Publications by authors named "Chaojun Song"

59 Publications

GASC1 promotes glioma progression by enhancing NOTCH1 signaling.

Mol Med Rep 2021 May 2;23(5). Epub 2021 Mar 2.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.

Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133+ U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1‑knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133+ U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ‑Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.
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http://dx.doi.org/10.3892/mmr.2021.11949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974312PMC
May 2021

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas.

Int J Med Sci 2020 23;17(18):3174-3189. Epub 2020 Oct 23.

Department of Neurosurgery, Zhongnan hospital of Wuhan university, Wuhan, Hubei 430071, P.R. China.

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.
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http://dx.doi.org/10.7150/ijms.51176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646122PMC
October 2020

Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways.

Int J Mol Med 2021 Jan 5;47(1):113-124. Epub 2020 Nov 5.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.

As hyperprolactinemia is observed in patients with bromocriptine‑resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase‑2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine‑resistant prolactinoma cells. A reduction in phospho‑STAT5, cyclin D1 and B‑cell lymphoma extra‑large (Bcl‑xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem‑like cells, and reduced the protein expression of the cancer stem cell markers, CD133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5‑knockdown primary culture cells of human bromocriptine‑resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. Collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl‑xL and STAT5/cyclin D1 signaling pathways.
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http://dx.doi.org/10.3892/ijmm.2020.4784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723514PMC
January 2021

The Establishment and Application Studies on Precise Lysosome pH Indicator Based on Self-Decomposable Nanoparticles.

Nanoscale Res Lett 2020 Jul 8;15(1):143. Epub 2020 Jul 8.

Department of Pharmaceutical Analysis, School of Pharmacy, Air Force Medical University, Xi'an, 710032, Shaanxi, China.

Acidic pH of lysosomes is closely related to autophagy; thus, well known of the precise lysosomes, pH changes will give more information on the autophagy process and status. So far, however, only pH changes in a relatively broad range could be indicated, the exact lysosomes pH detection has never arrived. In our study, we established an endo/lysosome pH indicator based on the self-decomposable SiO nanoparticle system with specific synthesis parameters. The central concentrated methylene blue (MB) in the central-hollow structural nanoparticles presented sensitive release as a function of pH values from pH 4.0-4.8, which is exactly the pH range of lysosomes. The linear correlation of the optical density (OD) values and the pH values has been built up, which has been used for the detection of lysosomes pH in 6 different cell lines. Moreover, by this system, we succeeded in precisely detecting the pH average changes of lysosomes before and after black mesoporous silicon (BPSi) NP endocytosis, clarifying the mechanism of the autophagy termination after BPSi endocytosis. So, the self-decomposable nanoparticle-based luminal pH indicator may provide a new methodology and strategy to know better of the lysosome pH, then indicate more details on the autophagy process or other important signaling about metabolisms.
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http://dx.doi.org/10.1186/s11671-020-03367-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343700PMC
July 2020

BCAP31, a cancer/testis antigen-like protein, can act as a probe for non-small-cell lung cancer metastasis.

Sci Rep 2020 03 4;10(1):4025. Epub 2020 Mar 4.

Department of Immunology, the Fourth Military Medical University, No.169 Changle W. Rd., Xi'an, 710032, China.

Non-small-cell lung cancer (NSCLC) represents most of lung cancers, is often diagnosed at an advanced metastatic stage. Therefore, exploring the mechanisms underlying metastasis is key to understanding the development of NSCLC. The expression of B cell receptor-associated protein 31 (BCAP31), calreticulin, glucose-regulated protein 78, and glucose-regulated protein 94 were analyzed using immunohistochemical staining of 360 NSCLC patients. It resulted that the high-level expression of the four proteins, but particularly BCAP31, predicted inferior overall survival. What's more, BCAP31 was closely associated with histological grade and p53 status, which was verified by seven cohorts of NSCLC transcript microarray datasets. Then, three NSCLC cell lines were transfected to observe behavior changes BCAP31 caused, we found the fluctuation of BCAP31 significantly influenced the migration, invasion of NSCLC cells. To identify the pathway utilized by BCAP31, Gene Set Enrichment Analysis was firstly performed, showing Akt/m-TOR/p70S6K pathway was the significant one, which was verified by immunofluorescence, kinase phosphorylation and cellular behavioral observations. Finally, the data of label-free mass spectroscopy implied that BCAP31 plays a role in a fundamental biological process. This study provides the first demonstration of BCAP31 as a novel prognostic factor related to metastasis and suggests a new therapeutic strategy for NSCLC.
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http://dx.doi.org/10.1038/s41598-020-60905-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055246PMC
March 2020

[The reduced level of plasma melatonin in HFRS patients is correlated with disease severity and stage].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2018 Nov;34(11):1027-1031

Department of Immunology, Air Force Military Medical University, Xi'an 710032, China. *Corresponding author, E-mail:

Objective To investigate the changes of plasma melatonin (MLT) level in patients with hemorrhagic fever with renal syndrome (HFRS) and the relationships between the MLT level and the disease stage or severity. Methods The plasma samples were collected from 14 HFRS patients at acute stage or convalescent stage and 14 normal controls. After extraction, competitive enzyme-linked immunosorbent assay (CELISA) was used to detect the content of MLT in the plasma. The plasma MTL levels were compared between different severities or stages of HFRS patients and the normal controls. Meanwhile, the relationships between the MLT level and clinical indicators such as white blood cell (WBC) count were analyzed. Results The plasma MLT level of HFRS patients at the acute stage were significantly lower than that of the normal controls, and also significantly lower than that at the convalescence of HFRS. At the acute stage, the plasma MLT level of mild/severe HFRS patients was lower than that of critical patients. Moreover, the level of plasma MLT was negatively correlated with WBC count in HFRS patients at acute or convalescence stages. Conclusion MLT may be involved in the regulation of inflammatory responses in HFRS patients, which may affect the pathogenesis and disease progression of HFRS.
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November 2018

Ultra-high FRET efficiency NaGdF: Tb-Rose Bengal biocompatible nanocomposite for X-ray excited photodynamic therapy application.

Biomaterials 2018 11 5;184:31-40. Epub 2018 Sep 5.

School of Biomedical Engineering, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, PR China. Electronic address:

The limitation of light penetration depth invalidates the application of photodynamic therapy in deep-seated tumors. X-ray excited photodynamic therapy (X-PDT), which is based on X-rays excited luminescent nanoparticles (XLNP), provides a new strategy for PDT in deep tissues. However, the high X-ray dosage used and non-specific cytotoxicity of the nanoparticle-photosensitizer nanocomposite (NPs-PS) hamper in-vivo X-PDT applications. To address these problems, a simple and efficient NPs-PS nanocomposite using β-NaGdF: Tb nanoparticles and widely used PS called Rose Bengal (RB) was designed. With perfectly matched spectrum of NPs emission and RB absorption upon X-ray excitation and covalent conjugation of a large amount of RB on NP surfaces to minimize the energy transfer distance, the system demonstrated ultra-high FRET efficiency up to 99.739%, which leads to maximum production of singlet oxygen for PDT with significantly increased anti-tumor efficacy. By 2-aminoethylphosphonic acid surface modification of NPs, excellent biocompatibility was achieved even at a high concentration of 1 mg/mL. The in-vivo X-PDT efficacy was found around 90% of HepG2 tumor growth inhibition with X-ray dose of only 1.5 Gy, which shows the best anti-tumor efficacy at same X-ray dose level reported so far. The present work provides a promising platform for in-vivo X-PDT in deep tumors.
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http://dx.doi.org/10.1016/j.biomaterials.2018.09.001DOI Listing
November 2018

Noninvasive real-time monitoring of local drug release using nano-Au-absorbed self-decomposable SiO carriers.

Nanoscale 2018 Aug;10(32):15332-15338

Department of Pharmaceutical Analysis, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Real time monitoring of drug release at specific local sites by a non-invasive imaging method is critical in patient-specific drug administration in order to avoid insufficient or excess drug dosing. In the present work, we designed a specific carrier system for such a purpose using self-decomposable SiO2 nanoparticles (NPs) with the drug being loaded in the center and Au NPs on the SiO2 NPs as the imaging agent. We discovered a correlation between the drug release from the carrier and the morphological evolution of Au NPs, which also left the carrier and changed their aggregation states along with the drug release process. This finding enabled the real time monitoring of the drug release at local sites (e.g. tumor) in a quantitative manner by recording the CT signal evolution of the Au NPs, as demonstrated in vivo using mice bearing Colo-205 xenografts. The present work provided a promising platform for non-invasive real time tracking on the localized drug release, enabling a variety of personalized therapeutic applications.
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http://dx.doi.org/10.1039/c8nr03782eDOI Listing
August 2018

BAP31, a newly defined cancer/testis antigen, regulates proliferation, migration, and invasion to promote cervical cancer progression.

Cell Death Dis 2018 07 18;9(8):791. Epub 2018 Jul 18.

Department of Immunology, the Fourth Military Medical University, Xi'an, 710032, Shaanxi, People's Republic of China.

Malignant tumors typically undergo an atavistic regression characterized by the overexpression of embryonic genes and proto-oncogenes, including a variety of cancer/testis antigens (CTAs) that are testis-derived and are not expressed or expressed in trace amounts in somatic tissues. Based on this theory, we established a new method to identify unknown CTAs, the spermatogenic cells-specific monoclonal antibody-defined cancer/testis antigen (SADA) method. Using the SADA method, we identified BAP31 as a novel CTA and confirmed that BAP31 expression is associated with progression and metastasis of several cancers, particularly in cervical cancer. We found that BAP31 was significantly upregulated in stage I, II, and III cervical cancer patients and highly correlated with poor clinic outcomes. We further demonstrated that BAP31 regulates cervical cancer cell proliferation by arresting the cell cycle at the G0/G1 stage and that depletion of BAP31 inhibits hyper-proliferation. Moreover, depletion of BAP31 inhibits cervical cancer cell invasion and migration by regulating the expression and subcellular localization of Drebrin, M-RIP, SPECC1L, and Nexilin, and then affect the cytoskeleton assemblage. Finally, the depletion of BAP31 prevents cervical cancer progression and metastasis in vivo. These findings provide a new method for identifying novel CTAs as well as mechanistic insights into how BAP31 regulates cervical cancer hyper-proliferation and metastasis.
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http://dx.doi.org/10.1038/s41419-018-0824-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052025PMC
July 2018

[Establishment of a chemiluminescent immunoassay(CLIA) and its application].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2018 Apr;34(4):315-319

Department of Immunology, Air Force Military Medical University, Xi'an 710032, China.

Objective To establish a chemiluminescent immunoassay(CLIA) for the detection of soluble CD100 (sCD100) and evaluate its preliminary clinical application for the detection of sCD100 in clinical cerebrospinal fluid samples. Methods Ascites were prepared using two hybridomas secreting monoclonal antibody (mAb) to CD100, and the antibodies were purified. Based on sandwich ELISA, the experiment conditions were optimized and the CLIA for detecting sCD100 was established. The sensitivity and stability of CLIA were evaluated. The level of sCD100 in cerebrospinal fluid samples of patients (n=18) was detected. Results CLIA exhibited high performance within a dynamic range 0.098-12.5 ng/mL, and the limit of detection (LOD) was 0.12 ng/mL. The intra-assay coefficient variations (CV) were between 3.8%-6.6% and inter-assay CV were 6.2%-14.1%. Using CLIA, we examined the level of sCD100 in cerebrospinal fluid of viral encephalitis patients. The results showed the level of sCD100 in the patients were higher than that in normal controls. Two cases of them were 9.4 and 13.8 times higher than the normal mean value of control group. Conclusion A rapid, sensitive and stable CLIA for detecting sCD100 has been successfully established, which can be used for the quantitative detection of trace sCD100 in cerebrospinal fluid samples.
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April 2018

Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir.

Adv Sci (Weinh) 2018 02 9;5(2):1700289. Epub 2017 Nov 9.

Department of Physics The Chinese University of Hong Kong Shatin New Territories Hong Kong.

It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from the carrier into the cytosol and the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drug can be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drug from the NP carrier provides a feasible scheme for sustained drug release in cells, resulting in relatively stable cytosolic drug concentration level, particularly in the drug resistant case. By implementing an "optical switch" with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drug release is further promoted, which increases cytosolic drug concentration with good concentration retention. Enhanced drug efficacy in drug sensitive as well as resistant models is demonstrated both in vitro and in vivo. Such a mechanism is shown to efficiently circumvent multidrug resistance, and at the same time largely reduce the systemic toxicity of the anticancer drug.
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http://dx.doi.org/10.1002/advs.201700289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827467PMC
February 2018

Infection with a Brazilian isolate of Zika virus generates RIG-I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling.

Eur J Immunol 2018 07 6;48(7):1120-1136. Epub 2018 Apr 6.

Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from ZIKV infected cells potently activated the induction of type I interferons (IFNs). This effect was fully dependent on the mitochondrial antiviral signaling protein (MAVS), implicating RIG-I-like receptors (RLRs) as upstream sensors of viral RNA. Indeed, RIG-I and the related RNA sensor MDA5 contributed to type I IFN induction in response to RNA from infected cells. We found that ZIKV NS5 from a recent Brazilian isolate blocked type I IFN induction downstream of RLRs and also inhibited type I IFN receptor (IFNAR) signaling. We defined the ZIKV NS5 nuclear localization signal and report that NS5 nuclear localization was not required for inhibition of signaling downstream of IFNAR. Mechanistically, NS5 blocked IFNAR signaling by both leading to reduced levels of STAT2 and by blocking phosphorylation of STAT1, two transcription factors activated by type I IFNs. Taken together, our observations suggest that ZIKV infection induces a type I IFN response via RLRs and that ZIKV interferes with this response by blocking signaling downstream of RLRs and IFNAR.
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http://dx.doi.org/10.1002/eji.201847483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055886PMC
July 2018

Overexpression of ALK4 inhibits cell proliferation and migration through the inactivation of JAK/STAT3 signaling pathway in glioma.

Biomed Pharmacother 2018 Feb 27;98:440-445. Epub 2017 Dec 27.

Department of Neurosurgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China. Electronic address:

Aristaless-like homeobox 4 (ALK4) is a member of ALK proteins family and plays an important role in tumorigenesis. However, the expression and function of ALK4 in glioma remain largely unknown. The aim of our study was to elucidate its expression pattern in human glioma tissues and cell lines, as well as its functions in glioma cells. Our results demonstrated that ALK4 was lowly expressed in human glioma tissues and cell lines. Additionally, overexpression of ALK4 significantly suppressed the proliferation, migration and invasion of glioma cells, as well as inhibited the epithelial-mesenchymal transition (EMT) phenotype in glioma cells. Furthermore, overexpression of ALK4 significantly downregulated the phosphorylation levels of JAK2 and STAT3 in U87 cells. STAT3 inhibitor (Niclosamide) obviously enhanced ALK4-inhibted glioma cell proliferation and invasion. In conclusion, we demonstrated that overexpression of ALK4 suppressed glioma cell proliferation, migration and invasion through the inactivation of JAK/STAT3 signaling pathway. Thus, ALK4 may be a potential therapeutic target for the treatment of glioma.
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http://dx.doi.org/10.1016/j.biopha.2017.12.039DOI Listing
February 2018

TCTN2: a novel tumor marker with oncogenic properties.

Oncotarget 2017 Nov 24;8(56):95256-95269. Epub 2017 Aug 24.

Externautics SpA, Siena, Italy.

Tectonic family member 2 () encodes a transmembrane protein that belongs to the tectonic family, which is involved in ciliary functions. Previous studies have demonstrated the role of tectonics in regulating a variety of signaling pathways at the transition zone of cilia. However, the role of tectonics in cancer is still unclear. Here we identify that TCTN2 is overexpressed in colorectal, lung and ovary cancers. We show that different cancer cell lines express the protein that localizes at the plasma membrane, facing the intracellular milieu. TCTN2 over-expression in cancer cells resulted in an increased ability to form colonies in an anchorage independent way. On the other hand, downregulation of TCTN2 using targeted epigenetic editing in cancer cells significantly reduced colony formation, cell invasiveness, increased apoptosis and impaired assembly of primary cilia. Taken together, our results indicate that TCTN2 acts as an oncogene, making it an interesting cancer-associated protein and a potential candidate for therapeutic applications.
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http://dx.doi.org/10.18632/oncotarget.20438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707019PMC
November 2017

Lack of Truncated IFITM3 Transcripts in Cells Homozygous for the rs12252-C Variant That is Associated With Severe Influenza Infection.

J Infect Dis 2018 01;217(2):257-262

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University.

Interferon-induced transmembrane 3 (IFITM3) is known to restrict the entry of a range of enveloped viruses. The single nucleotide polymorphism rs12252-C within IFITM3 has been shown to be associated with severe influenza A virus infection. It has been suggested that rs12252-C results in expression of a truncated IFITM3 protein lacking the first 21 amino acids. By performing high-throughput RNA sequencing on primary dendritic cells and peripheral blood mononuclear cells isolated from pandemic H1N1 influenza and human immunodeficiency virus-1 (HIV-1) infected patients we show that full-length IFITM3 mRNA is dominantly expressed (>99%) across all rs12252 genotypes. Full-length IFITM3 protein can be detected in all genotypes.
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http://dx.doi.org/10.1093/infdis/jix512DOI Listing
January 2018

Synergistic chemo-photodynamic therapy by "big & small combo nanoparticles" sequential release system.

Nanomedicine 2018 01 18;14(1):109-121. Epub 2017 Sep 18.

Department of Pharmaceutical analysis, The Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Chemo-photodynamic combination has been manifested great potential for synergistic cancer therapy. Moreover, the synergistic efficacy could be significantly enhanced by well-designed sequential release manner of photosensitizers (PSs). Here we propose a "big & small combo nanoparticles (NP)" system for double loading PSs methylene blue (MB) and single absorbing chemotherapeutics drug Gemcitabine hydrochloride (GM·HCl). The "grown-in" MB from NP show two-peak sequential release profile, significantly improve the absorbed chemotherapeutic efficacy of GM·HCl. The corresponding two-peak sequential release profile can be illustrated by related mathematics function. The sequential release property was clearly observed through morphological evolution of NPs both in water and cells by TEM. Furthermore, NP demonstrate well EPR effect and improved synergistic efficacy from in vitro and in vivo results. Thus, NP chemo-photodynamic system and the programmable sequential release mechanism provide a promising platform that ensures an enhanced synergistic chemo-photodynamic effect in cancer treatment.
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http://dx.doi.org/10.1016/j.nano.2017.09.002DOI Listing
January 2018

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy.

J Exp Clin Cancer Res 2017 09 6;36(1):119. Epub 2017 Sep 6.

Department of Pharmaceutical analysis, School of Pharmacy, and The State Key Laboratory of Cancer Biology (CBSKL), The Fourth Military Medical University, 169th Changle West Road, Xi'an, Shaanxi, 710032, China.

Background: Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment.

Methods: PS drug methylene blue (MB) was encapsulated into the center of the NP, NP, and NP carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NP, NP, and NP carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NP and NP surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse T. Also, by adjusting the NP and NP configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy.

Results: In vitro and in vivo results demonstrated that these three pulses T and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment.

Conclusion: Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.
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http://dx.doi.org/10.1186/s13046-017-0586-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585930PMC
September 2017

ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer.

Oncotarget 2016 Sep;7(39):63596-63610

Externautics SpA, Siena, Italy.

Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are highly activated in cancer and involved in tumorigenesis and resistance to anti-cancer therapy. UPR is becoming a promising target of anti-cancer therapies. Thus, the identification of UPR components that are highly expressed in cancer could offer new therapeutic opportunity.In this study, we demonstrate that Endoplasmic Reticulum Metallo Protease 1 (ERMP1) is broadly expressed in a high percentage of breast, colo-rectal, lung, and ovary cancers, regardless of their stage and grade. Moreover, we show that loss of ERMP1 expression significantly hampers proliferation, migration and invasiveness of cancer cells. Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. Loss of ERMP1 also prevents the expression of GRP78/BiP, a UPR stress marker involved in the activation of the survival pathway. Finally, ERMP1 silencing in cells exposed to hypoxia leads to inhibition of the Nrf2-mediated anti-oxidant response and to reduction of accumulation of HIF-1, the master transcription factor instructing cells to respond to hypoxic stress. Our results suggest that ERMP1 could act as a molecular starter to the survival response induced by extracellular stresses. Moreover, they provide the rationale for the design of ERMP1-targeting drugs that could act by inhibiting the UPR initial adaptive response of cancer cells and impair cell survival.
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http://dx.doi.org/10.18632/oncotarget.11550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325388PMC
September 2016

FAT1: a potential target for monoclonal antibody therapy in colon cancer.

Br J Cancer 2016 06 21;115(1):40-51. Epub 2016 Jun 21.

Externautics SpA, Siena, Italy.

Background: Colorectal cancer (CRC) is one of the major causes of cancer-associated mortality worldwide. The currently approved therapeutic agents have limited efficacy.

Methods: The atypical cadherin FAT1 was discovered as a novel CRC-associated protein by using a monoclonal antibody (mAb198.3). FAT1 expression was assessed in CRC cells by immunohistochemistry (IHC), immunoblots, flow cytometry and confocal microscopy. In addition, in vitro and in vivo tumour models were done to assess FAT1 potential value for therapeutic applications.

Results: The study shows that FAT1 is broadly expressed in primary and metastatic CRC stages and detected by mAb198.3, regardless of KRAS and BRAF mutations. FAT1 mainly accumulates at the plasma membrane of cancer cells, whereas it is only marginally detected in normal human samples. Moreover, the study shows that FAT1 has an important role in cell invasiveness while it does not significantly influence apoptosis. mAb198.3 specifically recognises FAT1 on the surface of colon cancer cells and is efficiently internalised. Furthermore, it reduces cancer growth in a colon cancer xenograft model.

Conclusions: This study provides evidence that FAT1 and mAb198.3 may offer new therapeutic opportunities for CRC including the tumours resistant to current EGFR-targeted therapies.
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http://dx.doi.org/10.1038/bjc.2016.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931367PMC
June 2016

Anti-CD155 and anti-CD112 monoclonal antibodies conjugated to a fluorescent mesoporous silica nanosensor encapsulating rhodamine 6G and fluorescein for sensitive detection of liver cancer cells.

Analyst 2016 Aug;141(16):4933-40

Department of Immunology, The Fourth Military Medical University, China.

A novel method for sensitive detection of liver cancer cells using anti-CD155 and anti-CD112 monoclonal antibodies conjugated to ultrabright fluorescent mesoporous silica nanoparticles (FMSNs) encapsulating Rhodamine 6G and fluorescein was developed. The diameter of the obtained nanoparticles was 90 nm, and the quantum yield was 69%. Because the emission of fluorescein has a high degree of overlap with the excitation of Rhodamine 6G, and these two dyes were sufficiently close to each other on the nanoparticles, fluorescence resonance energy transfer can occur between these two dyes. This transfer not only maintains the original feature of the nanochannels and the skeletal network of the silica weakening the inner filtering of the dye, but also makes the excitation peak of the nanoparticles wider and increases the useful load amount of the dye. Because the wider Stokes shifts weaken the interference of excitation, the detection sensitivity is enhanced at the same time. The NaIO4 oxidation method does not use a cross-linker but rather uses covalent immobilization of the monoclonal antibodies on the FMSNs. This method can maintain the activity of the monoclonal antibodies more easily than the glutaraldehyde method. These advantages ensure that the nanosensor has high sensitivity and specificity for detecting liver cancer SMMC-7721 and HHCC cells. The in vivo imaging experiment also ensured that the biosensor can target tumor tissue in mice.
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http://dx.doi.org/10.1039/c5an01908gDOI Listing
August 2016

CD226 ligation protects against EAE by promoting IL-10 expression via regulation of CD4+ T cell differentiation.

Oncotarget 2016 Apr;7(15):19251-64

Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.

Treatment targeting CD226 can ameliorate experimental autoimmune encephalomyelitis (EAE), the widely accepted model of MS. However, the mechanisms still need to be elucidated. Here we showed that CD226 blockage by anti-CD226 blocking mAb LeoA1 efficiently promoted IL-10 production in human peripheral blood monocytes (PBMC) or in mixed lymphocyte culture (MLC) system, significantly induced the CD4+IL-10+ T cell differentiation while suppressing the generation of Th1 and Th17. Furthermore, CD226 pAb administration in vivo reduced the onset of EAE in mice by promoting IL-10 production and regulating T cell differentiation. Concomitantly, the onset and severity of EAE were reduced and the serum IL-10 expression levels were increased in CD226 knockout mice than that in control mice when both received EAE induction. These novel findings confirmed that CD226 played a pivotal role in mediating autoimmune diseases such as EAE. Furthermore, to our knowledge, we show for the first time that IL-10 is an important contributor in the inhibitory effects of CD226 ligation on EAE.
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http://dx.doi.org/10.18632/oncotarget.7834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991380PMC
April 2016

Supporting Data for Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs.

Data Brief 2016 Jun 15;7:148-51. Epub 2016 Feb 15.

Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Although nanoparticulate drug delivery systems (NDDSs) can preferentially accumulate in tumors, active targeting by targeting ligands (e.g. monoclonal antibody) is necessary for increasing its targeting efficacy in vivo. We conjugated mAb198.3 on the SiO2@AuNP system surface to make it obtain active targeting efficacy. The FAT1 targeting capability of SiO2@AuNP system is the first issue to be solved. Thus, flow cytometry analysis was attempted to demonstrate that the SiO2@AuNP system could bind to native FAT1 molecules on the surface of Colo205 cells. Also, together with the drug release behavior study of self-decomposable SiO2 NPs, the continuous morphological evolution needed to be clarified. Therefore, to characterize the morphological evolution in vitro, we analyzed the morphology of inner self-decomposable NPs in different time intervals using transmission electron microscopy (TEM). A more comprehensive analysis of this data may be obtained from the article "Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs" in Biomaterials.
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http://dx.doi.org/10.1016/j.dib.2016.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764893PMC
June 2016

Evolutionarily conserved primary TNF sequences relate to its primitive functions in cell death induction.

J Cell Sci 2016 Jan;129(1):108-20

Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK

TNF is a primitive protein that has emerged from more than 550 million years of evolution. Our bioinformatics study of TNF from nine different taxa in vertebrates revealed several conserved regions in the TNF sequence. By screening overlapping peptides derived from human TNF to determine their role in three different TNF-induced processes--apoptosis, necrosis and NF-κB stimulation--we found that TNF conserved regions are mostly related to cell death rather than NF-κB stimulation. Among the most conserved regions, peptides (P)12, P13 and P1213 (comprising P12 and P13) induced apoptosis, whereas P14, P15, P16 and P1516 (comprising P15 and P16) induced necrosis. Cell death induced by these peptides was not through binding to the TNF receptor. P16-induced necrosis was mainly through disruption of the cell membrane, whereas P1213-induced apoptosis involved activation of TRADD followed by formation of complex II. Finally, using a monoclonal antibody and a mutant TNF protein, we show that TNF-induced apoptosis is determined by a conserved linear sequence that corresponds to that within P1213. Our results reveal the determinant sequence that is key to the TNF primitive function of inducing apoptosis.
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http://dx.doi.org/10.1242/jcs.175463DOI Listing
January 2016

Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs.

Biomaterials 2016 01 27;76:399-407. Epub 2015 Oct 27.

Department of Immunology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address:

To achieve active tumor targeting and sequential release of 3 drugs to a tumor site in one nanoparticulate system, self-decomposable SiO2 nanoparticles modified by 3-aminopropyltriethoxysilane (APTS) as their inner structure were used to double load HCPT (in the NP core) and Dox (on the NP surface). Meanwhile, monoclonal antibodies (mAb198.3) against the FAT1 antigen and Bcl-2 siRNA were conjugated onto PEGylated Au-PEG-COOH nanoparticles. The obtained drug-loaded SiO2 nanoparticles were coated with the Au-PEG-mAb.198.3/siRNA nanoparticles through electrostatic interaction to form the SiO2@AuNP sequential drug delivery system, which featured the controlled and sequential release of siRNA, Dox and HCPT step by step to maximize its anticancer efficacy. The results revealed that the SiO2@AuNP sequential drug delivery system specifically targeted tumor cells and was internalize rapidly, followed by endosome escape and sequential drug release. Importantly, the sustainable release characteristics of SiO2 made the Tmax difference between HCPT and Dox approximately 8-12 h, and this enhanced the sensitizing efficiency of HCPT on Dox compared with co-administration. The in vivo antitumor results demonstrated that the tumor size after SiO2@AuNP treatment is 1/400 compared with the saline control group and approximately 1/40 of the HCPT/Dox co-treatment group without any noticeable systemic toxicity.
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http://dx.doi.org/10.1016/j.biomaterials.2015.10.069DOI Listing
January 2016

Stimuli-free programmable drug release for combination chemo-therapy.

Nanoscale 2016 Jul 11;8(25):12553-9. Epub 2015 Nov 11.

Department of pharmaceutical analysis, School of Pharmacy, The Fourth military medical university, Xi'an, Shaanxi, China 710032.

Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug binding to FAT1-expressing colon cancer cells. The loaded dual drugs were demonstrated to be delivered in a sequential manner with specific time intervals between their peak releases, which maximize the synergistic effect of the chemotherapeutics. These features led to significantly enhanced drug efficacy and reduced system toxicity. The tumor weight decreased by 1/350, together with a moderate increase in rats' body weight, which were observed when adopting the dual drug loaded nanoparticles, as compared to those of the control groups. The present system provides a simple and feasible method for the design of targeting and combination chemotherapy with programmed drug release.
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http://dx.doi.org/10.1039/c5nr06305aDOI Listing
July 2016

Expression profile of innate immune receptors, NLRs and AIM2, in human colorectal cancer: correlation with cancer stages and inflammasome components.

Oncotarget 2015 Oct;6(32):33456-69

The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

NLRs (nucleotide-binding domain leucine-rich repeat proteins or NOD-like receptors) are regulators of inflammation and immunity. A subgroup of NLRs and the innate immune receptor, AIM2 (absent-in-melanoma 2), can induce the assembly of a large caspase-1 activating complex called the inflammasome. Other NLRs regulate key signaling pathways such as NF-kB and MAPK. Since inflammation is a central component of colorectal cancer (CRC), this work was undertaken to analyze NLR and AIM2 expression in human CRC by combining bioinformatics analysis and experimental verification using clinical tissue samples. Additional experiments analyzed the association of (i) gene expression and cancer staging, and (ii) gene expression among inflammasome components.Ten public CRC datasets from the Oncomine® Platform were analyzed. Genes analyzed include NLRP1, NLRP3, NLRP6, NLRP12, NLRC3, NLRC4, NLRC5, NOD1, NOD2 and AIM2. Additionally, forty case-matched cancer samples and adjacent healthy control tissues isolated from a cohort of Chinese CRC patients were profiled.Three patterns of gene expression in CRC are shown. The expression of NLRC3, a checkpoint of inflammation, and the inflammasome components NLRP1, NLRP3, NLRC4 and AIM2 were reduced in CRC. NOD1 and NOD2 expression was increased in CRC, while NLRC5, NLRP6 and NLRP12 showed little difference compared to controls. Reduced expression of NLRC3 in CRC was verified in all available databases analyzed and confirmed with our patient cohort. Furthermore, the extent of NLRC3 and AIM2 gene reduction was correlated with cancer progression. This report reveals the potential value of NLR and AIM2 genes as biomarkers of CRC and cancer progression.
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http://dx.doi.org/10.18632/oncotarget.5587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741778PMC
October 2015

Negatively charged AuNP modified with monoclonal antibody against novel tumor antigen FAT1 for tumor targeting.

J Exp Clin Cancer Res 2015 Sep 15;34:103. Epub 2015 Sep 15.

Department of Immunology, the Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.

Background: Herein, we demonstrated the use of a newly generated anti FAT1 antibody (clone mAB198.3) for intracellular delivery of anionic gold NPs, to form active targeting Au nanoparticles with high payload characteristics.

Methods: In vitro characterizations were determined by DLS, confocal microscopy, TEM, western blot, MALDI-TOF MS/MS analysis, MTT, ICP-MS and flow cytometry analysis. In vivo targeting efficacy was investigated by in vivo bio-imaging study and ICP-MS.

Results: The specificity of the FAT1 recognition in colon cancer was confirmed by pre-adsorbing mAb198.3, adsorption dramatically abolished the antibody reactivity on colon cancer, thus confirming the binding specificity. The DLS size distribution profile of the AuCOOH, AuCOOH(Cy5)_ mAb198.3, AuCOOH(Cy5)_isotype has showed that the modified gold nanoparticles are well dispersed in water, PBS buffer and cell culture medium with 10 % FBS. By TEM measurement, the size of Au nanoparticles with spherical morphology is about 10-20 nm. AuCOOH_198.3 NPs were stable in an acidic environment, as well as in PBS buffer, cell culture media and media with 10 % serum. MTT results revealed that Au nanoparticles have well biocompatibility. TEM results indicated that conjugation of mAb198.3 on Au nanoparticles can be an effective delivery vehicle for negatively charged gold nanoparticles and increased its intracellular transport. It was also demonstrated by confocal microscopy that AuCOOH(Cy5)_mAb198.3 could attach to the cell membrane in very short time, then gradually delivered into cells. After 4 h incubation, almost all AuCOOH(Cy5)_mAb198.3 have been uptaken into or surrounding the cytoplasm and nucleus. In vivo results showed that only about 20 % of AuCOOH accumulated in tumor site due to EPR effect, while nearly 90 % of AuCOOH_mAb198.3 was found in tumor, providing sufficient evidence for receptor-specific targeting by mAb198.3.

Conclusion: According to in vitro and in vivo research results, the intracellular uptake of negatively charged AuCOOH_mAB198.3 particles is enhanced to a greater extent. Thus, AuCOOH_mAb198.3 holds significant potential to improve the treatment of cancer.
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http://dx.doi.org/10.1186/s13046-015-0214-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570718PMC
September 2015

BAP31, a promising target for the immunotherapy of malignant melanomas.

J Exp Clin Cancer Res 2015 Apr 18;34:36. Epub 2015 Apr 18.

Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, People Republic of China.

Purpose: Malignant melanoma's (MM) incidence is rising faster than that of any other cancer in the US and the overall survival at 5 years is less than 10%. B cell associated protein 31 (BAP31) is overexpressed in most MMs and might be a promising target for immunotherapy of this disease.

Experimental Design: Firstly, we investigated the expression profiles of human BAP31 (hBAP31) and mouse BAP31 (mBAP31) in human and mouse normal tissues, respectively. The expression level of hBAP31 in human MMs and mBAP31 in B16 melanoma cells was also analyzed. Then we constructed novel mBAP31 DNA vaccines and tested there ability to stimulate mBAP31-specific immune responses and antitumor immunity in B16 melanoma-bearing mice.

Results: For the first time, we found that protein expression of hBAP31 were dramatically upregulated in human MMs when compared with human normal tissues. Predominant protein expression of mBAP31 was found in mouse B16 melanoma cells but not in mouse important organs. When mice were immunized with mBAP31 DNA vaccines, strong cellular response to mBAP31 was observed in the vaccinated mice. CTLs isolated from immunized mice could effectively kill mBAP31-positive target mouse B16 melanoma tumor cells in vitro and vaccination with mBAP31 DNA vaccines had potent anti-tumor activity in therapeutic model using B16 melanoma cells.

Conclusions: These are the first data supporting a vaccine targeting BAP31 that is capable of inducing effective immunity against BAP31-expressing MMs and will be applicable to human MMs and hBAP31 DNA vaccine warrants investigation in human clinical trials.
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http://dx.doi.org/10.1186/s13046-015-0153-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405826PMC
April 2015

Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence.

Mol Neurobiol 2016 Jan 19;53(1):120-131. Epub 2014 Nov 19.

Department of Immunology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.

Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence.
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http://dx.doi.org/10.1007/s12035-014-8985-1DOI Listing
January 2016