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Pao-Wen Yen,1 Hsing-Yu Lin,2 Chien-Chih Wu,2 Tai-Chung Huang,3 Shang-Ju Wu,3 Szu-Yu Pan,1,4 Kuan-Yu Hung1,5 1Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 2Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan; 3Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 4Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei City, Taiwan; 5Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Chien-Chih Wu, Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email r93451011@gmail.com Kuan-Yu Hung, Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email kyhung@ntu.edu.twBackground: Acute kidney injury (AKI) is a serious complication following high-dose methotrexate (HD-MTX) treatment, despite established preventive measures. This study presents a case report and a retrospective review of patients treated with HD-MTX, aiming to identify risk factors for AKI and propose a modified treatment protocol.Methods: We report a case of a 43-year-old man with diffuse large B-cell lymphoma who developed severe AKI after HD-MTX therapy. Additionally, a retrospective review of 70 patients receiving HD-MTX at our institution was conducted to identify predictors of AKI. Serum methotrexate levels were analyzed to determine their significance in predicting AKI.Results: The index patient developed methotrexate intoxication and severe AKI despite receiving standard prophylactic measures, requiring temporary hemodialysis. The retrospective review identified serum methotrexate levels as a significant predictor of AKI (OR 11.84, 95% CI: 2.62– 53.53, p = 0.001). Higher initial serum methotrexate levels correlated with the development of AKI.Conclusion: Timely measurement of serum methotrexate levels is crucial in managing and preventing AKI in patients undergoing HD-MTX therapy. Based on our findings, we propose a modified HD-MTX treatment protocol to reduce the incidence of AKI. This includes earlier serum methotrexate level monitoring and adjustments in urine alkalization and leucovorin dosing strategies.Keywords: methotrexate, acute kidney injury

Hsin-Ying Lin,1 Chung-Han Ho,2,3 Yu-Shiuan Lin,1 Shu-Chun Kuo,1,4 Yi-Chen Chen,2 Yung-Jen Cheng5 1Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan; 2Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Information Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 4Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan; 5Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, TaiwanCorrespondence: Yung-Jen Cheng, Department of Radiation Oncology, National Cheng Kung University Hospital, No. 138, Sheng Li Road, Tainan, 704, Taiwan, Email n052337@mail.hosp.ncku.edu.twPurpose: Continuous advancements in medical diagnostic technology and the growing availability of resources suggest a potential for fluctuations in the incidence rate of retinoblastoma (Rb). This study aimed to analyze incidence data of Rb patients in Taiwan from 1999 to 2018, utilizing the nationwide Taiwan Cancer Registry (TCR) database. Additionally, we investigated the treatment modalities used for these Rb patients and compared them with those observed in other countries.Patients and Methods: We conducted a retrospective cohort study utilizing data from the TCR database. The study cohort comprised individuals who were newly diagnosed with Rb between 1999 and 2018. The incidence of Rb was calculated as the number of patients with Rb per million live births, both for the entire population and for different gender groups and time periods. The trends in Rb incidence from 1999 to 2018 across various age groups and sexes were presented with the linear trend test.Results: From 1999 to 2018, a total of 248 cases of Rb were identified. The overall incidence rate over this 20-year period was 60.20 cases per million live births, corresponding to 1 case per 16,611 live births. Incidence rates for each 5-year period between 1999 and 2018 exhibited no significant differences. The study cohort was predominantly male, with 134 cases (54.03%) being males and 114 cases (45.97%) being females, resulting in an overall male-to-female sex ratio of 1.18. Females had lower relative risk than males (RR: 0.92, 95% CI: 0.72– 1.19). Primary surgical intervention was the preferred treatment modality for over 75% of the cases.Conclusion: This retrospective epidemiology study, using TCR from 1999 to 2018, indicated that no discernible trend of retinoblastoma incidence in Taiwan. Nevertheless, continuous monitoring of incidence rates and exploration of treatment strategies for retinoblastoma within the Taiwanese population are important to address potential changes in developing medical practices.Keywords: retinoblastoma, incidence rate, treatment outcome, Taiwan cancer registry

Bang Liu,1,2,* Jia Liu,3,* Xuan Mei,1,* Zhi-Qiang Zhang,1,2 Jian Fang,4 Li-Li Zhou,2 Jiao-Long Zheng,2 Hai-Yan Lin,2 Xiu-Ling Zhu,2 Dong-Liang Li1,2 1Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, People’s Republic of China; 2Department of Hepatobiliary Disease, 900TH Hospital of Joint Logistics Support Force, Fuzhou, 350025, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 4Department of Hepatobiliary Medicine, The Third Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong-Liang Li, Department of Hepatobiliary Disease, Fuzong Clinical Medical College of Fujian Medical University & 900TH Hospital of Joint Logistics Support Force, Fuzhou, 350025, People’s Republic of China, Email ldliang900@163.comBackground: PVTT is a hallmark of advanced hepatocellular carcinoma (HCC). We aim to explore the influence of non-invasive biomarkers on the occurrence of PVTT and develop and validate models for predicting prognosis in HBV-related HCC patients without PVTT.Methods: A total of 1026 HBV-related HCC patients without PVTT were enrolled, with 515 in the training cohort, 216 in the internal validation cohort, and 295 in the external validation cohort. We conducted Cox regression analyses to discern the independent risk factors associated with PVTT events, PFS, and OS, then constructed and validated predictive models. The predictive and discriminatory capabilities of models were assessed using the calibration, time-dependent ROC, and DCA curves.Results: In our study, 136 patients (13.3%) experienced PVTT events during the follow-up period. The Cox regression analysis unveiled that male gender, AAPR ≤ 0.49, APRI > 0.48, extrahepatic metastasis, and multiple tumors were independent risk factors for PVTT. In the training cohort, non-invasive biomarkers (AAR and APRI), AFP, ascites, and tumor-related characteristics (extrahepatic metastasis, tumor diameter, tumor number, and PVTT event) were independent risk factors for both OS and PFS, whereas age and ALBI grade independently correlated with OS. The C-indexes of OS and PFS nomogram models were 0.795 and 0.733 in the training cohort, 0.765 and 0.716 in the internal validation cohort, and 0.780 and 0.722 in the external validation cohort, respectively. Our models demonstrated strong predictive and discriminative abilities in all cohorts and yielded a greater net benefit compared to three traditional staging systems.Conclusion: Non-invasive biomarkers are expected to be reliable predictors for assessing PVTT risk and predicting prognosis among HBV-related HCC patients without PVTT.Keywords: non-invasive biomarker, portal vein tumor thrombosis, HBV-related HCC, nomogram, prognosis

Jhe-Yuan Hsu,1 Hsuan-Yu Lin,2 Yuan-Po Yang3– 5 1Division of General Practice, Department of Medical Education, Changhua Christian Hospital, Changhua, Taiwan; 2Division of Hematology/Oncology, Changhua Christian Hospital, Changhua, Taiwan; 3Department of Cardiology, Changhua Christian Hospital, Changhua, Taiwan; 4Ph.D Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University and National Health Research Institutes, Taichung, Taiwan; 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, TaiwanCorrespondence: Yuan-Po Yang, Department of Cardiology, Changhua Christian Hospital, No. 135, St. Nan-xiao, Chang-Hua City, 500209, Taiwan, Tel +886-917-153-130, Fax +886 04-7232942, Email yuanpo@gmail.comBackground: The most common sites for metastasis from head and neck cancers are the lungs, bones, and liver. We present a rare case of squamous cell carcinoma of the buccal mucosa that metastasized to the right ventricle, pericardium, and bilateral lungs.Methods: A 61-year-old man with oral squamous cell carcinoma (cT4aN2cM0) exhibited mass-like echogenicity adhering to the right ventricular free wall that was accidentally discovered after concurrent chemoradiotherapy. A biopsy of the mass confirmed the oral origin of the metastasis.Results: The patient received palliative care and died 1 month after being diagnosed with cardiac involvement.Conclusion: Cardiac involvement is often not assessed because of its low prevalence. Cardiac metastasis should be considered in patients with malignancies presenting with nonspecific cardiac symptoms.Keywords: heart, metastasis, squamous cell carcinoma, head and neck cancer, biopsy

Chung-Lin Lee,1– 5 Chih-Kuang Chuang,6,7 Huei-Ching Chiu,1 Ru-Yi Tu,6 Yun-Ting Lo,5 Ya-Hui Chang,1,5 Shuan-Pei Lin,1,3,5,6,8 Hsiang-Yu Lin1,3– 6,9 1Department of Pediatrics, MacKay Memorial Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine, National Yang-Ming Chiao-Tung University, Taipei, Taiwan; 3Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; 4MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; 5Department of Rare Disease Center, MacKay Memorial Hospital, Taipei, Taiwan; 6Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; 7College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan; 8Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; 9Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, TaiwanCorrespondence: Shuan-Pei Lin; Hsiang-Yu LinDepartment of Pediatrics, MacKay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei, 10449, TaiwanTel +886-2-2543-3535 ext. 3090; +886-2-2543-3535 ext. 3089Fax +886-2-2543-3642Email 4535lin@gmail.com; lxc46199@ms37.hinet.netAbstract: Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive disorder and is one of the lysosomal storage diseases. Patients with MPS IVA have a striking skeletal phenotype but normal intellect. The phenotypic continuum of MPS IVA ranges from severe and rapid progress to mild and slow progress. The diagnosis of MPS IVA is usually suspected based on abnormal bone findings and dysplasia on physical examination and radiographic investigation in the preschool years. In the past, only supportive care was available. Due to the early and severe skeletal abnormalities, the orthopedic specialist was usually the main care provider. However, patients need aggressive monitoring and management of their systemic disease. Therefore, they need an interdisciplinary team for their care, comprising medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. After the US Food and Drug Administration approved elosulfase alfa in 2014, patients older than 5 years could benefit from this treatment. Clinical trials showed clinically meaningful improvements with once-a-week intravenous dosing (2.0 mg/kg per week), significantly improving the 6min walk test, the 3min stair climb test, and respiratory function when compared with placebo. Elosulfase alfa is well-tolerated, and there is a good response indicated by decreasing urine glycosaminoglycans.Keywords: elosulfasealfa, enzyme replacement therapy, GALNS, lysosomal storage disorder, Morquio A, MPS IVA, mucopolysaccharidosis

Jong-Ming Hsu,1– 3,* Sheng-Jie Shiue,4,* Kuender D Yang,5– 7,* Han-Shiang Shiue,8 Yi-Wei Hung,4 Pavani Pannuru,4 Raju Poongodi,4 Hsin-Yi Lin,9,10 Jen-Kun Cheng3,4,11 1Department of Urology, Mackay Memorial Hospital, Taipei 10449, Taiwan; 2Mackay Junior College of Medicine, Nursing, and Management, Taipei 11260, Taiwan; 3Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan; 4Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan; 5Institute of Biomedical Science, Mackay Medical College, New Taipei City 252, Taiwan; 6Department of Pediatrics, Mackay Memorial Hospital, Taipei 10449, Taiwan; 7Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan; 8Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan; 9Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106, Taiwan; 10Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 106, Taiwan; 11Department of Anesthesiology, Mackay Memorial Hospital, Taipei 10449, Taiwan*These authors contributed equally to this workCorrespondence: Hsin-Yi LinDepartment of Chemical Engineering and Biotechnology, National Taipei University of Technology, No. 1, Sec 3, Zhongxiao E. Road, Taipei 106, Taiwan, Email hsinyibrunken@gmail.comJen-Kun ChengDepartment of Anesthesiology, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Taipei City 10449, TaiwanEmail jkcheng@usa.netPurpose: Nerve injury-induced pain is difficult to treat. In this study, we developed an alginate scaffold with human umbilical cord mesenchymal stem cell exosomes (EX-SC) to treat nerve injury-induced pain.Materials and Methods: The scaffold was prepared and characterized for its physical traits and biocompatibility. In vitro studies of PC12 and HEK293 cells were used to evaluate the neuroprotective and neurotrophic effects of exosomes. Right L5/6 spinal nerve ligation (SNL) was performed in Sprague-Dawley rats to induce mechanical allodynia and thermal hyperalgesia, evaluated by von Frey hair and radiant heat tests. The EX-SC was wrapped around ligated L5/6 spinal nerves for treatment. Western blotting and immunofluorescence staining were used to evaluate neuron/glial activation, cytokines and neurotrophic factor of affected dorsal root ganglion (DRG).Results: In cell culture assay, the exosomes induce neurite outgrowth of PC12 cells and protect PC12 and HEK293 cells against formaldehyde acid treatment. On post-ligation day 21, rats receiving EX-SC had significantly higher median (interquartile range) withdrawal threshold and latency [14.1 (13.7– 15.5) g, 14.2 (13.7– 15.3) s] than saline-SC-treated rats [2.1 (1.7– 3.0) g, 2.0 (1.8– 2.4) s, P=0.02 and 0.002]. The EX-SC also attenuated SNL-induced up-regulation of c-Fos, GFAP, Iba1, TNF-α and IL-1β, while enhancing the level of IL-10 and GDNF, in the ipsilateral L5/6 DRG. After implantation for 21 days, the EX-SC enhanced the expression of myelin basic protein and IL-10 in injured L5/6 axons.Conclusion: We demonstrate the EX-SC possesses antinociceptive, anti-inflammation and pro-neurotrophic effects in the SNL pain model. It could be a promising therapeutic alternative for nerve injury-induced pain.Keywords: exosome, nerve injury, neuropathic pain, scaffold, spinal nerve ligation, stem cell

Hung-Yuan Lin,1– 3 Ting-Yu Lin,4 Ya-Jung Chuang,5 Li-Ju Lai,6 Pi-Jung Lin7 1Department ofOpthalmology, Universal Eye Center, Zhong-Li, Taiwan, Republicof China; 2Department of Optometry, Central Taiwan University of Science and Technology, Taichung City, Taiwan, Republicof China; 3Department of Ophthalmology, Shanghai Ruidong Hospital, Shanghai, People’s Republic ofChina; 4Department of Chemistry, Barnard College, Columbia University New York, New York, NY, USA; 5Department of Ophthalmology, Universal Eye Center, Long-Tan, Taiwan, Republicof China; 6Department of Ophthalmology, Universal Eye Center, Chia-Yi, Taiwan, Republic ofChina; 7Department of Ophthalmology, Universal Eye Center, Taipei, Taiwan, Republic ofChinaCorrespondence: Ya-Jung Chuang Tel + 886-983308370Email rannyposh@gmail.comPurpose: The purpose of this study was to evaluate the efficacy of a novel double-docking technique, incorporating the use of femtosecond laser arcuate keratotomy (FSAK) in correcting low-degree astigmatism and Malyugin ring, in a patient with intraoperative floppy iris syndrome (IFIS).Methods: A case report of a 72-year-old man with grade 4 cataract, low-degree astigmatism (< 2D), and IFIS (pupil size < 4 mm, intraoperatively) is presented. The patient underwent cataract surgery using a femtosecond laser to treat low-degree astigmatism because the patient requested for the use of a multifocal intraocular lens (IOL). The first docking was performed to complete arcuate keratotomy, produce the mainparacentesis incisions, and create clear corneal incisions. Insertion of the Malyugin ring was performed after the first docking, whereas the second one was executed to complete continuous curvilinear capsulotomy and lens fragmentation. The patient’s uncorrected visual acuity (UCVA) was measured pre- and post-operatively. The complications were evaluated post-operatively and 3 months later during the follow-up visit.Results: The patient’s UCVA for distance improved from 0.3 (6/12 Snellen equivalent) to 0 (6/6 Snellen equivalent) logMAR post-operatively. During the follow-up visit, the patient’s uncorrected near visual acuity was at J2. His corneal astigmatism changed from − 1.0 Diopter @177° pre-operative to − 0.12 D @173° post-operative. No other intraoperative or post-operative complications were observed.Conclusion: The double-docking technique, with the use of FSAK, and Malyugin ring produced successful surgical outcomes for the patient. The benefits of this technique allow surgeons to avoid changing the shape of the patient’s cornea from the injection of the viscoelastic device into the anterior chamber, which could lower the femtosecond laser’s precision and docking location.Keywords: femtosecond laser arcuate keratotomy, Malyugin ring, low-degree, astigmatism, intraoperative floppy iris syndrome

Chia-Yi Lee,1,2,* Cheng-Chao Ching,1,* Chi-Chin Sun,3,4 Hung-Chi Chen,5–7 Hung-Yu Lin1,8–111Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua, Taiwan; 2Department of Optometry, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan; 3Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan; 4Department of Chinese Medicine, Chang Gung University, Taoyuan City, Taiwan; 5Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan; 6Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan; 7Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan; 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Department of Optometry, Chung Shan Medical University, Taichung, Taiwan; 10Department of Optometry, Yuanpei University of Medical Technology, Hsinchu, Taiwan; 11Department of Exercise and Health Promotion, Chung Chou University of Science and Technology, Changhua, Taiwan*These authors contributed equally to this workAbstract: Here we reported a rare case of the implantation of a dexamethasone intravitreal implant (DEX) in which decreased retinal vessel density (VD) was found by optical coherence tomography angiography (OCTA). A 74-year-old male with diabetes mellitus presented with bilateral macular edema. The best-corrected visual acuity (BCVA) was 0.6 in the right eye. Diabetic macular edema (DME) was diagnosed. A DEX for the right eye was planned, and the preoperative evaluation showed a superficial VD of 48.74 percent, a deep VD of 53.12 percent, and a foveal avascular zone (FAZ) 0.165 mm2 in size by OCTA. The BCVA in the right eye recovered to 0.8, and a notably lower superficial VD of 45.97 percent and a deep VD of 45.40 percent were observed with an enlarged FAZ of 0.294 mm2 one month postoperatively. Moreover, BCVA in the right eye was maintained at 0.8, while further reductions in both superficial (40.07 percent) and deep (40.91 percent) VD were noted with a FAZ measured at 0.305 mm2 two months postoperatively. In conclusion, retinal superficial and deep VD decreased, while the FAZ increased, after the implantation of the DEX in a patient with DME.Keywords: dexamethasone, Ozurdex, optical coherence tomography angiography, diabetic macular edema, retina

Wei-Quan Liang,1,* De Zeng,2,* Chun-Fa Chen,1 Shu-Ming Sun,1 Xiao-Feng Lu,1 Chun-yan Peng,3 Hao-Yu Lin1 1Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, People’s Republic of China; 2Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, People’s Republic of China; 3Department of Clinical Laboratory, Taihe Hospital of Hubei University of Medicine, Hubei 442008, People’s Republic of China *These authors contributed equally to this work Background: Growing evidence has indicated that the long noncoding RNA H19 (lncRNA H19), frequently deregulated in almost all tumor types tested, acted as a pivotal contributor to both cancer initiation and progression. However, the role of lncRNA H19 in human papillary thyroid carcinoma (PTC) remains controversial. The aim of the study was to investigate the expression and potential function of lncRNA H19 in human PTC.Patients and methods: The lncRNA H19 level was determined by quantitative real-time (RT)-PCR analyses in 58 PTC tissue samples and their paired paracancerous tissue samples. RNA interference, RT-PCR analysis, and Western blot assay were used to determine the impact of lncRNA H19 on epithelial-mesenchymal transition (EMT) markers in human PTC cells. The migratory and invasive capacities of PTC cells were determined by wound-healing and transwell migration and invasion assays.Results: lncRNA H19 expression was 2.417-fold higher in PTC tissues than their paired paracancerous tissue (95% CI: 1.898–2.935, P

Hung-Yuan Lin,1–3 Ya-Jung Chuang,4 Pi-Jung Lin,5 Yi-Ju Ho6 1Universal Eye Center, Zhong-Li, Taiwan, Republic of China; 2Department of Optometry, Central Taiwan University of Science and Technology, Taichung City, Taiwan, Republic of China; 3Ophthalmology Department, Shanghai Ruidong Hospital, Shanghai, China; 4Universal Eye Center, Long-Tan, Taiwan, Republic of China; 5Universal Eye Center, Taipei, Taiwan, Republic of China; 6Department of Ophthalmology, Chang Gung Memorial Hospital, Chiayi, Taiwan, Republic of China Purpose: To investigate the feasibility of a new method involving the use of the Verion image-guided system in preventing cyclorotation during femtosecond laser-assisted cataract surgery (FLACS). Patients: Our preliminary data included details of 24 consecutive patients. All patients underwent cataract surgery at Universal Eye Center, Zhong-Li, Taiwan, between December 2016 and January 2017. Methods: We developed a technique to use the Verion image-guided system in FLACS and evaluated whether this new technique is compatible with Femto LDV Z8. The Verion image-guided system was used to prevent misalignments. The only additional step in this technique is using a marking tool to place ink on the corneal limbus (at 3 and 9 o’clock positions) guided by the Verion digital marker system. Remaining procedures could be performed using the touchscreen of Femto LDV Z8 to calibrate the horizontal reference axis. Results: This study included 24 patients who underwent cataract surgery. The technique used could effectively neutralize misalignments at an average of 8.08° and 2.66° in clockwise and counterclockwise directions, respectively. Conclusion: This technique combines the advantages of iris fingerprinting technology and mobile features of Femto LDV Z8, has fewer transfer steps, improves centration of the eyes, and, most importantly, can prevent misalignments through cyclotorsion or docking procedures. Furthermore, this method can improve the accuracy of arcuate incisions and toric intraocular lens alignment in astigmatism correction. Keywords: cyclotorsion, astigmatism, alignment, fingerprint technology, toric

De Zeng,1,* Yingsheng Xiao,2,* Jianling Zhu,3 Chunyan Peng,4 Weiquan Liang,5 Haoyu Lin5 1Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China; 2Department of Thyroid Surgery, Shantou Central Hospital, Shantou 515000, China; 3Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou 515031, China; 4Department of Clinical Laboratory, Taihe Hospital of Hubei University of Medicine, Hubei 442008, China; 5Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, China *These authors contributed equally to this work Background: NPM1 is a multifunctional phosphoprotein that commutes between the cytoplasm and nucleus in cell cycle process, which appears to be actively involved in tumorigenesis. Herein, we sought to investigate the possible role and prognostic value of NPM1 in triple-negative breast cancer (TNBC). Methods: An array of public databases, including bc-GenExMiner v4.0, GOBO, GEPIA, UALCAN, ONCOMINE database and Kaplan-Meier plotter, were used to investigate the expression feature and potential function of NPM1 in TNBC. Immunohistochemistry, immunofluorescence, proliferation and colony formation, flow cytometry and western-blotting assays were used to analyze and verify the function and relevant mechanism of NPM1 in TNBC tissues and cells. Results: According to analysis from bc-GenExMiner, the expression level of NPM1 was significantly higher in basal-like subtypes than luminal-A, HER-2 or normal-like subtypes of breast cancer (P

Hsin-Ying Lin, Kai-Ling Peng Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan Abstract: Corneal bloodstaining, which is brown or dark yellow in color, is induced by hemoglobin deposition, and its breakdown products extend into the corneal stroma. In this article, we report a rare case of corneal bloodstaining induced by total hyphema after rebleeding for traumatic hyphema. The patient underwent irrigation of the anterior chamber (AC) and cataract surgery of the right eye after trauma. After oral and topical treatment the imprint of corneal bloodstaining faded, and it nearly disappeared after the procedures. Corneal bloodstaining is undoubtedly a vision-threatening complication of total hyphema after ocular trauma, surgical intervention, and even rebleeding. Removal of the total hyphema as soon as possible decreases the severity of corneal bloodstaining, shortens the course of spontaneous healing, and thus improves vision. Keywords: corneal bloodstaining, total hyphema, traumatic hyphema, rebleeding, corneal imprint

Shih-Chun Chao,1–3,* Chia-Yi Lee,1,* Chan-Wei Nien,1 Shih-Hao Tzeng,1 Hung-Yu Lin1,4–6 1Department of Ophthalmology, Show Chwan Memorial Hospital, Changhua, Taiwan, Republic of China; 2Department of Electrical and Computer Engineering, National Chiao Tung University, Hsinchu, Taiwan, Republic of China; 3Department of Optometry, Central Taiwan University of Science and Technology, Taichung, Taiwan, Republic of China; 4Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 5Department of Optometry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 6Department of Optometry, Yuanpei University of Medical Technology, Hsinchu, Taiwan, Republic of China *These authors contributed equally to this work Background: Postoperative endophthalmitis is a dreaded postsurgery complication which may lead to legal blindness. In addition to typical risk factors, some minor episodes may also lead to the occurrence of endophthalmitis. The purpose of the current study was to report a case of acute postoperative endophthalmitis caused by Staphylococcus hyicus in a patient with a contact history of felines.Case presentation: A 58-year-old Taiwanese female who had a history of contact with felines due to her occupation had received clear lens extraction surgery of the left eye on July 10, 2015. One day after the surgery, the best-corrected visual acuity (BCVA) of the left eye was 20/40, which rapidly deteriorated to light perception with hypopyon formation. She was admitted for acute postoperative endophthalmitis and received antibiotic therapy with topical levofloxacin instillation and intravitreal vancomycin plus amikacin injection. Trans pars plana vitrectomy (TPPV) was then performed 1 day after admission. The specimen obtained from the vitreous and anterior chambers yielded the growth of S. hyicus. The patient was discharged with BCVA measured by counting fingers. Another TPPV was arranged for the persistent vitreous opacity on October 20, 2015, and the BCVA recovered to 20/32 at the last visit.Conclusion: To our knowledge, this is the first case of acute postoperative endophthalmitis caused by S. hyicus due to feline contact. Unusual pathogens in the environment and personal hygiene status should be validated preoperatively to prevent the development of postoperative endophthalmitis. Keywords: Staphylococcal hyicus, feline, endophthalmitis, clear lens extraction

Hung-Yuan Lin,1,* Hsin-Yang Chen,1,2,* Han Bor Fam,3 Ya-Jung Chuang,1 Ronald Yeoh,4 Pi-Jung Lin5 1Universal Eye Center, Zhongli Branch, Zhongli County, TaoYuan City, Taiwan, Republic of China; 2Ophthalmology Department, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 3Ophthalmology Department, Tan Tock Seng Hospital, Jalan Tan Tock Seng, 4Ophthalmology Department, Eye and Retina Surgeons, Camden Medical Centre, Singapore; 5Universal Eye Center, Xinnan Branch, Taipei City, Taiwan, Republic of China *These authors contributed equally to this work Purpose: To assess the corneal keratometric values obtained using the VERION image-guided surgery system and other devices.Methods: This study evaluated the right eyes of 115 cataract patients before intraocular lens (IOL) implantation through consecutive tests using 5 devices: VERION Reference Unit , Placido-based corneal topography (OPD-Scan III), monochromatic light-emitting diodes (LenStar LS900 and AL-Scan), and rotary prism technology (auto kerato-refractometer KR-8800). Analyzed parameters were corneal steep and flat keratometric values (Ks and Kf) and corneal astigmatism and axis. These parameters were evaluated using the one-sample two-tailed t-test and the 95% limits of agreement (95% LOAs) between the devices.Results: The mean corneal cylinder value measurements were -0.97±0.63 D, -0.88± 0.60 D, -0.90±0.69 D, -0.90±0.67 D, and -0.83±0.60 D with VERION, LenStar, AL-Scan (2.4 mm), OPD III, and KR-8800, respectively. Only KR-8800 showed a significant difference from VERION in the corneal cylinder value (P

You-Sin Jian,1 Ching-Wen Chen,1 Chih-An Lin,2 Hsiu-Ping Yu,1 Hua-Yang Lin,3 Ming-Yuan Liao,1 Shu-Huan Wu,1 Yan-Fu Lin,1 Ping-Shan Lai1,2,4,5 1Department of Chemistry, 2PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, 3Preclinical Development Research Department, Holy Stone Healthcare Co., Ltd., Taipei, 4Research Center for Sustainable Energy and Nanotechnology, 5Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan Abstract: Carrier-mediated drug delivery systems are promising therapeutics for targeted delivery and improved efficacy and safety of potent cytotoxic drugs. Nimesulide is a multifactorial cyclooxygenase 2 nonsteroidal anti-inflammatory drug with analgesic, antipyretic and potent anticancer properties; however, the low solubility of nimesulide limits its applications. Drugs conjugated with hyaluronic acid (HA) are innovative carrier-mediated drug delivery systems characterized by CD44-mediated endocytosis of HA and intracellular drug release. In this study, hydrophobic nimesulide was conjugated to HA of two different molecular weights (360 kDa as HA with high molecular weight [HAH] and 43kDa as HA with low molecular weight [HAL]) to improve its tumor-targeting ability and hydrophilicity. Our results showed that hydrogenated nimesulide (N-[4-amino-2-phenoxyphenyl]methanesulfonamide) was successfully conjugated with both HA types by carbodiimide coupling and the degree of substitution of nimesulide was 1%, which was characterized by 1H nuclear magnetic resonance 400 MHz and total correlation spectroscopy. Both Alexa Fluor® 647 labeled HAH and HAL could selectively accumulate in CD44-overexpressing HT-29 colorectal tumor area in vivo, as observed by in vivo imaging system. In the in vitro cytotoxic test, HA–nimesulide conjugate displayed >46% cell killing ability at a nimesulide concentration of 400 µM in HT-29 cells, whereas exiguous cytotoxic effects were observed on HCT-15 cells, indicating that HA–nimesulide causes cell death in CD44-overexpressing HT-29 cells. Regarding in vivo antitumor study, both HAL–nimesulide and HAH–nimesulide caused rapid tumor shrinkage within 3 days and successfully inhibited tumor growth, which reached 82.3% and 76.4% at day 24 through apoptotic mechanism in HT-29 xenografted mice, without noticeable morphologic differences in the liver or kidney, respectively. These results indicated that HA–nimesulide with improved selectivity through HA/CD44 receptor interactions has the potential to enhance the therapeutic efficacy and safety of nimesulide for cancer treatment. Keywords: COX-2 inhibitor, nimesulide, hyaluronic acid, CD44, colorectal cancer

Hung-Yuan Lin,1–3 Yi-Ting Fang,4 Ya-Jung Chuang,5 Justin N Karlin,6 Hsin-Yang Chen,7 Szu-Yuan Lin,8 Pi-Jung Lin,9 Ming Chen10 1Universal Eye Center, Zhong-Li, Taiwan, Republic of China; 2Department of Optometry, Central Taiwan University of Science and Technology, Taichung, Taiwan, Republic of China; 3Department of Ophthalmology, Fu-Jian Medical University, People’s Republic of China; 4Universal Eye Center, Taoyuan, Taiwan, Republic of China; 5Universal Eye Center, Long-Tan, Taiwan, Republic of China; 6Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA; 7Department of Ophthalmology, Ningbo First Hospital, People’s Republic of China; 8Department of Ophthalmology, Cathay General Hospital, 9Universal Eye Center, Taipei, Taiwan, Republic of China; 10Department of Surgery, Division of Ophthalmology, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA Abstract: During toric intraocular lens (IOL) implantation, surgeons must take particular care to ensure that inaccurate preoperative measurement and intraoperative misalignment do not cause unexpected postoperative residual astigmatism. This retrospective, comparative case series study aimed to analyze the rotational deviation, or cyclotorsion, of three corneal marking methods: VERION digital marker (VDM; reference), horizontal slit beam marking (HSBM), and subjective direct visual marking (SDVM) on the table (using a bevel knife tip). Subjects included 81 eyes of 61 patients (mean age: 65.70±13.14 years; range: 32–91 years) undergoing scheduled cataract surgery. A preoperative reference image was taken of each eye. Subsequently, a slit lamp with the light beam turned to the horizontal meridian was used to align the seated patient’s head, and two reference marks were placed at the 3- and 9-o’clock positions of the corneal limbus using a 27-gauge needle and marking pen (HSBM). Upon transfer to the surgical table, the VDM was used to display a real-time dial scale on the patient’s eye, with the entrance of the temporal clear corneal incision (CCI) at 0° (horizontal meridian). Simultaneously, a bevel knife tip was used to create a marker based on the surgeon’s visual determination of the temporal 0° point (SDVM). We used the VDM to quantitatively evaluate the accuracy of axis alignment via deviation from the horizontal reference meridian. Compared with the reference meridian, the SDVM (–3.46°±7.32°, range: –18° to 13°) exhibited greater average relative cyclotorsion versus the HSBM (0.41°±4.92°, range: –10° to 10°). Furthermore, the mean average misalignment was significantly less in the HSBM group versus the SDVM group (t=4.179, P

Thangirala Sudha,1 Dhruba J Bharali,1 Murat Yalcin,1,2 Noureldien HE Darwish,1,3 Melis Debreli Coskun,1,4 Kelly A Keating,1 Hung-Yun Lin,5,6 Paul J Davis,1,7 Shaker A Mousa1 1The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA; 2Department of Physiology, Veterinary Medicine Faculty, Uludag University, Gorukle, Bursa, Turkey; 3Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 4Department of Biology, Faculty of Arts and Sciences, Uludag University, Gorukle, Bursa, Turkey; 5PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, 6Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; 7Department of Medicine, Albany Medical College, Albany, NY, USA Abstract: The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P

Seung-Hun Kim,1,* Chun-Yen Liu,1,* Po-Wei Fan,1 Chang-Heng Hsieh,1 Hsuan-Yuan Lin,1 Ming-Chung Lee,2 Kang Fang1 1Department of Life Science, National Taiwan Normal University, Taipei, 2Brion Research Institute of Taiwan, New Taipei City, Taiwan *These authors contributed equally to this work Abstract: As a practical and safe herbal medicine, the seeds of Brucea javanica (L.) Merr., were used to cure patients suffering from infectious diseases such as malaria. Recent advances revealed that the herb could also be a useful cancer therapy agent. The study demonstrated that aqueous B. javanica (BJ) extract attenuated the growth of human non-small-lung cancer cells bearing mutant L858R/T790M epidermal growth factor receptor (EGFR). The reduced cell viability in H1975 cells was attributed to apoptosis. Transfection of EGFR small hairpin RNA reverted the sensitivities. When nude mice were fed BJ extract, the growth of xenograft tumors, as established by H1975 cells, was suppressed. Additional histological examination and fluorescence analysis of the resected tissues proved that the induced apoptosis mitigated tumor growth. The work proved that the BJ extract exerted its effectiveness by targeting lung cancer cells carrying mutated EGFR while alleviating tumorigenesis. Aqueous BJ extract is a good candidate to overcome drug resistance in patients undergoing target therapy. Keywords: Brucea javanica, target therapy, epidermal growth factor receptor, human lung, herbal medicine, apoptosis

Kuo-Hsuan Chang,1,* I-Cheng Chen,1,* Hsuan-Yuan Lin,2 Hsuan-Chiang Chen,2 Chih-Hsin Lin,1 Te-Hsien Lin,2 Yu-Ting Weng,1 Chih-Ying Chao,1 Yih-Ru Wu,1 Jung-Yaw Lin,2 Guey-Jen Lee-Chen,2 Chiung-Mei Chen1 1Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 2Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China *These authors contributed equally to this work Background: Alzheimer’s disease (AD) and several neurodegenerative disorders known as tauopathies are characterized by misfolding and aggregation of tau protein. Although several studies have suggested the potential of traditional Chinese medicine (TCM) as treatment for neurodegenerative diseases, the role of TCM in treating AD and tauopathies have not been well explored.Materials and methods: Tau protein was coupled to the DsRed fluorophore by fusing a pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) with DsRed. The ΔK280 tauRD-DsRed fusion gene was then used to generate Tet-On 293 and SH-SY5Y cell clones as platforms to test the efficacy of 39 aqueous extracts of TCM in reducing tau misfolding and in neuroprotection.Results: Seven TCM extracts demonstrated a significant reduction in tau misfolding and reactive oxidative species with low cytotoxicity in the ΔK280 tauRD-DsRed 293 cell model. Glycyrrhiza inflata and Panax ginseng also demonstrated the potential to improve neurite outgrowth in the ΔK280 tauRD-DsRed SH-SY5Y neuronal cell model. G. inflata further rescued the upregulation of ERN2 (pro-apoptotic) and downregulation of unfolded-protein-response-mediated chaperones ERP44, DNAJC3, and SERP1 in ΔK280 tauRD-DsRed 293 cells.Conclusion: This in vitro study provides evidence that G. inflata may be a novel therapeutic for AD and tauopathies. Future applications of G. inflata on animal models of AD and tauopathies are warranted to corroborate its effect of reducing misfolding and potential disease modification. Keywords: Alzheimer’s disease, tauopathy, tau misfolding, TCM extracts, G. inflata, UPR-mediated chaperones

Ding-Siang Huang,1,* Hsuan-Yuan Lin,1,2,* Guey-Jen Lee-Chen,1 Hsiu-Mei Hsieh-Li,1 Chung-Hsin Wu,1 Jung-Yaw Lin1,21Department of Life Science, National Taiwan Normal University, 2Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei City, Taiwan, Republic of China*These authors contributed equally to this workAbstract: Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extract, EGb 761, contains flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The neuroprotective effects of EGb 761 are obvious, but whether the EGb 761 has therapeutic effects in SCA 17 is still unclear. To manage our issues, we have generated TBP/79Q-expressing SH-SY5Y cells and SCA 17 transgenic mice with the mutant hTBP gene. In in vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate-insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In in vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneal injection per day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can be a remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cell and animal models. Therefore, we suggest that EGb 761 may be a potential therapeutic agent for treating SCA 17.Keywords: spinocerebellar ataxia type 17, excitotoxicity, EGb 761, polyQ diseases, apoptosis

Hung-Yin Lin1,2, James L Thomas3, Huan-Wen Chen1, Chih-Min Shen4, Wen-Jen Yang2, Mei-Hwa Lee41Department of Chemical and Materials Engineering, National University of Kaohsiung, Kaohsiung, Taiwan; 2Institute of Biotechnology, National University of Kaohsiung, Kaohsiung, Taiwan; 3Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM; 4Department of Materials Science and Engineering, I-Shou University, Kaohsiung, TaiwanAbstract: There is increasing interest in using natural products as anticancer agents, as many have antioxidative properties that may help to prevent cellular damage that can lead to cancer. In addition, there is the expectation that many natural products will have low toxicity and few side effects. However, most anticancer and antioxidative agents are hydrophobic, reducing their bioavailability in vivo and making them problematic to deliver. Curcumin provides a good model system for study. In low doses it shows both anticancer and antioxidation effects, whereas in high doses and delivered locally it could be cytotoxic for cancer cells. In this paper, curcumin microemulsions were formed with food-grade chemicals, including soybean lecithin, soybean oil, and Tween 80, a Food and Drug Administration-approved surfactant. The optimized composition formed curcumin microemulsions with a mean size of 40–50 nm, carrying a concentration of curcumin as high as 15 µM. The stability of curcumin microemulsions refrigerated at 5°C over at least 968 days was assessed by size distribution and zeta potential. The effects of low-frequency ultrasound on two oral squamous cell carcinoma cell lines (OSCC-4 and OSCC-25), and the synergy between treatment with curcumin microemulsions and low-frequency sonic stimulation, were tested. Finally, microscopic imaging of the cells confirmed the toxic effects of the curcumin microemulsions, showing damaged and ruptured cells after treatment. Brief exposure to the curcumin-containing microemulsions did have cytotoxic effects, but the addition of ultrasound strongly enhanced those effects, especially on OSCC-25 cells.Keywords: oral squamous cell carcinoma (OSCC), curcumin, microemulsion, ultrasound, controlled release

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value