Publications by authors named "Ting Chang"

76 Publications

Thymectomy and Risk of Generalization in Patients with Ocular Myasthenia Gravis: A Multicenter Retrospective Cohort Study.

Neurotherapeutics 2021 Oct 8. Epub 2021 Oct 8.

Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, 569 XinSi Road, Xi'an, 710038, China.

This study aims to investigate the association between thymectomy and the risk of generalization in patients with ocular myasthenia gravis (MG). Data on patients with ocular MG from seven neurological centers in China were retrospectively reviewed. Ocular MG naïve to immunotherapy was categorized according to whether thymectomy was performed (thymectomized group vs. nonsurgical group). Patients in the thymectomized group all underwent surgery within 2 years since ocular symptom onset. The main outcome measure was the generalization. The follow-up period was defined from the date of ocular symptom onset to the date of generalization confirmation, immunotherapy initiation, or last follow-up (defined as 60 months). Of 519 eligible patients (mean [SD] age, 48.7 [15.2] years, 46.6% women), 31 (23.7%) of 131 generalized in the thymectomized group and 122 (31.4%) of 388 did in the nonsurgical group during a median follow-up of 19 months (IQR 8.0-50.0). Thymectomy was independently associated with reduced generalization risk (adjusted HR 0.41, 95% CI 0.25-0.66, P < 0.001). Multivariable stratified analysis also verified this association across the subgroups. Kaplan-Meier curves showed that the 5-year cumulative rate was significantly lower in the thymectomized group than in the nonsurgical group. To conclude, thymectomy may be considered effective in modifying the progression from ocular to generalized MG irrespective of thymoma.
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http://dx.doi.org/10.1007/s13311-021-01129-zDOI Listing
October 2021

Group 2 innate lymphoid cells suppress the pathology of neuromyelitis optica spectrum disorder.

FASEB J 2021 Nov;35(11):e21856

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe central nervous system (CNS) autoimmune disease that primarily damages the optic nerves and spinal cord. Group 2 innate lymphoid cells (ILC2) are potent producers of type 2 cytokines that orchestrate immune and inflammatory responses. However, the role of ILC2 in CNS autoimmune diseases remains unknown. In patients with NMOSD, we identified a significant reduction of ILC2 in peripheral blood, which was correlated with disease severity. Using a mouse model of NMOSD induced by intracerebral injection of NMOSD-IgG with complement, we found CNS infiltration of ILC2 mainly expressing interleukin (IL)-5 and IL-13. The depletion of ILC2 led to increased CNS lesion volume, reduced CNS glucose metabolism, and augmented astrocyte injury and demyelination. The exacerbated NMOSD pathology was accompanied by increased accumulation of Iba1 cells and complement activity in CNS lesions. In addition, the expansion of ILC2 using IL-33 attenuated NMO pathology. Collectively, these findings suggest a beneficial role of ILC2 in NMOSD, which deserves further investigation for future design of immune therapies to treat patients with NMOSD.
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http://dx.doi.org/10.1096/fj.202100673RDOI Listing
November 2021

Nomogram for short-term outcome assessment in AChR subtype generalized myasthenia gravis.

J Transl Med 2021 06 30;19(1):285. Epub 2021 Jun 30.

Department of Neurology, Huashan Hospital Fudan University, No.12 Middle Wulumuqi Road, Shanghai, 200040, China.

Background: An accurate prediction for prognosis can help in guiding the therapeutic options and optimizing the trial design for generalized myasthenia gravis (gMG). We aimed to develop and validate a predictive nomogram to assess the short-term outcome in patients with the anti-acetylcholine receptor (AChR) subtype gMG.

Methods: We retrospectively reviewed 165 patients with AChR subtype gMG who were immunotherapy naïve at the first visit from five tertiary centers in China. The short-term clinical outcome is defined as the achievement of minimal symptom expression (MSE) at 12 months. Of them, 120 gMG patients from Huashan Hospital were enrolled to form a derivation cohort (n = 96) and a temporal validation cohort (n = 24) for the nomogram. Then, this nomogram was externally validated using 45 immunotherapy naïve AChR subtype gMG from the other four hospitals. Multivariate logistic regression was used to screen independent factors and construct the nomogram.

Results: MSE was achieved in 70 (72.9%), 20 (83.3%), and 33 (73.3%) patients in the training, temporal validation, and external validation cohort, respectively. The duration ≤ 12 months (p = 0.021), ocular score ≤ 2 (p = 0.006), QMG score > 13 (p = 0.008), and gross motor score ≤ 9 (p = 0.006) were statistically associated with MSE in AChR subtype gMG. The nomogram has good performance in predicting MSE as the concordance indexes are 0.81 (95% CI, 0.72-0.90) in the development cohort, 0.944 (95% CI, 0.83-1.00) in the temporal validation cohort, and 0.773 (95% CI, 0.63-0.92) in the external validation cohort.

Conclusion: The nomogram achieved an optimal prediction of MSE in AChR subtype gMG patients using the baseline clinical characters.
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http://dx.doi.org/10.1186/s12967-021-02961-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247112PMC
June 2021

Modeling and improving arrayed microalgal biofilm attached culture system.

Bioresour Technol 2021 Jul 29;331:124931. Epub 2021 Mar 29.

Center for Biorefining and Department of Bioproducts and Biosystems Engineering, University of Minnesota-Twin Cities, Saint Paul, MN 55108, USA. Electronic address:

A microalgal biofilm-attached-system is an alternative cultivation method, that offers potential advantages of improved biomass productivity, efficient harvesting, and water saving. These biofilm systems have been widely tested and utilized for microalgal biomass production and wastewater treatment. This research a microalgal growth model for the biofilm attached culture system has been developed and experimentally validated, both, in single and arrayed biofilm systems. It has been shown that the model has the capability to accurately describe microalgae growth. Moreover, via the model simulation, it was observed that system structural parameters, light dilution rate, and light intensity significantly affected the culture performance. The limitations, and improvement aspects of the model, are also discussed in this study. To our knowledge, this is the first time that a mathematical model for an arrayed-biofilm-attached-system has been developed and validated. This model will certainly be helpful in the design, improvement, optimization, and evaluation of the biofilm-attached-systems.
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http://dx.doi.org/10.1016/j.biortech.2021.124931DOI Listing
July 2021

Suramin Targets the Conserved Ligand-Binding Pocket of Human Raf1 Kinase Inhibitory Protein.

Molecules 2021 Feb 21;26(4). Epub 2021 Feb 21.

Key Laboratory of Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

Suramin was initially used to treat African sleeping sickness and has been clinically tested to treat human cancers and HIV infection in the recent years. However, the therapeutic index is low with numerous clinical side-effects, attributed to its diverse interactions with multiple biological macromolecules. Here, we report a novel binding target of suramin, human Raf1 kinase inhibitory protein (hRKIP), which is an important regulatory protein involved in the Ras/Raf1/MEK/ERK (MAPK) signal pathway. Biolayer interference technology showed that suramin had an intermediate affinity for binding hRKIP with a dissociation constant of 23.8 µM. Both nuclear magnetic resonance technology and molecular docking analysis revealed that suramin bound to the conserved ligand-binding pocket of hRKIP, and that residues K113, W173, and Y181 play crucial roles in hRKIP binding suramin. Furthermore, suramin treatment at 160 µM could profoundly increase the ERK phosphorylation level by around 3 times. Our results indicate that suramin binds to hRKIP and prevents hRKIP from binding with hRaf1, thus promoting the MAPK pathway. This work is beneficial to both mechanistically understanding the side-effects of suramin and efficiently improving the clinical applications of suramin.
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http://dx.doi.org/10.3390/molecules26041151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926937PMC
February 2021

Melatonin exerts immunoregulatory effects by balancing peripheral effector and regulatory T helper cells in myasthenia gravis.

Aging (Albany NY) 2020 11 2;12(21):21147-21160. Epub 2020 Nov 2.

Department of Neurology, Tangdu Hospital, The Air Force Medical University, Xi’an, Shaanxi Province, P.R. China.

Myasthenia gravis (MG) is a prototypic organ-specific autoimmune disorder that, in most cases, is mainly mediated by antibodies against the acetylcholine receptor. Evidence implicates CD4 T helper (Th) cells in the development of MG, whereas regulatory T cells (Tregs) are associated with disease resolution. Melatonin has important immunoregulatory effects in many T cell-mediated autoimmune diseases. However, there are few studies on the role of melatonin in MG. In the present study, we investigated serum melatonin levels and melatonin receptor expression in MG patients and healthy controls (HCs). We also evaluated the impact of melatonin administration on peripheral CD4 Th cells and related cytokine production. Serum melatonin levels were lower in MG patients than in HCs, and MT1 expression was lower in PBMCs from MG patients than in those from HCs. Administration of melatonin significantly decreased Th1 and Th17 cell responses and proinflammatory cytokine production. Further investigation revealed that melatonin administration increased FoxP3 and IL-10 expression in CD4 T cells from MG patients and enhanced the suppressive function of Tregs. These findings indicate that melatonin exerts immunoregulatory activity in MG by balancing effector and regulatory Th cell populations as well as by suppressing proinflammatory cytokine production.
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http://dx.doi.org/10.18632/aging.103785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695404PMC
November 2020

An Update of Outcome Measures in Systemic Sclerosis.

Arthritis Care Res (Hoboken) 2020 10;72 Suppl 10:110-133

University of Western Ontario and St. Joseph's Health Care London, London, Ontario, Canada.

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http://dx.doi.org/10.1002/acr.24258DOI Listing
October 2020

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.

Nat Commun 2020 10 9;11(1):5099. Epub 2020 Oct 9.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

Mutations in the skeletal muscle Ca release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.
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http://dx.doi.org/10.1038/s41467-020-18865-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547078PMC
October 2020

Development of integrated culture systems and harvesting methods for improved algal biomass productivity and wastewater resource recovery - A review.

Sci Total Environ 2020 Dec 21;746:141039. Epub 2020 Jul 21.

Center for Biorefining and Department of Bioproducts and Biosystems Engineering, University of Minnesota-Twin Cities, Saint Paul, MN 55108, USA.

Microalgae biomass has been considered as a potential feedstock for the production of renewable chemicals and biofuels. Microalgae culture combined with wastewater treatment is a promising approach to improve the sustainability of the business model. However, algae culture and harvest account for the majority of the high costs, hindering the development of the microalgae-based wastewater utilization. Cost-effective culture systems and harvesting methods for enhancing biomass yield and reducing the cost of resource recovery have become extremely urgent and important. In this review, different commonly used culture systems for microalgae are discussed; the current harvesting methods with different culture systems have also been evaluated. Also, the inherent characteristics of inefficiency in algae wastewater treatment are elaborated. Current literature collectively supports that a biofilm type device is a system designed for higher biomass productivity, and offers ease of harvesting, in small-scale algae cultivation. Additionally, bio-flocculation, which uses one kind of flocculated microalgae to concentrate on another kind of non-flocculated microalgae is a low-cost and energy-saving alternative harvesting method. These findings provide insight into a comprehensive understanding of integrated culture systems and harvesting methods for microalgae-based wastewater treatment.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141039DOI Listing
December 2020

Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma.

Transl Oncol 2020 Apr 21;13(4):100758. Epub 2020 Mar 21.

State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China, 710032; Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China, 710032. Electronic address:

Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.
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http://dx.doi.org/10.1016/j.tranon.2020.100758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097522PMC
April 2020

Multi-Access Networking with Wireless Ultrasound-Powered Implants.

IEEE Biomed Circuits Syst Conf 2019 Oct 5;2019. Epub 2019 Dec 5.

Electrical Engineering, Stanford University, Stanford, CA, 94305, USA.

Multi-access networking with miniaturized wireless implantable devices can enable and advance closed-loop medical applications to deliver precise diagnosis and treatment. Using ultrasound (US) for wireless implant systems is an advantageous approach as US can beamform with high spatial resolution to efficiently power and address multiple implants in the network. To demonstrate these capabilities, we use wirelessly powered mm-sized implants with bidirectional communication links; uplink data communication measurements are performed using time, spatial, and frequency-division multiplexing schemes in tissue phantom. A 32-channel linear transmitter array and an external receiver are used as a base station to network with two implants that are placed 6.5 cm deep and spaced less than 1 cm apart. Successful wireless powering and uplink data communication around 100 kbps with a measured bit error rate below 10 are demonstrated for all three networking schemes, validating the multi-access networking feasibility of US wireless implant systems.
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http://dx.doi.org/10.1109/BIOCAS.2019.8919144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984356PMC
October 2019

Ultrasonic Implant Localization for Wireless Power Transfer: Active Uplink and Harmonic Backscatter.

IEEE Int Ultrason Symp 2019 Oct 9;2019:818-821. Epub 2019 Dec 9.

Department of Electrical Engineering, Stanford University, Stanford, CA, USA.

Efficient ultrasonic power transfer to implantable devices requires precise transmitter beamforming to the receiver and can quickly degrade with small changes in implant location. Ultrasound localization can be used to find and track implants in the body to maintain an efficient link. We present a framework to calculate localization accuracy showing that sub-mm accuracy is obtainable using only three receive channels. A harmonic backscatter approach, which passively provides contrast in the frequency domain without active load modulation is compared to active uplink from the implant. The localization accuracy using both active uplink and harmonic backscatter from the implant power receiver is characterized using a linear array probe. The measured location standard deviation is nearly two orders of magnitude smaller than the half-power beamwidth of the array focal spot. Finally, beamforming using the measured location information increases the available power by over 20 × compared to an unfocused beam.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984372PMC
October 2019

Assessment of miniaturized ultrasound-powered implants: an in vivo study.

J Neural Eng 2020 02 25;17(1):016072. Epub 2020 Feb 25.

Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD, United States of America. Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States of America. Jesse Vo and Ting Chia Chang contributed equally to this work.

Objective: Therapeutic applications of implantable active medical devices have improved the quality of patient life. Numerous on-going research in the field of neuromodulation and bioelectronic medicine are exploring the use of these implants for treating diseases and conditions. Miniaturized implantable medical devices that are wirelessly powered by ultrasound (US) can be placed close to the target sites deep inside the body for effective therapy with less invasiveness. In this study, we assessed the long-term in vivo performance of miniaturized US powered implants (UPI) using a rodent model.

Approach: Prototype UPI devices were implanted in rodents and powered wirelessly using an unfocused US transmitter over 12 weeks, and the corresponding device output was recorded. Structural integrity of UPI before and after implantation was studied using scanning electron microscopy (SEM). We also conducted qualitative histological assessment of skin and muscle surrounding the UPI and compared it to naïve control and US exposed tissues.

Main Results: We found that it is feasible to power UPI devices wirelessly with US over long-term. The encapsulation of UPIs did not degrade over time and the tissues surrounding the UPI were comparable to both naïve control and US exposed tissues.

Significance: This study is the first to assess the long-term performance of miniaturized UPI devices using a rodent model over 12-weeks. The set of tests used in this study can be extended to assess other US-powered miniaturized implants.
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http://dx.doi.org/10.1088/1741-2552/ab6fc2DOI Listing
February 2020

mutation status in patients with metachronous breast and ovarian malignancies: clues towards the implementation of genetic counseling.

J Gynecol Oncol 2020 May 25;31(3):e24. Epub 2019 Oct 25.

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center and Chang Gung University, College of Medicine, Taoyuan, Taiwan.

Objective: The characteristics of patients with metachronous breast and ovarian malignancies and the pathogenic role of mutations remain poorly understood. We investigated these issues through a review of hospital records and nationwide Taiwanese registry data, followed by mutation analysis in hospital-based cases.

Methods: We retrospectively retrieved consecutive clinical records of Taiwanese patients who presented with these malignancies to our hospital between 2001 and 2017. We also collected information from the Data Science Center of the Taiwan Cancer Registry (TCR) between 2007 and 2015. Next-generation sequencing and multiplex ligation-dependent probe amplification were used to identify mutations and large genomic rearrangements, respectively. When mutations were identified in index cases, pedigrees were reconstructed and genetic testing was offered to family members.

Results: A total of 12,769 patients with breast cancer and 1,537 with ovarian cancer were retrieved from our hospital records. Of them, 28 had metachronous breast and ovarian malignancies. We also identified 113 cases from the TCR dataset. Eighteen hospital-based cases underwent sequencing and germline pathogenic mutations were detected in 7 patients (38.9%, 5 in and 2 in ). All mutation carriers had ovarian high-grade serous carcinomas. Of the 12 patients who were alive at the time of analysis, 5 were mutation carriers. All of them had family members with -associated malignancies.

Conclusions: Our results provide pilot evidence that mutations are common in Taiwanese patients with metachronous breast and ovarian malignancies, supporting the clinical utility of genetic counseling.
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http://dx.doi.org/10.3802/jgo.2020.31.e24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189074PMC
May 2020

[Effects of Different Concentrations of Ammonia Nitrogen on the Growth and Enzyme Activity of Four Common Algae Strains].

Huan Jing Ke Xue 2019 Aug;40(8):3642-3649

College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315211, China.

Treating swine wastewater with a high ammonia nitrogen content with microalgae cultures has proved difficult. In this paper, the strains , , , and were tested. Ammonia nitrogen concentrations of 50 mg·L, 500 mg·L, and 2000 mg·L applied to the media according to the concentrations of biogas slurry. This allowed the effect of different concentrations of ammonia nitrogen on the growth and cell enzyme activity of microalgae to be tested. The results showed that the growth of 715 and was inhibited at different concentrations of ammonia nitrogen, and the biomass and biomass productivities were lower than for the normal media. However, the biomass and biomass productivity of in 50 mg·L ammonia nitrogen were 1.78 g·L and 0.16 g·(L·d), respectively, which were higher than the values obtained using KOCK medium. Furthermore, the biomass and biomass productivity of 357 in 500 mg·L ammonia nitrogen were 1.95 g·L and 0.18 g·(L·d), respectively, which were higher than the values obtained using BG11 medium. The SOD, POD, and CAT of all algae species showed a decreasing tendency in response to an increase in the concentration of ammonia nitrogen, as did MDA. These results provide a theoretical basis for the treatment of swine wastewater with high ammonia nitrogen content using microalgae cultures.
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http://dx.doi.org/10.13227/j.hjkx.201811224DOI Listing
August 2019

The effects of refractory pollutants in swine wastewater on the growth of sp. with biofilm attached culture.

Int J Phytoremediation 2020 1;22(3):241-250. Epub 2019 Sep 1.

School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China.

Microalgae have been widely used for treatment of swine wastewater. However, the research on combined treatment of refractory pollutants ammonia nitrogen, Cu (II) and antibiotics from swine wastewater was still scattered. This study, the growth and removal efficiency of NHCl, CuSO, tetracycline, norfloxacin and sulfadimidine with selected sp. was investigated by biofilm attached culture. The results showed that low concentration of ammonia nitrogen had little effect on algae growth. The highest biomass productivity was 6.2 g/(md) at the concentration of NHCl of 50.0 mg/L, which was similar to that of a standard growth medium BG 11. Cu (II) concentration of 1.0 mg/L could accelerate the growth of sp., and the highest biomass was 57.2 g/m in 8 days. Moreover, the highest biomass mean values was 59.5 g/m, 57.1 g/m and 58.1 g/m, respectively, when tetracycline concentration was 20.0 mg/L, norfloxacin concentration was 100.0 mg/L and sulfadimidine concentration was 10.0 mg/L. The removal efficiency of ammonia nitrogen, copper, tetracycline, norfloxacin and sulfadimidine with sp. at their optimal initial concentration by biofilm attached culture was 85.2%, 64.6%, 74.6%,71.2%, and 62.3%, respectively. This study provides a theoretical basis for the purification of refractory substances from swine wastewater.
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http://dx.doi.org/10.1080/15226514.2019.1658706DOI Listing
February 2020

Glucobrassicin Metabolites Ameliorate the Development of Portal Hypertension and Cirrhosis in Bile Duct-Ligated Rats.

Int J Mol Sci 2019 Aug 26;20(17). Epub 2019 Aug 26.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan.

Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3'-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.
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http://dx.doi.org/10.3390/ijms20174161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747388PMC
August 2019

Primary central nervous system small lymphocytic lymphoma in the bilateral ventricles: two case reports.

BMC Neurol 2019 Aug 19;19(1):200. Epub 2019 Aug 19.

Department of Neurology, Tangdu Hospital, the Air Force Medical University, 569 Xinsi Road, Xi'an, Shaanxi Province, 710038, People's Republic of China.

Background: Primary central nervous system (CNS) small lymphocytic lymphoma (SLL), as a type of low-grade lymphoma, is extremely rare. The diagnosis of CNS SLL is challenging due to its variable clinical and radiological features, which may overlap with those of diffuse large B-cell lymphoma (DLBCL). Primary CNS SLL differs from DLBCL in that it has an indolent clinical course and a good prognosis. Thus, it is important to distinguish SLL from DLBCL. By reviewing the literature, only two cases of low-grade SLL, primarily located in the CNS and involving the brain parenchyma and dura, have been reported. To our knowledge, primary CNS SLL in the bilateral ventricles has never been reported. Interestingly, the two cases in our report are identical in terms of the clinical presentations, magnetic resonance imaging (MRI) features, pathological results and prognoses.

Case Presentation: Both patients presented with headaches. MRI suggested solid lesions located in the bilateral ventricles that were isointense on T1-weighted images and hypointense on T2-weighted images. After the injection of contrast agent (gadolinium, Gd), the intraventricular lesions were homogeneously enhanced and hyperperfused. CSF cytology revealed malignant cells. Brain biopsy revealed diffuse proliferation of small lymphocytes with positive labelling of B-cell immunomarkers. The primary origin in the CNS was confirmed with no evidence of systemic lymphoma. Two patients were given high doses of methotrexate-based chemotherapy and were free from symptoms and progression for more than 1-year of follow-up.

Conclusions: The presence of homogeneously enhanced intraventricular MRI lesions should raise the suspicion of primary CNS SLL.
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http://dx.doi.org/10.1186/s12883-019-1430-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699128PMC
August 2019

Isocitrate dehydrogenase1 mutation reduces the pericyte coverage of microvessels in astrocytic tumours.

J Neurooncol 2019 Jun 19;143(2):187-196. Epub 2019 Apr 19.

Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.

Introduction: Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear.

Methods: Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-β (PDGFR-β), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG.

Results: The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells.

Conclusions: Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.
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http://dx.doi.org/10.1007/s11060-019-03156-5DOI Listing
June 2019

Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score.

Bone 2019 05 14;122:76-81. Epub 2019 Feb 14.

Yale University School of Medicine, New Haven, CT, USA.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.
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http://dx.doi.org/10.1016/j.bone.2019.02.010DOI Listing
May 2019

Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis.

Neurol Sci 2019 Mar 10;40(3):479-487. Epub 2018 Dec 10.

Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.

Background: Autologous hematopoietic stem-cell transplantation (AHSCT) has been utilized as a treatment option for multiple sclerosis (MS) since 1995. However, this procedure has not been widely implemented in clinical practice owing to its mortality risk. Here, we conduct a meta-analysis to evaluate the long-term efficacy and safety of AHSCT in MS treatment, aiming to optimize the benefit/risk ratio of this therapeutic strategy.

Methods: We searched the PubMed Web site and clinicaltrials.gov databases. The efficacy endpoints were progression-free survival (PFS) and disease activity-free survival. The safety outcomes were transplant-related mortality (TRM) and overall deaths.

Results: Eighteen eligible studies with a total of 732 participants were enrolled. The PFS was 75% (95% CI, 0.69-0.81), and the estimate of disease activity-free survival was 61% with 48-month follow-up. Subgroups analysis showed that low- and intermediate-intensity regimens were associated with higher PFS 80%. Relapsing remitting MS (RRMS) benefited more from AHSCT than other MS subtypes with PFS 85%. Patients with Gd+ lesions at baseline MRI responded better to AHSCT with PFS 77%. The estimate of TRM was 1.34% (95% CI, 0.39-2.30), and the overall mortality was 3.58%. TRM was significantly higher in high-intensity regimen studies (3.13%) and in older studies (1.93%) performed before 2006.

Conclusions: This meta-analysis provides evidences that AHSCT can induce long-term remissions for MS patients with a high degree of safety. We indicate low- and intermediate-intensity regimens and RRMS patients with the presence of Gd+ lesions at baseline MRI can obtain the optimal benefit/risk ratio from AHSCT.
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http://dx.doi.org/10.1007/s10072-018-3670-1DOI Listing
March 2019

Long-term in vivo performance of novel ultrasound powered implantable devices.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:2985-2988

Neuromodulation devices have been approved for the treatment of epilepsy and seizures, with many other applications currently under research investigation. These devices rely on implanted battery powered pulse generators, that require replacement over time. Miniaturized ultrasound powered implantable devices have the potential to eliminate the need for batteries in neuromodulation devices. While these devices have been assessed in vitro, long-term in vivo assessment is required to determine device safety and performance. In this study, we developed a multi-stage long-term test platform to assess the performance of miniaturized ultrasound powered implantable devices.
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http://dx.doi.org/10.1109/EMBC.2018.8512978DOI Listing
July 2018

Catheter Ablation of Ventricular Tachycardia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

Korean Circ J 2018 Oct;48(10):890-905

Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is predominantly an inherited cardiomyopathy with typical histopathological characteristics of fibro-fatty infiltration mainly involving the right ventricular (RV) inflow tract, RV outflow tract, and RV apex in the majority of patients. The above pathologic evolution frequently brings patients with ARVD/C to medical attention owing to the manifestation of syncope, sudden cardiac death (SCD), ventricular arrhythmogenesis, or heart failure. To prevent future or recurrent SCD, an implantable cardiac defibrillator (ICD) is highly desirable in patients with ARVD/C who had experienced unexplained syncope, hemodynamically intolerable ventricular tachycardia (VT), ventricular fibrillation, and/or aborted SCD. Notably, the management of frequent ventricular tachyarrhythmias in ARVD/C is challenging, and the use of antiarrhythmic drugs could be unsatisfactory or limited by the unfavorable side effects. Therefore, radiofrequency catheter ablation (RFCA) has been implemented to treat the drug-refractory VT in ARVD/C for decades. However, the initial understanding of the link between fibro-fatty pathogenesis and ventricular arrhythmogenesis in ARVD/C is scarce, the efficacy and prognosis of endocardial RFCA alone were limited and disappointing. The electrophysiologists had broken through this frontier after better illustration of epicardial substrates and broadly application of epicardial approaches in ARVD/C. In recent works of literature, the application of epicardial ablation also successfully results in higher procedural success and decreases VT recurrences in patients with ARVD/C who are refractory to the endocardial approach during long-term follow-up. In this article, we review the important evolution on the delineation of arrhythmogenic substrates, ablation strategies, and ablation outcome of VT in patients with ARVD/C.
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http://dx.doi.org/10.4070/kcj.2018.0268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158456PMC
October 2018

End-to-End Design of Efficient Ultrasonic Power Links for Scaling Towards Submillimeter Implantable Receivers.

IEEE Trans Biomed Circuits Syst 2018 10 20;12(5):1100-1111. Epub 2018 Sep 20.

We present an analytical framework for optimizing the efficiency of ultrasonic wireless power links for implantable devices scaled down to sub-mm dimensions. Key design insights and tradeoffs are considered for various parameters including the operating frequency, the transmission depth, the size of the transmitter, the impedance and the aperture efficiency of the miniaturized receiver, and the interface between the receiver and the power recovery chain on the implant. The performance of spherically focused transducers as ultrasonic transmitters is analyzed to study the limits and the tradeoffs. Two optimization methods are presented: "Focal Peak" sets the focus of transducers at target depths, and "Global Maximum" maximizes the efficiency globally with off-focus operation. The results are also compared to phased array implementations. To investigate the efficiency of implants, miniaturized receivers made from single crystalline piezoelectric material, PMN-PT, are used as they have resonances in the derived optimal carrier frequency range (∼1-2 MHz). A methodology to achieve an efficient interface to the power electronics is then provided using an optogenetic stimulator as an example platform. The analytical results are verified through both simulations and measurements. Finally, an example ultrasonic link using a spherical transmitter with a radius of 2 cm is demonstrated; link efficiencies of 1.93-0.23% are obtained at 6-10 cm depths with sub-mm receivers for the optogenetic application.
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http://dx.doi.org/10.1109/TBCAS.2018.2871470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269189PMC
October 2018

Anti-leprosy drug Clofazimine binds to human Raf1 kinase inhibitory protein and enhances ERK phosphorylation.

Acta Biochim Biophys Sin (Shanghai) 2018 Oct;50(10):1062-1067

Department of Chemical Biology, Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.

Human Raf1 kinase inhibitory protein (hRKIP) is an important modulator of the Ras/Raf1/MEK/ERK signaling pathway. Here, we demonstrated that anti-leprosy drug Clofazimine can bind to hRKIP with a significantly stronger affinity than the endogenous substrate phosphatidylethanolamine (PE) by using Biolayer interference technology. Moreover, we identified that residues P74, S75, K80, P111, P112, V177, and P178 play crucial roles in the binding of hRKIP to Clofazimine by using a combination of Nuclear Magnetic Resonance spectroscopy and molecular docking approach. These residues are located at the conserved ligand-binding pocket of hRKIP. Furthermore, we found that 3.2 μM Clofazimine could significantly increase the ERK phosphorylation level by about 37%. Our results indicate that Clofazimine can enhance Ras/Raf1/MEK/ERK signaling transduction pathway via binding to hRKIP. This work provides valuable hints for exploiting Clofazimine as a potential lead compound to efficiently treat the diseases related to RKIP or the Ras/Raf/MEK/ERK pathway.
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http://dx.doi.org/10.1093/abbs/gmy095DOI Listing
October 2018

Cerebrospinal fluid NFL in the differential diagnosis of parkinsonian disorders: A meta-analysis.

Neurosci Lett 2018 10 20;685:35-41. Epub 2018 Jul 20.

Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, PR China. Electronic address:

Neurofilament light chain (NFL) in cerebrospinal fluid (CSF) is a promising biomarker candidate which may discriminate atypical parkinsonian disorders (APD), mainly including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), from Parkinson's disease (PD). We aim to evaluate the diagnostic accuracy of CSF NFL level as a differentiating biomarker between APD and PD. Databases of PubMed, OVID and Web of Science were searched for studies (published until May 31, 2017) that reported on CSF NFL as a diagnostic biomarker between APD and PD. Eight studies were pooled in this meta-analysis, including 341 PD and 396 APD patients and 388 healthy controls. The pooled sensitivity was 82% (95% CI, 68%-91%) and specificity was 85% (95% CI, 79%-89%) in differentiating APD from PD. The pooled positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were 5.4 (95% CI, 3.6%-8.1%), 0.21 (95% CI, 0.11%-0.40%), and 25 (95% CI, 9%-69%) respectively; and the area under the curve (AUC) was 0.89 (95% CI, 0.86%-0.91%). Subgroup analysis revealed sensitivity and specificity were significantly influenced by study design. The APD subtypes, disease duration and severity were the main heterogeneity sources in specificity. The results of Deeks' test revealed a low risk of publication bias. The CSF NFL level may be used as a biomarker in discriminating APD from PD with high diagnostic accuracy at an early stage of disease. Large and longitudinal studies are still needed on individuals who are suspected to have APD.
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http://dx.doi.org/10.1016/j.neulet.2018.07.030DOI Listing
October 2018

A mm-Sized Wireless Implantable Device for Electrical Stimulation of Peripheral Nerves.

IEEE Trans Biomed Circuits Syst 2018 04;12(2):257-270

A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm, 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 μA amplitude, ∼14 to 470 μs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves.
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http://dx.doi.org/10.1109/TBCAS.2018.2799623DOI Listing
April 2018

High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1-6 patients without cirrhosis.

J Hepatol 2018 08 16;69(2):293-300. Epub 2018 Mar 16.

AbbVie Inc., North Chicago, IL, USA.

Background & Aims: Glecaprevir plus pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection. In nine phase II or III clinical trials, G/P therapy achieved rates of sustained virologic response 12 weeks after treatment (SVR12) of 93-100% across all six major HCV genotypes (GTs). An integrated efficacy analysis of 8- and 12-week G/P therapy in patients without cirrhosis with HCV GT 1-6 infection was performed.

Methods: Data were pooled from nine phase II and III trials including patients with chronic HCV GT 1-6 infection without cirrhosis who received G/P (300 mg/120 mg) for either 8 or 12 weeks. Patients were treatment naïve or treatment experienced with peginterferon, ribavirin, and/or sofosbuvir; all patients infected with HCV GT 3 were treatment naïve. Efficacy was evaluated as the SVR12 rate.

Results: The analysis included 2,041 patients without cirrhosis. In the intent-to-treat population, 943/965 patients (98%) achieved SVR12 when treated for eight weeks, and 1,060/1,076 patients (99%) achieved SVR12 when treated for 12 weeks; the difference in rates was not significant (p = 0.2). A subgroup analysis demonstrated SVR12 rates > 95% across baseline factors traditionally associated with lower efficacy. G/P was well tolerated, with one DAA-related serious adverse event (<0.1%); grade 3 laboratory abnormalities were rare.

Conclusions: G/P therapy for eight weeks in patients with chronic HCV GT 1-6 infection without cirrhosis achieved an overall SVR12 rate of 98% irrespective of baseline patient or viral characteristics; four additional weeks of treatment did not significantly increase the SVR12 rate, demonstrating that the optimal treatment duration in this population is eight weeks.

Lay Summary: In this integrated analysis of nine clinical trials, patients with chronic HCV genotype 1-6 infection without cirrhosis were treated for either 8 or 12 weeks with the direct-acting antiviral regimen glecaprevir/pibrentasvir (G/P). The cure rate was 98% and 99% following 8 and 12 weeks of treatment, respectively; the difference in rates was not significant (p = 0.2), nor was there a significant difference in the cure rates across the two treatment durations on the basis of baseline patient or viral characteristics. These results, along with a favourable safety profile, indicate that G/P is a highly efficacious and well-tolerated pangenotypic eight-week therapy for most patients with chronic HCV infection.
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http://dx.doi.org/10.1016/j.jhep.2018.03.007DOI Listing
August 2018

Letter by Guo et al Regarding Article, "Prevalence and Natural History of Superficial Siderosis: A Population-Based Study".

Stroke 2018 04 22;49(4):e168. Epub 2018 Feb 22.

Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Shaanxi Province, China.

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http://dx.doi.org/10.1161/STROKEAHA.117.020539DOI Listing
April 2018

Effect of sirolimus on liver cirrhosis and hepatic encephalopathy of common bile duct-ligated rats.

Eur J Pharmacol 2018 Apr 11;824:133-139. Epub 2018 Feb 11.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Cheng-Hsin General Hospital, Taipei, Taiwan, ROC.

Cirrhosis is often associated with portal hypertension and portal-systemic collateral vessels formation attributed to angiogenesis, which leads to severe complications as hepatic encephalopathy. Sirolimus has anti-fibrosis and anti-angiogenesis effects, but whether it influences the severity of portal-systemic collaterals and hepatic encephalopathy is unknown. This study was thus designed to address this issue in rats with common bile duct ligation-induced liver cirrhosis. Sham-operated rats were surgical controls. Rats were intraperitoneally administered with 0.5 and 2 mg/kg/day sirolimus or vehicle for 2 weeks. Four weeks post operations, motor activities, body weight, biochemistry and hemodynamic data were measured. The liver was dissected for histopathology, immunohistochemical stains and protein analysis. On the parallel cirrhotic groups, the portal-systemic shunting was determined. The results showed that the body weight gain was significantly lower in sirolimus-treated rats. Sirolimus reduced portal pressure and plasma levels of alanine aminotransferase, aspartate aminotransferase and ammonia, and attenuated hepatic inflammation and fibrosis in cirrhotic rats. In addition, the hepatic phosphorylated mammalian target of rapamycin (mTOR) and P70S6K protein expressions were significantly downregulated and endothelial nitric oxide synthase (eNOS) expression upregulated by sirolimus. Sirolimus did not influence portal-systemic shunting and motor activities of cirrhotic rats. In conclusion, sirolimus significantly improved hepatic inflammation and fibrosis accompanied by portal pressure reduction in cirrhotic rats, in which down-regulated mTOR/P70S6K and up-regulated eNOS expressions might play a role. However, sirolimus did not significantly change the severity of portal-systemic collaterals and motor activities, suggesting that the multifactorial pathogenesis of hepatic encephalopathy could not be fully overcome by sirolimus.
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http://dx.doi.org/10.1016/j.ejphar.2018.02.016DOI Listing
April 2018
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