Publications by authors named "Changhong Shi"

53 Publications

Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model.

Front Oncol 2021 30;11:632364. Epub 2021 Mar 30.

Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.632364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042335PMC
March 2021

Intestinal microbiota: A potential target for enhancing the antitumor efficacy and reducing the toxicity of immune checkpoint inhibitors.

Cancer Lett 2021 Jul 14;509:53-62. Epub 2021 Apr 14.

Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address:

Accumulating evidence suggests that the intestinal microbiota is associated with the antitumor efficacy of immune checkpoint inhibitors (ICIs) and the occurrence of immune-related adverse events (irAEs) following ICI treatment. However, the mechanisms underlying these interactions remain unclear. Recent technological advances have allowed more extensive investigation into the interplay between the intestinal microbiota and the tumor immune microenvironment. Breakthroughs by two research groups revealed that Bifidobacterium enhanced the efficacy of ICIs via the stimulator of interferon genes (STING) and adenosine 2A receptor (AR) signaling pathways, highlighting the molecular mechanisms through which the intestinal microbiota modulates immunotherapy. In this review, we summarize recent findings related to the potential role and mechanisms of the gut microbiota in ICI therapy, available microbiota-targeting strategies, and ongoing clinical trials. Further we discuss the associated challenges that remain in this field of research. The current review aims to evaluate the potential of the intestinal microbiota in maximizing the antitumor efficacy of ICIs while minimizing their toxic effects and guiding the development of more specific treatment regimens.
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http://dx.doi.org/10.1016/j.canlet.2021.04.001DOI Listing
July 2021

The Diagnostic and Immunotherapeutic Value of CD248 in Renal Cell Carcinoma.

Front Oncol 2021 12;11:644612. Epub 2021 Mar 12.

Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Renal cell carcinoma (RCC) is the most common malignancy in the urinary system. Despite substantial improvements in available treatment options, the survival outcome of advanced RCC is unsatisfactory. Identifying novel biomarkers to assist in early diagnosis and to screen patients who are sensitive to immunotherapy would be beneficial. CD248 is a promising candidate that deserves to be investigated. The Cancer Genome Atlas (TCGA) data set and clinical specimens were adopted to analyze the expression of CD248 between normal and tumor tissues. Univariate and multivariate Cox regression analyses were employed to identify independent prognostic factors and construct a CD248-based prognostic signature. The correlation among the present signature, tumor-infiltrating immune cells (TIICs), the tumor mutation burden (TMB), and immunomodulatory molecules was evaluated. The weighted gene co-expression network analysis (WGCNA), the enrichment analysis, and the miRNA correlation analysis were performed to explore the underlying mechanism of CD248 in the progression of RCC. The overexpression of CD248 in RCC was related to a poor prognosis, and a CD248-based prognostic signature could precisely stratify patients with RCC with different survival outcomes regardless of the training or testing cohort. The present signature could reflect the immunosuppressive landscape of RCC (i.e., increased infiltration of regulatory T cells and upregulated immune checkpoints), accompanied by deteriorated clinicopathologic indexes. The TMB and immunostimulatory molecules expression also increased with the risk score generated from the present signature. CD248 co-expressed gene sets were identified through the WGCNA algorithm, and several immunosuppressive Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched. The result of CD248-correlated miRNA further emphasized the importance of CD248 in RCC. CD248 is a valuable biomarker to improve the diagnostic and therapeutic efficiency of RCC. The immunosuppressive effect of CD248 co-expressed genes may provide insight for the present study, and miRNA would help to reveal the mechanism of the expressive regulation of CD248.
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http://dx.doi.org/10.3389/fonc.2021.644612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006336PMC
March 2021

Queuing Models of Gene Expression: Analytical Distributions and Beyond.

Biophys J 2020 10 9;119(8):1606-1616. Epub 2020 Sep 9.

School of Mathematics and Computational Science and Guangdong Province Key Laboratory of Computational Science, Sun Yat-Sen University, Guangzhou, China.

Activation of a gene is a multistep biochemical process, involving recruitments of transcription factors and histone kinases as well as modification of histones. Many of these intermediate reaction steps would have been unspecified by experiments. Therefore, classical two-state models of gene expression established based on the memoryless (or Markovian) assumption would not well describe the reality in gene expression. Recent experimental data have indicated that the inactive phases of gene promoters are differently distributed, showing strong memory. Here, we use a nonexponential waiting-time distribution to model the complex activation process of a gene, and then analyze a queuing model of stochastic transcription. We successfully derive the analytical expression of the stationary mRNA distribution, which provides insight into the effect of molecular memory created by complex activating events on the mRNA expression. We find that the reduction in the waiting-time noise may result in the increase in the mRNA noise, contrary to the previous conclusion. Based on the derived distribution, we also develop a method to infer the waiting-time distribution from a known mRNA distribution. Data analysis on a realistic example verifies the validity of this method.
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http://dx.doi.org/10.1016/j.bpj.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642270PMC
October 2020

Interaction with CD68 and Regulation of GAS6 Expression by Endosialin in Fibroblasts Drives Recruitment and Polarization of Macrophages in Hepatocellular Carcinoma.

Cancer Res 2020 09 26;80(18):3892-3905. Epub 2020 Jun 26.

Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.

Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment. SIGNIFICANCE: These findings highlight CAF-expressed endosialin as a primary regulator of macrophage recruitment and polarization and demonstrate endosialin inhibition as a potential treatment strategy for HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3892/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2691DOI Listing
September 2020

Volume-regulated anion channel as a novel cancer therapeutic target.

Int J Biol Macromol 2020 Sep 20;159:570-576. Epub 2020 May 20.

Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address:

Volume-regulated anion channel (VRAC) is ubiquitously expressed in vertebrate cells and in various types of cancer cells. Leucine-rich repeat containing 8A (LRRC8A) and its four homologous family members (LRRC8B-E) assemble into heterogeneous VRAC complexes of ~800 kDa. The main components of VRAC, LRRC8A and LRRC8D have been implicated in the proliferation, migration, death, and multidrug resistance of cancer cells through their involvement in various signal pathways. This review summarizes recent findings concerning the involvement of VRAC in cancer development and progression, including the molecular structure, function, and regulation of VRAC and its roles in various cancers, and highlights the remaining challenges in the field. Our aim is to evaluate the potential of VRAC as a therapeutic target for cancer therapies and to discuss the major problems to be solved.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.05.137DOI Listing
September 2020

Establishment and characterization of patient-derived xenografts for hormone-naïve and castrate-resistant prostate cancers to improve treatment modality evaluation.

Aging (Albany NY) 2020 02 24;12(4):3848-3861. Epub 2020 Feb 24.

Division of Cancer Biology, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Prostate cancer (PC) is a heterogeneous disease characterized by variable morphological patterns. Thus, establishing a patient-derived xenograft (PDX) model that retains the key features of the primary tumor for each type of PC is important for appropriate evaluation. In this study, we established PDX models of hormone-naïve (D17225) and castration-resistant (B45354) PC by implanting fresh tumor samples, obtained from patients with advanced PC under the renal capsule of immune-compromised mice. Supplementation with exogenous androgens shortened the latent period of tumorigenesis and increased the tumor formation rate. The PDX models exhibited the same major genomic and phenotypic features of the disease in humans and maintained the main pathological features of the primary tumors. Moreover, both PDX models showed different outcomes after castration or docetaxel treatment. The hormone-naïve D17225 PDX model displayed a range of responses from complete tumor regression to overt tumor progression, and the development of castrate-resistant PC was induced after castration. The responses of the two PDX models to androgen deprivation and docetaxel were similar to those observed in patients with advanced PC. These new preclinical PC models will facilitate research on the mechanisms underlying treatment response and resistance.
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http://dx.doi.org/10.18632/aging.102854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066917PMC
February 2020

Development of patient-derived xenograft models of prostate cancer for maintaining tumor heterogeneity.

Transl Androl Urol 2019 Oct;8(5):519-528

Division of Cancer Biology, Laboratory Animal Center, the Fourth Military Medical University, Xi'an 710032, China.

Prostate cancer (Pca) is a heterogeneous disease with multiple morphological patterns. Thus, the establishment of a patient-derived xenograft (PDX) model that retains key features of the primary tumor is of great significance. This review demonstrates the characteristics and advantages of the Pca PDX model and summarizes the main factors affecting the establishment of the model. Because this model well recapitulates the diverse heterogeneity observed in the clinic, it was extensively utilized to discover new therapeutic targets, screen drugs, and explore metastatic mechanisms. In the future, clinical phenotype and different stages of the Pca patient might be faithfully reflected by PDX model, which provides tremendous potential for understanding Pca biology and achieving individualized treatment.
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http://dx.doi.org/10.21037/tau.2019.08.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842779PMC
October 2019

Biological Characteristics of Severe Combined Immunodeficient Mice Produced by CRISPR/Cas9-Mediated and Mutation.

Front Genet 2019 30;10:401. Epub 2019 Apr 30.

Laboratory Animal Center, Air Force Medical University, Xi'an, China.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9 is a novel and convenient gene editing system that can be used to construct genetically modified animals. Recombination activating gene 2 () is a core component that is involved in the initiation of V(D)J recombination during T- and B-cells maturation. Separately, the interleukin-2 receptor gamma chain gene () encoded the protein-regulated activity of natural killer (NK) cells and shared common receptors of some cytokines. and mutations cause immune system disorders associated with T-, B-, and NK cell function and some cytokine activities. In the present study, 2 single-guide RNAs (sgRNAs) targeted on and genes were microinjected into the zygotes of BALB/c mice with Cas9 messenger RNA (mRNA) to create / double knockout mice, and the biological characteristics of the mutated mice were subsequently analyzed. The results showed that CRISPR/Cas9-induced indel mutation displaced the frameshift of and genes, resulting in a decrease in the number of T-, B-, and NK cells and the destruction of immune-related tissues like the thymus and spleen. 85B antigen could not induce cellular and humoral immune response in mice. However, this aberrant immune activity compromised the growth of several tumor heterogenous grafts in the mutated mice, including orthotopic and subcutaneous transplantation tumors. Thus, knockout mice possessed features of severe combined immunodeficiency (SCID), which is an ideal model for human xenograft.
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http://dx.doi.org/10.3389/fgene.2019.00401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524690PMC
April 2019

Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury.

Aging Dis 2019 Feb 1;10(1):116-133. Epub 2019 Feb 1.

1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.

Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.
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http://dx.doi.org/10.14336/AD.2018.0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345330PMC
February 2019

In Silico Discovery of a Small Molecule Suppressing Lung Carcinoma A549 Cells Proliferation and Inducing Autophagy via mTOR Pathway Inhibition.

Mol Pharm 2018 11 22;15(11):5427-5436. Epub 2018 Oct 22.

Laboratory Animal Center , Air Force Medical University , No. 169 Changle West Road , Xi'an , Shaanxi Province 710032 , China.

Mammalian target of rapamycin (mTOR) kinase is vital to the regulation of cell growth and proliferation, and it has been taken as a promising target to develop cancer therapies. By reference to the crystal structure of mTOR-PP242, we explored to discover potential ATP-competitive inhibitors of mTOR. Through the integrated use of multiple in silico screenings, the tremendous amount of compounds from the SPECS database were finally reduced to 30. After several rounds of convincing biological tests in A549 cells, the newfound C-4 was identified as a potential ATP-competitive inhibitor of mTOR. Besides A549 cell proliferation suppression caused by C-4, autophagy was also determined through autophagosome observation and autophagy flux detection in C-4 treated A549 cells. We demonstrated that C-4 could inhibit cell growth and proliferation, and this inhibition may be associated with autophagy.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00996DOI Listing
November 2018

Multi-focused psychosocial residential rehabilitation interventions improve quality of life among cancer survivors: a community-based controlled trial.

J Transl Med 2018 09 6;16(1):250. Epub 2018 Sep 6.

Key Lab of Public Health Safety of Ministry of Education and Key Lab of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, No. 130 Dongan RD, Xuhui District, Shanghai, Zip code: 200032, China.

Background: Even though multi-focused psychosocial residence rehabilitation intervention (MPRRI) programs are widely implemented by the Shanghai Cancer Rehabilitation Club, these programs have not been rigorously evaluated. In this study, we evaluated the effects of a 21-day MPRRI program, on the quality of life (QoL) among cancer survivors.

Methods: A total of 388 cancer patients were enrolled to either receive the 21-day MPRRI (n = 129) intervention or a waiting-list comparison (WLC) intervention (n = 259). The intervention group was offered community-based 21-day MPRRI program, combining supportive-expressive group, cognitive-behavioral therapy, and Guolin Qigong. QoL was measured using the European Organization for Research and Treatment Quality of Life Version 3 Questionnaire. Multivariable linear models were used to compare changes in QoL values between the two groups.

Results: After adjustment for the QoL score and other covariates at baseline, there was no significant difference in global health status (mean = 3.8, 95% CI - 1.3-9.0, P = 0.14) between the two groups after 6 months intervention. While compared with the WLC group, the intervention group showed significant improvements in the QoL score (all P < 0.05); however, there were no clinically relevant changes in subscales including emotional functioning (ES = 0.58), cognitive functioning (ES = 0.53), pain (ES = 0.52), physical functioning (ES = 0.36), and insomnia (ES = 0.30).

Conclusions: These preliminary results suggest the MPRRI program is both feasible and acceptable intervention for cancer survivors in community settings and is effective in significant improving QoL above.
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http://dx.doi.org/10.1186/s12967-018-1618-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127902PMC
September 2018

NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye.

Contrast Media Mol Imaging 2018 8;2018:4979746. Epub 2018 Mar 8.

State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 10/cm tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide Ga (Ga-MHI-148) for PET tracing. We applied the dual-modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm × 0.3 cm) and rabbits (1.2 cm × 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC.
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http://dx.doi.org/10.1155/2018/4979746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863326PMC
July 2019

Insights into Macrophage Autophagy in Latent Tuberculosis Infection: Role of Heat Shock Protein 16.3.

DNA Cell Biol 2018 May 20;37(5):442-448. Epub 2018 Feb 20.

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University , Xi'an, China .

Tuberculosis (TB) is a major bacterial infectious disease worldwide that is predominantly caused by Mycobacterium tuberculosis (Mtb). The comorbidity of multiple drug-resistant TB strains with HIV and diabetes is widespread. In the presence of these diseases, host immunity is weakened, allowing the recovery of dormant bacilli and leading to recurrent TB infection. As an important component of the host innate and adaptive immune responses, macrophage autophagy plays a significant role in protecting the host against TB. However, dormant bacilli can escape from autophagosomes and/or suppress autophagy, thus surviving within the host for an extended period of time, although the underlying mechanism remains elusive. Heat shock protein 16.3 (Hsp16.3, HspX, Rv2031c, and Acr) is one of the immunodominant proteins expressed during latent TB infection (LTBI). It may help maintain the protein stability and long-term viability of Mtb by inhibiting macrophage autophagy, resulting in LBTI. In this review, we discuss how dormant bacilli escape from autophagosomes, and we focus on the role of Hsp16.3 in regulating macrophage autophagy in LTBI so as to provide a firm basis for further studies. Hsp16.3 may represent a potential biomarker of LTBI and novel pharmacological target for anti-tubercular drugs.
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http://dx.doi.org/10.1089/dna.2017.4066DOI Listing
May 2018

Effects of Mycobacterium tuberculosis Mutant Strain Hsp16.3 Gene on Murine RAW 264.7 Macrophage Autophagy.

DNA Cell Biol 2018 Jan 25;37(1):7-14. Epub 2017 Oct 25.

Division of Infection and Immunology, Laboratory Animals Center, Fourth Military Medical University , Xi'an, China .

Heat shock protein Hsp16.3 is closely related to latent Mycobacterium tuberculosis (MTB) infection and plays an important role in sustained survival when MTB is dormant. In this study, the Hsp16.3 gene mutant MTB H37Rv strain (Hsp16.3ΔMTB) was obtained through gene recombination and infected into murine RAW 264.7 macrophages. Western blotting and immunofluorescence showed increased expression of the autophagy-related protein LC3, and transmission electron microscopy showed significantly increased macrophage autophagosomes, suggesting that Hsp16.3ΔMTB facilitates murine macrophage autophagy. These findings have implications for preventing and controlling tuberculosis.
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http://dx.doi.org/10.1089/dna.2016.3599DOI Listing
January 2018

Heptamethine carbocyanine DZ-1 dye for near-infrared fluorescence imaging of hepatocellular carcinoma.

Oncotarget 2017 Aug 24;8(34):56880-56892. Epub 2017 May 24.

Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Near-infrared fluorescence (NIRF) dyes have recently emerged as promising tools for non-invasive imaging of different types of cancers. Here, we explored the potential utility of a NIRF DZ-1 dye, with dual imaging and tumour targeting functions, in hepatocellular carcinoma (HCC). We showed the preferential uptake of DZ-1 by HCC cells and in derived subcutaneous/orthotopic tumour xenografts, accompanied by a minimal effect on normal cells. DZ-1 simplified tumour growth profiling as well, since we were able to correlate NIRF signals with tumour volume and/or tumour-emitting luminescence in mice. Using both orthotopic tumour transplantation and cirrhosis models in parallel, we demonstrated the ability of DZ-1 to differentiate liver tumour from cirrhosis. DZ-1 showed superiority in HCC imaging over indocyanine green by demonstrating significantly enhanced tumour-targeting specificity. At the cellular level, DZ-1 was mainly retained in mitochondria and lysosomes. Additionally, DZ-1 fluorescence spectroscopy has been used for the intraoperative navigation of rabbit liver cancer, to determine surgical margins. We showed that tumor hypoxia and select organic anion-transporting polypeptide genes mediate NIRF dye uptake in HCC, which was supported by clinical evidence. All these findings represent the first evidence that DZ-1 is an effective molecular probe for tumour-specific imaging in HCC, and provide insights into the development of a new generation of imaging agents for intraoperative guidance of cancer surgery.
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http://dx.doi.org/10.18632/oncotarget.18131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593610PMC
August 2017

The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma.

Int J Mol Sci 2017 Jun 21;18(6). Epub 2017 Jun 21.

Laboratory Animal Center, the Fourth Military Medical University, Xi'an 710032, China.

Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC.
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http://dx.doi.org/10.3390/ijms18061332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486152PMC
June 2017

MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.

Cancer Cell 2017 03;31(3):368-382

Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.
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http://dx.doi.org/10.1016/j.ccell.2017.02.003DOI Listing
March 2017

Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death.

Cancer Lett 2017 01 31;385:128-136. Epub 2016 Oct 31.

Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address:

Itraconazole is a common antifungal which may have promise for treating various human cancers. We report that itraconazole was cytotoxic to MCF-7 and SKBR-3 breast cancer cell lines via apoptosis by altering mitochondria membrane potential, reducing BCL-2 expression and elevating caspase-3 activity. Itraconazole also induced autophagic cell death via LC3-II expression upregulation, P62/SQSTM1 degradation, autophagosome formation and increases in autophagic puncta. Itraconazole treatment inhibited hedgehog pathway key molecular expression, such as SHH and Gli1, resulting in promotion of apoptosis and autophagy. The anti-proliferation effect of itraconazole-induced apoptosis and autophagy via hedgehog pathway inhibition was confirmed with Gli1 inhibitor GANT61 and SHH siRNA, GANT61 and SHH siRNA synergistically enhanced cytotoxicity induced by itraconazole. A human xenograft nude mouse model corroborated the anti-breast cancer activity as evidenced by reduced tumor size, and increased tumor tissue apoptosis and autophagy. Thus, itraconazole has a potent anti-breast cancer activity that may be improved when combined with hedgehog pathway inhibitors.
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http://dx.doi.org/10.1016/j.canlet.2016.10.034DOI Listing
January 2017

Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death.

Mol Med Rep 2016 Oct 19;14(4):3013-20. Epub 2016 Aug 19.

Laboratory Animal Center, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue‑derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3‑II expression and increased LC3 puncta. Cabazitaxel‑induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3‑methyladenine protected cells from cabazitaxel‑induced cell death, thus confirming that cabazitaxel‑induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042750PMC
http://dx.doi.org/10.3892/mmr.2016.5648DOI Listing
October 2016

Optical imaging of gastric cancer with near-infrared heptamethine carbocyanine fluorescence dyes.

Oncotarget 2016 Aug;7(35):57277-57289

Laboratory Animal Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the tumor-specific targeting ability of NIRF heptamethine carbocyanine MHI-148 dye in cultured gastric cancer cells, gastric cancer cell-derived and patient-derived tumor xenograft (PDX) models. We show that the NIRF dye specifically accumulated in tumor regions of both xenograft models, suggesting the potential utility of the dye for tumor-specific imaging and targeting in gastric cancer. We also demonstrated significant correlations between NIRF signal intensity and tumor volume in PDX models. Mechanistically, the higher cellular uptake of MHI-148 in gastric cancer cells than in normal cells was stimulated by hypoxia and activation of a group of organic anion-transporting polypeptide (OATP) genes. Importantly, this NIRF dye was not retained in inflammatory stomach tissues induced by gastric ulcer in mice. In addition, fresh clinical gastric tumor specimens, when perfused with NIR dye, exhibited increased uptake of NIR dye in situ. Together, these results show the possibility of using NIRF dyes as novel candidate agents for clinical imaging and detection of gastric cancer.
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http://dx.doi.org/10.18632/oncotarget.10031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302988PMC
August 2016

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy.

J Biomed Opt 2016 05;21(5):50901

University of Virginia, Department of Radiology, Charlottesville, Virginia 22908, United States.

A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.
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http://dx.doi.org/10.1117/1.JBO.21.5.050901DOI Listing
May 2016

Post-transcriptional regulation tends to attenuate the mRNA noise and to increase the mRNA gain.

Phys Biol 2015 Aug 12;12(5):056002. Epub 2015 Aug 12.

School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China.

Post-transcriptional regulation is ubiquitous in prokaryotic and eukaryotic cells, but how it impacts gene expression remains to be fully explored. Here, we analyze a simple gene model in which we assume that mRNAs are produced in a constitutive manner but are regulated post-transcriptionally by a decapping enzyme that switches between the active state and the inactive state. We derive the analytical mRNA distribution governed by a chemical master equation, which can be well used to analyze the mechanism of how post-transcription regulation influences the mRNA expression level including the mRNA noise. We demonstrate that the mean mRNA level in the stochastic case is always higher than that in the deterministic case due to the stochastic effect of the enzyme, but the size of the increased part depends mainly on the switching rates between two enzyme states. More interesting is that we find that in contrast to transcriptional regulation, post-transcriptional regulation tends to attenuate noise in mRNA. Our results provide insight into the role of post-transcriptional regulation in controlling the transcriptional noise.
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http://dx.doi.org/10.1088/1478-3975/12/5/056002DOI Listing
August 2015

Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor.

Biomaterials 2015 Oct 16;67:1-10. Epub 2015 Jul 16.

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.
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http://dx.doi.org/10.1016/j.biomaterials.2015.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736505PMC
October 2015

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer.

Oncotarget 2015 May;6(14):12392-404

Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xian, China.

Circulating tumor cells (CTCs) are important for metastasis in prostate cancer. T-LAK cell-originated protein kinase (TOPK) is highly expressed in cancer cells. Herein, we established a xenograft animal model, isolated and cultured the CTCs, and found CTCs have significantly greater migratory capacity than parental cells. TOPK is more highly expressed in the CTCs than in parental cells and is also highly expressed in the metastatic nodules caused by CTCs in mice. Knocking down TOPK decreased the migration of CTCs both in vitro and in vivo. TOPK was modulated by the PI3K/PTEN and ERK pathways during the metastasis of prostate cancer. High levels of TOPK in the tumors of patients were correlated with advanced stages of prostate cancer, especially for high-risk patients of Gleason score≥8, PSA>20ng/ml. In summary, TOPK was speculated to be one of a potential marker and therapeutic target in advanced prostate cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494946PMC
http://dx.doi.org/10.18632/oncotarget.3630DOI Listing
May 2015

Protective and therapeutic effects of the resuscitation-promoting factor domain and its mutants against Mycobacterium tuberculosis in mice.

Pathog Dis 2015 Apr 5;73(3). Epub 2015 Jan 5.

Division of Infection and Immunology, Laboratory Animal Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China

The resuscitation-promoting factor (Rpf), a secretory protein first reported in Micrococcus luteus, plays a critical role in mycobacterial survival and infection. There are five functionally redundant Rpf-like proteins identified in M. tuberculosis (Mtb). All these Rpfs share a conserved Rpf domain (Rpfd) composed of approximately 70 amino acids, which possesses the same biological functions as the full-length Rpf protein. Glutamic acid at position 54 in Rpfd (E54) has been implicated in mediating multiple physiological processes, and a single amino acid substitution at residue E54 can affect the protein biological activity. In order to determine the effects of different amino acid substitutions of E54 in Rpfd on its immunogenic activity, we generated three recombinant Rpfd mutants, Rpfd1 (E54K), Rpfd2 (E54A) and Rpfd3 (E54K and D48A), based on T-cell epitope prediction and tested their potential protective/therapeutic effects against Mtb in mice. Our results demonstrated that replacement of E54 by different amino acids in Rpfd distinctively influenced its resuscitation-promoting activities and Th1-type immune responses induced in mice. Administration of Rpfd2 mutant enhanced Th1-type cellular responses (IFN-γ and IL-2) in mice (P < 0.05, Rpfd2 versus control) and provided effective protection against Mtb in mice by significantly inhibiting the growth of Mtb during the initial stage of infection. Four weeks after the challenge, the slightest pathological injury in lung was observed in the Rpfd2-immunized group among all three Rfpd mutant-immunized groups. Furthermore, Rpfd2 therapy significantly decreased the bacterial load in lung and alleviated histopathological damage in Mtb-infected mice. Together, our results suggest Rpfd2 as a novel effective vaccine candidate against Mtb.
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http://dx.doi.org/10.1093/femspd/ftu025DOI Listing
April 2015

[Associations between physical exercise and quality of life in breast cancer patients].

Zhonghua Zhong Liu Za Zhi 2014 Nov;36(11):871-5

Email:

Objective: To investigate the associations between physical exercise and quality of life in breast cancer patients.

Methods: A cross-sectional study was conducted among 3 344 community breast cancer patients between April and July 2013 in Shanghai, China. Data were collected using a questionnaire, including socio-demographic situation, cancer survival and health behaviors, and scores of EORTC QLQ-C30 Simplified Chinese version and FACT-G Simplified Chinese version.

Results: Among a total of 3 344 breast cancer patients, the patients doing exercise reported significantly higher EORTC physical functioning scores, role functioning scores, emotional functioning scores, global health scores, and FACT-G physical well-being scores, social well-being scores, emotional well-being scores, functional well-being scores, and FACT-G total scores than the patients who didn't take exercise (P < 0.05, P(Adjusted)<0.05) . Breast cancer patients who did exercise more than or equal to 5 times/week reported significantly higher EORTC role functioning scores, cognitive functioning scores, emotional functioning scores, global health scores and FACT-G physical well-being scores, functional well-being scores, and FACT-G total scores than patients who did exercise less than 5 times/week (P < 0.05, P(Adjusted)<0.05 ).

Conclusions: There are active associations between physical exercise and quality of life in breast cancer patients. Engagement in physical exercise is beneficial to breast cancer patients with long-term survival.
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November 2014

[Associations between vegetables and fruit intake and quality of life in breast cancer patients].

Zhonghua Yu Fang Yi Xue Za Zhi 2014 Nov;48(11):990-4

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Objective: To investigate the associations between vegetables and fruit intake and quality of life in breast cancer patients.

Methods: A total of 3 344 community breast cancer patients were selected through cluster sampling method between April and July 2013, in Shanghai, China. Data were collected using a questionnaire, which included socio-demographic situation, cancer survival and health behaviors(i.e. vegetables or fruit intake, exercise), European Organization for Research and Treatment (EORTC) QLQ-C30 Simplified Chinese version(3rd edition) and Functional Assessment of Cancer Therapy scale (FACT-G) Simplified Chinese version(4th edition) were used to evaluate the quality of life. Crude quality of life scores were compared between groups. Multiple linear models were used to calculate and compare adjusted means of quality of life between groups, controlling relevant factors.

Results: After adjusting relevant factors, breast cancer patients who ate more than 250 g vegetables reported higher EORTC physical functioning scores, cognitive functioning scores, emotional functioning scores, global health scores than patients who ate equal or less than 250 g vegetables(respectively (80.79 ± 0.85) vs (79.34 ± 0.82), (80.07 ± 1.03) vs (77.84 ± 0.99), (84.17 ± 0.95) vs (82.76 ± 0.92), (65.75 ± 1.50) vs (62.92 ± 1.45)), t values respectively were 2.76, 3.54, 2.40, 3.17, all P values were <0.05; and breast cancer patients who ate more than 250 g vegetables reported higher FACT-G social well-being scores, function well-being scores, FACT-G total scores than patients who ate equal or less than 250 g vegetables (respectively (17.92 ± 0.40) vs (17.31 ± 0.39), (14.86 ± 0.42) vs (14.34 ± 0.40), (74.78 ± 1.01) vs (73.05 ± 0.97)), t values respectively were 2.49, 2.05, 2.90, all P values were <0.05. After adjusting relevant factors, breast cancer patients who ate fruit everyday reported higher EORTC physical functioning scores, role functioning scores, cognitive functioning scores, emotional functioning scores, social functioning scores, global health scores than patients who didn't eat fruit everyday (respectively (80.40 ± 0.82) vs (79.22 ± 0.87), (89.81 ± 1.00) vs (88.06 ± 1.05), (79.78 ± 0.99) vs (77.11 ± 1.04), (84.43 ± 0.92) vs (81.56 ± 0.97), (77.95 ± 1.25) vs (75.56 ± 1.31), (65.48 ± 1.44) vs (61.74 ± 1.51)), t values respectively were 2.15, 2.64, 4.07, 4.71, 2.89, 4.02, all P values were <0.05; and breast cancer patients who ate fruit everyday reported higher FACT-G physical well-being scores, social well-being scores, emotional well-being scores, functional well-being scores, FACT-G total scores than patients who didn't eat fruit everyday(respectively (23.35 ± 0.26) vs (22.85 ± 0.28), (17.91 ± 0.39) vs (16.98 ± 0.41), (18.59 ± 0.22) vs (18.18 ± 0.23), (14.79 ± 0.40) vs (14.17 ± 0.42), (74.71 ± 0.97) vs (72.17 ± 1.02)), t values respectively were 2.92, 3.65, 2.91, 2.35, 4.05 , all P values were <0.05.

Conclusion: There are active associations between vegetables / fruit intake and quality of life in breast cancer patients. Proper diet may help improve quality of life in breast cancer patients.
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November 2014

Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1α/OATPs signaling axis.

Oncotarget 2014 Oct;5(20):10114-26

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259409PMC
http://dx.doi.org/10.18632/oncotarget.2464DOI Listing
October 2014

Mycobacterium tuberculosis Secreted Proteins As Potential Biomarkers for the Diagnosis of Active Tuberculosis and Latent Tuberculosis Infection.

J Clin Lab Anal 2015 Sep 17;29(5):375-82. Epub 2014 Aug 17.

Division of Infection and Immunology, Laboratory Animal Center, Fourth Military Medical University, Xi'an, P.R. China.

Background: The detection of Mycobacterium tuberculosis (Mtb) specific human antibodies has been an important diagnostic aid in the diagnosis of tuberculosis (TB) cases with smear-negative sputum samples, especially for the screening of high-risk population. This study focused on the analysis and comparison of the four potential Mtb-secreted proteins (ESAT6, CFP10, Ag85B, Hsp16.3) and the fusion protein Ag85B-Hsp16.3 as new markers in the serodiagnosis between active TB and latent TB infection (LTBI).

Methods: These five recombinant proteins were produced and used in optimized ELISA to detect IgG serum antibodies against the four secreted proteins. The capacity of identifying infection was evaluated either in active TB patients or LTBI individuals, which was compared with the control groups consisting of hospitalized non-TB individuals.

Results: The results showed that Ag85B-Hsp16.3/ESAT6 and Hsp16.3/ESAT6 were the best-associated antigens for serology diagnosis of the active TB and LTBI individuals because of their specificity, sensitivity, YI values, and positive rates, respectively. ELISA test demonstrated that 41.67% (25/60) of blood donors respond to Ag85B-Hsp16.3/ESAT6. The consistency of this positive respond with clinical diagnosis almost reached 84% (21/25).

Conclusion: Thus, a combined test of multiple Mtb-secreted proteins Ag85B, Hsp16.3, and ESAT6 may be the ascendant preliminary screening antigens for active TB or LTBI patients.
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http://dx.doi.org/10.1002/jcla.21782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807157PMC
September 2015