Publications by authors named "Yuan Zhuang"

326 Publications

Adrenocorticotropic Hormone: An Expansion of Our Current Understanding of the Treatment for Nephrotic Syndrome.

Steroids 2021 Oct 11:108930. Epub 2021 Oct 11.

Department of Paediatrics, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou city, Sichuan province, China. Electronic address:

In clinical practice, we may encounter a treatment dilemma where in some patients with nephrotic syndrome are resistant to glucocorticoids or immunosuppressive agents. Thus, we currently lack viable treatment options and eagerly await the availability of new drugs. Adrenocorticotropic hormone (ACTH) had earlier been used to treat nephrotic syndrome in children, but has now become less popular owing to the advent of oral glucocorticoids. However, in recent studies, ACTH was reportedly used again for treating nephrotic syndrome, reducing proteinuria and protecting renal function, indicating a possibility for its use in the treatment of refractory nephrotic syndrome. This review analysed the validity of ACTH in these studies, focusing on the mechanism of action, application in both paediatric and adult patients with nephrotic syndrome, particularly in children, and possible side effects. We anticipate that our findings will help clinicians in treatment decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.steroids.2021.108930DOI Listing
October 2021

Interferon-γ-Induced Myeloid-Derived Suppressor Cells Aggravate Kidney Ischemia-Reperfusion Injury by Regulating Innate Immune Cells.

Nephron 2021 Sep 21:1-11. Epub 2021 Sep 21.

Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China.

Objective: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context.

Methods: The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice.

Results: MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro. The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b+Ly6G-Ly6Chigh monocytic-MDSC phenotype decreased, whereas cells with a CD11b+Ly6G+Ly6Clow polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4+ and CD8+ T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice.

Conclusions: Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000518876DOI Listing
September 2021

The Effects of Adoptively Transferred IL-23/IL-18-Polarized Neutrophils on Tumor and Collagen-Induced Arthritis in Mice.

J Inflamm Res 2021 16;14:4669-4686. Epub 2021 Sep 16.

Department of State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.

Background: Neutrophils present great diverse phenotypes in various microenvironments and play different immune regulatory functions. Neutrophils generally classified into inflammatory phenotype N1 and anti-informatory phenotype N2. Our recent studies showed that IL-23 alone stimulated neutrophils to express IL-17A, IL-17F and IL-22 and displayed a gene transcriptional profile similar to Th17 cells. In the present study, we tried to identify potential cytokines to promote IL-23-induced neutrophil polarization.

Methods: Mouse bone marrow-derived neutrophils and human peripheral blood neutrophils were treated with IL-23 (10 ng/mL) plus IL-18 (25 ng/mL) to induce Th17-like subset in vitro and detected by real-time PCR, flow cytometry, ELISA, immunofluorescence and RNA-seq assays. In vivo, collagen-induced arthritis (CIA) mouse model and EL4 tumor-bearing mouse model were used to characterize the potential roles of N(IL-23+IL-18) in inflammation and tumor.

Results: Real-time PCR, ELISA and flow cytometry assays showed that IL-18 could significantly enhance IL-23-induced IL-17A, IL-17F and IL-22 expressions in mouse and human neutrophils in a synergistic way, although IL-18 alone failed to induce these cytokines expression. RNA-seq and molecular studies showed that the polarization of N(IL-23+IL-18) is mainly mediated by the JNK/p38-STAT3-BATF signaling pathway. Adoptive transfer of the induced N(IL-23+IL-18) neutrophils significantly accelerated the tumor growth in EL4 tumor-bearing mice and enhanced disease progression in the CIA mouse model. IL-17A-deficient N(IL-23+IL-18) neutrophils failed to enhance the CIA pathogenesis in this model, suggesting that IL-17A may be involved in the N(IL-23+IL-18) neutrophils-promoted arthritis in mice.

Conclusion: The Th17-type subpopulation N(IL-23+IL-18) has pro-tumor and pro-inflammatory properties. Recognizing the different functional polarization of neutrophils would significantly help us to understand the distinctive protective/pathological roles of neutrophils in physiological and different pathological situations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/JIR.S329528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453247PMC
September 2021

Vaccination induces rapid protection against bacterial pneumonia via training alveolar macrophage in mice.

Elife 2021 09 20;10. Epub 2021 Sep 20.

West China Biopharmaceutical Research Institute,West China Hospital, Sichuan University, Chengdu, China.

Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here, we demonstrated that a single intranasal immunization of inactivated whole cell of elicits rapid protection against broad -infected pneumonia via training of innate immune response in mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF-α production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in and pneumonia models, but not in and model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.69951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455131PMC
September 2021

PMA induces the differentiation of monocytes into immunosuppressive MDSCs.

Clin Exp Immunol 2021 Nov 9;206(2):216-225. Epub 2021 Sep 9.

Institute of Uro-Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

The induction of immune tolerance without the use of immunosuppressive drugs is a crucial problem in organ transplantation. The use of myeloid-derived suppressor cells (MDSCs) as a cell-based adjuvant immunosuppressive therapy is a bright clinical prospect in organ transplantation. MDSCs with stable immunosuppressive activities can be used to treat immune-related diseases. In this study, macrophage colony-stimulating factor (M-CSF) was used to promote myeloid progenitor cell differentiation, and phorbol 12-myristate 13-acetate (PMA) was added to induce MDSCs at the later stage of induction in vitro. Cell phenotypes were detected by flow cytometry and mRNA was detected by real-time-polymerase chain reaction (RT-PCR). A mouse skin transplantation model was used to investigate the cell inhibitory function. The combination of PMA and M-CSF induced the differentiation of myeloid-derived monocytes into MDSCs. MDSCs were found to induce immune tolerance by inhibiting the proliferation and activation of T cells, promoting cytokine secretion and inducing T cell transformation to regulatory T cells (T ). PMA significantly up-regulated the expression of Arg-1 and the Arg-1 protein expression in MDSCs and arginase 1 (Arg-1) inhibitor nor-NOHA reversed the MDSC immunosuppressive activity, indicating the involvement of the Arg-1 pathway in MDSC-mediated immunosuppression. M-CSF + PMA-induced MDSCs also significantly prolonged the survival time of skin grafts in mice, showing that MDSCs exert immunosuppressive effects in vivo. We describe a novel scheme to induce immunosuppressive MDSCs in vitro. MDSCs induced by M-CSF with PMA showed stable immunosuppression. MDSCs induced by this protocol may benefit patients with organ transplantation through immune regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cei.13657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506123PMC
November 2021

Steatosis, inflammasome upregulation, and fibrosis are attenuated in miR-155 deficient mice in a high fat-cholesterol-sugar diet-induced model of NASH.

Lab Invest 2021 Aug 27. Epub 2021 Aug 27.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease globally. miRNAs (miRs) regulate various cellular events that lead to NAFLD. In this study we tested the hypothesis that miR-155 is an important regulator of steatohepatitis and fibrosis pathways. Wild type (WT) or miR-155 deficient (KO) mice received a high fat-high cholesterol-high sugar-diet (HF-HC-HS) for 34 weeks and liver tissues were analyzed. In patients with nonalcoholic steatohepatitis and in the mouse model of HF-HC-HS diet we found increased miR-155 levels in the liver compared to normal livers. Upon HF-HC-HS diet feeding, miR-155 KO mice displayed less liver injury, decreased steatosis, and attenuation in fibrosis compared to WT mice. ALT, triglyceride levels, and genes involved in fatty acid metabolic pathway were increased in WT mice whereas miR-155 KO mice showed attenuation in these parameters. HF-HC-HS diet-induced significant increase in the expression of NLRP3 inflammasome components in the livers of WT mice compared to chow fed diet. Compared to WT mice, miR-155 KO showed attenuated induction in the NLRP3, ASC, and caspase1 inflammasome expression on HF-HC-HS diet. Fibrosis markers such as collagen content and deposition, αSMA, Zeb2, and vimentin were all increased in WT mice and miR-155 KO mice showed attenuated fibrosis marker expression. Overall, our findings highlight a role for miR-155 in HF-HC-HS diet-induced steatosis and liver fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-021-00626-1DOI Listing
August 2021

The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors.

Front Pharmacol 2021 26;12:713715. Epub 2021 Jul 26.

Department of Neurosurgery and Beijing Key Laboratory of Central Nervous System Injury, Beijing Tiantan Hospital and Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.713715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350576PMC
July 2021

Measuring urban integrated water use efficiency and spatial migration path in China: A dynamic two-stage recycling model within the directional distance function.

J Environ Manage 2021 Nov 3;298:113379. Epub 2021 Aug 3.

Business School, Hohai University, Changzhou, 213022, China. Electronic address:

Improving water use efficiency from a recycling perspective is claimed to be a better way to ensure prosperity in a water-stressed world. Although many studies have focused on the efficiency of integrated water use system, such as a water use and wastewater treatment (WUWT) system, few studies have observed the dynamic change involving a two-stage recycling structure. This research thus proposes a dynamic two-stage recycling model within the directional distance function (DDF) by taking reused water in the WT stage as a recycled product for WU stage's input in the next period. This paper reveals the dynamic evolution and spatial migration path of this efficiency in China. Results are as follows. (1) The average overall efficiency of the urban WUWT system for 30 provinces during 2011-2018 was 0.78. The central region's lower WUWT efficiency was caused by the expanding provincial differences in WU efficiency. (2) The urban WU sub-system performed poorer than that of the urban WT sub-system due to underutilizing reused water, such as in Jiangxi, Guangxi, Yunnan, and Jilin. (3) Narrowing the spatial imbalance of economic development and water use between the eastern and western regions is of great importance for promoting China's spatial imbalance of urban WUWT efficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jenvman.2021.113379DOI Listing
November 2021

M-CSF and prostratin induced Mregs promote immune tolerance in transplanted mice through Arg-1 pathway.

Int Immunopharmacol 2021 Oct 29;99:108014. Epub 2021 Jul 29.

Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China. Electronic address:

Objective: Regulatory macrophages (Mregs) are a group of heterogeneous macrophages. These cells could induce immunosuppressive effects through the expression of immune regulatory molecules and cytokines.

Methods: The differentiation of Mregs was induced by treating bone marrow cells with M-CSF and prostratin in vitro. The cell-phenotypes and immunosuppressive function were determined by flow cytometry. Rt-PCR was employed to assess the mechanisms of Mregs. Skin grafted mouse model was used for in vivo validation.

Results: Mregs induced by M-CSF + prostratin had a strong inhibitory effect on T cell proliferation and cytokines production. The phenotype of induced bone marrow cells changed towards Mregs. These Mregs could induce the differentiation of Tregs in vivo. Arg-1 expression in these cells were significantly upregulated. Inhibition of arginase (Arg) or arginine supplement significantly reversed the immunosuppressive function. In mice skin-grafted models, adoptive transfer of these Mregs significantly prolonged allograft survival. In mice models, Arg-1 expression significantly elevated on skin grafts cells and Tregs increased in graft tissues.

Conclusions: We successfully developed a Mregs-inducing protocol with the combination of M-CSF and prostratin in vitro. M-CSF + prostratin induced Mregs prevented mice skin graft rejection through upregulating the expression Arg-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2021.108014DOI Listing
October 2021

Simultaneously Enhanced Efficiency and Operational Stability of Nonfullerene Organic Solar Cells via Solid-Additive-Mediated Aggregation Control.

Small 2021 Sep 22;17(35):e2102558. Epub 2021 Jul 22.

School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China.

The additive strategy is widely used in optimizing the morphology of organic solar cells (OSCs). The majority of additives are liquid with high boiling points, which will be trapped within device and consequently deteriorate performance during operation. In this work, solid but volatile additives 2-(4-fluorobenzylidene)-1H-indene-1,3(2H)-dione (INB-F) and 2-(4-chlorobenzylidene)-1H-indene-1,3(2H)-dione (INB-Cl) are designed to replace the common 1,8-diiodooctane (DIO) in nonfullerene OSCs. These additives present during solution casting but evaporate after moderate heating. Molecular dynamics simulations show that they can reduce the adsorption energy to improve π-π stacking among nonfullerene acceptor (NFA) molecules, an effect that enhances light absorption and electron mobility. Both INB-F and INB-Cl enhance efficiency, with INB-F achieving a maximum efficiency of 16.7% from 15.1% of the reference PBDB-T-2F (PM6):BTP-BO-4F (Y6-BO) cell, and outperforming DIO. Remarkably, they can simultaneously enhance the operational stability, with the INB-F-treated OSC maintaining over 60% of the initial efficiency after 1000 h operation, demonstrating a T lifetime of 523 h, which is a significant improvement over T values of 66.2 h for the reference and 6.6 h for DIO-treated OSC. The simultaneously enhanced efficiency and operational lifetime are also effective in PM6:BTP-BO-4Cl (Y7-BO) OSCs, demonstrating a universal strategy to improve the performance of OSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.202102558DOI Listing
September 2021

Uncovering the Subtype-Specific Molecular Characteristics of Breast Cancer by Multiomics Analysis of Prognosis-Associated Genes, Driver Genes, Signaling Pathways, and Immune Activity.

Front Cell Dev Biol 2021 1;9:689028. Epub 2021 Jul 1.

Department of Pathology, Harbin Medical University, Harbin, China.

Breast cancer is a heterogeneous malignant disease with different prognoses and has been divided into four molecular subtypes. It is believed that molecular events occurring in breast stem/progenitor cells contribute to the carcinogenesis and development of different breast cancer subtypes. However, these subtype-specific molecular characteristics are largely unknown. In this study, we employed 1217 breast cancer samples from The Cancer Genome Atlas (TCGA) database for a multiomics analysis of the molecular characteristics of different breast cancer subtypes based on PAM50 algorithms. We detected the expression changes of subtype-specific genes and revealed that the expression of particular subtype-specific genes significantly affected prognosis. We also investigated the mutations and copy number variations (CNVs) of breast cancer driver genes and the representative genes of ten signaling pathways in different subtypes and revealed several subtype-specifically altered genes. Moreover, we detected the infiltration of various immune cells in different subtypes of breast cancer and showed that the infiltration levels of major immune cell types are different among these subtypes. Additionally, we investigated the factors affecting the immune infiltration level and the immune cytolytic activity in different breast cancer subtypes, namely, the mutation burden, genome instability and cancer-associated fibroblast (CAF) infiltration. This study may shed light on the molecular events contributing to carcinogenesis and development and provide potential markers and targets for the clinical diagnosis and treatment of different breast cancer subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.689028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280810PMC
July 2021

Iron particle formation under chlorine disinfection considering effects of deoxidizers in drinking water.

J Hazard Mater 2021 10 7;420:126581. Epub 2021 Jul 7.

Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Iron oxidation inevitably occurs in drinking water distribution systems (DWDSs) and can cause water quality problems such as increased turbidity and discoloration of tap water. Considering that chlorine disinfection is also widely used in DWDSs, the role of disinfectant and disinfection byproducts (DBPs) in iron oxidation should not be neglected. Interestingly, here the well-known deoxidizer ascorbic acid (VC), which is also a food additive, could induce the formation of FeO besides FeOOH resulting in the color change from yellow to black in the presence of trichloroacetic acid (TCA, one of the most typical DBPs) and NaClO (disinfectant). The oxygen-containing functional groups in TCA and VC may bind Fe(II) to guide the crystal growth. Though the particles generated in the presence of TCA and NaClO together with VC had higher content FeO which would be more difficult to suspend, once disturbance happened, these particles could increase the turbidity and color of water into higher value than the particles formed without VC and those generated in the absence of TCA and NaClO. Therefore, the deoxidizer VC may control "yellow water" without disinfectant, but may deteriorate the water quality under disinfection conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2021.126581DOI Listing
October 2021

Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury.

Neural Regen Res 2022 Feb;17(2):386-394

Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute; Beijing Key Laboratory of Central Nervous System Injury and Department of Neurosurgery, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University; Nerve Injury and Repair Center of Beijing Institute for Brain Disorders; China National Clinical Research Center for Neurological Diseases, Beijing, China.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that tsRNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether tsRNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated tsRNA and messenger RNA (mRNA) transcriptome sequencing were used. The results revealed that 103 tsRNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 tsRNAs were upregulated and 47 tsRNAs were downregulated. Based on microRNA-like seed matching and Pearson correlation analysis, 57 differentially expressed tsRNA-mRNA interaction pairs were identified, including 29 tsRNAs and 26 mRNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that tsRNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 20190411) on April 11, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.314315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463968PMC
February 2022

Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway.

Metabolism 2021 Sep 29;122:154823. Epub 2021 Jun 29.

The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced hepatic steatosis with impaired glucose tolerance in mice. However, the underlying mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fasted C57BL/6 J mice or db/db mice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment. Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling pathway in db/db mice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis. The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis. The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part, by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression. SOCS2 may represent a new therapeutic target for the treatment of diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2021.154823DOI Listing
September 2021

The role of ADAM17 during liver damage.

Biol Chem 2021 Aug 30;402(9):1115-1128. Epub 2021 Jun 30.

Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany.

A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/hsz-2021-0149DOI Listing
August 2021

Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer.

Clin Transl Med 2021 06;11(6):e484

National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China.

Rationale: Neutrophils constitute massive cellular constituents in inflammatory human gastric cancer (GC) tissues, but their roles in pathogenesis of inflammatory T helper (Th) subsets are still unknown.

Methods: Flow cytometry analysis and immunohistochemistry were used to analyze the responses and phenotypes of neutrophils in different samples from 51 patients with GC. Kaplan-Meier plots and Multivariate analysis for the survival of patients were used by log-rank tests and Cox proportional hazards models. Neutrophils and CD4 T cells were purified and cultured for ex vivo, in vitro and in vivo regulation and function assays.

Results: GC patients exhibited increased tumoral neutrophil infiltration with GC progression and poor patient prognosis. Intratumoral neutrophils accumulated in GC tumors via CXCL6/CXCL8-CXCR1-mediated chemotaxis, and expressed activated molecule CD54 and co-signaling molecule B7-H2. Neutrophils induced by tumors strongly expressed CD54 and B7-H2 in both dose- and time-dependent manners, and a close correlation was obtained between the expressions of CD54 and B7-H2 on intratumoral neutrophils. Tumor-derived tumor necrosis factor-α (TNF-α) promoted neutrophil activation and neutrophil B7-H2 expression through ERK-NF-κB pathway, and a significant correlation was found between the levels of TNF-α and CD54 or B7-H2 neutrophils in tumor tissues. Tumor-infiltrating and tumor-conditioned neutrophils effectively induced IL-17A-producing Th subset polarization through a B7-H2-dependent manner ex vivo and these polarized IL-17A-producing Th cells exerted protumorigenic roles by promoting GC tumor cell proliferation via inflammatory molecule IL-17A in vitro, which promoted the progression of human GC in vivo; these effects could be reversed when IL-17A is blocked. Moreover, increased B7-H2 neutrophils and IL-17A in tumors were closely related to advanced GC progression and predicted poor patient survival.

Conclusion: We illuminate novel underlying mechanisms that TNF-α-activated neutrophils link B7-H2 to protumorigenic IL-17A-producing Th subset polarization in human GC. Blocking this pathological TNF-α-B7-H2-IL-17A pathway may be useful therapeutic strategies for treating GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ctm2.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236123PMC
June 2021

Blocking the CCL5-CCR5 Axis Using Maraviroc Promotes M1 Polarization of Macrophages Cocultured with Irradiated Hepatoma Cells.

J Hepatocell Carcinoma 2021 18;8:599-611. Epub 2021 Jun 18.

Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.

Purpose: The C-C chemokine ligand 5 (CCL5)-C-C chemokine receptor (CCR5) axis facilitates tumor progression via multiple mechanisms. Herein, we elucidated the effect of a CCR5 antagonist (maraviroc [MVC]; blocking the CCL5-CCR5 axis) on the phenotype of macrophages cocultured with irradiated hepatoma cells. In addition, we investigated whether modulation of macrophage polarization can alter tumor cell sensitivity to radiation.

Materials And Methods: Quantitative reverse-transcription polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assays were applied to examine the levels of macrophage-associated markers. The mechanisms of macrophage polarization were explored by Western blotting in an in vitro model of coculture of human hepatoma cells with macrophages. The radiation sensitivity was examined in a clonogenic radiosensitivity assay. Tumor cell apoptosis was detected by Western blotting and flow cytometry. A mouse model of a subcutaneous tumor was also established.

Results: CCL5 skewed THP-1 M0 macrophages toward an M2-like phenotype. In coculture with hepatoma cells, macrophages manifested high levels of interleukin (IL) 10, IL-12, tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), arginase 1 (ARG1), and IL-1β. Tumor cell irradiation further upregulated these markers in macrophages. After incubation of macrophages with MVC for 24 h, levels of M1 cytokines significantly increased, whereas those of M2 phenotype factors ARG1, TGF-β1, and IL-10 decreased, accompanied by the activation of signal transducer and activator of transcription 3 (STAT3) and downregulation of suppressor of cytokine signaling 3 (SOCS3). The macrophage phenotype reverted to M2 states after treatment with a STAT3 inhibitor. The shift of macrophages toward the M1 phenotype enhanced the radiosensitivity and apoptosis of hepatoma cells. Mice receiving a combination of X-ray irradiation and MVC experienced a better antitumor effect than those receiving either MVC or irradiation alone did.

Conclusion: M2 polarization of macrophages induced by CCL5-CCR5 signaling can be inhibited using MVC via the STAT3-SOCS3 pathway. The shift of macrophages toward the M1 phenotype promotes the sensitivity of human hepatoma cells to X-ray irradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/JHC.S300165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219307PMC
June 2021

Detect-seq reveals out-of-protospacer editing and target-strand editing by cytosine base editors.

Nat Methods 2021 06 7;18(6):643-651. Epub 2021 Jun 7.

Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

Cytosine base editors (CBEs) have the potential to correct human pathogenic point mutations. However, their genome-wide specificity remains poorly understood. Here we report Detect-seq for the evaluation of CBE specificity. It enables sensitive detection of CBE-induced off-target sites at the genome-wide level. Detect-seq leverages chemical labeling and biotin pulldown to trace the editing intermediate deoxyuridine, thereby revealing the editome of CBE. In addition to Cas9-independent and typical Cas9-dependent off-target sites, we discovered edits outside the protospacer sequence (that is, out-of-protospacer) and on the target strand (which pairs with the single-guide RNA). Such unexpected off-target edits are prevalent and can exhibit a high editing ratio, while their occurrences exhibit cell-type dependency and cannot be predicted based on the sgRNA sequence. Moreover, we found out-of-protospacer and target-strand edits nearby the on-target sites tested, challenging the general knowledge that CBEs do not induce proximal off-target mutations. Collectively, our approaches allow unbiased analysis of the CBE editome and provide a widely applicable tool for specificity evaluation of various emerging genome editing tools.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41592-021-01172-wDOI Listing
June 2021

Anti-tumor effects of an ID antagonist with no observed acquired resistance.

NPJ Breast Cancer 2021 May 24;7(1):58. Epub 2021 May 24.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-021-00266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144414PMC
May 2021

Exogenous insulin antibody syndrome treated with plasma exchange after an incomplete response to immunosuppressive therapy.

J Clin Apher 2021 Aug 20;36(4):664-667. Epub 2021 May 20.

Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing, China.

A 43-year-old man with a 23-year history of type II diabetes presented with uncontrolled hyperglycemia with frequent episodes of ketoacidosis. He was diagnosed with exogenous insulin antibody syndrome, and received high-dose methylprednisolone to treat insulin resistance. Ketoacidosis relapsed 2 years later, and the patient showed an incomplete response to glucocorticoids. We decided to administer therapeutic plasma exchange, which resulted in rapid lowering of the daily insulin requirement and improved glycemic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jca.21905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453898PMC
August 2021

Expression, regulation and clinical significance of B7-H3 on neutrophils in human gastric cancer.

Clin Immunol 2021 06 1;227:108753. Epub 2021 May 1.

National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China. Electronic address:

Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54 phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54 neutrophils and B7-H3 neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3 neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3 neutrophils to be potential biomarkers in GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2021.108753DOI Listing
June 2021

L-Plastin Promotes Gastric Cancer Growth and Metastasis in a -ERK-SP1-Dependent Manner.

Mol Cancer Res 2021 06 26;19(6):968-978. Epub 2021 Mar 26.

National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, P.R. China.

Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of ()-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in -associated gastric cancer and found that, mechanistically, infection induced gastric cancer cells to express L-plastin via -activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration and facilitated the growth and metastasis of gastric cancer . Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by , and a new function of L-plastin-facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer. IMPLICATIONS: Our results elucidate a novel mechanism of L-plastin expression induced by in gastric cancer, and a new function of L-plastin-facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-20-0936DOI Listing
June 2021

Granulocyte-Macrophage Colony-Stimulating Factor-Activated Neutrophils Express B7-H4 That Correlates with Gastric Cancer Progression and Poor Patient Survival.

J Immunol Res 2021 1;2021:6613247. Epub 2021 Mar 1.

Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

Neutrophils are prominent components of gastric cancer (GC) tumors and exhibit distinct phenotypes in GC environment. However, the phenotype, regulation, and clinical relevance of neutrophils in human GC are presently unknown. Here, immunohistochemistry, real-time PCR, and flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 41 patients with GC, and also isolated, stimulated, and/or cultured neutrophils for regulation assays. Finally, we performed Kaplan-Meier plots for overall survival by using the log-rank test to evaluate the clinical relevance of neutrophils and their subsets. In our study, neutrophils in tumor tissues were significantly higher than those in nontumor tissues and were positively associated with tumor progression but negatively correlated with GC patient survival. Most intratumoral neutrophils showed an activated CD54 phenotype and expressed high-level immunosuppressive molecule B7-H4. Tumor tissue culture supernatants from GC patients induced neutrophils to express CD54 and B7-H4 in both time-dependent and dose-dependent manners. Locally enriched CD54 neutrophils and B7-H4 neutrophils positively correlated with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) detection , and GM-CSF induced the expression of CD54 and B7-H4 on neutrophils in a time-dependent and dose-dependent manner. Moreover, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H4 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway activation. Furthermore, higher intratumoral B7-H4 neutrophil percentage/number was found in GC patients with advanced tumor node metastasis stage and reduced overall survival following surgery. Our results illuminate a novel regulating mechanism of B7-H4 expression on tumor-activated neutrophils in GC, suggesting that functional inhibition of these novel GM-CSF-B7-H4 pathways may be a suitable therapeutic strategy to treat the immune tolerance feature of GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/6613247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962878PMC
March 2021

The efficacy of therapeutic apheresis in patients with refractory neuromyelitis optica spectrum disorders: a single-center retrospective study.

Ann Palliat Med 2021 Mar 18;10(3):3105-3114. Epub 2021 Mar 18.

Department of Blood Transfusion Medicine, the First Medical Center, Chinese PLA General Hospital, Beijing, China.

Background: Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD.

Methods: This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR).

Results: Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts.

Conclusions: Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/apm-21-177DOI Listing
March 2021

Identification of an Individualized Immune-Related Prognostic Risk Score in Lung Squamous Cell Cancer.

Front Oncol 2021 3;11:546455. Epub 2021 Mar 3.

Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Lung squamous cell carcinoma (LUSC) is one of the most common histological subtypes of non-small cell lung cancer (NSCLC), and its morbidity and mortality are steadily increasing. The purpose of this study was to study the relationship between the immune-related gene (IRGs) profile and the outcome of LUSC in patients by analyzing datasets from The Cancer Genome Atlas (TCGA). We obtained publicly available LUSC RNA expression data and clinical survival data from The Cancer Genome Atlas (TCGA), and filtered IRGs based on The ImmPort database. Then, we identified risk immune-related genes (r-IRGs) for model construction using Cox regression analysis and defined the risk score in this model as the immune gene risk index (IRI). Multivariate analysis was used to verify the independent prognostic value of IRI and its association with other clinicopathological features. Pearson correlation analysis was used to explore the molecular mechanism affecting the expression of IRGs and the correlation between IRI and immune cell infiltration. We screened 15 r-IRGs for constructing the risk model. The median value of IRI stratified the patients and there were significant survival differences between the two groups ( = 4.271E-06). IRI was confirmed to be an independent prognostic factor ( < 0.001) and had a close correlation with the patients' age ( < 0.05). Interestingly, the infiltration of neutrophils or dendritic cells was strongly upregulated in the high-IRI groups ( < 0.05). Furthermore, by investigating differential transcription factors (TFs) and functional enrichment analysis, we explored potential mechanisms that may affect IRGs expression in tumor cells. In short, this study used 15 IRGs to build an effective risk prediction model, and demonstrated the significance of IRGs-based personalized immune scores in LUSC prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.546455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966508PMC
March 2021

Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense.

Cell Mol Gastroenterol Hepatol 2021 3;12(2):395-425. Epub 2021 Mar 3.

National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, China. Electronic address:

Background & Aims: Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown.

Methods: Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα and wild-type (littermate control) mice or these mice adoptively transferred with CD4 T cells from IFN-γ and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45CD11cLy6GCD11bCD68 myeloid cells and CD4 T cells were isolated, stimulated and/or cultured for Rev-erbα function assays.

Results: Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45CD11cLy6GCD11bCD68 myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response.

Conclusions: Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255816PMC
March 2021

Current Progress in CAR-T Cell Therapy for Hematological Malignancies.

J Cancer 2021 1;12(2):326-334. Epub 2021 Jan 1.

Henan Cell Therapy Group Co. LTD, Zhengzhou, Henan, China.

Immunotherapies, such as monoclonal antibody therapy and checkpoint inhibitor therapy, have shown inspiring clinical effects for the treatment of cancer. Chimeric antigen receptor T (CAR-T) cells therapy was an efficacious therapeutic approach treating hematological malignancies and encouraging results have been achieved. Three kinds of CAR-T cell therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), were approved for clinical application in 2017 and Tecartus (brexucabtagene autoleucel) was approved in 2020. Despite some progress have been made in treating multiple hematologic tumors, threats still remain for the application of CAR-T cell therapy considering its toxicities and gaps in knowledge. To further comprehend present research status and trends, the review concentrates on CAR-T technologies, applications, adverse effects and safety measures about CAR-T cell therapy in hematological neoplasms. We believe that CAR-T cell therapy will exhibit superior safety and efficacy in the future and have potential to be a mainstream therapeutic choice for the elimination of hematologic tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.48976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738987PMC
January 2021

Enhanced perfluorooctanoic acid (PFOA) accumulation by combination with in-situ formed Mn oxides under drinking water conditions.

Water Res 2021 Feb 20;190:116660. Epub 2020 Nov 20.

Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Particulate manganese oxide (MnOx) deposition in drinking water distribution systems (DWDS) gives rise to the risk of water discoloration at the consumers' tap; however, its role in the fate and transport of trace organic pollutants in DWDS is not clear. Perfluorooctanoic acid (PFOA), a persistent organic pollutant frequently detected in natural water, was selected to investigate the potential effect of MnOx on its transportation behavior under DWDS conditions through laboratory batch experiments. The results show that PFOA can be greatly combined with MnOx formed in-situ through a Mn(II) oxidation process by free chlorine. However, the accumulation of PFOA by preformed MnOx was negligible. It was found that 1 mg/L Mn captured over 50% of PFOA with an initial concentration of 50 ng/L during oxidation. The water compositions of actual water could contribute to the effect of PFOA accumulation to a certain extent. Characterization of the solid products revealed that PFOA is homogenously embedded into MnOx. The combination of PFOA with MnOx occurs through a bridging effect of Mn(II) between the surface hydroxyls of MnOx and the -COOH group of PFOA. The resulting MnOx-PFOA particles were more inclined to agglomerate, enabling possibly easy deposition onto the pipe wall than ordinary MnOx particles. This study provides insights into the co-occurrence of metal deposits with PFOA and the potential risks posed by PFOA accumulation to consumers through the water distribution process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.watres.2020.116660DOI Listing
February 2021

Statistical evaluation of on-road vehicle emissions measurement using a dual remote sensing technique.

Environ Pollut 2020 Dec 23;267:115456. Epub 2020 Aug 23.

Centre for Green Technology, School of Civil and Environmental Engineering, University of Technology Sydney, NSW, 2007, Australia; Faculty of Science and Technology, Technological and Higher Education Institute of Hong Kong, Hong Kong, China.

On-road remote sensing (RS) is a rapid, non-intrusive and economical tool to monitor and control the emissions of in-use vehicles, and currently is gaining popularity globally. However, a majority of studies used a single RS technique, which may bias the measurements since RS only captures a snapshot of vehicle emissions. This study aimed to use a unique dual RS technique to assess the characteristics of on-road vehicle emissions. The results show that instantaneous vehicle emissions are highly dynamic under real-world driving conditions. The two emission factors measured by the dual RS technique show little correlation, even under the same driving condition. This indicates that using the single RS technique may be insufficient to accurately represent the emission level of a vehicle based on one measurement. To increase the accuracy of identifying high-emitting vehicles, using the dual RS technique is essential. Despite little correlation, the dual RS technique measures the same average emission factors as the single RS technique does when a large number of measurements are available. Statistical analysis shows that both RS systems demonstrate the same Gamma distribution with ≥200 measurements, leading to converged mean emission factors for a given vehicle group. These findings point to the need for a minimum sample size of 200 RS measurements in order to generate reliable emission factors for on-road vehicles. In summary, this study suggests that using the single or dual RS technique will depend on the purpose of applications. Both techniques have the same accuracy in calculating average emission factors when sufficient measurements are available, while the dual RS technique is more accurate in identifying high-emitters based on one measurement only.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2020.115456DOI Listing
December 2020

ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15.

J Exp Clin Cancer Res 2020 Nov 27;39(1):264. Epub 2020 Nov 27.

Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, No. 36, Sanhao Street, Heping District, Liaoning, Shenyang, 110004, People's Republic of China.

Background: It is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear.

Materials And Methods: Immunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer.

Results: ZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells.

Conclusion: The results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-020-01770-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693506PMC
November 2020
-->