Publications by authors named "Gang Zeng"

114 Publications

Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine in a Subgroup of Healthy Adults in Chile.

Clin Infect Dis 2021 Sep 19. Epub 2021 Sep 19.

Hospital Clínico Félix Bulnes, Santiago, Chile.

Background: The development of effective vaccines against COVID-19 is a global priority. CoronaVac is an inactivated SARS-CoV-2 vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 in a phase 3 clinical trial.

Methods: Volunteers randomly received two doses of CoronaVac or placebo, separated by two weeks. 434 volunteers were enrolled, 397 aged 18-59 years, and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.

Results: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-RBD IgG were 86.67% in the 18-59 age group and 70.37% in the ≥60 age group, two and four weeks after the second dose. A significant increase in circulating neutralizing antibodies was detected two and four weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T cell responses characterized by the secretion of IFN-γupon stimulation with Mega Pools of peptides from SARS-CoV-2.

Conclusions: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γupon stimulation with SARS-CoV-2 antigens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab823DOI Listing
September 2021

Spatiotemporal Response of Hydrological Drought to Meteorological Drought on Multi-Time Scales Concerning Endorheic Basin.

Int J Environ Res Public Health 2021 Aug 27;18(17). Epub 2021 Aug 27.

The Center for Modern Chinese City Studies, Institute of Urban Development, East China Normal University, Shanghai 200062, China.

Under the controversial background of "Northwestern China is gradually developing towards warm and humid", how hydrological drought responds to meteorological drought at the endorheic basin is of great significance. To address this problem, we first analyzed the spatiotemporal variation of meteorological and hydrological droughts at Tarim Basin River from 1960 to 2014 by using the daily standardized precipitation index (SPI) and daily standardized terrestrial water storage index (SWSI) based on the reanalysis data. Thereafter, we explored the spatiotemporal response of hydrological drought to meteorological drought on the multi-time scale by using the cross-wavelet transform method, Ensemble Empirical Mode Decomposition (EEMD), and correlation analysis. We find that: (1) both meteorological and hydrological droughts signified a gradually weakened trend in time; (2) meteorological and hydrological drought have significant resonance periods on the 10-month time scale and the 8-year time scale; (3) hydrological drought generally lags behind the meteorological drought by 7 days in plains areas, while it can last as long as several months or even a year in mountainous areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18179074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431155PMC
August 2021

Study on the contrast of the MHC-peptide interaction of B2/B21 haplotype and MHC-related virus resistance in chickens.

Immun Inflamm Dis 2021 Sep 2. Epub 2021 Sep 2.

College of Biology and Agriculture (College of Food Science and Technology), Zunyi Normal College, Zunyi, Guizhou, China.

Introduction: Three-dimensional (3D) structures of MHC class I exert some influence by the MHC-peptide interaction over host resistance to the virus. The thesis aims at studying the connection between MHC-peptide interaction of B2/B21 haplotype and MHC-related resistance to the virus.

Methods: The structure of chicken MHC class I BF2*0201 from B2 haplotype was studied and contrasted with that of BF2*2101 from B21 haplotype by using DNAMAN and PyMol software.

Results: The amino acid difference resulted in the difference in size and changeability of the binding groove of the two, resulting in different choices on the binding polypeptide. 3bew's (the crystal structure of BF2*2101 bound to peptide RV10) small side chain His111 replaces the short side chain Tyr111 of 4cvx (the crystal structure of BF2*0201 bound to peptide YL9), and the very small amino acid of Ser69 and Ser97 make the middle of the 3bew's binding groove become apparently broad and bound restrictive of amino acid smaller. Moreover, due to the specific amino acids-Arg9, Asp24, and Asp73 of 4cvx and Arg9, Asp24, and His111 of 3bew, the effect of the polypeptide and the binding groove differ between the two, and 3bew tends to bind polypeptides with negatively charged amino acids, but the large space in the middle can also accommodate other amino acids. Contrasted with the binding groove characteristic of 4cvx, it can be said that the selectivity of 3bew is higher than that of 4cvx in the amino acid type of the binding polypeptide, so the B21 haplotype has more host resistance to the virus than that of the B2 haplotype in chicken.

Conclusion: There are usually various kinds of peptides presented by the BF2*2101 molecules of B21 haplotypes, resulting in resistance to pathogenic microorganisms, such as Rous sarcoma virus and/or Marek's disease virus. These findings may have an important theoretical foundation for screening of virus antigen, vaccine design, and genetic resistance breeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/iid3.520DOI Listing
September 2021

Does Technological Innovation Promote Green Development? A Case Study of the Yangtze River Economic Belt in China.

Int J Environ Res Public Health 2021 06 5;18(11). Epub 2021 Jun 5.

Center for Modern Chinese City Studies, East China Normal University, Shanghai 200062, China.

The role of technological innovation (TI) in green development is controversial. Based on 2003-2017 panel data of 108 cities in the Yangtze River Economic Belt (YREB), this study constructed an index system to evaluate urban green development and analyzed the role of TI on urban green development with the help of a panel econometric model. The results show that: (1) From 2003 to 2017, the levels of TI and green development of cities in the YREB have gradually improved, but the core-periphery structure is obvious, and the levels of TI and green development in the lower reaches are significantly higher than those in the middle and upper reaches. (2) TI has a significant positive role in promoting green development, showing a U-shaped nonlinear relationship, and this relationship varies from region to region. (3) TI has a significant impact on green development with direct and indirect effects. In the economic and social dimensions, TI has a positive impact on green development, while in the ecological dimension, the direct effect and indirect effect have opposite relationships. (4) TI has a significant threshold effect on green development, and there are differences in threshold characteristics between the three dimensions. These findings provide a scientific basis for policymaking about innovation-driven regional green development, and it can enrich the related theories of environmental economic geography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18116111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201148PMC
June 2021

Spatio-temporal evolution and mechanism of regional innovation efficiency: Evidence from Yangtze River Delta Urban Agglomeration of China.

PLoS One 2021 1;16(7):e0253598. Epub 2021 Jul 1.

Center for Modern Chinese City Studies, Institute of Urban Development, School of Urban & Regional Science, East China Normal University, Shanghai, China.

Regional innovation is an important research topic in economic geography, the spatio-temporal evolution and mechanism of regional innovation efficiency have recently become a hot for economic geographers. From the perspective of input and output efficiency, this paper constructs evaluation indicator of regional innovation, with the help of Constant Returns to Scale (CRS) and Variable Returns to Scale (VRS) models, and Malmquist indicator method of Data Envelopment Analysis (DEA), to analyze regional innovation performance, evolution trend, spatial differentiation, and evolution mechanism of Yangtze River Delta Urban Agglomeration (YRDUA) of China. The results show that: (i) Innovation efficiency of YRDUA is generally low, most of which is less than 80 percent of optimal efficiency; however, it kept rising from 2000 to 2015. (ii) Spatial inequality of regional innovation in YRDUA is significant, with a spatial pattern in the shape of "Z", composed by Hefei, Nanjing, Shanghai, Hangzhou and Ningbo, innovation efficiency of Shanghai is higher than Zhejiang, Anhui and Jiangsu. (iii) Technology progress is the most important influencing factor, all kinds of changing indicator show a trend of rise, and the total factor productivity is changing significantly. This research can provide theoretical reference for the YRDUA to achieve high-quality integration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253598PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248968PMC
July 2021

Increased high-temperature extremes and associated population exposure in Africa by the mid-21st century.

Sci Total Environ 2021 Oct 31;790:148162. Epub 2021 May 31.

Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, School of Environmental Science and Engineering, Nanjing University of Information Science and Technology, Nanjing 210044, China; Organization of African Academic Doctors (OAAD), Off Kamiti Road, P.O. Box 25305-00100, Nairobi, Kenya.

Previous studies warned that heat extremes are likely to intensify and frequently occur in the future due to climate change. Apart from changing climate, the population's size and distribution contribute to the total changes in the population exposed to heat extremes. The present study uses the ensemble mean of global climate models from the Coupled Model Inter-comparison Project Phase six (CMIP6) and population projection to assess the future changes in high-temperature extremes and exposure to the population by the middle of this century (2041-2060) in Africa compared to the recent climate taken from 1991 to 2010. Two Shared Socioeconomic Pathways (SSPs), namely SSP2-4.5 and SSP5-8.5, are used. Changes in population exposure and its contributors are quantified at continental and for various sub-regions. The intensity of high-temperature extremes is anticipated to escalate between 0.25 to 1.8 °C and 0.6 to 4 °C under SSP2-4.5 and SSP5-8.5, respectively, with Sahara and West Southern Africa projected to warm faster than the rest of the regions. On average, warm days' frequency is also expected to upsurge under SSP2-4.5 (26-59%) and SSP5-8.5 (30-69%) relative to the recent climate. By the mid-21st century, continental population exposure is expected to upsurge by ~25% (28%) of the reference period under SSP2-4.5|SSP2 (SSP5-8.5|SSP5). The highest increase in exposure is expected in most parts of West Africa (WAF), followed by East Africa. The projected changes in continental exposure (~353.6 million person-days under SSP2-4.5|SSP2 and ~401.4 million person-days under SSP5-8.5|SSP5) are mainly due to the interaction effect. However, the climate's influence is more than the population, especially for WAF, South-East Africa and East Southern Africa. The study findings are vital for climate change adaptation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2021.148162DOI Listing
October 2021

Cross-neutralization Capacity of Immune Serum from Different Dosage of Sabin Inactivated Poliovirus Vaccine Immunization against Multiple Individual Polioviruses.

Expert Rev Vaccines 2021 Jun 16;20(6):761-767. Epub 2021 May 16.

Clinical Research Department, Sinovac Biotech Co., Ltd., Beijing, China.

: Sabin strain inactivated poliovirus vaccine (sIPV) developed by Sinovac Biotech Co., Ltd., has shown good safety and immunogenicity against parental strains among infants in several finished pre-licensure clinical trials.: To further study the neutralizing capacity of investigational sIPV immune serum against Sabin, Salk and recently circulating poliovirus strains, neutralization assay against ten individual strains was performed on backup serum collected from 250 infant participants of the finished phase II clinical trial.: The sIPV can generate good immunogenicity against Sabin, Salk and recently circulating poliovirus strains. Taking into account its lower containment requirements and financial costs compared with the conventional Salk strain inactivated poliovirus vaccine, sIPV is an affordable and practical option for polio eradication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14760584.2021.1919091DOI Listing
June 2021

INSR mediated by transcription factor KLF4 and DNA methylation ameliorates osteoarthritis progression via inactivation of JAK2/STAT3 signaling pathway.

Am J Transl Res 2020 15;12(12):7953-7967. Epub 2020 Dec 15.

Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou 510000, Guangdong, China.

Objective: To probe into the role and regulatory mechanisms of INSR in pathogenesis of osteoarthritis (OA).

Methods: KLF4 and INSR expression was detected in cartilage tissues of 40 OA patients and 10 controls using RT-qPCR. IL-1β-induced OA chondrocytes and anterior cruciate ligament transection (ACLT)-induced OA models were respectively constructed. After overexpressing or silencing KLF4 or INSR, flow cytometry assay was utilized to detect chondrocyte apoptosis. Furthermore, JAK2/STAT3, cartilage markers and OA-related markers were examined by western blot. Dual luciferase report and CHIP assay were carried out to verify the interactions between KLF4 and INSR, followed by functional gain and loss assay. INSR promoter methylation was assessed by MS-PCR.

Results: Both KLF4 and INSR were down-regulated both in OA chondrocytes and cartilage tissues. Knockdown of KLF4 or INSR accelerated apoptosis of IL-1β-induced OA chondrocytes. However, overexpression of KLF4 or INSR ameliorated OA progression both in OA chondrocytes and OA mouse models. Moreover, INSR inactivated JAK2/STAT3 pathway in OA chondrocytes. Dual luciferase report and CHIP assay results confirmed that INSR was transcriptionally regulated by KLF4. As shown in MS-PCR results, INSR expression was mediated by DNA methylation in OA.

Conclusion: Our findings suggested that INSR, as a key regulator for OA, was regulated by transcription factor KLF4 and DNA methylation, thereby mediating the activation of JAK2/STAT3 signaling, which was considered as an underlying therapeutic target for OA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791516PMC
December 2020

Quadrivalent influenza vaccine (Sinovac Biotech) for seasonal influenza prophylaxis.

Expert Rev Vaccines 2021 01 1;20(1):1-11. Epub 2021 Feb 1.

School of Public Health, Southeast University; Nanjing, China.

Introduction: Quadrivalent Influenza Vaccine (Sinovac Biotech) is a quadrivalent split-virion-inactivated influenza vaccine approved in China in June 2020 for individuals ≥3 years of age. It contains 15 µg hemagglutinin per strain including A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, which could potentially improve protection against influenza B viruses.

Areas Covered: In this review, we summarize the development of quadrivalent influenza vaccines in China and foreign countries, and assess the immunogenicity and safety from the phase I and III clinical trials of Quadrivalent Influenza Vaccine in individuals ≥3 years of age. We also discuss the potential application of Quadrivalent Influenza Vaccine in young children 6-35 months of age according to the results of the phase III trial.

Expert Commentary: The immunogenicity and safety profiles of Quadrivalent Influenza Vaccine containing two A and two B strains were comparable to the trivalent vaccines for the shared strains. The addition of a second B strain to the trivalent vaccine could induce superior immune responses for the alternate B strain. Since the two B strains co-circulated worldwide, the introduction of quadrivalent influenza vaccines has been expected to be a cost-effective strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14760584.2021.1875823DOI Listing
January 2021

Immunogenicity and Safety of Inactivated Enterovirus 71 Vaccine in Children Aged 36-71 Months: A Double-Blind, Randomized, Controlled, Non-inferiority Phase III Trial.

J Pediatric Infect Dis Soc 2021 Apr;10(4):440-447

Yunnan Center for Disease Control and Prevention, Kunming, China.

Background: The Sinovac enterovirus 71 (EV71) vaccine has been given to children aged 6-35 months with good safety, immunogenicity, and efficacy. Further exploration is needed for the application of Sinovac EV71 vaccine in older children.

Methods: A phase III, double-blind, single-center, randomized, controlled, non-inferiority, and bridging-designed trial enrolled 300 participants aged 6-35 months and 600 participants aged 36-71 months. Non-inferiority and superiority analyses were made to determine the immunogenicity of Sinovac EV71 vaccine in older children (Older-S group), comparing with that of control EV71 vaccine in the same age group (Older-C group), or comparing with that of Sinovac EV71 vaccine in younger children (Younger-S group).

Results: The seroconversion rate of anti-EV71 in Older-S group (95.5%) was superior to that of Older-C group (86.0%), and non-inferior to that of Younger-S group (98.5%). For baseline seronegative participants, the geometric mean titer of Older-S group (370.0) was non-inferior to that of Older-C group (296.2) and superior to that of Younger-S group (176.5). Incidence of adverse reactions in Older-S group (47.0%) was similar to that of Older-C group (44.8%), or Younger-S group (49.8%).

Conclusions: This study showed good safety and immunogenicity of Sinovac EV71 vaccine in children aged 36-71 months.

Clinical Trials Registration: NCT03909074.

Url: https://clinicaltrials.gov/ct2/show/NCT03909074?term=NCT03909074&draw=2&rank=1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa129DOI Listing
April 2021

Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.

Lancet Infect Dis 2021 02 17;21(2):181-192. Epub 2020 Nov 17.

Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China. Electronic address:

Background: With the unprecedented morbidity and mortality associated with the COVID-19 pandemic, a vaccine against COVID-19 is urgently needed. We investigated CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated vaccine candidate against COVID-19, containing inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for its safety, tolerability and immunogenicity.

Methods: In this randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, healthy adults aged 18-59 years were recruited from the community in Suining County of Jiangsu province, China. Adults with SARS-CoV-2 exposure or infection history, with axillary temperature above 37·0°C, or an allergic reaction to any vaccine component were excluded. The experimental vaccine for the phase 1 trial was manufactured using a cell factory process (CellSTACK Cell Culture Chamber 10, Corning, Wujiang, China), whereas those for the phase 2 trial were produced through a bioreactor process (ReadyToProcess WAVE 25, GE, Umea, Sweden). The phase 1 trial was done in a dose-escalating manner. At screening, participants were initially separated (1:1), with no specific randomisation, into two vaccination schedule cohorts, the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and within each cohort the first 36 participants were assigned to block 1 (low dose CoronaVac [3 μg per 0·5 mL of aluminium hydroxide diluent per dose) then another 36 were assigned to block 2 (high-dose Coronavc [6 μg per 0·5 mL of aluminium hydroxide diluent per dse]). Within each block, participants were randomly assigned (2:1), using block randomisation with a block size of six, to either two doses of CoronaVac or two doses of placebo. In the phase 2 trial, at screening, participants were initially separated (1:1), with no specific randomisation, into the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and participants were randomly assigned (2:2:1), using block randomisation with a block size of five, to receive two doses of either low-dose CoronaVac, high-dose CoronaVac, or placebo. Participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after injection in all participants who were given at least one dose of study drug (safety population). The primary immunogenic outcome was seroconversion rates of neutralising antibodies to live SARS-CoV-2 at day 14 after the last dose in the days 0 and 14 cohort, and at day 28 after the last dose in the days 0 and 28 cohort in participants who completed their allocated two-dose vaccination schedule (per-protocol population). This trial is registered with ClinicalTrials.gov, NCT04352608, and is closed to accrual.

Findings: Between April 16 and April 25, 2020, 144 participants were enrolled in the phase 1 trial, and between May 3 and May 5, 2020, 600 participants were enrolled in the phase 2 trial. 743 participants received at least one dose of investigational product (n=143 for phase 1 and n=600 for phase 2; safety population). In the phase 1 trial, the incidence of adverse reactions for the days 0 and 14 cohort was seven (29%) of 24 participants in the 3 ug group, nine (38%) of 24 in the 6 μg group, and two (8%) of 24 in the placebo group, and for the days 0 and 28 cohort was three (13%) of 24 in the 3 μg group, four (17%) of 24 in the 6 μg group, and three (13%) of 23 in the placebo group. The seroconversion of neutralising antibodies on day 14 after the days 0 and 14 vaccination schedule was seen in 11 (46%) of 24 participants in the 3 μg group, 12 (50%) of 24 in the 6 μg group, and none (0%) of 24 in the placebo group; whereas at day 28 after the days 0 and 28 vaccination schedule, seroconversion was seen in 20 (83%) of 24 in the 3 μg group, 19 (79%) of 24 in the 6 μg group, and one (4%) of 24 in the placebo group. In the phase 2 trial, the incidence of adverse reactions for the days 0 and 14 cohort was 40 (33%) of 120 participants in the 3 μg group, 42 (35%) of 120 in the 6 μg group, and 13 (22%) of 60 in the placebo group, and for the days 0 and 28 cohort was 23 (19%) of 120 in the 3 μg group, 23 (19%) of 120 in the 6 μg group, and 11 (18%) of 60 for the placebo group. Seroconversion of neutralising antibodies was seen for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, and two (3%) of 60 in the placebo group at day 14 after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group, and none (0%) of 59 in the placebo group.

Interpretation: Taking safety, immunogenicity, and production capacity into account, the 3 μg dose of CoronaVac is the suggested dose for efficacy assessment in future phase 3 trials.

Funding: Chinese National Key Research and Development Program and Beijing Science and Technology Program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(20)30843-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832443PMC
February 2021

Maternal Diabetes Induces Immune Dysfunction in Autistic Offspring Through Oxidative Stress in Hematopoietic Stem Cells.

Front Psychiatry 2020 3;11:576367. Epub 2020 Sep 3.

Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen, China.

Autism spectrum disorders (ASD) have been found to be associated with immune dysfunction and elevated cytokines, although the detailed mechanism remains unknown. In this study, we aim to investigate the potential mechanisms through a maternal diabetes-induced autistic mouse model. We found that maternal diabetes-induced autistic offspring have epigenetic changes on the superoxide dismutase 2 (SOD2) promoter with subsequent SOD2 suppression in both hematopoietic stem cells (HSC) and peripheral blood mononuclear cells (PBMC). Bone marrow transplantation of normal HSC to maternal diabetes-induced autistic offspring transferred epigenetic modifications to PBMC and significantly reversed SOD2 suppression and oxidative stress and elevated inflammatory cytokine levels. Further, human study showed that SOD2 mRNA expression from PBMC in the ASD group was reduced to ~12% compared to typically developing group, and the SOD2 mRNA level-based ROC (Receiver Operating Characteristic) curve shows a very high sensitivity and specificity for ASD patients. We conclude that maternal diabetes induces immune dysfunction in autistic offspring through SOD2 suppression and oxidative stress in HSC. SOD2 mRNA expression in PBMC may be a good biomarker for ASD diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2020.576367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495463PMC
September 2020

Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac - PROFISCOV: A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Oct 15;21(1):853. Epub 2020 Oct 15.

PATH, Seattle, WA, USA.

Objectives: To evaluate the efficacy of two doses of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac in symptomatic individuals, with virological confirmation of COVID-19, two weeks after the completion of the two-dose vaccination regimen, aged 18 years or older who work as health professionals providing care to patients with possible or confirmed COVID-19. To describe the occurrence of adverse reactions associated with the administration of each of two doses of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac up to one week after vaccination in Adults (18-59 years of age) and Elderly (60 years of age or more).

Trial Design: This is a Phase III, randomized, multicenter, endpoint driven, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of the adsorbed vaccine COVID-19 (inactivated) produced by Sinovac. The adsorbed vaccine COVID-19 (inactivated) produced by Sinovac (product under investigation) will be compared to placebo. Voluntary participants will be randomized to receive two intramuscular doses of the investigational product or the placebo, in a 1: 1 ratio, stratified by age group (18 to 59 years and 60 years or more) and will be monitored for one year by active surveillance of COVID-19. Two databases will be established according to the age groups: one for adults (18-59 years) and one for the elderly (60 years of age or older). The threshold to consider the vaccine efficacious will be to reach a protection level of at least 50%, as proposed by the World Health Organization and the FDA. Success in this criterion will be defined by sequential monitoring with adjustment of the lower limit of the 95% confidence interval above 30% for the primary efficacy endpoint.

Participants: Healthy participants and / or participants with clinically controlled disease, of both genders, 18 years of age or older, working as health professionals performing care in units specialized in direct contact with people with possible or confirmed cases of COVID-19. Participation of pregnant women and those who are breastfeeding, as well as those intending to become pregnant within three months after vaccination will not be allowed. Participants will only be included after signing the voluntary Informed Consent Form and ensuring they undergo screening evaluation and conform to all the inclusion and exclusion criteria. All the clinical sites are located in Brazil.

Intervention And Comparator: Experimental intervention: The vaccine was manufactured by Sinovac Life Sciences (Beijing, China) and contains 3 μg/0.5 mL (equivalent to 600 SU per dose) of inactivated SARS-CoV-2 virus, and aluminium hydroxide as adjuvant. Control comparator: The placebo contains aluminium hydroxide in a 0.5 mL solution The schedule of both, experimental intervention and placebo is two 0.5 mL doses IM (deltoid) with a two week interval.

Main Outcomes: The primary efficacy endpoint is the incidence of symptomatic cases of virologically confirmed COVID-19 two weeks after the second vaccination. The virological diagnosis will be confirmed by detection of SARS-CoV-2 nucleic acid in a clinical sample. The primary safety endpoint is the frequency of solicited and unsolicited local and systemic adverse reactions during the period of one week after vaccination according to age group in adult (18-59 years old) and elder (60 years of age or older) subjects. Adverse reactions are defined as adverse events that have a reasonable causal relationship to vaccination.

Randomisation: There will be two randomization lists, one for each age group, based on the investigational products to be administered, i.e., vaccine or placebo at a 1: 1 ratio. Each randomization list will be made to include up to 11,800 (18-59 year-old) adults, and 1,260 elderly (60 y-o and older) participants, the maximum number of participants needed per age group. An electronic central randomization system will be used to designate the investigational product that each participant must receive.

Blinding (masking): This trial is designed as a double-blind study to avoid introducing bias in the evaluation of efficacy, safety and immunogenicity. The clinical care team, the professionals responsible for the vaccination and the participants will not know which investigational product will be administered. Only pharmacists or nurses in the study who are responsible for the randomization, separation and blinding of the investigational product will have access to unblinded information. The sponsor's operational team will also remain blind.

Numbers To Be Randomised (sample Size): The total number of participants needed to evaluate efficacy, 13,060 participants, satisfies the needed sample size calculated to evaluate safety. Therefore, the total number obtained for efficacy will be the number retained for the study. Up to 13,060 participants are expected to enter the study, with up to 11,800 participants aged 18 to 59 years and 1,260 elderly participants aged 60 and over. Half of the participants of each group will receive the experimental vaccine and half of them will receive the placebo. The recruitment of participants may be modified as recommended by the Data Safety Monitoring Committee at time of the interim unblinded analysis or blind assessment of the COVID-19 attack rate during the study.

Trial Status: Protocol version 2.0 - 24-Aug-2020. Recruitment started on July 21, 2020. The recruitment is expected to conclude in October 2020.

Trial Registration: ClinicalTrials.gov Identifier: NCT0445659 . Registry on 2 July 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04775-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558252PMC
October 2020

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine: A randomized, double-blind, controlled phase III study in healthy population aged ≥3 years.

Vaccine 2020 08 27;38(37):5940-5946. Epub 2020 Jul 27.

Clinical Research Department, Sinovac Biotech Co., LTD., Beijing 100085, China. Electronic address:

Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains (H1N1 and H3N2) and one strain from each B lineage (Victoria and Yamagata) may offer broader protection against seasonal influenza. This study examined the immunogenicity and safety of a candidate IIV4. A randomized, double-blind, controlled phase III clinical trial was conducted in healthy subjects aged ≥3 years. Subjects were randomly assigned into three groups in a 2:1:1 ratio, receiving single dose of IIV4 or inactivated trivalent influenza vaccine (IIV3) which contains either B/Victoria strain (BV) or B/Yamagata strain (BY). Blood samples were collected before and 28 days after vaccination to test hemagglutination inhibition (HI) antibodies of the four influenza strains. Safety information was collected for 28 days after vaccination. A total of 2320 subjects (IIV4: 1160, IIV3-BV: 580, IIV3-BY: 580) were enrolled in this study. After vaccination, the seroconversion rates of IIV4 against H1N1, H3N2, BV and BY strains were 77.15%, 81.93%, 60.14% and 64.57%, respectively. Geometric mean titers (GMTs) against the four influenza strains were 523.91, 274.13, 115.35 and 257.81, respectively. The investigational IIV4 was non-inferiority to IIV3 for the four strains, meanwhile superior to IIV3 for additional B strains (B/BV, B/BY). For safety, there had no significant difference in the incidence of the adverse reactions among the three groups (P = 0.5986). No serious adverse events related to vaccination occurred. The IIV4 had good immunogenicity and safety, which added an influenza B protection with no increased safety concerns. (ClinicalTrials.gov number: NCT03853993).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2020.06.071DOI Listing
August 2020

FRA1 contributes to MEK-ERK pathway-dependent PD-L1 upregulation by KRAS mutation in premalignant human bronchial epithelial cells.

Am J Transl Res 2020 15;12(2):409-427. Epub 2020 Feb 15.

Lung Cancer Research Program, Jonsson Comprehensive Cancer Center Los Angeles, CA, USA.

Oncogenic KRAS mutations are frequently found in non-small cell lung carcinoma (NSCLC) and cause constitutive activation of the MEK-ERK pathway. Many cancer types have been shown to overexpress PD-L1 to escape immune surveillance. FRA1 is a MEK/ERK-dependent oncogenic transcription factor and a member of the AP-1 transcriptional factor superfamily. This study assesses the hypothesis that KRAS mutation directly regulates PD-L1 expression through the MEK-ERK pathway mediated by FRA1. Premalignant human bronchial epithelial cell (HBEC) lines harboring the KRAS mutation, EGFR mutation, p53 knock-down, or both KRAS mutation and p53 knock-down were tested for levels of PD-L1, FRA1, and ERK activation (pERK). Our results showed that KRAS mutation alone, but not other genetic alterations, induced significantly higher expression of PD-L1 compared to its vector counterparts. The increased PD-L1 expression in the KRAS mutated cells was dramatically reduced by inhibition of ERK activation. Furthermore, the MEK-ERK pathway-dependent PD-L1 expression was markedly reduced by FRA1 silencing. Interestingly, FRA1 silencing led to inhibition of ERK activation, indicating that FRA1 plays a role in PD-L1 regulation via positive feedback of ERK activation. Correlation of PD-L1 and FRA1 mRNA expression was validated using human lung cancer specimens from The Cancer Genome Atlas (TCGA) and established NSCLC cell lines from Cancer Cell Line Encyclopedia (CCLE). FRA1 expression was significantly associated with PD-L1 expression, and high FRA1 expression was correlated with poor overall survival. Our findings suggest that oncogenic KRAS-driven PD-L1 expression is dependent on MEK-ERK and FRA1 in high risk, premalignant HBEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061839PMC
February 2020

Interchangeability of two Enterovirus 71 inactivated vaccines in Chinese children: A phase IV, open-label, and randomized controlled trial.

Vaccine 2020 03 14;38(12):2671-2677. Epub 2020 Feb 14.

Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, China; Academy of Preventive Medicine, Shandong University, Jinan, China. Electronic address:

Background: In China, three inactivated Enterovirus 71 (EV71) vaccines have been approved. Although the vaccines in an immunization series should be from a single manufacture, children sometimes have to receive EV71 vaccines from more than one manufacturers. The aim of this study was to evaluate the interchangeability and safety of vaccination with EV71 vaccines from two manufacturers among Chinese children.

Methods: We conducted an open label and randomized controlled study among children aged 6-35 months from November 2018 to January 2019. The participants were randomly assigned (1:1:1:1) to receive EV71 vaccines in one of the four different schedules (two using a single vaccine for all doses from one manufacture, and two mixed schedules using vaccines from two manufactures). Blood samples were collected pre-vaccination (Day 0) and one month after the second dose (Day 60) for neutralizing antibody assay. Immunogenicity was assessed in the per-protocol cohort and safety was assessed in the total vaccinated cohort.

Results: A total of 300 children were enrolled and randomized, of whom 89.0% (267/300) were included in the per-protocol cohort for immunogenicity analysis. The seroconversion rates of the EV71 neutralizing antibody in four groups ranged from 98.4% to 100.0%, and were not significantly different among the groups. Compared with other groups, geometric mean titer was higher in group D, in which the participants received Institute of Medical Biology Chinese Academy of Medical Sciences (CAMS) vaccine in the first dose and the Sinovac vaccine in the second dose. Safety profiles were similar among the four groups and no serious adverse events related to the vaccination were reported.

Conclusions: Interchangeability of EV71 vaccines from two manufactures to complete an immunization series showed good immunogenicity and safety. The antibody response levels may vary by vaccination sequences of EV71 vaccines from the two manufacturers.

Trial Registration: ClinicalTrials.govNCT03873740.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2020.02.013DOI Listing
March 2020

Immunogenicity persistence in children of hepatitis A vaccines Healive® and Havrix®: 11 years follow-up and long-term prediction.

Hum Vaccin Immunother 2020 10 10;16(10):2559-2564. Epub 2020 Feb 10.

Department of Immunization Planning, Center for Disease Control and Prevention of Changzhou City , Changzhou, Jiangsu, China.

: Hepatitis A vaccine has been used in mass and routine public vaccination programs in China. Long-term follow-up studies are required to determine the duration of protection and the need for booster vaccinations. : A prospective, randomized, open-label clinical trial was performed to compare the geometric mean concentration (GMC) and seroprotection rates of anti-Hepatitis A virus (HAV) antibodies elicited by the inactivated vaccines Healive and Havrix. 400 healthy children were randomly assigned 3:1 ratio to receive two doses of Healive or Havrix at 0 and 6 months. Persistence of anti-HAV antibodies for 5 years post immunization has been reported The current study reports new data at 11 years post immunization for the purpose of showing antibody persistence. Sensitivity analyzes were performed to assess the results. In addition, predictions for long-term antibody persistence were performed using a statistical model. Two different serological assays were used that were shown to be 98.3% concordant for detecting anit-HAV antibody. : GMCs were significantly higher following Healive compared to Havrix at 1, 6, 7, 66, 112 and 138 months post-vaccination. In addition, the GMCs obtained using sensitivity analysis were very similar to those obtained using the original models. Prediction analysis indicated that the duration of protection for both vaccines was at least 30 years after immunization, with a lower limit of the 95% confidence interval for GMC of greater than 20mIU/mL. : Healive is more immunogenic than Havrix in children at 11 years post full immunization. Prediction analysis indicated at least 30 years of antibody persistence for both vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21645515.2020.1715687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644183PMC
October 2020

Quantitative Proteomics for Monitoring Renal Transplant Injury.

Proteomics Clin Appl 2020 07 16;14(4):e1900036. Epub 2020 Feb 16.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Purpose: This study is aimed at developing a molecular diagnostics platform to enhance the interpretation of renal allograft biopsies using quantitative proteomic profiling of formalin-fixed and paraffin-embedded (FFPE) specimens.

Experimental Design: A quantitative proteomics platform composed of 1) an optimized FFPE protein sample preparation method, 2) a tandem mass tag TMT10-plex-based proteomic workflow, and 3) a systematic statistical analysis pipeline to reveal differentially expressed proteins has been developed. This platform is then tested on a small sample set (five samples per phenotype) to reveal proteomic signatures that can differentiate T-cell mediated rejection (TCMR) and polyomavirus BK nephropathy (BKPyVN) from healthy functionally stable kidney tissue (STA).

Results: Among 2798 quantified proteins, the expression levels of 740 BKPyVN and 638 TCMR associated proteins are significantly changed compared to STA specimens. Principal component analysis demonstrated good segregation of all three phenotypes investigated. Protein detection and quantitation are highly reproducible: replicate comparative analyses demonstrated 71-84% overlap of detected proteins, and the coefficient of variation for protein measurements is <15% in triplicate liquid chromatography-tandem mass spectrometry runs.

Conclusions And Clinical Relevance: Quantitative proteomics can be applied to archived FFPE specimens to differentiate different causes of renal allograft injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prca.201900036DOI Listing
July 2020

Short-term dynamic changes in neutralizing antibodies against enterovirus 71 after vaccination.

Hum Vaccin Immunother 2020 07 24;16(7):1595-1601. Epub 2020 Jan 24.

Department of Immunization Programme, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China.

Background: Short-term dynamic changes in neutralizing antibodies against EV71 and EV71-IgM after inactivated EV71 vaccine injection are unknown.

Methods: This study was designed as a randomized, open-label study and was registered at ClinicalTrials.gov (NCT03278132). In total, 120 healthy infants aged 6-35 months were randomized 1:1:1 to provide a second blood sample on day 10, day 20, or day 30 after the first vaccine dose, respectively.

Results: According to the per-protocol set, a rapid immune response against EV71 was observed 10 days after the first EV71 vaccine dose, with antibody titers ≥1:8 in 89.19% of participants (95% CI: 74.58-96.97%) on day 10, in 80.65% (95% CI: 62.53-92.55%) on day 20, in 66.67% (95% CI: 49.03-81.44%) on day 30, and in 100% (95% CI: 96.52%-.) on day 60. Based on an ELISA, the percentages of participants positive for EV71-IgM on day 0 and day 60 were 1.71% (2 out of 117) and 82.86% (87 out of 105), respectively.

Conclusions: The EV71 vaccine could be used for contingency vaccination to further control EV71-associated disease outbreaks. Caution should be taken in using the EV71-IgM test for rapid EV71 infection diagnosis after EV71 vaccine administration.

Clinical Trial Registration: ClinicalTrials.gov NCT03278132.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21645515.2020.1711678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482867PMC
July 2020

Comparison of outcomes of arthrodesis and reconstruction (advancement), posterior tibial tendon with excision of accessory tarsal navicular bone (Kidner procedure) in type 2 accessory navicula.

Foot Ankle Surg 2020 Dec 9;26(8):930-934. Epub 2020 Jan 9.

Department of Orthopaedics, Sun Yat-sen Memorial Hospital, 107 Riverside Road, Guangzhou, Guangdong Province 510120, China. Electronic address:

Background: The therapeutic outcome of the local arthrodesis surgery for type 2 accessory navicula (AN) is rarely reported. This study aimed to compare the clinical outcomes between Kidner and arthrodesis procedures for type 2 AN.

Methods: Sixteen patients (20 feet) with symptomatic type 2 AN receiving surgical treatment in our hospital between November 2013 and December 2015 were retrospectively included. Ten patients (13 feet) underwent the Kidner surgery (Kidner group) and 6 patients received local arthrodesis procedure (arthrodesis group). Radiographic indices before/after surgery were compared between the two groups. Patient's satisfaction with surgery outcome was evaluated by patient self-assessment questionnaire.

Results: The calcaneal pitch angle was significantly increased after surgery in both groups (bothp<0.01), while the talocalcaneal coverage angle and lateral talo-first metatarsal angle were not significantly changed after surgery. There was no significant difference regarding the postoperative changes in the three radiographic indices between the two groups. In the arthrodesis group, 3 patients (4 feet) had an excellent outcome, 2 patients (2 feet) a good outcome, and 1 patient (1 foot) had a fair outcome. In the Kidner group, 6 patients (8 feet), 2 patients (3 feet), 1 patient (1 foot) and 1 patient (1 foot) had excellent, good, fair, and poor treatment outcomes, respectively. The rate of good-to-excellent outcomes was comparable between the arthrodesis group and Kidner group (83% vs. 80%, p=0.696).

Conclusion: Our results suggested that both the Kidner surgery and arthrodesis surgery were an effective treatment for symptomatic type 2 AN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fas.2019.12.005DOI Listing
December 2020

Development and validation of a novel diagnostic model for assessing lung cancer metastasis in a Chinese population based on multicenter real-world data.

Cancer Manag Res 2019 29;11:9213-9223. Epub 2019 Oct 29.

Department of Laboratory Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, People's Republic of China.

Background: Accurate disease staging plays an important role in lung cancer's clinical management. However, due to the limitation of the CT scan, it is still an unmet medical need in practice. In the present study, we attempted to develop diagnostic models based on biomarkers and clinical parameters for assessing lung cancer metastasis.

Methods: This study consisted of 799 patients with pulmonary lesions from three regional centers in China. It included 274 benign lesions patients, 326 primary lung cancer patients without metastasis, and 199 advanced lung cancer patients with lymph node or organ metastasis. The patients were divided into nodules group and masses group according to tumor size.

Results: Four nomogram models based on patient characteristics and tumor biomarkers were developed and evaluated for patients with nodules and masses, respectively. In patients with pulmonary nodules, the AUC to identify metastatic lung cancer from unidentified nodules (including benign nodules and lung cancer, model 1) reached 0.859 (0.827-0.887, 95% CI). Model 2 was used to predict metastasis in patients with lung cancer with AUC of 0.838 (0.795-0.876, 95% CI). In patients with pulmonary masses, the AUC to identify metastatic lung cancer from unidentified masses (model 3) reached 0.773 (0.717-0.823, 95% CI). Model 4 was used to predict metastasis in patients with lung cancer and AUC reached 0.731 (0.771-0.793, 95% CI). Decision curve analysis corroborated good clinical applicability of the nomograms in predicting metastasis.

Conclusion: All new models demonstrated promising discrimination, allowing for estimating the risk of lymph node or organ metastasis of lung cancer. Such integration of blood biomarker testing with CT imaging results will be an efficient and effective approach to benefit the accurate staging and treatment of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S217970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827356PMC
October 2019

Effects of T5 Treatment on Microstructure and Mechanical Properties at Elevated Temperature of AZ80-Ag Alloy.

Materials (Basel) 2019 Sep 30;12(19). Epub 2019 Sep 30.

School of Materials Science and Engineering, Central South University, Changsha 410083, China.

Effects of T5 treatment on microstructure and mechanical properties at elevated temperature of hot-ring-rolled (HRRed) AZ80-Ag magnesium alloy were systematically investigated. Results show that, after aging at 175 °C for 36 h, discontinuous and continuous precipitates form inside grains, with the former one taking up a volume fraction of ~64.9%. T5 treatment improves the tensile strength at ambient temperature of the alloy but weakens its tensile strength and creep resistance at elevated temperatures (120-175 °C), indicating opposite effects of T5 on mechanical properties at ambient and elevated temperatures. During creep at 120-175 °C and under 70-90 MPa, the dynamic precipitation process in HRRed specimen is accelerated with increasing temperature. At 150-175 °C massive nucleation and growth of dynamic discontinuous precipitates could result in an atypical primary creep stage, consisting of deceleration and acceleration creep stages, which is reported in wrought Mg-Al-based alloy for the first time. Such primary creep stage can be eliminated by T5 treatment. Besides, diffusion-controlled dislocation creep is the dominant creep mechanism for both HRRed and T5 specimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma12193214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804265PMC
September 2019

Open Broström-Gould Repair vs Arthroscopic Anatomical Repair of the Anterior Talofibular Ligament for Chronic Lateral Ankle Instability.

Foot Ankle Int 2020 01 19;41(1):44-49. Epub 2019 Sep 19.

Department of Orthopaedics, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong Province, China.

Background: The comparative studies on open vs arthroscopic anterior talofibular ligament (ATFL) repair are limited. This study aimed to compare the early therapeutic efficacy and cost between the traditional open Broström-Gould repair and all-arthroscopic anatomical repair of the ATFL for chronic lateral ankle instability.

Methods: A total of 27 of patients with chronic lateral ankle instability undergoing repair of the ATFL between January 2013 and June 2015 were retrospectively included with a traditional open surgery (n = 10) group and arthroscopy (n = 17) group. The surgery duration, surgical cost, postoperative complications, and the preoperative/postoperative American Orthopaedic Foot & Ankle Society Score (AOFAS) and Karlsson-Peterson score were compared between groups.

Results: Compared to the arthroscopy group, the open surgery group had significantly shorter surgery duration and lower surgical cost. However, there was no significant difference in hospitalization duration between groups. At 3 years after operation, the AOFAS and Karlsson scores were significantly improved in both groups. Nevertheless, there was no significant difference in the AOFAS and Karlsson scores between groups at both preoperative and postoperative assessment. No significant difference was found in the incidence of postoperative complications between the 2 groups.

Conclusion: These results suggest that open Broström-Gould repair and all-arthroscopic anatomical repair of the ATFL have comparable therapeutic efficacy for chronic lateral ankle instability. The arthroscopic surgery had a smaller incision, while the open Broström-Gould had a shorter surgery duration and lower cost.

Level Of Evidence: Level III, comparative study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1071100719875964DOI Listing
January 2020

Wnt/β-Catenin Signaling Plays a Protective Role in the Mdr2 Knockout Murine Model of Cholestatic Liver Disease.

Hepatology 2020 05 31;71(5):1732-1749. Epub 2019 Dec 31.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Background And Aims: The Wnt/β-catenin signaling pathway has a well-described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL).

Approach And Results: To generalize these observations, we suppressed β-catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts. When β-catenin was knocked down (KD) in KO for 2 weeks, hepatic and biliary injury were exacerbated in comparison to KO given placebo, as shown by serum biochemistry, ductular reaction, inflammation, and fibrosis. Simultaneously, KO/KD livers displayed increased oxidative stress and senescence and an impaired regenerative response. Although the total liver BA levels were similar between KO/KD and KO, there was significant dysregulation of BA transporters and BA detoxification/synthesis enzymes in KO/KD compared with KO alone. Multiphoton intravital microscopy revealed a mixing of blood and bile in the sinusoids, and validated the presence of increased serum BA in KO/KD mice. Although hepatocyte junctions were intact, KO/KD livers had significant canalicular defects, which resulted from loss of hepatocyte polarity. Thus, in contrast to the protective effect of β-catenin KD in BDL model, β-catenin KD in Mdr2 KO aggravated rather than alleviated injury by interfering with expression of BA transporters, hepatocyte polarity, canalicular structure, and the regenerative response.

Conclusions: The resulting imbalance between ongoing injury and restitution led to worsening of the Mdr2 KO phenotype, suggesting caution in targeting β-catenin globally for all cholestatic conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058521PMC
May 2020

Detection of BKV encoded mature MicroRNAs in kidney transplant patients: Clinical and biologic insights.

J Clin Virol 2019 10 12;119:6-10. Epub 2019 Aug 12.

Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States. Electronic address:

Background: Polyomavirus BK (BKV) encodes two mature miRNAs that regulate the viral life cycle.

Objectives: This study investigated the autoregulatory and immunomodulatory effects of these miRNAs that have been defined in culture systems, but subject to only limited exploration in clinical samples.

Methods: BKV-miR-B1-5p, BKV-miR-BJ1-3p, BKV DNA and BKV VP-1 mRNA levels were measured in 32 paired obtained plasma & urine samples from kidney transplant patients with (a) early stage infection manifesting as viruria, and (b) later stage infections complicated by viremia.

Results: All patients showed abundant urine miRNAs (7.84E + 02-1.91E + 06 copies/ml, but plasma miRNA was below the limit of detection. There was no statistically significant difference in urinary miRNA levels between viruric and viremic patients. Median 5p miRNA load was 4-6 logs lower than the BKV genomic load. Higher miRNA levels in the urine were associated not with lower but higher urinary viral loads. BKV preferentially used the 3p miRNA for its interactions with host cell mRNAs. The mean ratio of 5p/3p in patients with viruria was 0.09, and 0.03 in patients with viremia.

Conclusions: The data suggest that immune evasion functions of BKV miRNAs over-ride the negative autoregulatory feedback effects in kidney transplant patients with active viral replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2019.07.006DOI Listing
October 2019

Cellular and viral miRNA expression in polyomavirus BK infection.

Transpl Infect Dis 2019 Oct 29;21(5):e13159. Epub 2019 Aug 29.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Polyomavirus BK (BKV) is an important pathogen in kidney transplant patients. Regulation of BKV encoded microRNAs (miRNAs) is not well understood. Therefore, tubular epithelial cells infected with BKV were examined for changes in small RNA expression. The observed changes were further evaluated by real-time PCR and RNA-seq analysis of renal allograft biopsies. BKV-miR-B1-5p and BKV-miR-B1-3p showed a 1000-fold increase over 12 days but did not prevent cell lysis. Downregulation of host miR-10b and miR-30a could be confirmed on all three platforms evaluated. Whereas, the BKV genome expressed more 3p than 5p miRNA species, the reverse was true for the human genome. Decreased expression of TP53INP2, and increased expression of BCL2A1, IL-6, IL8 and other proinflammatory cytokines were shown in biopsies with BKV nephropathy. No change in expression was seen in miR-10a dependent expression of NKG2D ligands ULBP3, MICA, or MICB. In conclusion, BKV infection results in regulation of cellular genes regulated by and possibly amenable to therapies targeting miR-10 and miR-30.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tid.13159DOI Listing
October 2019

β1,4-galactosyltransferase-I protects chondrocytes against TNF-induced apoptosis by blocking the TLR4 signaling pathway.

Am J Transl Res 2019 15;11(7):4358-4366. Epub 2019 Jul 15.

Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou, Guangdong, China.

Osteoarthritis (OA) is the most common degenerative disease of the cartilage and is characterized by inflammation of the synovial membrane and subchondral osteosclerosis. β1,4-galactosyltransferase-I (β1,4-GalT-I) is a crucial regulator of inflammation based on its role in the stimulation and sustenance of inflammation in OA. In the present study, we aimed at elucidating the expression pattern and potential biological activity of β1,4-GalT-I in chondrocytes isolated from OA patients. Chondrocytes were isolated from the cartilage and cultured. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze β1,4-GalT-I expression. Isolated chondrocytes were stimulated with tumor necrosis factor (TNF). Our results indicate significantly enhanced expression of β1,4-GalT-I in cultivated chondrocytes upon stimulation with TNF. β1,4-GalT-I inhibited the inflammation and cell death triggered by TNF. In addition, β1,4-GalT-Iinhibited the expression of Toll-like receptor 4 (TLR4) and phosphorylation of p65 and IKK. In conclusion, our findings suggest the protective effect of β1,4-GalT-I in chondrocytes against OA induced by TNF based on its ability to block the TLR4 signaling pathway. Our results also indicate significant contribution of β1,4-GalT-I towards the anti-inflammation in the cartilage of patients suffering from OA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684904PMC
July 2019

Female Condom Use and Its Acceptability Among HIV-serodiscordant Couples in China.

J Assoc Nurses AIDS Care 2019 Jul-Aug;30(4):428-439

Lahong Ju, MD, is an Associate Professor, National Center for AIDS/STD Control and Prevention and National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China. Cynthia X. Shi, MSc, is a Doctoral Student, Department of Epidemiology of Microbial Diseases and Center for Interdisciplinary Research on AIDS, Yale School of Public Health, Yale University, New Haven, Connecticut, USA. Fan Lv, PhD, is a Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Houlin Tang, PhD, is an Associate Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Gang Zeng, PhD, is an Associate Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Peng Xu, PhD, is a Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Wanying Chen, MD, is an Assistant Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Huijing He, MD, is an Assistant Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Liping Ma, MD, is an Assistant Professor, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Linglin Zhang, MD, is a Professor, Sichuan Center for Disease Control and Prevention, Sichuan, China. Xi Chen, MD, is a Professor, Hunan Center for Disease Control and Prevention, Hunan, China.

Intimate partners of people living with HIV are at risk of HIV infection. We assessed the acceptability of female condom use among 89 married, heterosexual, HIV-serodiscordant couples from Sichuan and Hunan provinces in China for this prospective observational cohort study. Participants used female condoms for 3 months, reporting use and attitudes in written logs and questionnaires. At the end of the study, 58.4% of couples expressed willingness to continue using female condoms. Factors associated with willingness to use female condoms were (a) the female partner reporting having experienced forced sex by the male partner, (b) applying a lubricant to the penis, (c) understanding the correct application method, (d) being married more than 20 years, and (e) experiencing no difficulty during the first use. Most HIV-serodiscordant couples found female condoms to be acceptable. Increasing access to female condoms could be an acceptable alternative barrier method to male condoms for preventing HIV transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JNC.0000000000000004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620342PMC
April 2020

Defining housekeeping genes suitable for RNA-seq analysis of the human allograft kidney biopsy tissue.

BMC Med Genomics 2019 06 17;12(1):86. Epub 2019 Jun 17.

Department of Pathology, University of Pittsburgh Medical Center, E737 UPMC-Montefiore Hospital, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA.

Background: RNA-seq is poised to play a major role in the management of kidney transplant patients. Rigorous definition of housekeeping genes (HKG) is essential for further progress in this field. Using single genes or a limited set HKG is inherently problematic since their expression might be altered by specific diseases in the patients being studied.

Methods: To generate a HKG set specific for kidney transplantation, we performed RNA-sequencing from renal allograft biopsies collected in a variety of clinical settings. Various normalization methods were applied to identify transcripts that had a coefficient of variation of expression that was below the 2nd percentile across all samples, and the corresponding genes were designated as housekeeping genes. Comparison with transcriptomic data from the Gene Expression Omnibus (GEO) database, pathway analysis and molecular biological functions were utilized to validate the housekeeping genes set.

Results: We have developed a bioinformatics solution to this problem by using nine different normalization methods to derive large HKG gene sets from a RNA-seq data set of 47,611 transcripts derived from 30 biopsies. These biopsies were collected in a variety of clinical settings, including normal function, acute rejection, interstitial nephritis, interstitial fibrosis/tubular atrophy and polyomavirus nephropathy. Transcripts with coefficient of variation below the 2nd percentile were designated as HKG, and validated by showing their virtual absence in diseased allograft derived transcriptomic data sets available in the GEO. Pathway analysis indicated a role for these genes in maintenance of cell morphology, pyrimidine metabolism, and intracellular protein signaling.

Conclusions: Utilization of these objectively defined HKG data sets will guard against errors resulting from focusing on individual genes like 18S RNA, actin & tubulin, which do not maintain constant expression across the known spectrum of renal allograft pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-019-0538-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580566PMC
June 2019

RGS1 silencing inhibits the inflammatory response and angiogenesis in rheumatoid arthritis rats through the inactivation of Toll-like receptor signaling pathway.

J Cell Physiol 2019 11 22;234(11):20432-20442. Epub 2019 Apr 22.

Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.

Emerging evidence shows that rheumatoid arthritis (RA) progression can be induced by the activation of Toll-like receptor (TLR) signaling pathway. Regulator of G-protein signaling 1 (RGS1) is observed to be a candidate biomarker for arthritis. Accordingly, the present study aims to determine the potential effects of RGS1 mediating TLR on RA. A rat model of collagen-induced arthritis (CIA) was established to mimic the features of RA by injection of bovine type II collagen. The rats with CIA were treated with short hairpin RNA (shRNA) against RGS1 or TLR pathway activator Poly I:C to elucidate the role of RGS1 in RA progression. The inflammatory factors were measured, and the thoracic gland and spleen indexes as well as the vascular density were determined. The expression levels of RGS1, TLR3, vascular endothelial growth factor (VEGF), metalloproteinase-2 (MMP-2), MMP-9, and interleukin 1 receptor-associated kinase-4 (IRAK4) were determined. RGS1 was robustly increased in RA. The TLR signaling pathway was suppressed by RGS1 silencing. shRNA-mediated depletion of RGS1 was shown to significantly enhance thoracic gland index and inhibit the serum levels of TNF-α, IL-1β, and IL-17, spleen index, vascular density, and the expression levels of TLR3, VEGF, MMP-2, MMP-9, and IRAK4. However, when the rats with CIA were treated with Poly I:C, the trend of effects was opposite. These findings highlight that functional suppression of RGS1 inhibits the inflammatory response and angiogenesis by inactivating the TLR signaling pathway in rats with CIA, thereby providing a novel therapeutic target for RA treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.28645DOI Listing
November 2019
-->