in a chain along the a-axis direction. One Cu atom has a distorted tetra-hedral geometry, coordinated by one P atom, one μ(2)-Cl and two μ(3)-Cl atoms, while the second Cu atom adopts a trigonal geometry, coordinated by one P atom, one μ(2)-Cl and one μ(3)-Cl atoms.