Publications by authors named "Ming Shi"

520 Publications

Arsenic transfer along the soil-sclerotium-stroma chain in Chinese cordyceps and the related health risk assessment.

PeerJ 2021 9;9:e11023. Epub 2021 Mar 9.

Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China.

Background: Chinese cordyceps (Lepidoptera: )is a larval-fungus complex. The concentration and distribution of arsenic (As) may vary during the stroma (ST) germination process and between the sclerotium (SC) and the ST. The soil-to-Chinese cordyceps system is an environmental arsenic exposure pathway for humans. We studied the As concentration in the soil, the SC, and the ST of Chinese cordyceps, and performed a risk assessment.

Methods: Soil and Chinese cordyceps samples were collected from the Tibetan Plateau in China. The samples were analyzed for the total As concentration and As species determination, which were conducted by inductively coupled plasma mass spectrometry (ICP-MS) and HPLC-ICP-MS, respectively.

Results: The concentration of total As in the soil was much higher than in SC and ST. The major As species in the soil was inorganic As. In SC and ST, organic As was predominant, and the majority of As was an unknown organic form. There are significant differences in the As distribution and composition in soil, SC, and ST. Our risk assessment indicated that chronic daily ingestion was higher than inhalation and dermal exposure in children and adults. The hazard index () of the non-carcinogenic and cancer risks () for human health were  ≤ 1 and  < 1 × 10, respectively.

Conclusion: The Chinese cordyceps possesses highly-efficient detoxifying characteristics and has a significant role in As transformation during its life cycle. We found that the levels of As in soils from the habitat of Chinese cordyceps were higher than the soil background values in China, but the probability for incurring health risks remained within the acceptable levels for humans.
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http://dx.doi.org/10.7717/peerj.11023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953876PMC
March 2021

Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy lenvatinib alone for advanced hepatocellular carcinoma.

Ther Adv Med Oncol 2021 25;13:17588359211002720. Epub 2021 Mar 25.

Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, P.R. China.

Background: Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma, but prognosis is still unsatisfactory. Recently, hepatic arterial infusion chemotherapy (HAIC), and immune checkpoint inhibitors showed promising results for advanced hepatocellular carcinoma. Considering different anti-malignancy mechanisms, combining these three treatments may improve outcomes. This study aimed to compare the efficacy and safety of lenvatinib, toripalimab, plus HAIC lenvatinib for advanced hepatocellular carcinoma.

Methods: This was a retrospective study including patients treated with lenvatinib [8 mg (⩽60 kg) or 12 mg (>60 kg) once daily] or lenvatinib, toripalimab plus HAIC [LeToHAIC group, lenvatinib 0-1 week prior to initial HAIC, 240 mg toripalimab 0-1 day prior to every HAIC cycle, and HAIC with FOLFOX regimen (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil bolus 400 mg/m on day 1, and 5-fluorouracil infusion 2400 mg/m for 46 h, every 3 weeks)]. Progression-free survival, overall survival, objective response rate, and treatment-related adverse events were compared.

Results: From February 2019 to August 2019, 157 patients were included in this study: 71 in the LeToHAIC group and 86 in the lenvatinib group. The LeToHAIC group showed longer progression-free survival (11.1 5.1 months,  < 0.001), longer overall survival (not reached 11 months,  < 0.001), and a higher objective response rate (RECIST: 59.2% 9.3%,  < 0.001; modified RECIST: 67.6% 16.3%,  < 0.001) than the lenvatinib group. In addition, 14.1% and 21.1% of patients in the LeToHAIC group achieved complete response of all lesions and complete response of the intrahepatic target lesions per modified RECIST criteria, respectively. Grade 3/4 treatment-related adverse events that were more frequent in the LeToHAIC group than in the lenvatinib group included neutropenia (8.5% 1.2%), thrombocytopenia (5.6% 0), and nausea (5.6% 0).

Conclusions: Lenvatinib, toripalimab, plus HAIC had acceptable toxic effects and might improve survival compared with lenvatinib alone in advanced hepatocellular carcinoma.
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http://dx.doi.org/10.1177/17588359211002720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010824PMC
March 2021

Discovery of [Formula: see text] rotation anomaly in topological crystalline insulator SrPb.

Nat Commun 2021 Apr 6;12(1):2052. Epub 2021 Apr 6.

Beijing National Laboratory for Condensed Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing, China.

Topological crystalline insulators (TCIs) are insulating electronic states with nontrivial topology protected by crystalline symmetries. Recently, theory has proposed new classes of TCIs protected by rotation symmetries [Formula: see text], which have surface rotation anomaly evading the fermion doubling theorem, i.e., n instead of 2n Dirac cones on the surface preserving the rotation symmetry. Here, we report the first realization of the [Formula: see text] rotation anomaly in a binary compound SrPb. Our first-principles calculations reveal two massless Dirac fermions protected by the combination of time-reversal symmetry [Formula: see text] and [Formula: see text] on the (010) surface. Using angle-resolved photoemission spectroscopy, we identify two Dirac surface states inside the bulk band gap of SrPb, confirming the [Formula: see text] rotation anomaly in the new classes of TCIs. The findings enrich the classification of topological phases, which pave the way for exploring exotic behavior of the new classes of TCIs.
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http://dx.doi.org/10.1038/s41467-021-22350-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024327PMC
April 2021

Comparison of HBV reactivation between patients with high HBV-DNA and low HBV-DNA loads undergoing PD-1 inhibitor and concurrent antiviral prophylaxis.

Cancer Immunol Immunother 2021 Apr 3. Epub 2021 Apr 3.

Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China.

Background: Programmed cell death protein-1 (PD-1) inhibitor is recommended to treat advanced hepatocellular carcinoma (HCC). However, the safety of PD-1 inhibitor in patients with high HBV-DNA load is unknown because of the potential risk of hepatitis B virus (HBV) reactivation. This study was to compare the HBV reactivation between patients with low HBV-DNA loads and high HBV-DNA loads undergoing antiviral prophylaxis and PD-1 inhibitor.

Methods: This was a retrospective study including consecutive hepatitis B surface antigen-positive HCC patients who received PD-1 inhibitor and concurrent antiviral prophylaxis for prevention of clinical hepatitis. Patients were divided into low HBV-DNA group (low group, ≤ 500 IU/ml) and high HBV-DNA group (high group, > 500 IU/ml) according to the baseline HBV-DNA level. The incidences of HBV reactivation, HBV-associated hepatitis, and PD-1 inhibitor disruption were compared between the two groups.

Results: Two hundred two eligible patients were included: 94 in the low group and 108 in the high group. Seven patients (5 in the low group and 2 in the high group) developed HBV reactivation, and all recovered from HBV reactivation and HBV-associated hepatitis. The incidence of HBV reactivation in the two groups was low (5.3% vs 1.9%, P = 0.34). There was also no difference in the incidence of HBV-associated hepatitis (P = 0.56), or PD-1 inhibitor disruption (P = 0.82). The multivariable analysis showed PD-1 inhibitor with hepatic arterial infusion chemotherapy was the only significant risk factor for HBV reactivation (P = 0.04) and hepatitis (P = 0.002).

Conclusion: With concurrent antiviral prophylaxis, HBV-DNA load higher than 500 IU/ml should not be a contraindication for PD-1 inhibitor.
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http://dx.doi.org/10.1007/s00262-021-02911-wDOI Listing
April 2021

Anti-PD-1 Immunotherapy Improves the Efficacy of Hepatic Artery Infusion Chemotherapy in Advanced Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 25;8:167-176. Epub 2021 Mar 25.

Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China.

Background: Hepatic artery infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising outcomes in patients with advanced hepatocellular carcinoma (HCC), respectively. However, the combination of the two treatments has not been reported. In this study, we compared the efficacy of HAIC combined with anti-PD-1 immunotherapy (HAICAP) and HAIC in patients with advanced HCC.

Methods: Between November 2018 and December 2019, advanced HCC patients that were treated with either HAICAP or HAIC were retrospectively recruited and reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.

Results: As a result, 229 patients were included in this study. Patients were divided into HAICAP group (n = 81) and HAIC group (n = 148) accordingly. The follow-up time ranged from 1.0 to 21.6 months, with a median of 11.0 months. The median overall survival was 18.0 months in the HAICAP group and 14.6 months in the HAIC group (p = 0.018; HR = 0.62; 95% CI 0.34-0.91). The median progression-free survival was 10.0 months in the HAICAP group and 5.6 months in the HAIC group (p = 0.006; HR = 0.65; 95% CI 0.43-0.87). The disease control rate in overall response (83% vs 66%; p = 0.006) and intrahepatic response (85% vs 74%, respectively; p = 0.045) were higher in the HAICAP group than in the HAIC group.

Conclusion: In comparison to HAIC, HAICAP was associated with a better treatment response and survival benefits for patients with advanced HCC.
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http://dx.doi.org/10.2147/JHC.S298538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007560PMC
March 2021

Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Immunoglobulin D Multiple Myeloma.

Transplant Cell Ther 2021 Mar 19;27(3):273.e1-273.e5. Epub 2020 Dec 19.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, Jiangsu, China. Electronic address:

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM that carries a worse prognosis than non-IgD subtypes. Compared with non-IgD subtypes, IgD MM is associated with a shorter survival time. The application of chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory multiple myeloma (R/R MM) has increasing evidence as an efficacious treatment. This study was designed to investigate efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory IgD MM (R/R IgD MM). In this single-arm, phase 2 trial, patients diagnosed with R/R IgD MM were infused with either a combination of anti-B-cell maturation antigen and anti-CD19 CAR T-cells or anti-CD19 CAR T-cells alone, with subsequent evaluation of therapeutic response and treatment-related toxicities. At the data cutoff date, 7 patients were enrolled in our study, and all patients achieved response based on the International Myeloma Working Group Uniform Response Criteria. Six patients achieved stringent complete remission (sCR) within 60 days after CAR T-cell infusion (median time 58 days, range 18 to 90 days), and 1 patient with extramedullary disease achieved minimal response (MR) at 30 days after infusion. Bone marrow minimal residual disease (MRD) negativity was achieved in all patients, and the median time to achieve MRD negativity was 22 days (range 14 to 60 days). The most common grade 3 to 4 treatment-related toxicities were hematological toxicities. All patients experienced cytokine release syndrome (CRS), although CAR T-cell-related neurotoxicity was not observed. In our study, CAR T-cell therapy showed encouraging efficacy in the patients with R/R IgD MM, achieving high rates of sCR and MRD negativity. Aside from CRS and prolonged hematologic toxicities, other adverse reactions were mild, suggesting that this is a well-tolerated treatment with a high therapeutic potential.
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http://dx.doi.org/10.1016/j.jtct.2020.12.017DOI Listing
March 2021

Skewed CD39/CD73/adenosine pathway contributes to B-cell hyperactivation and disease progression in patients with chronic hepatitis B.

Gastroenterol Rep (Oxf) 2021 Jan 30;9(1):49-58. Epub 2020 Aug 30.

Medical School of Chinese PLA, Beijing, P. R. China.

Background: The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus (HBV) infection remain largely undefined. The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B (CHB).

Methods: We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients. B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.

Results: CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA, HBeAg positivity, high HBsAg levels, and active liver inflammation, and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction. However, CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments. Furthermore, CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers. , B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade. Contrastingly, metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.

Conclusions: The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden, liver inflammation, and antiviral efficacy in CHB patients, and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation. Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBV-induced immune pathogenesis.
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http://dx.doi.org/10.1093/gastro/goaa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962744PMC
January 2021

MicroRNA-191 blocking the translocation of GLUT4 is involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway.

Ecotoxicol Environ Saf 2021 Jun 18;215:112130. Epub 2021 Mar 18.

Center for Global Health, The Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. Electronic address:

Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112130DOI Listing
June 2021

HRD1 attenuates the high uptake of [F]FDG in hepatocellular carcinoma PET imaging.

Nucl Med Biol 2021 Mar 11;96-97:27-34. Epub 2021 Mar 11.

Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, Jiangsu, China. Electronic address:

Introduction: Due to individual deviations in tumor tissue uptake, the role of [F]fluorodeoxyglucose ([F]FDG) positron emission tomography (PET) in hepatocellular carcinoma (HCC) diagnosis is limited. β-Hydroxy β-methylglutaryl-CoA reductase degradation 1 (HRD1) plays a key role in clearing misfolded proteins. This study is aimed to investigate the role and mechanism of HRD1 in [F]FDG uptake for the diagnosis of HCC.

Methods: HRD1 expression level was detected using immunohistochemical (IHC) staining in 9 HCC patients. [F]FDG PET/CT scans were conducted before treatment. [F]FDG uptakes in HRD1 overexpressed and knockdown transgenic models were measured by γ-counter and microPET imaging. The GLUT1-HRD1 complex was examined by co-immunoprecipitation and IHC assays. GLUT1 expression in different cell lines, xenograft models and HCC patients was evaluated by Western blot and IHC assays.

Results: HRD1 was highly expressed in the HCC tumors of patients with low [F]FDG uptake, while the HRD1 expression was obviously low in the higher [F]FDG uptake group. Both in vitro and in vivo studies found that HRD1 significantly inhibited [F]FDG uptake in HCC Huh7 cell lines and animal models. Furthermore, the co-location and interaction of HRD1 with GLUT1 were detected, and the results also indicate that HRD1 could induce the degradation of GLUT1 in vitro and in vivo.

Conclusion: HRD1 inhibits the high uptake of [F]FDG in HCC tumor cells by inducing degradation of GLUT1, which leads to decreased diagnostic efficiency of [F]FDG PET imaging for HCC.

Advances In Knowledge: This study suggests that HRD1 inhibits the high uptake of [F]FDG in HCC tumor by inducing degradation of GLUT1.

Implications For Patient Care: HCC diagnosis with [F]FDG PET should be accompanied by determination of HRD1 expression, and patients with high tumor HRD1 expression might be unsuitable for [F]FDG PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.02.006DOI Listing
March 2021

NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1-infected patients.

J Clin Invest 2021 Mar;131(6)

Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.
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http://dx.doi.org/10.1172/JCI138861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954596PMC
March 2021

Hepatic Arterial Infusion Chemotherapy Combined With PD-1 Inhibitors Plus Lenvatinib PD-1 Inhibitors Plus Lenvatinib for Advanced Hepatocellular Carcinoma.

Front Oncol 2021 25;11:618206. Epub 2021 Feb 25.

Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: Lenvatinib combined with programmed cell death protein-1 (PD-1) inhibitors has resulted in good survival outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) has also attracted attention due to its high response rates and favorable survival for advanced HCC patients. The present study aimed to compare the efficacy of HAIC combined with PD-1 inhibitors plus lenvatinib (HPL) and PD-1 inhibitors plus lenvatinib (PL) in patients with advanced HCC.

Methods: Between July 2018 and December 2019, patients diagnosed with advanced HCC who initially received HPL or PL treatment were reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.

Results: In total, 70 patients met the criteria and were included in the present study, and they were divided into the HPL group (n = 45) and PL group (n = 25). The overall response rate (40.0 . 16.0%, respectively; p = 0.038) and disease control rate (77.6 . 44.0%, respectively; p < 0.001) were higher in the HPL group than in the PL group. The median overall survival was 15.9 months in the HPL group and 8.6 months in the PL group (p = 0.0015; HR = 0.6; 95% CI 0.43-0.83). The median progression-free survival was 8.8 months in the HPL group and 5.4 months in the PL group (p = 0.0320; HR = 0.74; 95% CI 0.55-0.98).

Conclusion: Compared to PL, HPL was associated with a significantly better treatment response and survival benefits for patients with advanced HCC.
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http://dx.doi.org/10.3389/fonc.2021.618206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947809PMC
February 2021

Giant bilateral primary scrotal lipoma along with lipomas in multiple sites of the body: a case report and literature review.

Transl Androl Urol 2021 Feb;10(2):983-990

Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.

Mesenchymal neoplasms of the scrotum are extremely rare in the clinical practices, in which lipoma is the most common benign neoplasm of them. Primary scrotal lipoma refers to the lipoma originated from scrotal wall. We reported a rare case of a 47-year-old man who suffered from bilateral giant primary scrotal lipoma along with lipomas in multiple sites of the body. Scrotal ultrasound indicated that huge hypoechogenic masses were observed in the bilateral scrotums. Contrast-enhanced computed tomography (CT) indicated increased fat density in the scrotal areas. Surgical resection was performed on both scrotal neoplasms. Diagnosis of lipoma was confirmed by the pathological examination through the morphological observation as well as the absence of murine double minute2 (MDM2) gene amplification in the fluorescence in situ hybridization (FISH) test. After five months of follow-up, the wound of the patient recovered well and no sign of local recurrence was observed. Based on the literature review, very few cases of primary scrotal lipoma were reported in the scientific literature up to date, and this is the first report of bilateral primary scrotal lipoma along with multiple lipomas of the body. We presented this case as a rare phenomenon. Although primary scrotal lipoma is rare, clinicians should take it into account when encountering similar scrotal lesions and know the methods for diagnosis and how to make differential diagnosis with other diseases, which is associated with the patient's treatment strategy and prognosis.
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http://dx.doi.org/10.21037/tau-20-1073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947464PMC
February 2021

Characteristics and Risk Factors of Cytokine Release Syndrome in Chimeric Antigen Receptor T Cell Treatment.

Front Immunol 2021 23;12:611366. Epub 2021 Feb 23.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Clinical trials have confirmed that chimeric antigen receptor (CAR) T cell therapies are revolutionizing approaches for treating several relapsed or refractory hematological tumors. Cytokine release syndrome (CRS) is an adverse event with high incidence during CAR-T treatment. A further understanding of the characteristics and related risk factors of CRS is important for effective management. A total of 142 patients with relapsed or refractory acute lymphocyte leukemia (ALL), lymphoma, or multiple myeloma (MM) received lymphodepletion chemotherapy followed by infusion of CAR-T cells. The characteristics of CRS at different time points after treatment were monitored and risk factors were analyzed. The incidence of CRS for ALL, lymphoma, and multiple myeloma were 82%, 90%, and 90% respectively. Fever was observed on a median of day 3 for ALL, day 1 for lymphoma, and day 8.5 for MM after CAR-T cell infusion, and the duration was different between grade 1-2 CRS and grade 3-5 CRS. Disease types, peak concentration of IL-6, and CRP were associated with CRS. For patients with ALL, numbers of lymphoblast in bone marrow before lymphodepletion, peak concentration of IL-6, and CRP were independent risk factors of CRS. Clinical stage of lymphoma patients and high tumor burden in marrow of MM patients were independent risk factors of CRS. In conclusion, the characteristics and risk factors of CRS in different B-cell hematological tumors are different and should be managed individually during CAR-T cell therapy.
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http://dx.doi.org/10.3389/fimmu.2021.611366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940756PMC
February 2021

Triphenyl phosphate disturbs the lipidome and induces endoplasmic reticulum stress and apoptosis in JEG-3 cells.

Chemosphere 2021 Feb 15;275:129978. Epub 2021 Feb 15.

School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China. Electronic address:

Triphenyl phosphate (TPP) is a frequently used aryl organophosphate flame retardant. Epidemiological studies have shown that TPP and its metabolite diphenyl phosphate (DPP) can accumulate in the placenta, and positively correlated with abnormal birth outcomes. TPP can disturb placental hormone secretion through the peroxisome proliferator-activated receptor γ (PPARγ) pathway. However, the extent and mechanism of placental toxicity mediation by TPP remains unknown. In this study, we used JEG-3 cells to investigate the role of PPARγ-regulated lipid metabolism in TPP-mediated placental toxicity. The results of lipidomic analysis showed that TPP increased the production of triglycerides (TG), fatty acids (FAs), and phosphatidic acid (PA), but decreased the levels of phosphatidylethanol (PE), phosphatidylserine (PS), and sphingomyelin (SM). TG accumulation was accompanied by increased levels of sterol regulatory element binding transcription factor 1 (SREBP1), acetyl-coA carboxylase (ACC), and fatty acid transport protein (CD36). Although PPARγ and its target CCAAT/enhancer binding proteins (C/EBPα) was decreased, the TG content and gene expression of SREBP1, ACC, and CD36 decreased when TPP was co-exposed to the PPARγ antagonist GW9662. TPP also induced inflammatory responses, endoplasmic reticulum stress (ERS), and cell apoptosis. Expression of genes related to ERS and apoptosis were attenuated by GW9662. Together, these results show that TPP can disturb lipid metabolism and cause lipid accumulation through PPARγ, induce ERS, and cell apoptosis. Our findings reveal that the developmental toxicity of TPP through placental toxicity should not be ignored.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129978DOI Listing
February 2021

Combined Treatment of Radiotherapy and Immunotherapy for Urological Malignancies: Current Evidence and Clinical Considerations.

Cancer Manag Res 2021 24;13:1719-1731. Epub 2021 Feb 24.

Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Although it has always been believed that radiation has immunosuppressive effects, more and more preclinical and clinical trials have shown that the combination of radiotherapy and immunotherapy has a potential synergistic effect to treat cancers including urological malignancies. When radiotherapy is combined with immunotherapy, improved prognosis has been observed in different urinary tumors. However, there is no standard treatment, such as the optimal dose/fractionation and the sequence of immunotherapy and radiotherapy. In this review, we discussed the effects of radiotherapy on the cancer immune system and emphasized the synergy of radiotherapy combined with immunotherapy. Although it has significantly improved the prognosis of tumors, there are still some unresolved questions about how to best use this combination in clinical practice. Ongoing trials will provide further information on the interaction of radiotherapy combined with immunotherapy, and are expected to guide clinical practice and improve clinical outcomes.
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http://dx.doi.org/10.2147/CMAR.S288337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917304PMC
February 2021

Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial.

Signal Transduct Target Ther 2021 02 10;6(1):58. Epub 2021 Feb 10.

Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 10 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.
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http://dx.doi.org/10.1038/s41392-021-00488-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873662PMC
February 2021

Ginkgolide B promotes oligodendrocyte precursor cell differentiation and survival via Akt/CREB/bcl-2 signaling pathway after white matter lesion.

Exp Biol Med (Maywood) 2021 Feb 8:1535370221989955. Epub 2021 Feb 8.

Department of Neurology, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China.

White matter lesion (WML) is caused by chronic cerebral hypoperfusion, which are usually associated with cognitive impairment. Evidence from recent studies has shown that ginkgolide B has a neuroprotective effect that could be beneficial for the treatment of ischemia; however, it is not clear whether ginkgolide B has a protective effect on WML. Our data show that ginkgolide B can promote the differentiation of oligodendrocyte precursor cell (OPC) into oligodendrocytes and promote oligodendrocyte survival following a WML. Ginkgolide B (5, 10, 20 mg/kg) or saline is administered intraperitoneally every day after WML. After 4 weeks, the data of Morris water maze suggested that rats' memory and learning abilities were impaired, and the administration of ginkgolide B enhanced behavioral achievement. Also, treatment with ginkgolide B significantly attenuated this loss of myelin. Our result suggests that ginkgolide B promotes the differentiation of OPC into oligodendrocytes. We also found that ginkgolide B ameliorates oligodendrocytes apoptosis. Furthermore, ginkgolide B enhanced the expression of phosphorylated Akt and CREB. In conclusion, our data firstly show that ginkgolide B promotes oligodendrocyte genesis and oligodendrocyte myelin following a WML, possibly involving the Akt and CREB pathways.
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http://dx.doi.org/10.1177/1535370221989955DOI Listing
February 2021

Neuroprotective Effects of a GLP-2 Analogue in the MPTP Parkinson's Disease Mouse Model.

J Parkinsons Dis 2021 ;11(2):529-543

Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan province, China.

Background: Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer's disease related memory impairments. Parkinson's disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively.

Objective: The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model.

Methods: In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for 14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group.

Results: The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH.

Conclusion: The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model.
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http://dx.doi.org/10.3233/JPD-202318DOI Listing
January 2021

Evaluation of Antiemetic Therapy for Hepatic Arterial Infusion Chemotherapy with Oxaliplatin, Fluorouracil, and Leucovorin.

Ther Clin Risk Manag 2021 22;17:73-77. Epub 2021 Jan 22.

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

Purpose: Our aim was to compare the antiemetic efficacy of the triple combination of aprepitant, dolasetron and dexamethasone with the combination of dolasetron and dexamethasone for chemotherapy-induced nausea and vomiting (CINV) in hepatocellular carcinoma (HCC) patients receiving hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (FOLFOX).

Patients And Methods: This was a retrospective study. In the dolasetron plus dexamethasone group (D group), the patients received dolasetron (100 mg, i.v., on day 1) and dexamethasone (10 mg, i.v., on day 1) 30 min before starting administration of chemotherapeutic drugs. In the aprepitant plus dolasetron and dexamethasone group (AD group), the patients received dolasetron and dexamethasone as described above, and aprepitant (125 mg, p.o.) on day 1 followed by 80 mg on days 2 and 3. The primary endpoint was the complete response rate (CR, defined as no emetic episodes and no rescue medication use) during the first cycle of hepatic arterial infusion chemotherapy.

Results: Between January 2018 and August 2019, 302 eligible patients were included: 197 in AD group and 105 in D group. Patients in AD group had significantly higher complete response rates than those in D group during the first cycle (85.8% vs 71.4%, P = 0.003) and all cycles (73.6% vs 49.5%, P<0.001). Patients in AD group had lower rescue therapy (1.5% vs 26.7%, P<0.001) and lower incidence of disruption related to chemotherapy-induced nausea and vomiting (0.5% vs 6.7%, P = 0.002) than patients in D group.

Conclusion: Aprepitant, dolasetron plus dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients treated with FOLFOX-HAIC therapy than dolasetron plus dexamethasone.
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http://dx.doi.org/10.2147/TCRM.S283192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837558PMC
January 2021

miR-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells.

J Cell Physiol 2021 Jan 22. Epub 2021 Jan 22.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.

Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic-induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA-21 (miR-21), phosphorylated mammalian target of rapamycin (p-mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite-induced miR-21, p-mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP-1 monocytes (THP-M), which caused secretion of fibrogenic cytokines, including transforming growth factor-β1. Coculture of arsenite-treated, THP-M with LX-2 cells induced α-SMA and collagen I in the LX-2 cells and resulted in the activation of these cells. Downregulation of miR-21 in THP-M inhibited arsenite-induced M2 polarization and activation of LX-2 cells, but cotransfection with PTEN siRNA or a miR-21 inhibitor reversed this inhibition. Moreover, knockout of miR-21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR-21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR-21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis-induced fibrosis.
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http://dx.doi.org/10.1002/jcp.30288DOI Listing
January 2021

Blockade of AIM2 inflammasome or α1-AR ameliorates IL-1β release and macrophage-mediated immunosuppression induced by CAR-T treatment.

J Immunother Cancer 2021 Jan;9(1)

Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China

Background: Interleukin (IL) 1 released from monocytes/macrophages is one of the critical determinants in mediating the adverse events of chimeric antigen receptor T cell (CAR-T) therapy, including cytokine release syndrome and neurotoxicity. However, the molecular mechanisms of IL-1 production during CAR-T therapy remain unknown.

Methods: The roles of AIM2 and α1-adrenergic receptor (α1-AR) in CAR-T treatment-induced IL-1β release were evaluated by gene silencing, agonist or antagonist treatment. The phenotype switch of macrophages in response to CAR-T treatment was analyzed concerning cytotoxicity of CAR-T cells and proliferation of activated T cells.

Results: This study provided the experimental evidence that CAR-T treatment-induced activation of AIM2 inflammasome of macrophages resulted in the release of bioactive IL-1β. CAR-T treatment-induced α1-AR-mediated adrenergic signaling augmented the priming of AIM2 inflammasome by enhancing IL-1β mRNA and AIM2 expression. Meanwhile, tumor cell DNA release triggered by CAR-T treatment potentiated the activation of AIM2 inflammasome in macrophages. Interestingly, an apparent phenotypic switch in macrophages occurred after interacting with CAR-T/tumor cells, which greatly inhibited the cytotoxicity of CAR-T cells and proliferation of activated T cells through upregulation of programmed cell death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO) in the macrophages. Blockade of AIM2 inflammasome or α1-AR reversed the upregulation of PD-L1 and IDO and the phenotypic switch of the macrophages.

Conclusion: Our study implicates that CAR-T therapy combined with the blockade of AIM2 inflammasome or α1-AR may relieve IL-1β-related toxic side effects of CAR-T therapy and ensure antitumor effects of the treatment.
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http://dx.doi.org/10.1136/jitc-2020-001466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797290PMC
January 2021

Transcriptome profiling unveils GAP43 regulates ABC transporters and EIF2 signaling in colorectal cancer cells.

BMC Cancer 2021 Jan 5;21(1):24. Epub 2021 Jan 5.

School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.

Background: The growth- and plasticity-associated protein-43 (GAP43) is biasedly expressed in indigestive system and nervous system. Recent study has shown that GAP43 is responsible for the development of neuronal growth and axonal regeneration in normal nervous tissue, while serves as a specific biomarker of relapsed or refractory neuroblastoma. However, its expression pattern and function in digestive system cancer remains to be clarified.

Methods: In this study, we examined the GAP43 status with qRT-PCR and bisulfite genomic sequencing in colorectal cancer (CRC). We investigated the effect of overexpressed GAP43 in CRC cells with RNA-seq. The RNA-seq data was analyzed with DAVID and IPA.

Results: GAP43 was downregulated in CRC compared to the adjacent tissues. DNA methylase inhibitor 5-Aza-CdR treatment could significantly induce GAP43, indicated that the silencing of GAP43 gene in CRC is closely related to DNA methylation. Bisulfite genomic sequencing confirmed the promoter methylation of GAP43 in CRC. To explore the transcriptional alterations by overexpressed GAP43 in CRC, we performed RNA-seq and found that upregulated genes were significantly enriched in the signaling pathways of ABC transporters and ECM-receptor interaction, while downregulated genes were significantly enriched in Ribosome signaling pathway. Further Ingenuity Pathway Analysis (IPA) showed that EIF2 signaling pathway was significantly repressed by overexpression of GAP43.

Conclusion: Our findings provide a novel mechanistic insight of GAP43 in CRC. Transcriptome profiling of overexpressed GAP43 in CRC uncovered the functional roles of GAP43 in the development of human CRC.
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http://dx.doi.org/10.1186/s12885-020-07728-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786480PMC
January 2021

Biocontrol potential of Bacillus amyloliquefaciens LYZ69 against anthracnose of alfalfa (Medicago sativa L.).

Phytopathology 2020 Dec 16. Epub 2020 Dec 16.

Lanzhou University, 12426, College of Pastoral Agriculture Science and Technology, Lanzhou, Gansu, China;

Anthracnose is a destructive disease of alfalfa (Medicago sativa L.) that causes severe yield losses. Biological control can be an effective and eco-friendly approach to control this alfalfa disease. In the present study, Bacillus amyloliquefaciens LYZ69, previously isolated from healthy alfalfa roots, showed a strong in vitro antifungal activity against Colletotrichum truncatum, an important causal agent of anthracnose of alfalfa. The strain LYZ69 protected alfalfa plants (biocontrol efficacy of 82.59%) from anthracnose under greenhouse conditions. The cell-free culture (CFC) of LYZ69 (20%; v/v) caused 60% and 100% inhibition of mycelial growth and conidial germination, respectively. High-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) separated and identified cyclic lipopeptides (LPs) such as bacillomycin D and fengycin in the CFC of LYZ69. Light microscopy and scanning electron microscopy (SEM) revealed that the mixture of cyclic LPs produced by LYZ69 caused drastic changes in mycelial morphology. Fluorescence microscopy showed that the LPs induced reactive oxygen species (ROS) accumulation and caused apoptosis-like cell death in C. truncatum hyphae. In summary, our findings provide evidence to support B. amyloliquefaciens LYZ69 as a promising candidate for the biological control of anthracnose in alfalfa.
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http://dx.doi.org/10.1094/PHYTO-09-20-0385-RDOI Listing
December 2020

Close Homolog of L1 Deficiency Exacerbated Intestinal Epithelial Barrier Function in Mouse Model of Dextran Sulfate Sodium-Induced Colitis.

Front Physiol 2020 6;11:584508. Epub 2020 Nov 6.

Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing, China.

The cell adhesion molecule CHL1, which belongs to the immunoglobulin superfamily, functions in a variety of physiological and pathological processes, including neural development, tissue injury, and repair. We previously found that the loss of CHL1 exacerbated the dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, we further addressed the role of CHL1 in mouse model of DSS-induced colitis and its' potential mechanism. Colon tissues were collected from CHL1, CHL1, and CHL1 mice after DSS induction to investigate the effects of CHL1 on the development of colitis. The data showed that CHL1 was expressed in intestine tissue, and expression of CHL1 was increased by DSS-induced inflammation. CHL1 deficiency induced more pronounced colitis features, exacerbated inflammation, and damage to colonic tissues in DSS-induced mice. Moreover, colonic tissues of CHL1 mice showed a marked increase in neutrophil and macrophage infiltration, be accompanied by more severe damage to intestinal epithelial cells and higher fluorescein isothiocyanate (FITC) leakage. Our results revealed deficiency of CHL1 exacerbated DSS-induced colitis, and this pathogenesis was potentially mediated by disruption of intestinal barrier integrity, indicating that CHL1 may be an attractive therapeutic target for inflammatory bowel diseases (IBDs) in mice.
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http://dx.doi.org/10.3389/fphys.2020.584508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677258PMC
November 2020

LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure.

Environ Pollut 2021 Jan 27;268(Pt A):115810. Epub 2020 Oct 27.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. Electronic address:

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 μM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-β1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.envpol.2020.115810DOI Listing
January 2021

Immune restoration in HIV-1-infected patients after 12 years of antiretroviral therapy: a real-world observational study.

Emerg Microbes Infect 2020 Dec;9(1):2550-2561

National Center for AIDS/STD Control and Prevention, China Center for Disease Control and Prevention, Beijing, People's Republic of China.

Using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might be not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. Totally, 91,805 HIV-1 patients from 17 tertiary hospitals in China during 2005-2018 were included in this study. Immune restoration and mortality were assessed. Patients initiated ART with baseline CD4 counts <50, 50-199, 200-349, 350-499, and ≥500 cells/μL, and results showed an increase in the median CD4 counts to 445 (12-year), 467 (12-year), 581 (11-year), 644 (7-year), and 768 cells/µL (5-year), as well as the CD4/CD8 ratio to 0.59 (12-year), 0.65 (12-year), 0.79 (11-year), 0.82 (7-year), 0.9 (5-year), respectively. The median CD8 count was relatively high (median range 732-845 cells/μL), regardless of the baseline CD4 counts. Furthermore, the probabilities of death in patients achieving CD4 counts ≥500 cells/μL and CD4/CD8 ratio ≥0.8 simultaneously were significantly lower than those in patients achieving either CD4 counts ≥500 cells/μL (2.77% vs 3.50%, =0.02) or CD4/CD8 ≥ 0.8 (2.77% vs 4.28%, <0.001) after 12-year of ART. In this study, a new binary-indicator would accurately assess immune restoration in the era of "treat all."
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http://dx.doi.org/10.1080/22221751.2020.1840928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733958PMC
December 2020

Kinetics of immune reconstitution after anti-CD19 chimeric antigen receptor T cell therapy in relapsed or refractory acute lymphoblastic leukemia patients.

Int J Lab Hematol 2021 Apr 28;43(2):250-258. Epub 2020 Oct 28.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.

Introduction: Anti-CD19 chimeric antigen receptor (CAR) -T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti-CD19 CAR-T cell therapy.

Methods: Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti-CD19 CAR-T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow-up within 60 days post-infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution.

Results: CD8+ cells were the first to recover with a median time on day 21(7-87), followed by CD16/CD56+ cells on day 28(14-87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post-infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41-118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post-infusion. IgG recovered in 6 patients with a median time on day 184(89-346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients.

Conclusions: Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti-CD19 CAR-T cell therapy.
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http://dx.doi.org/10.1111/ijlh.13375DOI Listing
April 2021