Publications by authors named "Mei Chen"

704 Publications

Screening of chemical linkers for development of pullulan bioconjugates for intravitreal ocular applications.

Eur J Pharm Sci 2021 Mar 2:105785. Epub 2021 Mar 2.

University of Padova, Department of Pharmaceutical and Pharmacological Sciences, Via F. Marzolo 5, 35131 Padova, Italy. Electronic address:

The treatment of posterior segment disorders of the eye requires therapeutic strategies to achieve drug effects over prolonged times. Innovative colloidal delivery systems can be designed to deliver drugs to the retina and prolong their intravitreal permanence. In order to exploit pullulan (Pull) as polymeric drug carrier for intravitreal drug delivery, derivatives of hydrophobic model molecule rhodamine B (RhB) were conjugated to the pullulan backbone through linkers with different stability, namely ether (Et), hydrazone (Hy) or ester (Es) bond to obtain Pull-Et-RhB, Pull-Hy-RhB and Pull-Es-RhB, respectively. Dynamic light scattering and transmission electron microscopy analyses showed that the polymer conjugates self-assembled into 20-25 nm particles. Pull-Et-RhB was fairly stable at all tested pH values. At the vitreal pH of 7.4, 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 11 and 6 days, respectively. At endosomal pH (5.5), 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 4 and 1 days, respectively. Multiple particle tracking analyses in ex vivo porcine eye model showed that the diffusivity of the bioconjugates in the vitreous was about 10 times lower than in water. Flow cytometry and confocal microscopy analyses showed that bioconjugates are remarkably taken up by the retinal RPE cells. In vivo studies showed that after intravitreal injection to mice, the bioconjugates localize in the ganglion cell layer and in the inner and outer plexiform layers. Pull-Hy-RhB particles were detected also inside the retinal blood vessels. These results demonstrate that pullulan with tailored linkers for drug conjugation is a promising vehicle for long-acting intravitreal injectables that are capable to permeate to the retina.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2021.105785DOI Listing
March 2021

Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis.

Cancer Gene Ther 2021 Mar 4. Epub 2021 Mar 4.

Department of Dermatology and the Norris Comprehensive Cancer Centre, University of Southern California Keck Medical Center, Los Angeles, CA, USA.

Hypoxia-inducible factor-1 (HIF-1), a master transcriptional factor for protecting cells from hypoxia, plays a critical role in spermatogenesis and tumorigenesis. For the past two decades, numerous small molecule inhibitors that block mRNA synthesis, protein translation, or DNA binding of HIF-1α have entered clinical trials. To date, few have advanced to FDA approval for clinical applications due to limited efficacy at their toxicity-tolerable dosages. New windows for developing effective and safe therapeutics require better understanding of the specific mechanism of action. The finding that a chaperone-defective mutant heat shock protein-90-alpha (Hsp90α) blocks spermatogenesis, a known hypoxia-driven process in mouse testis prompted us to focus on the role of Hsp90α in HIF-1α. Here we demonstrate that Hsp90α gene knockout causes a dramatic reduction of the high steady-state level of HIF-1α in the testis, blocking sperm production and causing infertility of the mice. In HIF-1α-dependent tumor cells, we found that Hsp90α forms protein complexes with hypoxia-elevated HIF-1α and Hsp90α knockout prevents hypoxia-induced HIF-1α accumulation. In contrast, downregulation of Hsp90β had little effect on hypoxia-induced accumulation of HIF-1α. Instead, Hsp90β protects signaling molecules responsible for cellular homeostasis from assault by 17-AAG (17-N-allylamino-17-demethoxygeldanamycin), a general ATPase inhibitor of both Hsp90α and Hsp90β. Since targeting Hsp90β gene is lethal in both cultured cells and in mice, our new finding explains the toxicity of the previous inhibitor trials and identifies the specific binding of Hsp90α to HIF-1α as a new therapeutic window for developing safer and more effective treatment of male infertility and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41417-021-00316-6DOI Listing
March 2021

The changing accuracy of traffic forecasts.

Transportation (Amst) 2021 Feb 26:1-22. Epub 2021 Feb 26.

Department of Civil Engineering, University of Kentucky, Lexington, KY USA.

Researchers have improved travel demand forecasting methods in recent decades but invested relatively little to understand their accuracy. A major barrier has been the lack of necessary data. We compiled the largest known database of traffic forecast accuracy, composed of forecast traffic, post-opening counts and project attributes for 1291 road projects in the United States and Europe. We compared measured versus forecast traffic and identified the factors associated with accuracy. We found measured traffic is on average 6% lower than forecast volumes, with a mean absolute deviation of 17% from the forecast. Higher volume roads, higher functional classes, shorter time spans, and the use of travel models all improved accuracy. Unemployment rates also affected accuracy-traffic would be 1% greater than forecast on average, rather than 6% lower, if we adjust for higher unemployment during the post-recession years (2008 to 2014). Forecast accuracy was not consistent over time: more recent forecasts were more accurate, and the mean deviation changed direction. Traffic on projects that opened from the 1980s through early 2000s was higher on average than forecast, while traffic on more recent projects was lower on average than forecast. This research provides insight into the degree of confidence that planners and policy makers can expect from traffic forecasts and suggests that we should view forecasts as a range of possible outcomes rather than a single expected outcome.

Supplementary Information: The online version contains supplementary material available at 10.1007/s11116-021-10182-8.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11116-021-10182-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908952PMC
February 2021

Clinical significance of cytogenetic and molecular genetic abnormalities in 634 Chinese patients with myelodysplastic syndromes.

Cancer Med 2021 Feb 20. Epub 2021 Feb 20.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Purpose: To explore the relevance of cytogenetic or molecular genetic abnormalities to clinical variables, including clinical and laboratory characteristics and prognosis in Chinese patients with myelodysplastic syndromes (MDS).

Methods: A total of 634 consecutive patients diagnosed with MDS at The First Affiliated Hospital, Zhejiang University School of Medicine from June 2008 to May 2018 were retrospectively included in this study. All patients had evaluable cytogenetic analysis, and 425 patients had MDS-related mutations sequencing.

Results: 38.6% of patients displayed abnormal karyotypes. The most common cytogenetic abnormality was +8 (31%). Sole +8 was related to female (p = 0.002), hemoglobin >10 g/dL (p = 0.03), and <60 years old (p = 0.046). TP53 mutations were associated with complex karyotype (CK) (p < 0.001). DNMT3A mutations correlated with -Y (p = 0.01) whereas NRAS mutations correlated with 20q- (p = 0.04). The overall survival (OS) was significantly inferior in patients with +8 compared with those with normal karyotype (NK) (p = 0.003). However, the OS of sole +8 and +8 with one additional karyotypic abnormality was not different from NK (p = 0.16), but +8 with two or more abnormalities had a significantly shorter OS than +8 and +8 with one additional karyotypic abnormality (p = 0.02). In multivariable analysis, ≥60 years old, marrow blasts ≥5% and TP53 mutations were independent predictors for poor OS (p < 0.05), whereas SF3B1 mutations indicated better prognosis. Male IDH1 and IDH2 mutations and marrow blasts ≥5% were independent risk factors for worse leukemia free survival (LFS) (p < 0.05).

Conclusion: In this population of Chinese patients, trisomy 8 is the most common karyotypic abnormality. Patients with +8 showed a poorer OS compared with patients with NK. Sole +8 and +8 with one additional karyotypic abnormality had similar OS with NK, whereas +8 with two or more abnormalities had a significantly shorter OS. DNMT3A mutations correlated with -Y and NRAS mutations correlated with 20q-. TP53 mutations were associated with CK and had a poor OS. SF3B1 mutations indicated a favorable OS. IDH1 and IDH2 mutations independently indicated inferior LFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3786DOI Listing
February 2021

Microglia increase tight-junction permeability in coordination with Müller cells under hypoxic condition in an in vitro model of inner blood-retinal barrier.

Exp Eye Res 2021 Feb 16:108490. Epub 2021 Feb 16.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, United Kingdom. Electronic address:

Microglia and Müller cells (MCs) are believed to be critically involved in hypoxia-induced blood-retinal barrier (BRB) disruption, which is a major pathogenic factor of various retinopathies. However, the underlying mechanism remains poorly defined. The inner BRB (iBRB) is primarily formed of microvascular endothelial cells (ECs) with tight junction (TJ), which are surrounded and supported by retinal glial cells. We developed a novel in vitro iBRB model sheet by sandwiching Transwell membrane with layered mouse brain microvascular ECs (bEnd.3) and mouse retinal MCs (QMMuC-1) on each side of the membrane. Using this model, we tested the hypothesis that under hypoxic condition, activated microglia produce inflammatory cytokines such as interleukin (IL)-1β, which may promote vascular endothelial growth factor (VEGF) production from MCs, leading to TJ disruption. The iBRB model cell sheets were exposed to 1% oxygen for 6 h with or without mouse brain microglia (BV2) or IL-1β. TJ structure and function were examined by zonula occludens (ZO)-1 immunostaining and fluorescein isothiocyanate permeability assay, respectively. Relative gene expression of IL-1β in BV2 under normoxic and hypoxic conditions was examined by real-time reverse transcription-polymerase chain reaction. VEGF protein concentration in QMMuC-1 supernatants was measured by enzyme-linked immunosorbent assay. The bEnd.3 cell sheet incubated with BV2 in hypoxic condition or with IL-1β in normoxic condition showed abnormal localization of ZO-1 and aberrated barrier function. Under normoxic condition, EC-MC iBRB model cell sheet showed lower permeability than bEnd.3 cell sheet. Under hypoxic conditions, the barrier function of EC-MC iBRB model cell sheet was more deteriorated compared to bEnd.3 cell sheet. Under hypoxic condition, incubation of EC-MC iBRB model cell sheet with BV2 cells or IL-1β significantly increased barrier permeability, and hypoxia-treated BV2 cells expressed significantly higher levels of IL-1β mRNA. Incubation of QMMuC-1 with IL-1β increased VEGF production. These results suggest that under hypoxic condition, microglia are activated to release proinflammatory cytokines such as IL-1β that promote VEGF production from MCs, leading to disruption of iBRB function. Modulating microglia and MCs function may be a novel approach to treat hypoxia-induced retinal BRB dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2021.108490DOI Listing
February 2021

Deletion of Socs3 in LysM cells and Cx3cr1 resulted in age-dependent development of retinal microgliopathy.

Mol Neurodegener 2021 Feb 18;16(1). Epub 2021 Feb 18.

The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, Belfast, Northern Ireland, UK.

Background: We generated a mouse model of primary microglial dysfunction by deleting two negative immune regulatory genes, Cx3cr1 and Socs3 (in LysM cells). This study aimed to understand how primary microglial dysfunction impacts retinal neurons during aging.

Methods: The LysMCre-Socs3Cx3cr1 double knockout (DKO), LysMCre-Socs3, Cx3cr1 and Socs3 mice were maintained up to 12 months. Eyes were collected and processed for immunohistochemistry of IBA-1, cone arrestin, secretagogin, PKCα and GABA. Brain microglia from DKO and WT mice were stimulated with LPS + IFN-γ or IL-4. The expression of TNF-α, IL-1β, IL-6, iNOS, IL-12p40, IL-23p19, CCL2, CCL5, CXCL2, IL-10, CD206 and Arg1 were examined by qRT-PCR and protein production was measured by Luminex assay. Retinal explants from C57BL/6 J mice were co-cultured with microglia from DKO or WT mice for 24 h, after which the number of cone arrestin cells in retinal flatmount were quantified.

Results: In 3-5 month old mice, the number of microglia in retinal ganglion cell layer (GCL) and inner plexiform layer (IPL) were comparable in all strains of mice. The DKO mice had a significantly higher number of microglia in the outer plexiform layer (OPL) but significantly lower numbers of cone arrestin, secretagogin and GABA cells compared to Socs3 and single KO mice. During aging, 57% of the DKO mice died before 12 months old. The 10-12 months old DKO mice had significantly higher numbers of microglia in GCL/IPL and OPL than age-matched Socs3 and single KO mice. The aged DKO mice developed retinal pigment epithelial (RPE) dysmorphology accompanied by subretinal microglial accumulation. The number of photoreceptors, bipolar cells (Secretagogin or PKCα) and GABA amacrine cells was significantly lower in aged DKO mice compared to age-matched Socs3 and single KO mice. Microglia from DKO mice showed significantly higher levels of phagocytic activity and produced higher levels of TNF-α, IL-6, CCL2, CCL5, CXCL2 and CXCL10 compared to microglia from Socs3 mice. Co-culture of retinal explants with LPS + IFN-γ or IL-4 pre-treated DKO microglia significantly reduced cone photoreceptor survival.

Conclusions: The LysMCre-Socs3Cx3cr1 DKO mice displayed primary microglial dysfunction and developed age-related retinal microgliopathy characterized by aggragated microglial activation and multiple retinal neuronal and RPE degeneration.

Trial Registration: Not applicable. The article does not contain any results from human participants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13024-021-00432-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891019PMC
February 2021

Enterovirus 71 induces autophagy in mice via mTOR inhibition and ERK pathway activation.

Life Sci 2021 Feb 11;271:119188. Epub 2021 Feb 11.

School of Basic Medicine, Jiamusi University, Jiamusi 154007, China. Electronic address:

Aims: Enterovirus 71 (EV71) is one of the main viruses that cause hand-foot-mouth disease; however, its pathogenic mechanism remains unclear. This study characterized the relationship between EV71 infection and autophagy in vivo and explored the molecular mechanism underlying EV71-induced autophagy.

Materials And Methods: A mouse model of EV71 infection was prepared by intraperitoneally injecting one-day-old BALB/c suckling mice with 30 μL/g of EV71 virus stock solution for 3 days. The behavior, fur condition, weight, and mice mortality were monitored, and disease scores were calculated. The pathological damage to the brain, lung, and muscle tissues after the viral infection was assessed by hematoxylin and eosin staining. Western blot and immunofluorescence analyses were used to detect the expression levels of viral protein 1, Beclin-1, microtubule-associated protein light chain 3B, mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, extracellular signal-regulated protein kinase (ERK) 1/2, and p-ERK.

Key Findings: EV71 infection can trigger autophagy in the brains, lungs, and muscles of infected mice. The autophagy response triggered by EV71 is achieved by the simultaneous mTOR inhibition and the ERK pathway activation. Blocking the mTOR pathway may aggravate autophagy, whereas ERK inhibition alleviates autophagy but cannot completely prevent it.

Significance: EV71 infection can induce autophagy in mice, involving mTOR and ERK signaling pathways. These two signaling pathways are independent and do not interfere with each other.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2021.119188DOI Listing
February 2021

A novel biosensor for the ultrasensitive detection of the lncRNA biomarker MALAT1 in non-small cell lung cancer.

Sci Rep 2021 Feb 11;11(1):3666. Epub 2021 Feb 11.

Clinical Laboratory, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, People's Republic of China.

Long non-coding RNAs (lncRNAs) have been proposed as diagnostic biomarkers for the screening of non-small cell lung cancer and monitoring disease progression. Accordingly, new, rapid, and cost-effective lncRNA biosensors that can be used clinically are urgently needed. Herein, a novel effective and ultrasensitive electrochemical biosensor was developed based on a gold nanocage coupled with an amidated multi-walled carbon nanotube (Au NCs/MWCNT-NH)-decorated screen-printed carbon electrode (SPCE). Because of its large surface area, superior conductivity, and excellent biocompatibility, this SPCE Au NCs/MWCNT-NH lncRNA biosensor showed a wide linear range (10-10 M) and low limit of detection limit (42.8 fM) coupled with satisfactory selectivity and stability. Compared to traditional RT-PCR, the proposed method exhibits acceptable stability, good selectivity, is simpler to operate, has faster detection, and uses less costly raw materials. In summary, this biosensor may be a powerful tool for detecting lncRNAs for efficient clinical prognosis and cancer diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-83244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878801PMC
February 2021

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of Double Knock-Out Mice.

Int J Mol Sci 2021 Feb 8;22(4). Epub 2021 Feb 8.

Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland.

Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 () and peroxisome proliferator-activated receptor gamma coactivator 1-α () genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of and (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch's membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of and genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915526PMC
February 2021

Real-world data of chronic myelomonocytic leukemia: A chinese single-center retrospective study.

Cancer Med 2021 Feb 8. Epub 2021 Feb 8.

Myelodysplastic Syndrome Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Chronic myelomonocytic leukemia (CMML) is a rare disease of elderly people characterized by the presence of sustained peripheral blood monocytosis, overlapping features of myeloproliferation, and myelodysplasia. We present a large retrospective study of 156 CMML patients in China. Mean age at diagnosis was 68 years old (range 23-91). According to the CMML-specific prognostic scoring system (CPSS), 10 patients (8.3%) were low risk, 27 patients (22.5%) were intermediate-1 risk, 72 patients (60%) were intermediate-2 risk, and 11 patients (9.2%) were high risk. A total of 90 patients (57.7%) received hypomethylating agents (HMAs) treatment, 19 patients (12.2%) received chemotherapy and 47 patients (30.1%) received the best supportive care. Seventeen patients (10.9%) underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) after HMAs treatment or chemotherapy. With a median follow-up of 35.3 months, overall response rate (ORR) was 69.5% in the HMAs ± chemotherapy group, 79.5% in the HMAs monotherapy group, 60.0% in the HMAs + chemotherapy group, and 37.5% in the chemotherapy group. HMAs monotherapy group had prolonged OS compared with the chemotherapy group (23.57 months vs. 11.73 months; p = 0.035). Patients who achieved ORR had prolonged OS (25.83 months vs. 8.00 months; p < 0.001) and LFS (20.53 months vs. 6.80 months; p < 0.001) compared with those not achieved ORR in the HMA ± chemotherapy group. By univariate analysis, only higher hemoglobulin (≥80 g/L) and lower serum LDH levels (<300 U/L) predicted for better OS and LFS. By multivariate analysis, only Hb ≥ 80 g/L predicted for prolonged OS, Hb ≥ 80 g/L, and monocytes < 3 × 109/L predicted for prolonged LFS. In summary, our study highlights the benefit of HMAs therapy in CMML, but we still need to develop novel therapeutics to achieve better outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3774DOI Listing
February 2021

Cell membranes targeted unimolecular prodrug for programmatic photodynamic-chemo therapy.

Theranostics 2021 19;11(7):3502-3511. Epub 2021 Jan 19.

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R China.

Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic effect was still hampered by the short life span, limited diffusion distance and ineluctable depletion of singlet oxygen (O), as well as the hypoxic microenvironment in the tumor tissue. Such problems have limited the application of PDT and appropriate solutions are highly demand. Herein, a programmatic treatment strategy is proposed for the development of a smart molecular prodrug (), which comprise a two-photon photosensitizer and a hypoxia-activated chemotherapeutic prodrug. A rhodamine dye was designed to connect them and track the drug release by the fluorescent signal generated through azo bond cleavage. The prodrug () can stay on the cell membrane and enrich at the tumor site. Upon light irradiation, the therapeutic effect was enhanced by a stepwise treatment: (i) direct generation of O on the cell membrane induced membrane destruction and promoted the uptake; (ii) deep tumor hypoxia caused by two-photon PDT process further triggered the activation of the chemotherapy prodrug. Both and experiments, have exhabited excellent tumor treatment effect. The innovative treatment strategy provides new strategy for the design of follow-up anticancer drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.55014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847693PMC
January 2021

Case Report: Identification of Mutations in in Two Chinese Infants With Danon Disease.

Front Genet 2020 11;11:589838. Epub 2021 Jan 11.

Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Danon disease (DD) is a monogenic lysosomal storage disorder characterized by cardiomyopathy, skeletal myopathy, and variable degrees of intellectual disability. It is caused by a deficiency of lysosomal-associated membrane protein 2 (). Two unrelated boys who presented with severe hypertrophic cardiomyopathy and elevated levels of liver enzymes, and were diagnosed with Danon disease at a very young age, were investigated. One boy was diagnosed at 4 months old and died soon after; his mother also died of hypertrophic cardiomyopathy shortly after his birth. Another developed hypertrophic cardiomyopathy at 3 months old but reported no significant cardiovascular symptoms during more than 5 years follow-up. Genetic screening found compound variants of and in both of them. This report highlights the clinical heterogeneity in DD. The timely identification of mutation plays a critical role in their treatment and family counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.589838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831386PMC
January 2021

LC/MS-Based Global Metabolomic Identification of Serum Biomarkers Differentiating Hepatocellular Carcinoma from Chronic Hepatitis B and Liver Cirrhosis.

ACS Omega 2021 Jan 4;6(2):1160-1170. Epub 2021 Jan 4.

Department of Infectious Diseases, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, Zhejiang 310014, China.

Chronic hepatitis B virus (CHB) infection is one of the primary risk factors associated with the development of hepatocellular carcinoma (HCC). Despite having been extensively studied, diagnosing early-stage HCC remains challenging, and diagnosed patients have a poor (3-5%) survival rate. Identifying new approaches to detect changes in the serum metabolic profiles of patients with CHB and liver cirrhosis (LC) may provide a valuable approach to better detect HCC at an early stage when it is still amenable to treatment, thereby improving patient prognosis and survival. In the present study, we, therefore, employed a liquid chromatography-mass spectrometry (LC-MS)-based approach to evaluate the serum metabolic profiles of 30 CHB patients, 29 LC patients, and 30 HCC patients. We then employed appropriate statistical methods to identify those metabolites that were best able to distinguish HCC cases from LC and CHB controls. A mass-based database was then used to putatively identify these metabolites. We then confirmed the identities of a subset of these metabolites through comparisons with the MS/MS fragmentation patterns and retention times of reference standards. The serum samples were then reanalyzed to quantify the levels of these selected metabolites and of other metabolites that have previously been identified as potential HCC biomarkers. Through this approach, we observed clear differences in the metabolite profiles of the CHB, LC, and HCC patient groups in both positive- and negative-ion modes. We found that the levels of taurodeoxy cholic acid (TCA) and 1,2-diacyl-3-β-d-galactosyl--glycerol rose with the progression from CHB to LC to HCC, whereas levels of 5-hydroxy-6,8,11,14,17-eicosapentaenoic acid, and glycyrrhizic acid were gradually reduced with liver disease progression in these groups. The ROC analysis showed that taurodeoxy cholic acid (TCA), 1,2-diacyl-3-β-d-galactosyl--glycerol, 5-hydroxy-6,8,11,14,17-eicosapentaenoic acid, and glycyrrhizic acid had a diagnosis performance with liver disease progression. These four metabolites have a significant correlation with alpha fetal protein (AFP) level and age. Our results highlight novel metabolic biomarkers that have the potential to be used for differentiating between CHB, LC, and HCC patients, thereby facilitating the identification and treatment of patients with early-stage HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c04259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818305PMC
January 2021

Association of outdoor air pollution with the medical expense of ischemic stroke: The case study of an industrial city in western China.

Int J Health Plann Manage 2021 Jan 21. Epub 2021 Jan 21.

Business School, Sichuan University, Chengdu, China.

Ischemic stroke, the most frequent cause of severe disability, imposes a significant mental and economic burden on patients and their families. There is increasing evidence to indicate that air pollution contributes to the risk of ischemic stroke. This study aimed to examine the correlation between air pollution and the expense imposed by an ischemic stroke. Data were obtained from hospitals and environmental monitoring stations in an industry city, Longspring, in western China. We used a generalized additive model to estimate the associations between the two factors, measured during 2015-2017. Counter-intuitively, the medical expenses arising from ischemia were negatively associated with the level of air pollution. The corresponding ER for per interquartile range increase of PM2.5, PM10, SO , and NO in lag10 was -0.17% (95% confidence interval (95% CI -0.31%, -0.03%), -0.11% (95% CI -0.2%, -0.02%), -1.04% (95% CI -1.92%, -0.17%) and -0.44% (95% CI -0.66%, -0.22%), respectively (p < 0.05). Subgroups based on gender, age, and season were considered in the analysis. The results indicated that pollutants had significant effects on ischaemia's medical expenses, which were stronger for older people, patients who survived, and warm seasons. This study is the first step in optimizing medical resources, which are essential for policymaking and service planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hpm.3115DOI Listing
January 2021

A case of encapsulated peritoneal sclerosis after peritoneal dialysis-related peritonitis.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2020 Dec;45(12):1499-1503

Department of Renal Rheumatology and Immunology, Third Xiangya Hospital, Central South University, Changsha 410013, China.

Encapsulating peritoneal sclerosis (EPS) is a rare but severe complication of peritoneal dialysis. A total of 50% of the patients died within 12 months after being diagnosed. There are no obvious clinical symptoms in the early stage of EPS, which is easy to be missed. And there are few case reports of EPS in early stage. On December 22, 2018, a 70-year-old male patient undergoing peritoneal dialysis for 17 months, who was diagnosed as EPS, was admitted to the Department of Nephrology, the Third Xiangya Hospital, Central South University. The patient's peritoneal dialysis catheter was obstructed after peritonitis. The peritoneal dialysis fluid couldn't be drain in and out of the abdominal cavity. Therefore, the laparoscopy was performed to repair the catheter. The operation in progress showed that the peritoneum was slightly thickened and the ileocecal intestinal tube was closely adhered to the parietal peritoneum where the catheter was wrapped, indicating the early stage of EPS. Peritoneal relaxation was performed. The patient's catheter was normal after adhesiolysis. He underwent hemodialysis, nutritional supporting as well as peritoneal dialysis transition, etc. The peritonitis was controlled after 10 days and the peritoneal dialysis was resumed. After discharge from hospital, the patient took moxifloxacin for 2 more weeks. We followed up the patient for 6 months. The automated peritoneal dialysis is maintained, and everything remains normal. Clinicians need to improve understanding of EPS. Early diagnosis and laparoscopic adhesiolysis is helpful to continue peritoneal dialysis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11817/j.issn.1672-7347.2020.190351DOI Listing
December 2020

Spatio-Temporal Mitosis Detection in Time-Lapse Phase-Contrast Microscopy Image Sequences: A Benchmark.

IEEE Trans Med Imaging 2021 Jan 19;PP. Epub 2021 Jan 19.

In this paper, we report the results of the first international contest on mitosis detection in phase-contrast microscopy image sequences (https://www.ititju.org/mitosisdetection), which was held at the workshop of computer vision for microscopy image analysis (CVMI) in CVPR 2019. This contest aims to promote research on spatiotemporal mitosis detection under microscopy images. In this contest, we released a large-scale time-lapse phase-contrast microscopy image dataset (C2C12-16) for the mitosis detection task. Compared with the previous popular datasets (e.g., C2C12, C3H10), C2C12-16 contains more annotated mitotic events and more diverse cell culture environments. A total of ten different mitosis detection methods were submitted in the contest and evaluated on the test sets of four different cell culture environments in C2C12-16. In this benchmark, we describe all methods and conduct a thorough analysis based on their performances and discuss a feasible direction for mitosis detection. To the best of our knowledge, this is the first benchmark for the mitosis detection problem using a time-lapse phase-contrast microscopy spatiotemporal image sequence model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TMI.2021.3052854DOI Listing
January 2021

Over-expression of stromal periostin correlates with poor prognosis of cutaneous squamous cell carcinomas.

Exp Dermatol 2021 Jan 15. Epub 2021 Jan 15.

Department of Dermatology, The Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Periostin, an extracellular matrix macromolecule implicated in tumorigenesis, serves as a prognostic marker for many cancer types. However, there are no data on periostin expression in cutaneous squamous cell carcinoma (cSCC). This study examined periostin expression in patients with cSCC and explored its clincopathological relationship and prognosis. Using immunohistochemistry and ImageJ analysis, we compared periostin expression in 95 cSCCs across a spectrum of cSCC aggressiveness: cSCC in situ (SCCIS) (n = 25), low-risk cSCC (LR-cSCC) (n = 26), high-risk cSCC (HR-cSCC) (n = 38), and cSCC in recessive dystrophic epidermolysis bullosa patients (RDEB cSCC) (n = 6). Immunohistochemistry demonstrated periostin expression within the intra-tumoral stroma but not within tumor cells. Periostin levels significantly (P < 0.001) increased from SCCIS, LR-cSCC, HR-cSCC to RDEB SCC. The stroma of most of the cSCCs we evaluated contained cancer-associated fibroblasts with a myofibroblastic (α -SMA-positive) phenotype. Co-localization of periostin with α-SMA, evidence of fibroblast periostin expression, and absence of keratinocyte or tumor cell periostin expression suggest that, in cSCC, periostin is a product of the peritumoral microenvironment and not the tumor cells themselves. Our data indicate that fibroblast periostin expression is highly correlated with the aggressiveness of cSCC, and may thereby provide a molecular marker that will be useful for subtyping and diagnosing cSCCs according to their biological nature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.14281DOI Listing
January 2021

Novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments: Design, synthesis and bioactivity.

Bioorg Med Chem 2021 Feb 6;32:115999. Epub 2021 Jan 6.

State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang, Guizhou 550025, China. Electronic address:

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC values of 0.64 and 0.63 μM, which were better than that of gemcitabine (1.40 μM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.115999DOI Listing
February 2021

Impact of mutational variant allele frequency on prognosis in myelodysplastic syndromes.

Am J Cancer Res 2020 1;10(12):4476-4487. Epub 2020 Dec 1.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003, Zhejiang Province, P. R. China.

The clinical relevance of variant allele frequency (VAF) of recurrent mutations in myelodysplastic syndromes (MDS) has been increasingly reported. However, the prognostic value of mutational VAF across the genetic spectrum of MDS has not been extensively evaluated. In this study, we profiled the mutational spectrum of 382 newly diagnosed MDS patients using targeted next-generation sequencing. Exploratory analysis found that mutational VAF of some genes including , , and had significant associations with patient survival. Specifically, VAF ≥ 32% (HR 1.69, P = 0.025) and VAF ≥ 27% (HR 3.58, P < 0.001) were independently associated with shorter overall survival (OS). In contrast, VAF ≥ 15% had an independent association with better prognosis (HR 0.52, P = 0.048). In addition, high VAF was associated with an increased response to hypomethylating agents relative to low VAF (P = 0.009). Patients with high VAF more often possessed complex karyotypes than those with low VAF (P = 0.034). And patients with high VAF were more frequently classified as MDS with ring sideroblasts (MDS-RS) category than those with low VAF (P = 0.012). Meanwhile, we found that for some other genes like and , once their mutations appeared, it meant poor survival regardless of mutational VAF. These findings suggest that mutational VAF of certain genes should be considered into the routine prognostic prediction and risk stratification of MDS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783761PMC
December 2020

Acupuncture for chronic persistent asthma based on the theory of Meridian-viscera Association: study protocol for a multi-center randomized controlled trial in China.

Trials 2021 Jan 6;22(1):17. Epub 2021 Jan 6.

Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 37# Shierqiao Road, Chengdu, 610075, Sichuan, China.

Background: Acupuncture is effective in symptom and quality of life improvement of chronic asthma, but the efficacy differences between different acupoints are uncertain. In terms of the theory of Meridian-viscera Association, the study aims to investigate the different effectiveness between acupoints in Lung meridian and the acupoints in Heart meridian, so as to provide the evidence to develop a better prescription of the acupuncture treatment of chronic persistent asthma.

Methods: This study is a multicentral randomized controlled trial. A total of 68 chronic persistent asthma patients will be randomly allocated into two groups: the Lung meridian group and the Heart meridian group. This trial will include a 2-week baseline period, a 4-week treatment period with 12 sessions' acupuncture, and an 8-week follow-up period. The primary outcome is the Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes are the Asthma Control Test (ACT), Peak Expiratory Flow (PEF), and Forced Expiratory Volume in 1 s (FEV1). The AQLQ and ACT will be collected at baseline, week 4, week 8, and week 12 after randomization. PEF, FEV1, the Self-rating Anxiety Scale (SAS), and the Self-rating Depression Scale (SDS) will be assessed at baseline and week 4.

Discussion: The results will provide evidence for acupuncture prescription selection and the clinical efficacy improvement. The results of this trial will also be used to determine whether or not a full definitive trial will go ahead, which will further confirm the theory of Meridian-viscera Association.

Trial Registration: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/showproj.aspx?proj=43803 ) ChiCTR1900027284. Registered on 7 November 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04844-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789474PMC
January 2021

Identification of Aroma Composition and Key Odorants Contributing to Aroma Characteristics of White Teas.

Molecules 2020 Dec 21;25(24). Epub 2020 Dec 21.

Tea Research Institute, Chinese Academy of Agricultural Sciences, No. 9 Meiling South Road, West lake District, Hangzhou 310008, China.

The identification of aroma composition and key odorants contributing to aroma characteristics of white tea is urgently needed, owing to white tea's charming flavors and significant health benefits. In this study, a total of 238 volatile components were identified in the three subtypes of white teas using headspace solid-phase microextraction (HS-SPME) combined with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOFMS). The multivariate statistical analysis demonstrated that the contents of 103 volatile compounds showed extremely significant differences, of which 44 compounds presented higher contents in Baihaoyinzhen and Baimudan, while the other 59 compounds exhibited higher contents in Shoumei. The sensory evaluation experiment carried out by gas chromatography-olfactometry/mass spectrometry (GC-O/MS) revealed 44 aroma-active compounds, of which 25 compounds were identified, including 9 alcohols, 6 aldehydes, 5 ketones, and 5 other compounds. These odorants mostly presented green, fresh, floral, fruity, or sweet odors. Multivariate analyses of chemical characterization and sensory evaluation results showed that high proportions of alcohols and aldehydes form the basis of green and fresh aroma characteristic of white teas, and phenylethyl alcohol, γ-Nonalactone, trans-β-ionone, trans-linalool oxide (furanoid), α-ionone, and cis-3-hexenyl butyrate were considered as the key odorants accounting for the different aroma characteristics of the three subtypes of white tea. The results will contribute to in-depth understand chemical and sensory markers associated with different subtypes of white tea, and provide a solid foundation for tea aroma quality control and improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25246050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767441PMC
December 2020

[Screening of endophytic fungi against southern blight disease pathogen-Sclerotium delphinii in Dendrobium catenatum].

Zhongguo Zhong Yao Za Zhi 2020 Nov;45(22):5459-5464

National Forestry Dendrobium Catenatum Engineering Technology Research Center, State Key Laboratory of Subtropical Silviculture, Zhejiang A&F University Lin'an 311300, China.

In order to screen the endophytic fungi that can enhance the host(Dendrobium catenatum) resistance to Sclerotium delphinii, the antagonism between each of the 43 endophytic fungi and the pathogen S. delphinii were tested. The results showed that 6 endophytic fungi(DCR2, DCR5, DCR21, DCR22, DCR42, DCR43) have strong activities against the pathogen, the inhibition rates were 49.2%, 49.2%, 47.2%, 56.2%, 53.2%, 48.0%, respectively. Then D. catenatum plantlets were inoculated with both S. delphinii and each of these six endophytic fungi. As a result, the incidence rates of leaves and stems of the D. catenatum plantlets inoculated with DCR2 and the pathogen were both significantly lower than those with other treatments, and the plantlet death rate was 0. It showed that DCR2 Trichoderma polysporum could effectively inhibit the southern blight disease of D. catenatum. Through the endophytic fungal re-isolation test, it was found that DCR2 can colonize in the roots, stems, and leaves of D. catenatum. The research will provide new ideas for the prevention and treatment of the southern blight disease of D. catenatum. It is also significant for reducing pesticide use, ensuring food safety, and promoting the sustainable development of D. catenatum industry. Furthermore, it will provide a basis for the disease control in other crops.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200816.102DOI Listing
November 2020

Antimicrobial evaluation of myricetin derivatives containing benzimidazole skeleton against plant pathogens.

Fitoterapia 2021 Mar 11;149:104804. Epub 2020 Dec 11.

State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China. Electronic address:

A series of novel myricetin derivatives containing benzimidazole skeleton were constructed. The structure of compound 4g was further corroborated via X-ray single crystal diffractometer. The antimicrobial bioassays showed that all compounds exhibited potent inhibitory activities against Xanthomonas axonopodis pv. Citri (Xac), Ralstonia solanacearum (Rs) and Xanthomonas oryzae pv. Oryzae (Xoo) in vitro. Significantly, compound 4q showed the best inhibitory activities against Xoo, with the EC value of 8.2 μg/mL, which was better than thiodiazole copper (83.1 μg/mL) and bismerthiazol (60.1 μg/mL). In vivo experimental studies showed that compound 4q can treat rice bacterial leaf blight at 200 μg/mL, and the corresponding curative and protection efficiencies were 45.2 and 48.6%, respectively. Meanwhile, the antimicrobial mechanism of the compounds 4l and 4q were investigated through scanning electron microscopy (SEM). Studies showed that compounds 4l or 4q can cause deformation or rupture of Rs or Xoo cell membrane. These results indicated that novel benzimidazole-containing myricetin derivatives can be used as a potential antibacterial reagent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fitote.2020.104804DOI Listing
March 2021

Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis.

Immun Ageing 2020 Nov 14;17(1):35. Epub 2020 Nov 14.

Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.

Background: Previously, we and others have reported higher populations of circulating neutrophils in patients with neovascular age-related macular degeneration (nAMD). Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin-2, LCN2), an important innate immune mediator, is known to be critically involved in sterile inflammation-mediated organ failure, fibrosis, cancer progression and retinal degeneration. This study investigated the plasma levels of LCN2, matrix metalloproteinase 9 (MMP9) and LCN2/MMP9 complex in different types of nAMD and examined whether the levels were related to patients' responsiveness to anti-VEGF therapy.

Results: One hundred and seventy-four nAMD patients, including 108 with choroidal neovascularisation (CNV), 32 with retinal angiomatous proliferation (RAP), 23 with polypoidal choroidal vasculopathy (PCV) and 11 unclassified patients, and 43 healthy controls were recruited to this case-control study. Fifty-eight nAMD patients had macular fibrosis and 110 patients did not. Out of the 174 nAMD patients, 80 patients responded completely, 90 responded partially, and 4 did not respond to the anti-VEGF therapy. The plasma levels of LCN2 in nAMD patients (181.46 ± 73.62 ng/ml) was significantly higher than that in healthy controls (152.24 ± 49.55 ng/ml, P = 0.047). However, the difference disappeared after adjusting for age. A positive correlation between plasma level of LCN2 and age was observed in nAMD patients (r = 0.29, P = 0.0002) but not in healthy controls. The plasma level of LCN2 was also positively correlated with circulating neutrophils in nAMD patients (r = 0.34, p = 0.0007) but not in healthy controls (r = 0.057, p = 0.77). No correlation was observed between age and circulating neutrophils. Further analysis of nAMD subtypes uncovered a significantly higher level of LCN2 in patients with macular fibrosis even after adjusting for age. No relationship was observed between plasma levels of LCN2 and patients' responsiveness to anti-VEGF therapy. The plasma levels of MMP9 and LCN2/MMP9 complex were comparable between nAMD and controls.

Conclusions: Our results suggest that higher plasma levels of LCN2 in nAMD are related to ageing and increased population of circulating neutrophils. Our results also suggest that higher levels of LCN2 may increase the risk of macular fibrosis in nAMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12979-020-00205-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666483PMC
November 2020

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.

Lancet Oncol 2020 12 23;21(12):1563-1573. Epub 2020 Oct 23.

Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Background: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.

Methods: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.

Findings: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.

Interpretation: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30436-8DOI Listing
December 2020

Knowledge, attitudes and practices of the Chinese public with respect to coronavirus disease (COVID-19): an online cross-sectional survey.

BMC Public Health 2020 Nov 30;20(1):1816. Epub 2020 Nov 30.

Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.

Background: Coronavirus disease (COVID-19) has become a pandemic. The knowledge, attitudes, and practices (KAP) of the public play a major role in the prevention and control of infectious diseases. The objective of the present study was to evaluate the KAP of the Chinese public and to assess potential influencing factors related to practices.

Methods: A cross-sectional online survey was conducted in China in February 2020 via a self-designed questionnaire comprising 33 questions assessing KAP.

Results: For the 2136 respondents from 30 provinces or municipalities in China, the accurate response rate for the knowledge section ranged from 72.7 to 99.5%, and the average was 91.2%. Regarding attitude section, the percentage of positive attitudes ("strongly agree" and "agree") ranged from 94.7 to 99.7%, and the average value was 98.0%. The good practices ("always" and "often") results ranged from 76.1 to 99.5%, and the average value was 96.8%. The independent samples t-test revealed that gender and ethnic differences had no effect on knowledge, attitude or behaviour (P > 0.05). However, knowledge was associated with age (t = 4.842, p < 0.001), marital status (t = - 5.323, p < 0.001), education level (t = 8.441, p < 0.001), occupation (t = - 10.858, p < 0.001), and place of residence (t = 7.929, p < 0.001). Similarly, attitude was associated with marital status (t = - 2.383, p = 0.017), education level (t = 2.106, p = 0.035), occupation (t = - 4.834, p < 0.001), and place of residence (t = 4.242, p < 0.001). The multiple linear regression analysis results showed that the factors influencing practices were knowledge (t = - 3.281, p = 0.001), attitude (t = 18.756, p < 0.001), occupation (t = - 3.860, p < 0.001), education level (t = 3.136, p = 0.002), and place of residence (t = 3.257, p = 0.001).

Conclusions: The Chinese public exhibited a good level of knowledge of COVID-19, a positive attitude, and high adherence to good practices. COVID-19-related knowledge, attitudes and practices were affected by age, marital status, education level, occupation, and place of residence to varying degrees. In addition, practices were affected by knowledge and attitudes towards COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12889-020-09961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702204PMC
November 2020

Concurrent infection of Avibacterium paragallinarum and fowl adenovirus in layer chickens.

Poult Sci 2020 Dec 25;99(12):6525-6532. Epub 2020 Sep 25.

Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Municipal Academy of Agriculture and Forestry, Beijing, China. Electronic address:

The diagnosis of a concurrent infection of Avibacterium paragallinarum and fowl adenovirus (FAdV) in an infectious coryza-like outbreak in the outskirt of Beijing is reported. The primary signs of the infection were acute respiratory signs, a drop in egg production, and the presence of hydropericardium-hepatitis syndrome-like gross lesions. Laboratory examination confirmed the presence of A. paragallinarum by bacterial isolation and a species-specific PCR test. In addition, conventional serotyping identified the isolates as Page serovar A. Fowl adenovirus was isolated from chicken liver specimen and identified by hexon gene amplification. In addition, histopathologic analysis and transmission electron microscopy examination further confirmed the presence of the virus. Both hexon gene sequencing and phylogenetic analysis defined the viral isolate as FAdV-4. The pathogenic role of A. paragallinarum and FAdV was evaluated by experimental infection of specific-pathogen-free chickens. The challenge trial showed that combined A. paragallinarum and FAdV infection resulted in more severe clinical signs than that by FAdV infection alone. The concurrent infection caused 50% mortality compared with 40% mortality by FAdV infection alone and zero mortality by A. paragallinarum infection alone. To our knowledge, this is the first report of A. paragallinarum coinfection with FAdV. The case implies that concurrent infections with these 2 agents do occur and more attention should be given to the potential of multiple agents during disease diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psj.2020.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704954PMC
December 2020

Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration.

J Neuroinflammation 2020 Nov 25;17(1):355. Epub 2020 Nov 25.

The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.

Background: Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis.

Methods: Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo.

Results: Approximately 20~30% of F4/80 (or Iba-1) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4 lesions. The treatment did not significantly alter collagen-1 fibrotic lesions.

Conclusions: MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch's membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-020-02033-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690191PMC
November 2020

New Ophiobolins from the Deep-Sea Derived Fungus sp. WHU0154 and Their Anti-Inflammatory Effects.

Mar Drugs 2020 Nov 20;18(11). Epub 2020 Nov 20.

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China.

Deep-sea fungi have become a new arsenal for the discovery of leading compounds. Here five new ophiobolins -, together with six known analogues -, obtained from a deep-sea derived fungus WHU0154. Their structures were determined by analyses of IR, HR-ESI-MS, and NMR spectra, along with experimental and calculated electronic circular dichroism (ECD) analysis. Pharmacological studies showed that compounds and exhibited obvious inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine macrophage RAW264.7 cells. Mechanical study revealed that compound could inhibit the inducible nitric oxide synthase (iNOS) level in LPS-stimulated RAW264.7 cells. In addition, compounds , , and could significantly inhibit the expression of cyclooxygenase 2 (COX 2) in LPS-induced RAW264.7 cells. Preliminary structure-activity relationship (SAR) analyses revealed that the aldehyde group at C-21 and the α, β-unsaturated ketone functionality at A ring in ophiobolins were vital for their anti-inflammatory effects. Together, the results demonstrated that ophiobolins, especially for compound , exhibited strong anti-inflammatory effects and shed light on the discovery of ophiobolins as new anti-inflammatory agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md18110575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699878PMC
November 2020

Thermophilic Solid-State Anaerobic Digestion of Corn Straw, Cattle Manure, and Vegetable Waste: Effect of Temperature, Total Solid Content, and C/N Ratio.

Archaea 2020 11;2020:8841490. Epub 2020 Nov 11.

Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, 8 Jiangwangmiao Street, Nanjing 210042, China.

Thermophilic solid-state anaerobic digestion (SS-AD) of agricultural wastes, i.e., corn straw, cattle manure, and vegetable waste, was carried out in this study. The effects of temperature (40-60°C), initial solid content (ISC, 17.5-32.5%), and C/N ratio (15-32 : 1) on biogas production were evaluated using a Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). The results showed that optimization of process parameters is important to promote the SS-AD performance. All the factors, including interactive terms (except the ISC), were significant in the quadratic model for biogas production with SS-AD. Among the three operation parameters, the C/N ratio had the largest effect on biogas production, followed by temperature, and a maximum biogas yield of 241.4 mL gVS could be achieved at 47.3°C, ISC = 24.81%, and C/N = 22.35. After 20 d of SS-AD, the microbial community structure under different conditions was characterized by high-throughput sequencing, showing that , , , and dominated the bacterial community, and that had a competitive advantage over at elevated temperatures. The biogas production values and relative abundance of and after 20 d of SS-AD can be fitted well using a quadratic model, implying that and play important roles in the methanogenic metabolism for agricultural waste thermophilic SS-AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8841490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673934PMC
November 2020