Publications by authors named "Jianhua Yu"

296 Publications

Clinical characteristics, diagnosis, and predictors of neurosyphilis patients with human immunodeficiency virus co-infection: A retrospective study at infectious diseases hospitals in two cities of China.

Medicine (Baltimore) 2021 Oct;100(42):e27430

Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China.

Abstract: This study aimed to compare between the clinical and laboratory characteristics of neurosyphilis and those of syphilis in human immunodeficiency virus (HIV) positive and explore the risk factors associated with the occurrence of neurosyphilis in the HIV infected.In-patients diagnosed with HIV and syphilis co-infection who underwent a lumbar puncture and completed cerebrospinal fluid (CSF) examination were divided into neurosyphilis group and syphilis group. The demographic characteristics, symptoms and signs, and laboratory tests of the 2 groups were comparatively analyzed. Logistic regression analysis was used to explore the risk factors associated with the occurrence of neurosyphilis.Among 81 patients, 33 patients were assigned to the neurosyphilis group, and 48 to the syphilis group. There were no significant differences in the age, gender, marital status, acquired immunodeficiency syndrome course, opportunistic infections, serum HIV viral load, and history of syphilis treatment. The difference in HIV transmission route between the 2 groups was statistically significant (P = .010), and the patients from the neurosyphilis group were mainly infected via heterosexual contact. The proportion of serum toludine red unheated serum test (TRUST) titer ≥1:16 in the neurosyphilis group were 78.8%, which was significantly higher compared to the syphilis group (48.9%). The level of CSF white blood cell count, CSF protein, and CSF HIV viral load in the neurosyphilis group were significantly higher than those of the syphilis group. The proportion of patients with neurological symptoms and signs in the neurosyphilis group was significantly higher compared to the syphilis group (P < .001). Multivariate logistic regression analysis showed that heterosexual contact transmission route, not received antiretroviral therapy, lower CD4 cell count and higher serum TRUST titer, untreated with syphilis, and neurological symptoms and signs were risk factors associated with the occurrence of neurosyphilis.The serum TRUST titer, CSF white blood cell count, CSF protein level, CSF HIV viral load, and the percentage of neurological symptoms and signs in the neurosyphilis group were higher. Heterosexual transmission route, not received antiretroviral therapy, and untreated with syphilis prompted the possibility of neurosyphilis occurrence.
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http://dx.doi.org/10.1097/MD.0000000000027430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542171PMC
October 2021

The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus.

J Virol 2021 Oct 20:JVI0096421. Epub 2021 Oct 20.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA.

A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2×10 and 2×10 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2×10 and 2×10 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in post-mortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human post-mortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases and caused nearly 5 million deaths worldwide as of October 2021, has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.
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http://dx.doi.org/10.1128/JVI.00964-21DOI Listing
October 2021

Targeting Fc receptor-mediated effects and the "don't eat me" signal with an oncolytic virus expressing an anti-CD47 antibody to treat metastatic ovarian cancer.

Clin Cancer Res 2021 Oct 13. Epub 2021 Oct 13.

Department of Hematology & Hematopoietic Cell Transplantation, City Of Hope National Medical Center.

Monoclonal antibodies (mAbs) blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the "don't eat me" pathway. However, this strategy is associated with severe toxicity. To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G1). Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47-SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. , these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared to OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared to OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection. Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1248DOI Listing
October 2021

An oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma.

Nat Commun 2021 10 8;12(1):5908. Epub 2021 Oct 8.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.

Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.
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http://dx.doi.org/10.1038/s41467-021-26003-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501058PMC
October 2021

Expression of Th17/Treg Cells in Peripheral Blood and Related Cytokines of Patients with Ulcerative Colitis of Different Syndrome Types and Correlation with the Disease.

Evid Based Complement Alternat Med 2021 23;2021:4600947. Epub 2021 Sep 23.

Department of Gastroenterology, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China.

Objective: To explore the expression of helper cells 17 (Th17)/regulatory cells (Treg) in peripheral blood and related cytokines of patients with different types of ulcerative colitis (UC) and analyze their correlation with the disease.

Methods: From January 2018 to December 2019, 53 patients diagnosed with UC in our hospital were selected. According to their medical syndromes, they were divided into the damp-heat internal accumulation group ( = 35) and the spleen-kidney yang deficiency group ( = 18). 21 healthy volunteers were selected as the control group. The Mayo scoring standard was used to determine the severity of the patient's condition. The expression levels of Th17/Treg cells and related cytokines in peripheral blood were compared between the groups. Pearson correlation was used to analyze the correlation between the ratio of Th17 and Treg cells in the peripheral blood of UC patients and the ratio of TH17/Treg with Mayo score.

Results: The peripheral blood Th17 cell ratio and Th17/Treg ratio of the damp-heat internal accumulation and spleen-kidney yang deficiency group were higher than those of the control group; the Treg cell ratio was lower than that of the control group; the peripheral blood Th17 cell ratio and Th17/Treg ratio of the damp-heat internal accumulation group were higher those of the spleen-kidney yang deficiency group; and the proportion of Treg cells was lower than that of the spleen-kidney yang deficiency group ( < 0.05). The expression levels of serum IL-6, IL-17, IL-22, and TNF- in the damp-heat internal accumulation and spleen-kidney yang deficiency group were higher than those of the control group; IL-10 and TGF- were lower than those of the control group; the levels of serum IL-6, IL-17, IL-22, and TNF- in the damp-heat internal accumulation group were higher than those of the spleen-kidney yang deficiency group; and both IL-10 and TGF- were lower than those of the spleen-kidney yang deficiency group ( < 0.05). The peripheral blood Th17 cell ratio and Th17/Treg ratio in the moderately active period group and severely active period group were higher than those of the lightly active period group; the Treg cell ratio was lower than that of the lightly active period group; the peripheral blood Th17 cell ratio and Th17/Treg ratio in the severely active period group were higher than those in the moderately active period group; and the proportion of Treg cells was lower than that of the moderately active period group. Pearson correlation analysis showed that the proportion of Th17 cells and Th17/Treg in peripheral blood of UC patients were both positively correlated with Mayo score ( = 0.762,  = 0.777, < 0.001). Treg was negatively correlated with Mayo score ( = -0.790, < 0.001).

Conclusion: There are differences in the expression of peripheral blood Th17/Treg cells and related cytokines among UC patients with different syndromes, and the damp-heat content is the most significant. The higher the ratio of Th17 cells in peripheral blood and the degree of Th17/Treg imbalance, the lower the ratio of Treg cells, and the more severe the condition of UC patients, which can provide a preliminary quantitative basis for the TCM classification and severity of the diagnosis of UC.
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http://dx.doi.org/10.1155/2021/4600947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486524PMC
September 2021

Black raspberries attenuate colonic adenoma development in mice: Relationship to hypomethylation of promoters and gene bodies.

Food Front 2020 Sep 9;1(3):234-242. Epub 2020 Sep 9.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Recent studies have suggested that in addition to promoter region, DNA methylation in intragenic and intergenic regions also changes during physiological processes and disease. The current study showed that feeding of black raspberries (BRBs) to mice suppressed colon and intestinal tumors. MBDCap-seq suggested that dietary BRBs hypomethylated promoter, intragenic, and intergenic regions. Annotation of those regions highlighted genes in pathways involved in immune regulation, inflammatory signaling, production of nitric oxide and reactive oxygen species, and progression of colorectal cancer. BRB phytochemicals (e.g., ellagic acid, anthocyanins, oligosaccharides) and their gut bacterial metabolites (e.g., urolithin, protocatechuic acid, short-chain fatty acids) inhibited DNMT1 and DNMT3B activities in a cell-free assay. Our results suggest that BRBs' hypomethylating activities result from the combined effects of multiple BRB phytochemicals and their gut bacterial metabolites. Because similar substances are found in many plant products, our results with BRBs might also apply to commonly consumed fruits and vegetables.
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http://dx.doi.org/10.1002/fft2.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457619PMC
September 2020

The RNA binding protein QKI5 suppresses ovarian cancer via downregulating transcriptional coactivator TAZ.

Mol Ther Nucleic Acids 2021 Dec 29;26:388-400. Epub 2021 Jul 29.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.

RNA-binding proteins (RBPs) are a set of proteins involved in many steps of post-transcriptional regulation to maintain cellular homeostasis. Ovarian cancer (OC) is the most deadly gynecological cancer, but the roles of RBPs in OC are not fully understood. Here, we reported that the RBP QKI5 was significantly negatively correlated with aggressive tumor stage and worse prognosis in serous OC patients. QKI5 could suppress the growth and metastasis of OC cells both and . Transcriptome analysis showed that QKI5 negatively regulated the expression of the transcriptional coactivator TAZ and its downstream targets (e.g., CTGF and CYR61). Mechanistically, QKI5 bound to TAZ mRNA and recruited EDC4, thus decreasing the stability of TAZ mRNA. Functionally, TAZ was involved in the QKI5-mediated tumor suppression of OC cells, and QKI5 expression was inversely correlated with TAZ, CTGF, and CYR61 expression in OC patients. Together, our study indicates that QKI5 plays a tumor-suppressive role and negatively regulates TAZ expression in OC.
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http://dx.doi.org/10.1016/j.omtn.2021.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426461PMC
December 2021

SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response.

mBio 2021 Sep 21:e0233521. Epub 2021 Sep 21.

Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern Californiagrid.42505.36, Los Angeles, California, USA.

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.
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http://dx.doi.org/10.1128/mBio.02335-21DOI Listing
September 2021

Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

J Immunol 2021 09 20;207(6):1672-1682. Epub 2021 Aug 20.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH;

NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.
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http://dx.doi.org/10.4049/jimmunol.2100023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429221PMC
September 2021

PHLDA1 Modulates the Endoplasmic Reticulum Stress Response and is required for Resistance to Oxidative Stress-induced Cell Death in Human Ovarian Cancer Cells.

J Cancer 2021 25;12(18):5486-5493. Epub 2021 Jul 25.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, PR China.

Pleckstrin homology-like domain family A member 1 (PHLDA1) has been implicated in the regulation of apoptosis in a variety of normal cell types and cancers. However, its precise pathophysiological functions remain unclear. Here, we examined the expression of PHLDA1 in human ovarian cancer (OvCa), the most lethal gynecologic malignancy, and investigated its functions . The expression of PHLDA1 was detected by reverse-transcription quantitative PCR (RT-qPCR), immunohistochemical analysis, or western blotting, silencing of PHLDA was achieved by shRNA, cell proliferation was detected by MTT assay, apoptosis was detected by flow cytometric analysis, PHLDA1 transcriptional activity was detected by dual luciferase reporter assay. PHLDA1 mRNA levels were significantly higher in serous OvCa specimens compared with normal ovarian tissue, confirmed by immunohistochemical staining of PHLDA1 protein, which also indicated the expression was predominantly cytoplasmic. Bioinformatics analysis of publicly available datasets indicated that PHLDA1 expression in clinical specimens was significantly associated with disease stage, progression-free survival, and overall survival. In human OvCa cell lines, shRNA-mediated silencing of PHLDA1 expression enhanced apoptosis after exposure to oxidative stress- and endoplasmic reticulum stress-inducing agents. PHLDA1 silencing increased not the expression of anti-apoptotic or autophagy-related proteins, but the expression of ER stress response-associated proteins. PHLDA1 modulates the susceptibility of human OvCa cells to apoptosis the endoplasmic reticulum stress response pathway.
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http://dx.doi.org/10.7150/jca.45262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364641PMC
July 2021

TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell.

Int J Biol Sci 2021 26;17(11):2683-2702. Epub 2021 Jun 26.

Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China.

Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells . We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3β phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.
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http://dx.doi.org/10.7150/ijbs.61350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326125PMC
June 2021

Hijacking TYRO3 from Tumor Cells via Trogocytosis Enhances NK-cell Effector Functions and Proliferation.

Cancer Immunol Res 2021 Oct 29;9(10):1229-1241. Epub 2021 Jul 29.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.

Trogocytosis is a fast, cell-cell contact-dependent uptake of membrane patches and associated molecules by one cell from another. Here, we report our investigation of trogocytosis of TYRO3, a cell membrane protein, from tumor target cells to natural killer (NK) cells and the associated functional consequences for NK cells. We found that although NK cells did not express endogenous TYRO3 on the cell surface, activated NK cells rapidly acquired TYRO3 from tumor cells via trogocytosis and . NK cells that acquired TYRO3, which we termed TYRO3 NK cells, had significantly enhanced cytotoxicity and IFNγ production as well as higher expression of some activated surface markers compared with TYRO3 NK cells. Furthermore, the activation status of NK cells and TYRO3 expression levels on donor cells, either endogenous or ectopic, positively correlated with trogocytosis levels. When the antigen-presenting cell (APC) K562 leukemia cell line, a feeder cell line to expand NK cells, overexpressed TYRO3, TYRO3 was transferred to NK cells via trogocytosis, which improved NK-cell proliferation . This provides a strategy to manufacture NK cells or their engineered counterparts, such as chimeric antigen receptor NK cells, for the treatment of cancer or infectious diseases.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-1014DOI Listing
October 2021

Comparing Noninvasive Predictors of Neurosyphilis Among Syphilis Patients With and Without HIV Co-Infection Based on the Real-World Diagnostic Criteria: A Single-Center, Retrospective Cohort Study in China.

AIDS Res Hum Retroviruses 2021 Aug 20. Epub 2021 Aug 20.

Xixi Hospital of Hangzhou, Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

Diagnosis of neurosyphilis is currently based on the cerebrospinal fluid (CSF) assessments and CSF-Venereal Disease Research Laboratory (CSF-VDRL) is the traditional "gold standard." In the real world, CSF assessments and CSF-VDRL are not always available. This study aimed to identify noninvasive predictors of neurosyphilis based on real-world clinical parameters and diagnostic criteria in populations with different HIV status. In this retrospective cohort study, syphilis patients with different HIV statuses hospitalized for neurosyphilis screening were retrospectively recruited at an infectious disease hospital. Neurosyphilis was defined by real-world diagnostic criteria. Logistic regression and receiver operating characteristic curve analysis were used to investigate and evaluate predictors of neurosyphilis. In total, 528 patients were enrolled, including 143 syphilis patients without HIV infection and 385 HIV/syphilis-co-infected patients. One hundred twelve and 304 neurosyphilis patients were identified in the HIV-negative and HIV-positive groups, respectively. A high serum toluidine red unheated serum test (TRUST) titer was a robust predictor of neurosyphilis in all participants. An age ≥50 years old [adjusted odds ratio (aOR) = 5.062, 95% confidence interval (CI), 1.449-17.680] in the HIV-negative group and CD4 T cell count <330/μL (<300 as reference, aOR = 0.552, 95% CI, 0.315-0.966) in the HIV-positive group were predictors of asymptomatic neurosyphilis. In real-world situations, for asymptomatic syphilis patients, relatively old age and a high serum TRUST titer in HIV-negative populations, and CD4 T cells <330/μL and/or serum TRUST titer >1:64 in HIV-positive populations might predict neurosyphilis.
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http://dx.doi.org/10.1089/AID.2021.0085DOI Listing
August 2021

Effects of Dietary Interventions on Gut Microbiota in Humans and the Possible Impacts of Foods on Patients' Responses to Cancer Immunotherapy.

eFood 2020 Aug 27;1(4):279-287. Epub 2020 Aug 27.

Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou, China.

The gut microbiota-the community of microorganisms in the gut-has been implicated in many physical and mental disorders in addition to intestinal diseases. Diets are the most studied and promising factors for altering it. Indeed, certain dietary interventions that increase fiber intake rapidly change levels of certain nutrients that can modify the composition of the microbiota, promoting richness and diversity. Recent intriguing evidence from several human clinical trials suggested that the composition and diversity of patients' gut microbiotas at baseline can influence their responses to cancer immunotherapy. If the factors that influence the gut microbiota were fully understood, it is conceivable that manipulating them could boost therapeutic responses in cancer patients. In this review, we investigate the possibility of using fruits, vegetables, or whole grains to enhance response to cancer therapies in humans, as current evidence suggests that these dietary components can manipulate and enhance diversity of the gut microbiota. Accordingly, dietary interventions with locally available fruits, vegetables, and whole grains might be an affordable and safe approach to enhancing the diversity of the gut microbiota before immunotherapy, in turn improving patients' responses to their treatments.
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http://dx.doi.org/10.2991/efood.k.200824.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301224PMC
August 2020

Transplanting fecal material from wild-type mice fed black raspberries alters the immune system of recipient mice.

Food Front 2020 Sep 5;1(3):253-259. Epub 2020 Aug 5.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin.

By constantly stimulating intestinal immunity, gut microbes play important regulatory roles, and their possible involvement in human physical and mental disorders beyond intestinal diseases suggests the importance of maintaining homeostasis in the gut microbiota. Both transplantation of fecal microbiota and dietary interventions have been shown to restore microbial homeostasis in recipients. In the current study with wild-type mice, we combined these two approaches to determine if transplanting fecal material from mice fed black raspberries (BRB, 5%) altered recipients' immune system. The donors received a control or 5% BRB diet, and fecal transplantation was performed every other day 15 times into recipients fed control diet. Afterward, we used flow cytometry to analyze populations of CD3 T, CD4 T, CD8 T cells, and NK cells among bone marrow cells, splenocytes, and peripheral blood mononuclear cells (PBMCs) collected from the recipients. We found that BRB-fecal material that contained both fecal microbiota and their metabolites increased NK cell populations among bone marrow cells, splenocytes, and PBMCs, and raised levels of CD8 T cells in splenocytes. Our findings suggest that fecal transplantation can modulate the immune system and might therefore be valuable for managing a range of physical and mental disorders.
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http://dx.doi.org/10.1002/fft2.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301209PMC
September 2020

Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer.

Front Immunol 2021 23;12:692360. Epub 2021 Jun 23.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.
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http://dx.doi.org/10.3389/fimmu.2021.692360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261131PMC
June 2021

The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity.

J Exp Med 2021 Aug 23;218(8). Epub 2021 Jun 23.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA.

N 6-methyladenosine (m6A) is the most prevalent posttranscriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate antiviral and antitumor immunity. However, whether and how m6A modifications affect NK cell immunity remain unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell antitumor and antiviral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell antitumor immunity.
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http://dx.doi.org/10.1084/jem.20210279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225680PMC
August 2021

SIRT2 promotes murine melanoma progression through natural killer cell inhibition.

Sci Rep 2021 06 21;11(1):12988. Epub 2021 Jun 21.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

SIRT2, an NAD-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.
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http://dx.doi.org/10.1038/s41598-021-92445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217567PMC
June 2021

Dual roles of a novel oncolytic viral vector-based SARS-CoV-2 vaccine: preventing COVID-19 and treating tumor progression.

bioRxiv 2021 Jun 7. Epub 2021 Jun 7.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer patients are usually immunocompromised and thus are particularly susceptible to SARS-CoV-2 infection resulting in COVID-19. Although many vaccines against COVID-19 are being preclinically or clinically tested or approved, none have yet been specifically developed for cancer patients or reported as having potential dual functions to prevent COVID-19 and treat cancer. Here, we confirmed that COVID-19 patients with cancer have low levels of antibodies against the spike (S) protein, a viral surface protein mediating the entry of SARS-CoV-2 into host cells, compared with COVID-19 patients without cancer. We developed an oncolytic herpes simplex virus-1 vector-based vaccine named oncolytic virus (OV)-spike. OV-spike induced abundant anti-S protein neutralization antibodies in both tumor-free and tumor-bearing mice, which inhibit infection of VSV-SARS-CoV-2 and wild-type (WT) live SARS-CoV-2 as well as the B.1.1.7 variant in vitro. In the tumor-bearing mice, OV-spike also inhibited tumor growth, leading to better survival in multiple preclinical tumor models than the untreated control. Furthermore, OV-spike induced anti-tumor immune response and SARS-CoV-2-specific T cell response without causing serious adverse events. Thus, OV-spike is a promising vaccine candidate for both preventing COVID-19 and enhancing the anti-tumor response.

One Sentence Summary: A herpes oncolytic viral vector-based vaccine is a promising vaccine with dual roles in preventing COVID-19 and treating tumor progression.
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http://dx.doi.org/10.1101/2021.06.07.447286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202423PMC
June 2021

FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant.

bioRxiv 2021 Jun 8. Epub 2021 Jun 8.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 and . The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.
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http://dx.doi.org/10.1101/2021.06.07.447437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202421PMC
June 2021

A NIR-I light-responsive superoxide radical generator with cancer cell membrane targeting ability for enhanced imaging-guided photodynamic therapy.

Chem Sci 2020 Sep 5;11(37):10279-10286. Epub 2020 Sep 5.

Hefei National Laboratory for Physical Sciences at Microscale, iChem, University of Science and Technology of China Hefei P. R. China.

Photodynamic therapy (PDT), as an emerging treatment modality, which takes advantage of reactive oxygen species (ROS) generated upon light illumination to ablate tumours, has suffered from a limited treatment depth, strong oxygen dependence and short ROS lifespan. Herein, we developed a highly efficient NIR-I light (808 nm laser) initiated theranostic system based on a fluorescent photosensitizer (EBD-1) with cancer cell membrane targeting ability, which can realize large penetration depth in tissue, generate superoxide radicals (O ˙) to relieve the oxygen-dependence, confine the ROS oxidation at the cell membrane, and self-report the cell viability during the PDT process. experiments demonstrated that EBD-1 under 808 nm light successfully accomplished remarkable cancer ablation. This work will be beneficial for the design of novel photosensitizers for PDT-based theranostic systems.
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http://dx.doi.org/10.1039/d0sc03093gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162420PMC
September 2020

Activated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia.

Blood 2021 Oct;138(16):1465-1480

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA.

B- and T-cell acute lymphoblastic leukemia (B/T-ALL) may be refractory or recur after therapy by suppressing host anticancer immune surveillance mediated specifically by natural killer (NK) cells. We delineated the phenotypic and functional defects in NK cells from high-risk patients with B/T-ALL using mass cytometry, flow cytometry, and in silico cytometry, with the goal of further elucidating the role of NK cells in sustaining acute lymphoblastic leukemia (ALL) regression. We found that, compared with their normal counterparts, NK cells from patients with B/T-ALL are less cytotoxic but exhibit an activated signature that is characterized by high CD56, high CD69, production of activated NK cell-origin cytokines, and calcium (Ca2+) signaling. We demonstrated that defective maturation of NK cells into cytotoxic effectors prevents NK cells from ALL from lysing NK cell-sensitive targets as efficiently as do normal NK cells. Additionally, we showed that NK cells in ALL are exhausted, which is likely caused by their chronic activation. We found that increased frequencies of activated cytokine-producing NK cells are associated with increased disease severity and independently predict poor clinical outcome in patients with ALL. Our studies highlight the benefits of developing NK cell profiling as a diagnostic tool to predict clinical outcome in patients with ALL and underscore the clinical potential of allogeneic NK cell infusions to prevent ALL recurrence.
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http://dx.doi.org/10.1182/blood.2020009871DOI Listing
October 2021

An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma.

Cancer Res 2021 Jul 18;81(13):3635-3648. Epub 2021 May 18.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.

IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1-based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy and in multiple glioblastoma (GBM) mouse models. , soluble IL15/IL15Rα complex was secreted from OV-IL15C-infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8 T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector-transduced NK cells. , OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8 T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8 T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. SIGNIFICANCE: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0035DOI Listing
July 2021

Intrahepatic Cholangiocarcinoma Cells Promote Epithelial-mesenchymal Transition of Hepatocellular Carcinoma Cells by Secreting LAMC2.

J Cancer 2021 19;12(12):3448-3457. Epub 2021 Apr 19.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shaoxing University, Shaoxing, China.

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma cells are common primary hepatic tumor cells in the liver. Combined hepatocellular cholangiocarcinoma (CHC) contains both hepatocellular carcinoma cells and intrahepatic cholangiocarcinoma cells in one tumor lesion and these tumors show poor prognosis. Here we examined the potential interaction between hepatocellular carcinoma cells and intrahepatic cholangiocarcinoma cells using cell culture studies. The results showed that culture supernatant from intrahepatic cholangiocarcinoma cells induced endothelial-mesenchymal transition and facilitated the migration and invasion of hepatocellular carcinoma cells, although it did not accelerate the proliferation of hepatocellular carcinoma cells. Furthermore, culture supernatant from intrahepatic cholangiocarcinoma cells increased the chemoresistance of hepatocellular carcinoma cells. Laminin subunit gamma 2 (LAMC2) was detected in the culture supernatant of intrahepatic cholangiocarcinoma cells but not in that of hepatocellular carcinoma cells. Using established LAMC2 knockout intrahepatic cholangiocarcinoma cells, our results demonstrated that intrahepatic cholangiocarcinoma cells promoted the epithelial-mesenchymal transition of hepatocellular carcinoma cells through secreting LAMC2. Our results have revealed a novel mechanism of interaction between intrahepatic cholangiocarcinoma cells and hepatocellular carcinoma cells, which may provide new insight into developing effective treatments for CHC.
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http://dx.doi.org/10.7150/jca.55627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120174PMC
April 2021

Stoichiometry of multi-specific immune checkpoint RNA Abs for T cell activation and tumor inhibition using ultra-stable RNA nanoparticles.

Mol Ther Nucleic Acids 2021 Jun 13;24:426-435. Epub 2021 Mar 13.

Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA.

Immunotherapy has become a revolutionary subject in cancer therapy during the past few years. Immune checkpoint-targeting antibodies (Abs) could boost anticancer immune responses. However, certain protein-based immunotherapies revealed side effects and unfavorable biodistribution, so effective non-protein options with lower side effects are highly sought after. RNA's ability to form various three-dimensional configurations allows for the creation of a variety of ligands to bind different cell receptors. The rubber-like properties of RNA nanoparticles (NPs) allow for swift lodging to cancer vasculature with little accumulation in vital organs, resulting in a favorable pharmacokinetic/pharmacodynamic (PK/PD) profile and safe pharmacological parameters. Multi-specific drugs are expected to be the fourth wave of biopharmaceutical innovation. Herein, we report the development of multi-specific Ab-like RNA NPs carrying multiple ligands for immunotherapy. The stoichiometries and stereo conformations of the checkpoint-activating RNA NPs were optimized for T cell activation. When compared to mono- and bi-specific RNA NPs, the tri-specific Ab-like RNA NPs bound to the trimeric T cell receptor with the highest efficiency, showed the optimal T cell activation, and promoted the strongest anti-tumor function of immune cells. Animal trials demonstrated that the tri-specific RNA NPs inhibited cancer growth. This Ab-like RNA NP platform represents an alternative to protein Abs for tumor immunotherapy.
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http://dx.doi.org/10.1016/j.omtn.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042240PMC
June 2021

Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Mice: Relation to Metabolism and Gut Microbiota Composition.

J Cancer Prev 2021 Mar;26(1):32-40

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Free fatty acid receptor 2 () has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model ( ). deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, , and - mice. The relative abundance of and was significantly increased in the - mice compared to the mice. In addition, knocking-down in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.
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http://dx.doi.org/10.15430/JCP.2021.26.1.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020170PMC
March 2021

Evaluation of gliomas peritumoral diffusion and prediction of IDH1 mutation by IVIM-DWI.

Aging (Albany NY) 2021 03 26;13(7):9948-9959. Epub 2021 Mar 26.

Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.

Glioma characterized by high morbidity and mortality, is one of the most common brain tumors. The application of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) in differentiating glioma grading and IDH1 mutation status were poorly investigated. 78 glioma patients confirmed by pathological and imaging methods were enrolled. Glioma patients were measured using IVIM-DWI, then related parameters such as cerebral blood flow (CBF), perfusion fraction (f), pseudo diffusivity (D*), and true diffusivity (D), were derived. Receiver operating characteristic (ROC) curves were made to calculate specificity and sensitivity. The values of CBF1, CBF3, D*1, rCBF1-2, rCBF3-2, and age in group high-grade gliomas (HGG) were significantly higher than that of in group low-grade gliomas (LGG). The values of CBF1, CBF3, rCBF1-2, rCBF3-2, D*1, and age in group IDH1 were significantly lower than that of in group IDH1. The levels of D1 and f1 were remarkably higher in the group IDH1 than group IDH1. rCBF1-2 had a remarkably positive correlation with CBF1 (r=0.852, p<0.001). f1 showed a markedly negative correlation with CBF1 (r= -0.306, p=0.007). IVIM-DWI presented efficacy in differentiating glioma grading and IDH1 mutation status.
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http://dx.doi.org/10.18632/aging.202751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064166PMC
March 2021

Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer.

J Immunother Cancer 2021 03;9(3)

Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA

Background: Limited therapeutic options are available for triple-negative breast cancer (TNBC), emphasizing an urgent need for more effective treatment approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of Programmed Cell Removal (PrCR) provides a promising new immunotherapy for TNBC treatment.

Methods: CD47 is a critical self-protective "don't eat me" signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC preclinical models, we evaluated the efficacy of PrCR-based immunotherapy by blocking CD47. We performed high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment.

Results: We showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. Our high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in preclinical models. We demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated.

Conclusion: The combination of CD47 blockade and macrophage activation by cabazitaxel synergizes to vastly enhance the elimination of TNBC cells. Our results show that targeting macrophages is a promising and effective strategy for TNBC treatment.
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http://dx.doi.org/10.1136/jitc-2020-002022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986678PMC
March 2021

Developing nitrogen and Co/Fe/Ni multi-doped carbon nanotubes as high-performance bifunctional catalyst for rechargeable zinc-air battery.

J Colloid Interface Sci 2021 Jul 9;593:204-213. Epub 2021 Mar 9.

College of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China; Department of Physics, Hamline University, St. Paul 55104, USA. Electronic address:

Rational construction of advanced bifunctional catalysts with dual-active-sites is still challenging for both oxygen reduction (ORR) and oxygen evolution reactions (OER). Herein, metal-doped dicyandiamide formaldehyde resin is innovatively exploited to synthesize N/Co/Fe/Ni multi-doped carbon nanotubes (denoted as [email protected]) with metal-nitrogen-carbon (MNC) and CoFeNi nanoparticles as the ORR and OER active sites, respectively. Abundant active sites and high degree of graphitization enable [email protected] with a high ORR half-wave potential of 0.82 V and a low OER overpotential of 440 mV at 10 mA cm, which are comparable or superior to noble-metal catalysts. Particularly, the [email protected] air electrode of rechargeable Zn-air batteries shows remarkable open circuit potential (1.46 V), discharge power density (152.3 mW cm), specific capacity (814 mAh g), and cycling stability for more than 250 h. It is worth emphasizing that this synthesis strategy is rather simple, low-cost, high yield, and the proportion and amount of doped metal ions can be easily adjusted according to the needs for different applications.
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http://dx.doi.org/10.1016/j.jcis.2021.02.115DOI Listing
July 2021

Pterostilbene inhibits gallbladder cancer progression by suppressing the PI3K/Akt pathway.

Sci Rep 2021 Feb 23;11(1):4391. Epub 2021 Feb 23.

Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China.

Gallbladder cancer is the most common malignant tumor of the biliary system and is characterized by difficulty to diagnose in early stages, a high degree of malignancy, and poor prognosis. Finding new drugs may improve the prognosis for this dismal cancer. Herein, we investigated the potential application of pterostilbene (PTS) against gallbladder cancer in vivo and in vitro. PTS potently inhibited cell proliferation, migration and invasion of gallbladder cancer cells. Moreover, PTS also had a function of inducing apoptosis in vitro. Meanwhile, PTS reversed EMT with a correlated inhibition of PI3K/Akt activation. Tumor xenograft models showed that PTS inhibited tumor growth and had low toxicity in vivo, which were consistent with the in vitro data. These findings indicate that PTS arrests cell growth through inhibition of PI3K/AKT signaling and is a potential drug for the therapy of gallbladder cancer.
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http://dx.doi.org/10.1038/s41598-021-83924-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902850PMC
February 2021
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