Publications by authors named "Yu-Li Chen"

73 Publications

Perilla (Perilla frutescens) leaf extract inhibits SARS-CoV-2 via direct virus inactivation.

Biomed J 2021 Jan 28. Epub 2021 Jan 28.

Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address:

Background: While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presents with mild or no symptoms in most cases, a significant number of patients become critically ill. Remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19) in several countries, but its use as monotherapy has not substantially lowered mortality rates. Because agents from traditional Chinese medicine (TCM) have been successfully utilized to treat pandemic and endemic diseases, we designed the current study to identify novel anti-SARS-CoV-2 agents from TCM.

Methods: We initially used an antivirus-induced cell death assay to screen a panel of herbal extracts. The inhibition of the viral infection step was investigated through a time-of-drug-addition assay, whereas a plaque reduction assay was carried out to validate the antiviral activity. Direct interaction of the candidate TCM compound with viral particles was assessed using a viral inactivation assay. Finally, the potential synergistic efficacy of remdesivir and the TCM compound was examined with a combination assay.

Results: The herbal medicine Perilla leaf extract (PLE, approval number 022427 issued by the Ministry of Health and Welfare, Taiwan) had EC of 0.12 ± 0.06 mg/mL against SARS-CoV-2 in Vero E6 cells - with a selectivity index of 40.65. Non-cytotoxic PLE concentrations were capable of blocking viral RNA and protein synthesis. In addition, they significantly decreased virus-induced cytokine release and viral protein/RNA levels in the human lung epithelial cell line Calu-3. PLE inhibited viral replication by inactivating the virion and showed additive-to-synergistic efficacy against SARS-CoV-2 when used in combination with remdesivir.

Conclusion: Our results demonstrate for the first time that PLE is capable of inhibiting SARS-CoV-2 replication by inactivating the virion. Our data may prompt additional investigation on the clinical usefulness of PLE for preventing or treating COVID-19.
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http://dx.doi.org/10.1016/j.bj.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840404PMC
January 2021

The Biocontrol Agent Has the Highest Lethal Weight Ratio Compared with Its Prey and the Most Dramatic Body Weight Change during Pregnancy.

Insects 2021 May 25;12(6). Epub 2021 May 25.

Guizhou Provincial Key Laboratory for Agricultural Pest Management of the Mountainous Region, Institute of Entomology, Scientific Observing and Experimental Station of Crop Pest in Guiyang, Ministry of Agriculture, Guizhou University, Guiyang 550025, China.

spp. are small, toxic, ectoparasitic mites that suppress Coleoptera, Hemiptera, and Lepidoptera plant pests. To explore their potential use as a biocontrol agent, we studied the reproductive development, paralytic process, time to lethality and mortality, and searching ability of on different developmental stages of the oriental leafworm moth, . gained 14,826 times its body weight during pregnancy. One single female could rapidly kill one egg and first to third instar larvae, but not fourth to sixth instar larvae, prepupae, or pupae within 720 min. could develop on eggs, first to sixth larvae, and pupae, but only produced offspring on the eggs and pupae. A single female (an average weight of 23.81 ng) could paralyze and kill one third instar larvae (an average weight of 16.29 mg)-680,000 times its own weight. Mites significantly affected the hatch rate of eggs, which reduced with increasing mite densities on eggs. Releasing 50 or 100 in a 2 cm searching range resulted in significantly higher mortality rates of first instar larvae within 48 h compared to second and third instar larvae in searching ranges of 4.5 and 7.5 cm within 24 h. To the best of our knowledge, this is the first study to reveal that undergoes the greatest changes in weight during pregnancy of any adult female animal and has the highest lethal weight ratio of any biocontrol agent.
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http://dx.doi.org/10.3390/insects12060490DOI Listing
May 2021

Randialic acid B and tomentosolic acid block formyl peptide receptor 1 in human neutrophils and attenuate psoriasis-like inflammation in vivo.

Biochem Pharmacol 2021 May 6;190:114596. Epub 2021 May 6.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan. Electronic address:

Psoriasis is a long-lasting inflammatory skin disease lacking proper cure. Dysregulated activation of neutrophils is a major pathogenic factor in psoriasis. Formyl peptide receptor 1 (FPR1) triggers neutrophil activation in response to bacteria- or mitochondria-derived N-formyl peptides, but its significance in neutrophilic psoriasis remains unknown. In this study, we discovered two derivatives of ursolic acid, 3β-hydroxyurs-12,18-dien-28-oic acid (randialic acid B, RAB) and 3β-hydroxyurs-12,19-dien-28-oic acid (tomentosolic acid, TA), as FPR1 inhibitors in human neutrophils with ability to suppress psoriatic symptoms in mice. Both RAB and TA, triterpenoids of traditional medicinal plant Ilex kaushue, selectively inhibited reactive oxygen species production, elastase release, and CD11b expression in human neutrophils activated by FPR1, but not non-FPR1 agonists. Importantly, RAB and TA inhibited the binding of N-formyl peptide to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells, indicating FPR1 antagonism. Moreover, in assays induced by various concentrations of FPR1 agonist, both RAB and TA acted competitively for its binding to the FPR1 receptor. The FPR1-downstream signaling such as Ca mobilisation and activation of Akt and MAPKs was also competitively inhibited. In addition, imiquimod-induced psoriasis-like symptoms, including epidermal hyperplasia, desquamation with scaling, neutrophil skin infiltration, and transepidermal water loss were significantly reduced by both RAB and TA. The results illustrate a possible role of human neutrophils FPR1 receptor in psoriasis-like inflammation. Accordingly, triterpenoids RAB and TA represent novel FPR1 antagonists and exhibit therapeutic potential for treating neutrophilic inflammatory skin diseases.
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http://dx.doi.org/10.1016/j.bcp.2021.114596DOI Listing
May 2021

Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis.

Biomed Pharmacother 2021 Feb 26;134:111152. Epub 2020 Dec 26.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address:

Background: 5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health.

Methods: Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation sequencing technologies.

Results: Neutrophil elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level.

Conclusion: These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.
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http://dx.doi.org/10.1016/j.biopha.2020.111152DOI Listing
February 2021

Ovarian cancer risk score predicts chemo-response and outcome in epithelial ovarian carcinoma patients.

J Gynecol Oncol 2021 Mar 3;32(2):e18. Epub 2020 Dec 3.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Objective: Cytoreductive surgery followed by adjuvant chemotherapy is a standard frontline treatment for epithelial ovarian cancer (EOC). We aimed to develop an ovarian cancer risk score (OVRS) based on the expression of 10 ovarian-cancer-related genes to predict the chemoresistance, and outcomes of EOC patients.

Methods: We designed a case-control study with total 149 EOC women including 75 chemosensitives and 74 chemoresistants. Gene expression was measured using the quantitative real-time polymerase chain reaction. We tested for correlation between the OVRS and chemosensitivity or chemoresistance, disease-free survival (DFS), and overall survival (OS), and validated the OVRS by analyzing patients from the TCGA database.

Results: The chemosensitive group had lower OVRS than the chemoresistant group (5 vs. 15, p≤0.001, Mann-Whitney U test). Patients with disease relapse (13 vs. 5, p<0.001, Mann-Whitney U test) or disease-related death (13.5 vs. 6, p<0.001) had higher OVRS than those without. OVRS ≥10 (hazard ratio=3.29; 95% confidence interval=1.94-5.58; p<0.001) was the only predictor for chemoresistance in multivariate analysis. The median DFS (5 months vs. 24 months) and OS (39 months vs. >60 months) of patients with OVRS ≥10 were significantly shorter than those of patients with OVRS <10). The high OVRS group also had significantly shorter median OS than the low OVRS group in 255 patients in the TCGA database (39 vs. 49 months, p=0.046).

Conclusions: Specific genes panel can be clinically applied in predicting the chemoresistance and outcome, and decision-making of epithelial ovarian cancer.
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http://dx.doi.org/10.3802/jgo.2021.32.e18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930441PMC
March 2021

Clinical factors associated with prognosis in low-grade serous ovarian carcinoma: experiences at two large academic institutions in Korea and Taiwan.

Sci Rep 2020 11 17;10(1):20012. Epub 2020 Nov 17.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, Republic of Korea.

Low-grade ovarian serous carcinoma (LGSOC) has clinical features different from high-grade serous ovarian carcinoma (HGSOC) accounting for the majority of epithelial ovarian cancer. Because of its rarity, previous studies have only focused on the high-grade disease without considering the differences between the two subtypes. This study aimed to evaluate the effect of the clinical prognostic factors known for HGSOC on survival in patients with LGSOC. Based on the Federation of Gynecology and Obstetrics (FIGO) stage, progression-free survival (PFS) was markedly decreased in advanced disease compared with early disease. For stage I, patients with stage IC had poorer survival than those with stage IA and IB regardless of the number of cycles of adjuvant chemotherapy. For advanced disease, no gross residual disease after primary cytoreductive surgery was significantly associated with longer PFS when compared with gross residual disease. In multivariate analysis for PFS and overall survival (OS), age, preoperative CA-125, time interval from surgery to chemotherapy, and the number of cycles of adjuvant chemotherapy were not associated with prognosis. Complete cytoreduction was the only independent prognostic factor for PFS (HR 2.45, p = 0.045). Our study revealed that the known prognostic factors in HGSOC did not show any effect on the survival in LGSOC except for FIGO stage and complete cytoreduction.
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http://dx.doi.org/10.1038/s41598-020-77075-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672053PMC
November 2020

Outcome and Subsequent Pregnancy after Fertility-Sparing Surgery of Early-Stage Cervical Cancers.

Int J Environ Res Public Health 2020 09 28;17(19). Epub 2020 Sep 28.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

We aimed to investigate the outcomes and subsequent pregnancies of early-stage cervical cancer patients who received conservative fertility-sparing surgery. Women with early-stage cervical cancer who underwent conservative or fertility-sparing surgery in a tertiary medical center were reviewed from 2004 to 2017. Each patient's clinicopathologic characteristics, adjuvant therapy, subsequent pregnancy, and outcome were recorded. There were 32 women recruited, including 12 stage IA1 patients and 20 stage IB1 patients. Twenty-two patients received conization/LEEP and the other 10 patients received radical trachelectomy. Two patients did not complete the definite treatment after fertility-sparing surgery. There were 11 women who had subsequent pregnancies and nine had at least one live birth. The live birth rate was 73.3% (11/15). We conclude that patients with early-stage cervical cancer who undergo fertility-sparing surgery can have a successful pregnancy and delivery. However, patients must receive a detailed consultation before surgery and undergo definitive treatment, if indicated, and regular postoperative surveillance.
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http://dx.doi.org/10.3390/ijerph17197103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579067PMC
September 2020

Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-fold axis of capsid VP1 and cognate sulfated receptors.

Emerg Microbes Infect 2020 Dec;9(1):1194-1205

Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine, (Danshen), were screened for anti-EV-A71. We identified a natural product, rosmarinic acid (RA), as a potential inhibitor of EV-A71 by cell-based antiviral assay and mouse model. Results also show that RA may affect the early stage of viral infection and may target viral particles directly, thereby interfering with virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate interactions without abolishing the interaction between the virus and scavenger receptor B2 (SCARB2). Sequencing of the plaque-purified RA-resistant viruses revealed a N104K mutation in the five-fold axis of the structural protein VP1, which contains positively charged amino acids reportedly associated with virus-PSGL1 and virus-heparan sulfate interactions via electrostatic attraction. The plasmid-derived recombinant virus harbouring this mutation was confirmed to be refractory to RA inhibition. Receptor pull-down showed that this non-positively charged VP1-N104 is critical for virus binding to heparan sulfate. As the VP1-N104 residue is conserved among different EV-A71 strains, RA may be useful for inhibiting EV-A71 infection, even for emergent virus variants. Our study provides insight into the molecular mechanism of virus-host interactions and identifies a promising new class of inhibitors based on its antiviral activity and broad spectrum effects against a range of EV-A71.
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http://dx.doi.org/10.1080/22221751.2020.1767512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448925PMC
December 2020

Polysaccharide-containing fraction from Artemisia argyi inhibits tumor cell-induced platelet aggregation by blocking interaction of podoplanin with C-type lectin-like receptor 2.

J Food Drug Anal 2020 01 26;28(1):115-123. Epub 2019 Sep 26.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address:

Tumor cell-induced platelet aggregation (TCIPA) is a mechanism that involves the protection of tumor cells in the circulation and the promotion of tumor cell invasion and metastases. The C-type lectin-like receptor 2 (CLEC-2) that binds podoplanin (PDPN) is on the platelet surface and facilitates the TCIPA. Selective blockage of the PDPN-mediated platelet-tumor cell interaction is thereby a plausible strategy for inhibiting metastases. In a search for antagonists of PDPN- and tumor cell-induced platelet aggregation, traditional Chinese medicines were screened and it was found that the water extract of Artemisia argyi leaves selectively inhibited the PDPN-induced platelet aggregation. Bioactivity-guided fractionation analysis was performed for defining a polysaccharide-containing fraction (AAWAP) characterized by inhibition of PDPN activity and tumor cell-induced platelet aggregation. The pharmacological effects of AAWAP on PDPN-activated CLEC-2 signaling were determined by using Western blot and alpha screening analyses. AAWAP was non-toxic to the cells and platelets and it suppressed PDPN- and tumor cell-induced platelet aggregation by irreversibly blocking the interaction between PDPN and CLEC-2 in a dose-dependent manner. These findings indicate that AAWAP is an antagonist of the PDPN-CLEC-2 interaction. This action by AAWAP may result in the prevention of tumor cell metastases, and if so, could become an effective pharmacological agent in treating cancer patients.
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http://dx.doi.org/10.1016/j.jfda.2019.08.002DOI Listing
January 2020

The mechanism underlying silicon oxide based resistive random-access memory (ReRAM).

Nanotechnology 2020 Apr 17;31(14):145709. Epub 2019 Dec 17.

Institute of Nanoscience, National Chung Hsing University, Taichung 40227, Taiwan.

In this work, we have inspected the theoretical resistive switching properties of two ReRAM models based on heterojunction structures of Cu/SiO nanoparticles (NPs)/Si and Si/SiO NPs/Si, in which dielectric layers of the silica nanoparticles present dislocations at bicrystal interfaces. To validate the theoretical model, a charge storage device with the structure Cu/SiO /Si was fabricated and its ReRAM properties were studied. Our examinations on the electrical, thermal and structural aspects of resistive switching uncovered the switching behavior relies upon the material properties and electrical characteristics of the switching layers, as well as the metal electrodes and the interfacial structure of grains within the dielectric materials. We also determined that the application of an external electric field at Grain Boundaries (GB) is crucial to resistive switching behavior. Moreover, we have demonstrated that the switching behavior is influenced by variations in the atomic structure and electronic properties, at the atomic length scale and picosecond timescale. Our findings furnish a useful reference for the future development and optimization of materials used in this technology.
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http://dx.doi.org/10.1088/1361-6528/ab62caDOI Listing
April 2020

BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19 B lymphocytes.

J Immunother Cancer 2019 11 21;7(1):313. Epub 2019 Nov 21.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.

Background: The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate is poor. The purpose of this study was to investigate the therapeutic potential of chemotherapy combined with inhibition of B and T lymphocyte attenuator (BTLA) for clinical use to treat EOC.

Methods: Initially, we evaluated the potential application of chemotherapy combined with anti-BTLA antibody in an animal model. We then analyzed the distribution and regulation of BTLA expression on immunocytes in vitro. Finally, we examined the correlation between BTLA expression levels in cancerous tissues and prognosis in 254 EOC cases.

Results: The combination of chemotherapy and anti-BTLA antibody for inhibiting BTLA significantly reduced peritoneal tumor volume and extended survival in tumor-bearing mice. In addition, BTLA could be identified mostly on B lymphocytes, especially on CD19 B cells, rather than on T lymphocytes and natural killer cells. Under regulation of interleukins 6 and 10, more BTLACD19 B lymphocytes could be induced through AKT and STAT3 signaling pathways. Detectable BTLA expression in ovarian cancerous tissues was associated with worse disease-free and overall survivals of EOC patients.

Conclusions: BTLA detected in cancerous tissues can predict poor outcome of EOC patients. Inhibition of BTLA combined with chemotherapy can elevate immune activation and generate potent anti-tumor effects. Thus, the combination of chemotherapy and anti-BTLA antibody may hold potential clinical application for the treatment of EOC patients.

Trial Registration: The Trial Registration Number was NCT00854399.
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http://dx.doi.org/10.1186/s40425-019-0744-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868712PMC
November 2019

Blockade of PD-L1 Enhances Cancer Immunotherapy by Regulating Dendritic Cell Maturation and Macrophage Polarization.

Cancers (Basel) 2019 Sep 19;11(9). Epub 2019 Sep 19.

Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine tumor model, we investigated whether anti-PD-L1 antibody increased the antigen-specific immune response and anti-tumor effects induced by the antigen-specific protein vaccine, as well as the possible mechanisms regarding activation of APCs. Anti-PD-L1 antibody combined with the PEK protein vaccine generated more potent E7-specific immunity (including the number and cytotoxic activity of E7-specific cytotoxic CD8 T lymphocytes) and anti-tumor effects than protein vaccine alone. Anti-PD-L1 antibody enhanced the maturation of dendritic cells and the proportion of M1-like macrophages in tumor-draining lymph nodes and tumors in tumor-bearing mice treated with combinatorial therapy. PD-L1 blockade overturned the immunosuppressive status of the tumor microenvironment and then enhanced the E7 tumor-specific antigen-specific immunity and anti-tumor effects generated by an E7-specific protein vaccine through modulation of APCs in an E7-expressing small tumor model. Tumor-specific antigen (like HPV E7 antigen)-specific immunotherapy combined with APC-targeting modality by PD-L1 blockade has a high translational potential in E7-specific cancer therapy.
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http://dx.doi.org/10.3390/cancers11091400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769724PMC
September 2019

Impact of Adjuvant Modalities on Survival in Patients with Advanced Stage Endometrial Carcinoma: A Retrospective Analysis from a Tertiary Medical Center.

Int J Environ Res Public Health 2019 07 18;16(14). Epub 2019 Jul 18.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Adjuvant treatment in advanced-stage (stages III /IV) endometrial carcinomas in terms of tumor grades has not yet been explored. We retrospectively analyzed 194 patients with advanced-stage endometrioid endometrial carcinoma who received surgery, followed by adjuvant therapy, at National Taiwan University Hospital between January 1, 2000 and August 31, 2017. Adjuvant therapies included radiation (RT), chemotherapy alone (CT), and combined modality treatment (CMT: radiation and chemotherapy). The prognostic factors were determined from multivariate survival analyses using Cox regression models. Progression-free survival (PFS) and overall survival (OS) times were estimated with the Kaplan-Meier method. The median follow-up was 45.5 months (range: 6.2-207.9). In grade 1/2 endometrioid carcinoma, neither adjuvant CT nor CMT could prolong PFS significantly compared to RT (CT: HR 1.59, 95% CI 0.64-3.97; CMT: HR 2.03, 95% CI 0.72-5.74). Notably, maximal cytoreduction independently improved PFS (HR 0.31, 95% CI 0.10-0.90). No particular adjuvant treatment provided an OS advantage over the others for grade 1/2 endometrioid carcinomas. However, for grade 3 endometrioid carcinoma, CMT showed OS benefits (HR 0.15, 95% CI 0.03-0.89) compared to RT and CT. In conclusion, maximal cytoreduction should be the goal in patients with grade 1/2 advanced-stage endometrioid carcinomas. Based on our results, patients with grade 3 endometrioid carcinomas might benefit from adjuvant CMT.
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http://dx.doi.org/10.3390/ijerph16142561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678420PMC
July 2019

Bevacizumab Dose Affects the Severity of Adverse Events in Gynecologic Malignancies.

Front Pharmacol 2019 26;10:426. Epub 2019 Apr 26.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.

In this retrospective study, we investigated adverse events and outcomes in patients treated with bevacizumab for ovarian, fallopian tube, or primary peritoneal cancers at a single hospital. We determined the cumulative incidences of various bevacizumab-related adverse events and the correlation between dose and adverse event incidences. We analyzed data from 154 patients that received 251 rounds of bevacizumab as first-line, first salvage, >2 salvage treatments. Adverse events of any grade were observed in 121 (78.6%) patients; at least one grade 3 or 4 adverse event occurred in 32 (20.8%) patients. The two most common events were proteinuria (38.3%) and hypertension (33.8%). The first-line treatment group displayed significantly higher frequencies of hypertension (52.7% vs. 18.9% vs. 15.5%, < 0.001), wound complications (9.1% vs. 0% vs. 1.2%, = 0.010), arthralgia (29.1% vs. 11.3% vs. 8.3%, = 0.003), and reduced range of joint motion (14.5% vs. 5.7% vs. 3.6%, = 0.046), compared to those in the first and >2 lines salvage groups, respectively (Kruskal-Wallis test). The cumulative incidences of all grades and grades 3/4 of hypertension cumulative incidence plateaued at around 30% for all grades and 10% for grades 3 and 4, at bevacizumab doses above 8080 and 3510 mg, respectively. The proteinuria cumulative incidence plateaued at around 35% for all grades and 3% for grades 3 and 4, at bevacizumab doses above 11,190 and 4530 mg, respectively. We concluded that, in this realistic clinical population, different kinds and higher cumulative incidences of adverse events were observed compared to those reported in previous clinical trials. Moreover, bevacizumab doses showed cumulative toxicity and plateau effects on hypertension and proteinuria.
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http://dx.doi.org/10.3389/fphar.2019.00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498445PMC
April 2019

mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment.

Cancers (Basel) 2019 May 2;11(5). Epub 2019 May 2.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan.

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8 T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.
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http://dx.doi.org/10.3390/cancers11050617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562783PMC
May 2019

Clear Cell Carcinoma of the Abdominal Wall as a Rare Complication of General Obstetric and Gynecologic Surgeries: 15 Years of Experience at a Large Academic Institution.

Int J Environ Res Public Health 2019 02 14;16(4). Epub 2019 Feb 14.

Department of Obstetrics and Gynecology; National Taiwan University Hospital, Taipei 100, Taiwan.

The objective of this article was to report the clinicopathological characteristics, treatment modalities, and outcomes of patients with clear cell carcinoma (CCC) of the abdominal wall. Medical records of six patients diagnosed with CCC of the abdominal wall between May 2003 and May 2018 at the National Taiwan University Hospital were reviewed. All patients had prior obstetric or gynecologic surgeries. The primary clinical presentation was enlarging abdominal masses at previous surgical scars. Four patients underwent initial/primary surgeries with/without adjuvant chemotherapy. One patient received neoadjuvant chemotherapy followed by surgical intervention and adjuvant chemotherapy, the other received chemotherapy and sequential radiotherapy without any surgical intervention. Two of four patients undergoing initial/primary surgeries had disease recurrence and the remaining two cases without initial surgery experienced disease progression during primary treatment. Inguinal lymph nodes were the most frequent sites of recurrence. In conclusion, previous obstetric or gynecologic surgery can be a risk factor for CCC of the abdominal wall. Complete resection of abdominal wall tumor and suspected intra-abdominal lesions with hysterectomy and bilateral inguinal lymph nodes dissection may be the primary treatment. Adjuvant chemotherapy would be considered for potential benefits. For patients without bilateral inguinal lymph nodes dissection, careful inguinal lymph node palpation during postoperative surveillance is necessary. More cases are still needed to elucidate the clinical management of this disease.
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http://dx.doi.org/10.3390/ijerph16040552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406533PMC
February 2019

Design, Synthesis, and Biological Evaluation of Itaconic Acid Derivatives as Potential Anti-Influenza Agents.

J Med Chem 2019 03 22;62(5):2390-2403. Epub 2019 Feb 22.

Research Center for Chinese Herbal Medicine , Chang Gung University of Science and Technology , Taoyuan 33303 , Taiwan.

Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which render antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20 000 compounds, by performing a cell-based screening assay, as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents. The results of an in vitro pharmacological study showed that compounds 4 and 8 exhibited the most potent anti-IAV effect with half-maximal effective concentration values of 0.14 and 0.11 μM, respectively, in Madin-Darby canine kidney cells. The mechanism of action studies showed that lead agents 1 and 4 reduced virus replication by directly targeting IAV nucleoproteins and disrupting virus ribonucleoprotein export from the nucleus to the cytosol. On the basis of its high potential as an anti-IAV agent and its selectivity index >785, compound 4 was found to be a promising candidate for further development against IAVs.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01683DOI Listing
March 2019

Immune checkpoint Ab enhances the antigen-specific anti-tumor effects by modulating both dendritic cells and regulatory T lymphocytes.

Cancer Lett 2019 03 10;444:20-34. Epub 2018 Dec 10.

Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

We determined the anti-tumor effects and possible mechanisms of an antigen-specific DNA vaccine combined with PD-1 or CTLA-4 blockade. Using the HPV16 E6/E7 syngeneic mouse tumor model, we investigated whether anti-CTLA-4 antibody (Ab) or anti-PD-1 Ab increases the antigen-specific anti-tumor effects and immune response induced by CTGF/E7 chimeric DNA vaccine and the possible mechanisms. Anti-PD-1 Ab or anti-CTLA-4 Ab combined with E7-specific DNA vaccine generated more potent antigen-specific immunity, including anti-E7 Abs and the number and cytotoxic activity of E7-specific cytotoxic CD8 T lymphocytes, and anti-tumor effects than E7-specific DNA vaccine alone. In addition, the number of systemic and intratumoral Tregs was lower with the anti-PD-1 or anti-CTLA-4 Ab and E7-specific DNA vaccine. Furthermore, anti-PD-1 and anti-CTLA-4 Abs could enhance the maturation and abilities of intratumoral DCs to activate E7-specific cytotoxic CD8 T cells. Immune checkpoint blockade overcomes the immunosuppressive status of the tumor-microenvironment to enhance the antigen-specific immunity and anti-tumor effects generated by an antigen-specific DNA vaccine. Antigen-specific immunotherapy combined with immune checkpoint blockade can be a novel strategy in clinical cancer therapy.
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http://dx.doi.org/10.1016/j.canlet.2018.11.039DOI Listing
March 2019

Diabetic ketoacidosis further increases risk of Alzheimer's disease in patients with type 2 diabetes.

Diabetes Res Clin Pract 2019 Jan 24;147:55-61. Epub 2018 Nov 24.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. Electronic address:

Aim: Diabetes mellitus (DM) is a known risk factor for dementia. It is unclear whether diabetic ketoacidosis (DKA) further increases the risk of dementia in patients with type 2 DM.

Methods: This retrospective nationwide population-based cohort study was conducted using Taiwan's National Health Insurance database. We extracted claims data for 4451 patients with type 2 diabetes and DKA and 8902 diabetic controls matched for age, gender, diabetes complication severity index, frequency of clinic visits and baseline comorbidities between 2000 and 2002. Patients with type 1 diabetes or prior hypoglycemia before index date were excluded. All patients were tracked until new dementia diagnosis, death, or end of 2011.

Results: Of the 4451 DKA patients, 211 (4.7%) and 305 (3.4%) of the 8902 diabetic controls were diagnosed as having dementia during the follow-up period. The incidence rate ratio (IRR) for dementia was 1.62 (95% CI 1.35-1.93; P < 0.0001) for patients with DKA versus diabetic patients without DKA. After adjusting for age, baseline comorbidities, geographic area, and income, patients with DKA were found to have 1.86 times the risk of developing dementia, compared to controls (95% CI 1.56-2.22, P < 0.0001). They were found to have a higher risk of Alzheimer's dementia (HR:1.86; 95% CI 1.52-2.28, P < 0.0001) but not non-Alzheimer's dementia.

Conclusion: Type 2 diabetes patients with DKA are at increased risk of Alzheimer's dementia but not non-Alzheimer dementia.
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http://dx.doi.org/10.1016/j.diabres.2018.11.013DOI Listing
January 2019

Factors predicting parametrial invasion in patients with early-stage cervical carcinomas.

PLoS One 2018 18;13(10):e0204950. Epub 2018 Oct 18.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.

We aimed to identify factors predicting parametrial invasion in early-stage cervical cancer patients undergoing radical hysterectomy. We recruited women with invasive cervical cancer who underwent radical hysterectomy at a single medical institute from 2000-2011. The clinical and pathological characteristics and outcomes were retrospectively recorded, and the risk factors for parametrial invasion were analyzed. We enrolled 339 patients, including 7 with stage IA1 carcinomas, 10 with stage IA2, 266 with stage IB1, 39 with stage IB2, 14 with stage IIA1, and 3 with stage IIA2. The majority (237/339, 69.9%) had squamous cell carcinoma, while 32 (12.4%) had parametrial invasion. The 16 patients with stage IB1 tumors and parametrial invasion were older (55.9±9.5vs. 49.0±9.9 years, p = 0.005, Mann-Whitney U test), and had deeper cervical stromal invasion (9.59±4.87 vs. 7.47±5.48 mm, p = 0.048, Mann-Whitney U test), larger tumor size (2.32±1.15 vs. 1.74±1.14cm, p = 0.043, Mann-Whitney U test), higher incidences of lymphovascular space invasion (87.5% vs. 28.8%, p<0.001, chi-square test), and greater lymph node metastasis (68.8% vs. 10.8%, p<0.001, chi-square test) than the 260 patients without parametrial invasion. Among the patients with stage IB1 tumor size >2 cm,10% had parametrial invasion and 24.2% had lymph node metastasis compared with only 4% and 9.4% of stage IB1 patients with a tumor size <2 cm, respectively. Only one (0.9%) of the 109 patients aged less than 50 years had parametrial invasion compared with 6 (9.7%) of the 62 patients aged over 50 years. Patients with stage IA2 and IB1 tumors <2 cm may not need radical hysterectomy owing to the low incidence of parametrial invasion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193633PMC
March 2019

Data on the acceptance of a tourism navigation system applying structuring equation modeling analysis.

Data Brief 2018 Oct 6;20:1392-1396. Epub 2018 Sep 6.

Department of Media Design, Tatung University, Taipei, Taiwan, ROC.

The data presented in this article relate to the acceptance of an online tourism search technology by students from a Science and Technology University in Taiwan. The data were collected using quasi-experiment research design and a survey questionnaire. A structural equation modeling analysis was employed for data analysis using AMOS statistical software. For further study findings and interpretation, please refer to the research article entitled "Examining the Usability of an Online Virtual Tour-Guiding System for Cultural Tourism Education" (Chiao et al., 2018).
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http://dx.doi.org/10.1016/j.dib.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148738PMC
October 2018

A light-controllable specific drug delivery nanoplatform for targeted bimodal imaging-guided photothermal/chemo synergistic cancer therapy.

Acta Biomater 2018 10 19;80:308-326. Epub 2018 Sep 19.

Children's Hospital of Chongqing Medical University, 400014, PR China. Electronic address:

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform ([email protected]/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels ([email protected]/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that [email protected]/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible [email protected]/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.
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http://dx.doi.org/10.1016/j.actbio.2018.09.024DOI Listing
October 2018

CHI3L1 results in poor outcome of ovarian cancer by promoting properties of stem-like cells.

Endocr Relat Cancer 2019 01;26(1):73-88

Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.

The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and could protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and -knockdown transfectants. High expression of CHI3L1 was associated with poor outcome and chemoresistance in ovarian cancer patients. The mRNA expression of CHI3L1 in CA5171 ovarian cancer stem-like cells was 3-fold higher than in CA5171 parental cells. CHI3L1 promoted the properties of ovarian cancer stem-like cells including generating more and larger tumor spheroids and a higher percentage of ALDH+ in tumor cells and promoting resistance to cytotoxic drug-induced apoptosis. CHI3L1 could induce both the Akt (essential) and Erk signaling pathways, and then enhance expression of β-catenin followed by SOX2, and finally promote tumor spheroid formation and other properties of ovarian cancer stem-like cells. OVCAR3 CHI3L1-overexpressing transfectants were more tumorigenic in vivo, whereas CA5171 CHI3L1-knockdown transfectants were not tumorigenic in vivo. CHI3L1 critically enhances the properties of ovarian cancer stem-like cells. CHI3L1 or CHI3L1-regulated signaling pathways and molecules could be potential therapeutic targets in ovarian cancer.
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http://dx.doi.org/10.1530/ERC-18-0300DOI Listing
January 2019

PA/US dual-modality imaging to guide VEGFR-2 targeted photothermal therapy using ZnPc-/PFH-loaded polymeric nanoparticles.

Biomater Sci 2018 Jul;6(8):2130-2143

Chongging Key laboratory of Ultrasound Molecular Imaging, Chongqing, 400010, China.

Angiogenesis is a common pathological characteristic of many solid tumors and vulnerable atherosclerotic plaques. Photothermal therapy (PTT) is a promising method to reduce neovascularization. To increase the targeting ability and efficiency of PTT, a novel polymeric nanosystem that encapsulates phthalocyanine zinc (ZnPc) and perfluorohexane (PFH) was developed to target the new blood vessels of breast tumors. After being conjugated to the anti-VEGFR-2 antibody, the polymeric nanoparticles (NPs) targeted vascular endothelial cells efficiently. The photosensitizer (PS) in the NPs could convert laser energy into heat, generating local high temperatures to kill the surrounding cells under laser irradiation. In addition, the liquid-gas phase transition of PFH was induced, and an enhanced ultrasound (US) and photoacoustic (PA) image could be obtained. US/PA imaging enables visualization of the location of NPs, and laser irradiation position can be guided to the optimal location, resulting in fewer side effects than those from traditional treatments with a high targeting ability and an efficient synergistic effect from the PTT.
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http://dx.doi.org/10.1039/c8bm00213dDOI Listing
July 2018

Torsion of pedunculated subserous uterine leiomyoma: A rare complication of a common disease.

Taiwan J Obstet Gynecol 2018 Apr;57(2):300-303

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Objective: To evaluate the clinical presentations, diagnosis, management, and outcomes of torsion of the pedunculated subserous uterine leiomyoma.

Materials And Methods: We retrospectively reviewed medical records of patients with subserous uterine leiomyomas undergoing surgeries at National Taiwan University Hospital from January 2001 to December 2015.

Results: Five cases of torsion of pedunculated subserous uterine leiomyoma were identified. All presented with sudden onset abdominal pain. Two patients received emergent surgeries, the other three cases received scheduled surgeries. The postoperative courses of these five women were uneventful without sequelae.

Conclusions: Torsion of pedunculated subserous uterine leiomyoma is rare. Accurately diagnosing it prior to surgery is a major challenge. It should be one of the differential diagnosis in patients with uterine leiomyoma presenting with acute abdomen.
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http://dx.doi.org/10.1016/j.tjog.2018.02.021DOI Listing
April 2018

Immuno-modulators enhance antigen-specific immunity and anti-tumor effects of mesothelin-specific chimeric DNA vaccine through promoting DC maturation.

Cancer Lett 2018 07 27;425:152-163. Epub 2018 Mar 27.

Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan. Electronic address:

As a tumor antigen, mesothelin (MSLN) can be identified in various malignancies. MSLN is potential for antigen-specific cancer vaccines. We generated a novel chimeric DNA vaccine using antigen-specific connective tissue growth factor lined with MSLN (CTGF/MSLN). The anti-tumor effects of the CTGF/MSLN DNA vaccine combined with anti-CD40 Ab and toll-like receptor 3 ligand-poly(I:C) were validated in an MSLN-expressing model. CTGF/MSLN DNA with anti-CD40Ab and poly(I:C) vaccinated mice demonstrated potent anti-tumor effects with longer survival and less tumor volumes. An increase in MSLN-specific CD8 T cells and anti-MSLN Ab titers was also noted in CTGF/MSLN DNA with anti-CD40Ab and poly(I:C) vaccinated mice. The CTGF/MSLN DNA vaccine combined with immuno-modulator EGCG also generated potent anti-tumor effects. Immuno-modulators could enhance the antigen-specific anti-tumor effects of CTGF/MSLN DNA vaccine through promoting the DC maturation. In addition, MSLN-specific cell-based vaccine with AAV-IL-12 and the CTGF/MSLN DNA vaccine with anti-CD40Ab/polyp(I:C) generated more potent anti-tumor effects than the other combinational regimens. The results indicate that an MSLN-specific DNA vaccine combined with immuno-modulators may be an effective immunotherapeutic strategy to control MSLN-expressing tumors including ovarian and pancreastic cancers, and malignant mesothelioma.
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http://dx.doi.org/10.1016/j.canlet.2018.03.032DOI Listing
July 2018

Large cell neuroendocrine carcinoma of the endometrium: A case report and literature review.

Taiwan J Obstet Gynecol 2018 Feb;57(1):144-149

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Objective: To report a case and review published cases of large cell neuroendocrine carcinoma (LCNEC) of the endometrium.

Case Report: A 51-year-old female presented with postmenopausal bleeding and a palpable pelvic mass. An endometrial biopsy showed a malignant mixed Mullerian tumor (MMMT). Suboptimal debulking surgery was performed. The final pathology revealed stage IVB endometrial LCNEC. Post-operative adjuvant chemotherapy with cisplatin and etoposide was administered. Two months after discontinuing adjuvant chemotherapy, salvage chemotherapy with cisplatin and ifosfamide was administered due to tumor progression; however, obstructive ileus was noted 2 months later. A segmental small bowel resection and palliative colostomy were performed. She died secondary to a post-operative infection 8 days after the operation.

Conclusion: Endometrial LCNEC is a rare but aggressive disease. If diagnosed, combined therapies, including staging surgery, following by adjuvant radiotherapy and chemotherapy, should be performed.
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http://dx.doi.org/10.1016/j.tjog.2017.12.025DOI Listing
February 2018

β-Nitrostyrene derivatives attenuate LPS-mediated acute lung injury via the inhibition of neutrophil-platelet interactions and NET release.

Am J Physiol Lung Cell Mol Physiol 2018 04 11;314(4):L654-L669. Epub 2018 Jan 11.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , Taoyuan , Taiwan.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are high-mortality and life-threatening diseases that are associated with neutrophil activation and accumulation within lung tissue. Emerging evidence indicates that neutrophil-platelet aggregates (NPAs) at sites of injury increase acute inflammation and contribute to the development of ALI. Although numerous studies have increased our understanding of the pathophysiology of ALI, there is still a lack of innovative and useful treatments that reduce mortality, emphasizing that there is an urgent need for novel treatment strategies. In this study, a new series of small compounds of β-nitrostyrene derivatives (BNSDs) were synthesized, and their anti-inflammatory bioactivities on neutrophils and platelets were evaluated. The new small compound C7 modulates neutrophil function by inhibiting superoxide generation and elastase release. Compound C7 elicits protective effects on LPS-induced paw edema and acute lung injury via the inhibition of neutrophil accumulation, proinflammatory mediator release, platelet aggregation, myeloperoxidase activity, and neutrophil extracellular trap (NET) release. NET formation was identified as the bridge for the critical interactions between neutrophils and platelets by confocal microscopy and flow cytometry. This research provides new insights for elucidating the complicated regulation of neutrophils and platelets in ALI and sheds further light on future drug development strategies for ALI/ARDS and acute inflammatory diseases.
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http://dx.doi.org/10.1152/ajplung.00501.2016DOI Listing
April 2018

Irradiation Enhances Abscopal Anti-tumor Effects of Antigen-Specific Immunotherapy through Regulating Tumor Microenvironment.

Mol Ther 2018 02 21;26(2):404-419. Epub 2017 Nov 21.

Department of Obstetrics and Gynecology, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Oncology, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Clinical Medicine, Medicine College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address:

Ionizing radiation therapy is a well-established method of eradicating locally advanced tumors. Here, we examined whether local RT enhanced the potency of an antigen-specific DNA vaccine, and we investigated the possible underlying mechanism. Using the HPV16 E6/E7 syngeneic TC-1 tumor, we evaluated the combination of CTGF/E7 vaccination with local irradiation with regard to synergistic antigen-specific immunity and anti-tumor effects. Tumor-bearing mice treated with local RT (6 Gy twice weekly) and CTGF/E7 DNA vaccination exhibited dramatically increased numbers of E7-specific CD8 cytotoxic T cell precursors, higher titers of anti-E7 Abs, and significantly reduced tumor size. The combination of local RT and CTGF/E7 vaccination also elicited abscopal effects on non-irradiated local subcutaneous and distant pulmonary metastatic tumors. Local irradiation induced the expression of high-mobility group box 1 protein (HMGB-1) in apoptotic tumor cells and stimulated dendritic cell (DC) maturation, consequently inducing antigen-specific immune responses. Additionally, local irradiation eventually increased the effector-to-suppressor cell ratio in the tumor microenvironment. Overall, local irradiation enhanced the antigen-specific immunity and anti-tumor effects on local and distant metastatic tumors generated by an antigen-specific DNA vaccine. These findings suggest that the combination of irradiation with antigen-specific immunotherapy is a promising new clinical strategy for cancer therapy.
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http://dx.doi.org/10.1016/j.ymthe.2017.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835145PMC
February 2018

Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies.

Front Pharmacol 2017 6;8:800. Epub 2017 Nov 6.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.

We evaluated the prevalence of and risk factors for hypersensitivity reactions related to carboplatin, which is commonly used to treat gynecological malignancies. All women with pathologically documented ovarian, fallopian tube, or primary peritoneal cancer treated with carboplatin alone or a carboplatin-based combination chemotherapy regimen at a single hospital between January 2006 and December 2013 were retrospectively recruited. We analyzed the incidence, characteristics, risk factors, management, and outcomes of carboplatin-related hypersensitivity reactions among these patients. Among 735 eligible women, 75 (10.2%) experienced a total of 215 carboplatin-related hypersensitivity reaction events. The annual incidence of carboplatin-related hypersensitivity reactions gradually increased from 0.88% in 2006 to 5.42% in 2013. The incidence of carboplatin-related hypersensitivity was higher in patients with advanced stage disease ( < 0.001, Kruskal-Wallis test), serous and mixed histological types ( = 0.003, Kruskal-Wallis test), malignant ascites ( = 0.009, chi-square test), and history of other drug allergy ( < 0.001, chi-square test). Compared to women without hypersensitivity reactions, women who experienced hypersensitivity reactions had a significantly greater median cycle number (12 vs. 6, < 0.001, independent sample -test) and dose (6,816 vs. 3,844 mg, < 0.001, independent sample -test). The cumulative incidence of carboplatin-related hypersensitivity reactions dramatically increased with >8 cycles or dose >3,500 mg. Therefore, disease severity, histological type, malignant ascites, past drug allergies, and cumulative carboplatin dose are risk factors for carboplatin-related hypersensitivity reactions. Such reactions could potentially be reduced or prevented by slowing the infusion rate and using a desensitization protocol involving anti-allergy medications.
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http://dx.doi.org/10.3389/fphar.2017.00800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681487PMC
November 2017