Publications by authors named "Chunmin Liang"

24 Publications

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Sleep Deprivation Disturbs Immune Surveillance and Promotes the Progression of Hepatocellular Carcinoma.

Front Immunol 2021 3;12:727959. Epub 2021 Sep 3.

Laboratory of Tumor Immunology, Department of Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Sleep disturbance is common in patients with cancer and is associated with poor prognosis. However, the effects of sleep deprivation (SD) on immune surveillance during the development of hepatocellular carcinoma (HC) and the underlying mechanisms are not known. This was investigated in the present study using mouse models of SD and tumorigenesis. We determined that acute and chronic sleep deprivation (CSD) altered the relative proportions of various immune cell types in blood and peripheral organs. CSD increased tumor volume and weight, an effect that was enhanced with increasing CSD time. Expression of the cell proliferation marker Ki-67 was elevated in tumor tissues, and tumor cell infiltration into adjacent muscles was enhanced by CSD. Multicolor flow cytometry analysis revealed that CSD significantly reduced the numbers of antitumor CD3 T cells and natural killer (NK) cells and increased that of immunosuppressive CD11b cells infiltrating into the tumor microenvironment from the spleen the peripheral blood. These results indicate that CSD impairs immune surveillance mechanisms and promotes immunosuppression in the tumor microenvironment to accelerate tumor growth, underscoring the importance of alleviating sleep disturbance in HC patients in order to prevent HC progression.
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http://dx.doi.org/10.3389/fimmu.2021.727959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446513PMC
September 2021

The Efficacy of Ultrasound for Visualizing Radial Nerve Lesions with Coexistent Plate Fixation of Humeral Shaft Fractures.

Injury 2021 Mar 16;52(3):516-523. Epub 2020 Nov 16.

Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Department of Hand and Upper Extremity Surgery, Jing' an District Central Hospital, Shanghai, China; Limb Function Reconstruction Center, Jing' an District Central Hospital, Shanghai, China; National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China; Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai, China; Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China; Research unit of synergistic reconstruction of upper and lower limbs after brain injury, Chinese Academy of Medical Sciences, Shanghai, China.

Introduction: Ultrasound has been commonly employed for depicting the morphology of the lesions in patients with radial nerve neuropathy, including entrapment, tumor, trauma, and iatrogenic injury. However, few studies have evaluated the efficacy of ultrasound for visualizing radial nerve lesions with coexistent plate fixation of humeral shaft fractures. This study aimed to address this special clinical issue.

Methods: We retrospectively examined the efficacy of ultrasound for visualizing radial nerve lesions with coexistent plate fixation of humeral shaft fractures based on intraoperative findings in patients who were treated in our hospital from January 2007 to June 2019.

Results: Forty-six patients were included, and there was a 100% concordance between the ultrasound and intraoperative findings on radial nerve lesions. Ultrasonography revealed four types of lesions: radial nerve in continuity in thirty-one patients, neuroma in continuity in four patients, radial nerve stuck under the plate in three patients, and radial nerve transection in eight patients. The lesion radial nerve in continuity comprised two situations according to intraoperative electrodiagnostic test results, which could not be differentiated by ultrasonography, radial nerve in continuity treated with neurolysis in twenty-five patients and radial nerve in continuity treated with nerve graft in six patients.

Conclusion: Ultrasonography can accurately depict radial nerve lesions with coexistent plate fixation of humeral shaft fractures. It provides a basis for determining the extent of nerve damage in all patients except those with the lesion radial nerve in continuity, which is conducive to making treatment decisions as early as possible.
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http://dx.doi.org/10.1016/j.injury.2020.11.042DOI Listing
March 2021

CCR7 high expression leads to cetuximab resistance by cross-talking with EGFR pathway in PI3K/AKT signals in colorectal cancer.

Am J Cancer Res 2019 1;9(11):2531-2543. Epub 2019 Nov 1.

Laboratory of Tumor Immunology, Department of Anatomy, Histology, Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University Shanghai, P. R. China.

Cetuximab (C225), an anti-Epidermal Growth Factor receptor (EGFR) monoclonal antibody, has been widely used as a routine treatment for patients with metastatic colorectal cancer (mCRC); However, many patients who initially respond to cetuximab acquire resistance. The purpose of this study was to characterize new mechanism of acquired Cetuximab resistance. Firstly, tissue microarrays (TMA) comprising 191 CRC patients was constructed to evaluate the expression of chemokine receptor 7 (CCR7) by using immunohistochemistry (IHC). In CRC tumor tissues, CCR7 was significantly over-expressed compared with paired normal tissues ( < 0.001), and correlated with the infiltration depth ( = 0.03) and the regional lymph node metastasis ( = 0.006). Significant differences were also found in forms of overall survival (OS) and disease-free survival (DFS) between normal and tumor tissues (). More interestingly, EGFR was also highly expressed and co-localized with CCR7 in the tumor tissues from the patients who were insensitive to Cetuximab treatment. Secondly, we further explored the relationship between CCR7 expression and Cetuximab resistance by two CCR7 positive CRC cell lines, Caco-2 with wild-type ( ) and HCT116 with mutated ( ). By the treatment of secondary lymphoid tissue chemokine (SLC, an exogenous high-affinity legend of CCR7), the inhibition rate of Cetuximab significantly decreased in both cells. Furthermore, the activation of SLC/CCR7 axis promoted epithelial mesenchymal transformation (EMT) in CRC tumor cells by increasing the expression of Twist and β-catenin. By using of CCR7 neutralizing antibody and p-AKT inhibitor rescued the above effects. These findings suggested that CCR7 was a key factor in those CRC patients, who have poorer reaction to Cetuximab. So combined inhibition of CCR7 and p-AKT will represent a rational therapeutic strategy for Cetuximab resistance patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895444PMC
November 2019

Contralateral cervical seventh nerve transfer for spastic arm paralysis via a modified prespinal route: a cadaveric study.

Acta Neurochir (Wien) 2020 01 18;162(1):141-146. Epub 2019 Nov 18.

Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China.

Background: We proposed contralateral cervical seventh nerve transfer for spastic arm paralysis after central neurological injury in the New England Journal of Medicine (NEJM) in 2018. In this surgery, we applied a new surgical route for nerve transfer, the Huashan prespinal route. The objective of this study was to elaborate our new surgical technique, clarify its relationship to the vertebral artery, and provide anatomical data on this novel method.

Methods: The effectiveness and safety of the Huashan prespinal route in contralateral C7 nerve transfer were evaluated anatomically. Nine cadavers (4 males, 5 females) were available for this study. Among these, anatomical parameters of the vertebral artery were obtained from 6 cadavers, and the anastomosis of the bilateral cervical seventh nerve was observed on 3 cadavers undergoing contralateral C7 nerve transfer via the Huashan prespinal route.

Results: Tension-free anastomosis of the bilateral cervical seventh nerve was achieved through the Huashan prespinal route. The tilt angle of the vertebral artery to the sagittal plane (with thyroid cartilage as the origin) was 25.5 ± 4.5°, at 22.5 ± 1.6° and 28.7 ± 4.3° on the left and right side, respectively. The safe drilling angle to penetrate through the longus colli muscles for the creation of a longus colli muscle tunnel to avoid injury to the vertebral artery in our surgical technique was above 33.2°.

Conclusions: The cadaveric study confirms that the presented technique allowed simple, effective, and safe contralateral C7 nerve transfer. This technique can be used in the treatment of hemiplegia and brachial plexus injury. There is a safe scope of drilling angle for creating the longus colli muscle tunnel required for this surgical route. The anatomical parameters obtained in this study will be helpful for the performance of this operation.
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http://dx.doi.org/10.1007/s00701-019-04069-yDOI Listing
January 2020

The Recognition of the Distribution Features of Corticospinal Neurons by a Retrograde Trans-synaptic Tracing to Elucidate the Clinical Application of Contralateral Middle Trunk Transfer.

Neuroscience 2020 01 31;424:86-101. Epub 2019 Oct 31.

Department of Hand and Upper Extremity Surgery, Jing'an District Central Hospital of Shanghai, Fudan University, Shanghai 200040, China; Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Institutes of Brain Science, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center of Brain Science, Fudan University, Shanghai 200032, China; Priority Among Priorities of Shanghai Municipal Clinical Medicine Center, Shanghai 200040, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address:

Corticospinal neurons (CSNs) undertake direct cortical outputs to the spinal cord and innervate the upper limb through the brachial plexus. Our previous study has shown that the contralateral middle trunk transfer to the paralyzed upper extremity due to cerebral injury can reconstruct the functional cerebral cortex and improve the function of the paralyzed upper extremity. To interpret the cortical reconstruction and the motor improvement after the middle trunk transfer, we explored the distribution of CSNs connecting to the middle, upper, and lower trunk of the brachial plexus by retrograde trans-neuronal tracing using pseudorabies virus (PRV-EGFP or PRV-mRFP). We show that, rather than an individual specific area, these CSNs labelled by each trunk of the brachial plexus were widespread and mainly assembled within the primary motor cortex (M1), secondary motor cortex (M2), primary somatosensory cortex (S1), and slightly within the secondary somatosensory cortex (S2). The three trunk-labelled CSNs were intermingled in these cortices, and mostly connected to more than two trunks, especially the middle trunk-labelled CSNs with higher proportion of co-labelled neurons. Our findings revealed the distribution features of CSNs connecting to the adjacent spinal nerves that innervate the upper limb, which can improve our understanding of the corticospinal circuits associated with motor improvement and the functional cortical reconstruction after the middle trunk transfer.
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http://dx.doi.org/10.1016/j.neuroscience.2019.09.030DOI Listing
January 2020

CCL14 serves as a novel prognostic factor and tumor suppressor of HCC by modulating cell cycle and promoting apoptosis.

Cell Death Dis 2019 10 22;10(11):796. Epub 2019 Oct 22.

Laboratory of Tumor Immunology, Department of Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China.

CCL14 is a member of CC chemokines and its role in hepatocellular carcinoma (HCC) is still unknown. In this study, CCL14 expression were analyzed by tissue microarray (TMA) including 171 paired tumor and peritumor tissues of patients from Zhongshan Hospital of Fudan University. We found for the first time that CCL14 was downregulated in HCC tumor tissues compared with peritumor tissues (P = 0.01). Meanwhile, CCL14 low expression in HCC tumor tissues is associated with a poor prognosis (P = 0.035). CCL14 also displayed its predictive value in high differentiation (P = 0.026), liver cirrhosis (P = 0.003), and no tumor capsule (P = 0.024) subgroups. The underlying mechanisms were further investigated in HCC cell lines by CCL14 overexpression and knock-down in vitro. We found overexpression of CCL14 suppressed proliferation and promoted apoptosis of HCC cells. Finally, the effect was confirmed by animal xenograft tumor models in vivo. The results shown overexpression of CCL14 lead to inhibiting the growth of tumor in nude mice. Interestingly, our data also implied that CCL14 played these effects by inhibiting the activation of Wnt/β-catenin pathway. These findings suggest CCL14 is a novel prognostic factor of HCC and serve as a tumor suppressor.
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http://dx.doi.org/10.1038/s41419-019-1966-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805940PMC
October 2019

Application of CUBE-STIR MRI and high-frequency ultrasound in contralateral cervical 7 nerve transfer surgery.

Br J Neurosurg 2019 Mar 12:1-6. Epub 2019 Mar 12.

a Department of Hand Surgery, Huashan Hospital, Shanghai Medical College , Fudan University , Shanghai , China.

Objective: The objective of the study was to investigate the feasibility of CUBE-SITR MRI and high-frequency ultrasound for the structural imaging of the brachial plexus to exclude neoplastic brachial plexopathy or structural variation and measure the lengths of anterior and posterior divisions of the C7 nerve, providing guidelines for surgeons before contralateral cervical 7 nerve transfer.

Methods: A total of 30 patients with CNS and 20 with brachial plexus injury were enrolled in this retrospective study. All patients underwent brachial plexus CUBE-STIR MRI and high-frequency ultrasound, and the lengths of the anterior and posterior divisions of C7 nerve were measured before surgery. Precise length of anterior and posterior divisions of contralateral C7 nerve was measured during surgery.

Results: MRI-measured lengths of anterior and posterior divisions of C7 nerves were positively correlated with that measured during surgery (anterior division, r = 0.94, p < .01; posterior division, r = 0.92, p < .01). High agreement was found between MRI-measured and intra-surgery measured length of anterior and posterior divisions of C7 nerve by BLAD-ALTMAN analysis. Ultrasonography could feasibly image supraclavicular C7 nerve and recognize small variant branches derived from middle trunk of C7 nerve root, which could be dissected intra-operatively and confirmed by electromyography during the procedure of contralateral C7 nerve transfer.

Conclusion: CUBE-STIR MRI had advantages for the imaging of the brachial plexus and measurement of the length of root-trunk-anterior/posterior divisions of C7 nerve. The clinical role of ultrasonography may be a simple way of evaluating general condition of C7 nerve and provide guidelines for contralateral C7 nerve transfer surgery.
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http://dx.doi.org/10.1080/02688697.2019.1584661DOI Listing
March 2019

Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis.

J Oncol 2018 16;2018:5072987. Epub 2018 Sep 16.

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

Purpose: We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC).

Methods: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort.

Results: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed.

Conclusions: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.
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http://dx.doi.org/10.1155/2018/5072987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165607PMC
September 2018

Transcriptomic analyses of chemokines reveal that down-regulation of XCR1 is associated with advanced hepatocellular carcinoma.

Biochem Biophys Res Commun 2018 02 7;496(4):1314-1321. Epub 2018 Feb 7.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China. Electronic address:

Chemokines are essential coordinators of cellular migration and cell-cell interactions, therefore considerable attention has been paid to the application of chemokines to cancer immunotherapy. In this study, we screened for the expression levels of 58 human chemokines/chemokine receptors in hepatocellular carcinoma (HCC) by using samples from the TCGA LIHC cohort and found 16 consistently down-regulated and 11 up-regulated chemokine genes in HCC compared with normal samples. Furthermore, the expressions of XCR1 were verified by Western blot in liver cancer cell lines. We used CCK8, plate cloning formation, scratch-wound and transwell analysis to measure the ability of proliferation, metastasis and invasion, respectively. Protein expression was analyzed by cell immunofluorescence and western-blot. We found that silencing XCR1 promoted, while overexpressing XCR1 inhibited, HCC cell migration and invasion in vitro, its mechanism may involve in inhibition of Epithelial Mesenchymal Transition (EMT). However, the overexpression of XCR1 in HCCLM3 in vitro can restrain the growth partially due to the inhibition of MAPK and PI3K/AKT signaling pathway. Gene Set Enrichment Analysis (GSEA) showed that high expression of XCR1 is positively associated with EMT, which is closely associated with tumor migration and invasion. Our study provides the basis for further investigation of the molecular mechanism by which down-regulation of XCR1 promotes the development and progression of HCC.
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http://dx.doi.org/10.1016/j.bbrc.2018.02.008DOI Listing
February 2018

Tetraspanin-8 promotes hepatocellular carcinoma metastasis by increasing ADAM12m expression.

Oncotarget 2016 Jun;7(26):40630-40643

Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P. R. China.

Recent evidence indicates that tetraspanin-8 (TSPAN8) promotes tumor progression and metastasis. In this study, we explored the effects of TSPAN8 and the molecular mechanisms underlying hepatocellular carcinoma (HCC) metastasis using various HCC cell lines, tissues from 149 HCC patients, and animal models of HCC progression. We showed that elevated expression of TSPAN8 promoted HCC invasion in vitro and metastasis in vivo, but did not influence HCC cell proliferation in vitro. Increased TSPAN8 expression in human HCC was predictive of poor survival, and multivariate analyses indicated TSPAN8 expression to be an independent predictor for both postoperative overall survival and relapse-free survival. Importantly, TSPAN8 enhanced HCC invasion and metastasis by increasing ADAM12m expression. We therefore conclude that TSPAN8 and ADAM12m may be useful therapeutic targets for the prevention of HCC progression and metastasis.
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http://dx.doi.org/10.18632/oncotarget.9769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130032PMC
June 2016

Splenocytes derived from young WT mice prevent AD progression in APPswe/PSENldE9 transgenic mice.

Oncotarget 2015 Aug;6(25):20851-62

Department of Anatomy and Histology & Embryology, Shanghai Medical College of Fudan University, Shanghai, P. R. China.

Immunosenescence contributes to pathogenesis of Alzheimer's disease (AD) in the elderly. In this study, we explored the effects of young wild type (WT) splenocytes (ySCs) on Alzheimer's disease by transplanting ySCs into APPswe/PSENldE9 transgenic mice. Young WT splenocytes not only prevented AD, but also improved the spatial learning and memory of APPswe/PSENldE9 transgenic mice. Young WT splenocytes enhanced Aβ clearance, decreased astrogliosis and increased systemic growth differentiation factor 11 (GDF11) levels. Splenocytes derived from old AD mouse promoted AD. There was an increased number of regulatory T cells (Tregs) among old AD splenocytes. We suggest that alterations of GDF11 and Tregs are involved in AD progression and that rejuvenation of the immune system is a potential therapeutic strategy in AD.
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http://dx.doi.org/10.18632/oncotarget.4930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673234PMC
August 2015

CCR7 enhances TGF-β1-induced epithelial-mesenchymal transition and is associated with lymph node metastasis and poor overall survival in gastric cancer.

Oncotarget 2015 Sep;6(27):24348-60

Department of Anatomy and Histology & Embryology, Shanghai Medical College of Fudan University, Shanghai, P. R. China.

CCR7 is a G protein-coupled chemokine receptor. In this study, we used immunohistochemistry with tissue microarrays to measure CCR7 expression in tumor specimens from 122 patients with gastric cancer. We show that CCR7 expression is associated with lymph node metastasis (P = 0.022) and overall survival (OS; P = 0.025), and is an independent factor associated with poorer overall survival (P = 0.032). The CCR7 mechanism was predicted based on bioinformatic analysis and verified in gastric cancer cell lines and primary tumor samples. The data show that CCR7 contributes to TGF-β1-induced epithelial-mesenchymal transition (EMT) and that the effects of TGF-β1 are inhibited by a CCR7 neutralizing antibody or a NF-κB inhibitor. Increased TGF-β1 expression was accompanied by nuclear localization of NF-κB-p65 and higher levels of the mesenchymal marker vimentin in human gastric cancer samples. We conclude that the CCR7 axis mediates TGF-β1-induced EMT via crosstalk with NF-κB signaling, facilitating lymph node metastasis and poorer overall survival in patients with gastric cancer. These findings suggest CCR7 is a novel prognostic indicator and a potential target for gastric cancer therapy.
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http://dx.doi.org/10.18632/oncotarget.4484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695190PMC
September 2015

Lower serum soluble-EGFR is a potential biomarker for metastasis of HCC demonstrated by N-glycoproteomic analysis.

Discov Med 2015 May;19(106):333-41

Department of Anatomy, Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai, 200032, China.

Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world due to its high metastatic potential. By using the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative N-glycoproteomic analysis, 26 differentially expressed serum glycoproteins derived from defined stages in orthotopic xenograft tumor model were identified. Among them, expression level of soluble EGFR (sEGFR) was verified in HCC cell lines. We found that non-metastasis HCC cell lines express significantly more sEGFR than HCC cell lines with metastasis potential both in cell lysates and culture media. Serum samples from 28 non-metastatic HCC patients and 28 metastatic HCC patients were assayed. Compared with the non-metastatic HCC group, serum level of sEGFR in metastatic HCC group was statistically lower (p<0.01). All these results provide evidence that sEGFR is a potential candidate for metastasis-associated biomarkers of HCC. The related molecular mechanism deserves to be further explored.
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May 2015

Combined treatment of amyloid-β₁₋₄₂-stimulated bone marrow-derived dendritic cells plus splenocytes from young mice prevents the development of Alzheimer's disease in APPswe/PSENldE9 mice.

Neurobiol Aging 2015 Jan 3;36(1):111-22. Epub 2014 Jul 3.

Department of Anatomy, Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai, P.R. China. Electronic address:

Anti-amyloid-β (Aβ) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aβ immunotherapy. In this study, a combined treatment of Aβ₁₋₄₂-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aβ antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of CD68 positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aβ plaques. In conclusion, the Aβ₁₋₄₂-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.029DOI Listing
January 2015

Special role of Foxp3 for the specifically altered microRNAs in Regulatory T cells of HCC patients.

BMC Cancer 2014 Jul 7;14:489. Epub 2014 Jul 7.

Lab of Tumor Immunology, Department of Anatomy and Histology & Embryology, Shanghai Medical College of Fudan University, 138 Yixueyuan Road, 200032 Shanghai, PR China.

Background: Regulatory T cells (Tregs) exhibit functional abnormalities in the context of hepatocellular carcinoma (HCC). The microRNAs (miRNAs) are identified as the key modulators in Tregs. This study was to explore whether the expression profiles of miRNAs of Tregs were different in HCC-activated Tregs and whether Foxp3 had special effects on them.

Methods: We isolated HCC-activated Tregs from mice bearing HCC and compared the expression profiles of miRNAs between HCC-activated Tregs and control Tregs by microarray. RNA interference against Foxp3 was also performed through transfection of synthetic siRNAs to Tregs for analyzing the effect of Foxp3 on the expression of miRNAs. Tregs isolated from HCC patients (n = 12) and healthy controls (n = 7) were used for validation of the differentially expressed miRNAs. Finally, bioinformatic analysis was applied to infer their possible roles.

Results: We found nine specifically altered miRNAs in HCC-activated Tregs from the murine model. After transfection with siRNAs against Foxp3, control Tregs showed obvious reduction of Foxp3 and five miRNAs were significantly changed; HCC-activated Tregs exhibited a slight reduction of Foxp3 with three miRNAs significantly changed. Tregs from HCC patients and healthy controls finally confirmed the up-regulation of four miRNAs (hsa-miR-182-5p, hsa-miR-214-3p, hsa-miR-129-5p and hsa-miR-30b-5p). Following bioinformatic analysis suggested these altered miRNAs would target eight important signaling pathways that could affect the functions of Tregs.

Conclusions: Our studies provided the first evidence that Tregs in HCC had the specifically altered expression of miRNAs, which was affected by Foxp3. These results are useful both in finding new biomarkers and in further exploring the functions of Tregs in HCC patients.
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http://dx.doi.org/10.1186/1471-2407-14-489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099493PMC
July 2014

Aberrant expression of sphingosine-1-phosphate receptor 1 correlates with metachronous liver metastasis and poor prognosis in colorectal cancer.

Tumour Biol 2014 Oct 28;35(10):9743-50. Epub 2014 Jun 28.

Department of General Surgery, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.

There are currently no accurate predictive markers of metachronous liver metastasis from colorectal cancer. Recent studies demonstrated that the expression patterns of sphingosine-1-phosphate receptor 1 (S1PR1) are altered in several tumors, but in colorectal cancer, the patterns remain unknown. Our study was designed to evaluate the expression and prognostic significance of S1PR1 protein in patients with colorectal cancer. The expression of S1PR1 was detected using the tissue microarray technique and immunohistochemical method and compared with clinicopathological parameters in 153 colorectal cancer patients. The prognostic value of S1PR1 expression was evaluated by Kaplan-Meier and Cox regression analysis. A molecular prognostic stratification scheme incorporating S1PR1 expression was determined by using receiver operating characteristic (ROC) analysis. S1PR1 was significantly highly expressed in 70.6 % (108/153) of the colorectal cancer lesions compared to their high expressions in only 5.9 % (9/153) of the adjacent non-cancerous tissues. Upregulated expression of S1PR1 was significantly associated with depth invasion and metachronous liver metastasis. Increased S1PR1 expression in colorectal cancer was positively correlated with poor overall survival. Multivariate survival analysis suggested that S1PR1 expression was an independent prognostic indicator for the disease. Applying the prognostic value of S1PR1 density to TNM stage system showed a better prognostic value in patients with colorectal cancer. Aberrant S1PR1 expression in colorectal cancer was associated with metachronous liver metastasis and worse survival outcome, and also, it was an independent prognostic factor. According to our analysis, combined TNM stage and intratumoral expression of S1PR1 demonstrated a better prognostic value than any of these two parameters alone. Conclusively, we suggest that detection and analysis of S1PR1 expression in colorectal cancer tissue might be used for predicting prognosis of colorectal cancer.
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http://dx.doi.org/10.1007/s13277-014-2267-4DOI Listing
October 2014

TGF-β1-induced expression of Id-1 is associated with tumor progression in gastric cancer.

Med Oncol 2014 Jul 27;31(7):19. Epub 2014 May 27.

Laboratory of Tumor Immunology, Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China.

Transforming growth factor β1 (TGF-β1) and inhibitor of differentiation/DNA-binding 1 (Id-1) have been shown to be associated with aggressive metastatic behavior of cancer cells in many malignant tumors. However, their role in gastric cancer (GC) has not been established. In this study, we investigated the relationship between expression of Id-1 and TGF-β1 in GC as well as their association with GC progression. The immunohistochemical analysis of 71 human GC samples indicated that both Id-1 and TGF-β1 were markedly upregulated in tumor tissue compared with the adjacent tissue; in addition, a significant positive correlation was found between the expression levels of Id-1 and TGF-β1 by Pearson's correlation analysis. Furthermore, the investigation of the association of Id-1 and TGF-β1 with patient clinical characteristics revealed that Id-1 expression was significantly correlated with tumor differentiation, while TGF-β1 was associated with lymph node metastasis. The results were validated in vitro by using a GC cell line, AGS. The expression of Id-1 was upregulated at 24 and 48 h after the treatment with TGF-β1, whereas it did not affect the proliferation of cells. TGF-β1 also influenced the expression of N-cadherin and β-catenin. Our results suggested that Id-1 and TGF-β1 played important roles in the progression of GC, in which Id-1 might act as a downstream mediator of TGF-β1 signaling through a regulatory mechanism involving N-cadherin and β-catenin. The TGF-β1/Id-1 axis might serve as a future therapeutic target for GC.
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http://dx.doi.org/10.1007/s12032-014-0019-3DOI Listing
July 2014

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma.

Mol Cancer 2013 Dec 5;12(1):153. Epub 2013 Dec 5.

Principle Investigator of the Lab of Tumor Immunology, the Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, P R China.

Background: Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice.

Methods: C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro.

Results: Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy.

Conclusions: Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs.
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http://dx.doi.org/10.1186/1476-4598-12-153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914677PMC
December 2013

The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector.

Mol Biol Rep 2013 Oct;40(10):5615-23

To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene. AAV Helper-Free system was used for rAAV-SLC package. The anti-tumor effect of SLC was detected by bearing tumor established from Hepal-6 cells both in C57BL/6J and nude mice. Flow cytometry analysis and IHC for Tumor-infiltrating T cells and CD11c+DCs were also investigated to explore the immunological mechanism. rAAV-SLC was successfully packaged in AAV293 cells and transfected Hepal-6 tumor cells at high efficiency. The anti-tumor effect was demonstrated by less tumor weight and longer survival outcome. Coincident with the anti-tumor response, local elaboration of SLC within the tumor bed elicited a heavy infiltration of CD4+, CD8+T cells and CD11c+ dendritic cells into the tumor sites. More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs). Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect. The study also suggested that Tregs in the tumor microenvironment tampered the anti-tumor effect.
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http://dx.doi.org/10.1007/s11033-013-2663-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824217PMC
October 2013

CCR7 expression and intratumoral FOXP3+ regulatory T cells are correlated with overall survival and lymph node metastasis in gastric cancer.

PLoS One 2013 5;8(9):e74430. Epub 2013 Sep 5.

Department of Histology and Embryology, Tongji University School of Medicine, Shanghai, China.

The aim of this study was to investigate the prognostic value of chemokine receptor CCR7 expression and intratumoral FOXP3(+) regulatory T cells (Tregs) in gastric cancer. CCR7(+) tumor cells and FOXP3(+) Tregs were assessed by immunohistochemistry in tissue microarrays containing gastric cancer from 133 patients. Prognostic effects of low or high CCR7 and FOXP3 expression were evaluated by Cox regression and Kaplan-Meier analysis, as well as the correlation between CCR7 positive score and intratumoral FOXP3(+) cell number in a longitudinal assessment. The analysis showed that the high expression levels of CCR7 and FOXP3 were detected in 69.9% and 65.4% of cases, respectively. High CCR7 expression in gastric cancer cells was significantly associated with poor overall survival (OS) (P = 0.010) and lymph node metastasis (P = 0.009), and was an independent factor for worse OS (P = 0.023) by multivariate analysis. High numbers of intratumoral FOXP3(+) Tregs significantly correlated with shorter OS (P = 0.021) and lymph node metastasis (P = 0.024), and was also an independent factor for adverse OS (P = 0.035). Furthermore, there was a significantly positive correlation between CCR7 positive score and intratumoral FOXP3(+) cell number (r = 0.949, P<0.001). These results revealed that CCR7 expression in gastric cancer cells and intratumoral FOXP3(+) Tregs could be considered as a co-indicator of clinical prognosis of gastric cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764061PMC
June 2014

Depletion of CD4+ CD25+ regulatory T cells promotes CCL21-mediated antitumor immunity.

PLoS One 2013 2;8(9):e73952. Epub 2013 Sep 2.

Department of Histology and Embryology, Tongji University School of Medicine, Shanghai, China.

CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4(+) CD25(+) Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4(+), CD8(+) T cells and CD11c(+) DCs within the tumor, coincident with marked induction of tumor-specific CD8(+) cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759453PMC
April 2014

Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer.

J Cancer Res Clin Oncol 2010 Oct 11;136(10):1585-95. Epub 2010 Mar 11.

The General Surgery Department of Zhongshan Hospital, Fudan University, Shanghai, China.

Purpose: The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs and Tregs/CD8+ ratios in gastric cancer patients after R0 resection.

Patients And Methods: From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff.

Results: It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (chi(2) test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458).

Conclusions: Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.
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http://dx.doi.org/10.1007/s00432-010-0816-9DOI Listing
October 2010

SLC/CCR7 stimulates the proliferation of BMDCs by the pNF-kappaB p65 pathway.

Anat Rec (Hoboken) 2010 Jan;293(1):48-54

Department of Anatomy, Histology and Embryology, Shanghai Medical College of Fudan University, Shanghai 200032, China.

The chemokine receptor CCR7 is highly expressed in dendritic cells (DCs), T cells, and other immune effector cells. One of the high-affinity ligand that can bind to CCR7 is the secondary lymphoid tissue chemokine (SLC). The SLC/CCR7 axis plays an important role in the immune system by inducing the chemotaxis and migration of immune effector cells. In this study, we examined the effect of SLC at different concentrations (0, 50, 100, 200, 300, and 400 ng/mL) on the proliferation of bone-marrow-derived dendritic cells (BMDCs). ELC (CCL19), another high-affinity ligand for CCR7, was used as the control at the same time. We found that SLC directly stimulated the proliferation of BMDCs and enhanced the antigen-presenting function and CCR7 expression. Western blot analysis showed that pNF-kappaBp65 was involved in this mechanism. We also found that the NF-kappaB inhibitor PDTC could specifically block the proliferation and CCR7 expression of BMDCs induced by SLC or ELC (200 ng/mL). The results suggested that there were cross-talk signals between the chemotaxis and proliferation of BMDCs involving the SLC/CCR7 axis.
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http://dx.doi.org/10.1002/ar.21015DOI Listing
January 2010

Overexpression of suppressor of cytokine signaling 1 in islet grafts results in anti-apoptotic effects and prolongs graft survival.

Life Sci 2009 Jun 1;84(23-24):810-6. Epub 2009 Apr 1.

Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, 130 Dong An Road, Shanghai 200032, China.

Aims: A significant portion of islet grafts are destroyed by apoptosis and fail to become functional after transplantation. Strategies that enhance islet resistance to apoptosis may prevent graft loss. The aim of this study was to investigate whether overexpression of suppressor of cytokine signaling 1 (SOCS1) in islet grafts could achieve an anti-apoptotic effect and prolong graft survival.

Main Methods: We used a chimeric adenovirus vector (Ad5F35) to enhance SOCS1 expression in isolated rat islets, and assessed its protective action against TNF-alpha-induced apoptosis. After transplanting SOCS1-overexpressing islets into allogeneic recipients with streptozotocin-induced diabetes, graft survival and in situ apoptosis were analyzed using immunohistochemistry.

Key Findings: The isolated rat islets infected with Ad5F35-SOCS1 showed significantly higher SOCS1 expression than Ad5F35-EGFP and mock infected islets. The Ad5F35 transfection and SOCS1 overexpression on islets did not affect their insulin secretory function. After treatment with rat TNF-alpha and cycloheximide in vitro, Ad5F35-SOCS1 infected islets exhibited a lower apoptotic ratio than controls (Ad5F35-EGFP and mock infected islets). The diabetic recipients transplanted with Ad5F35-SOCS1 infected islets displayed longer time of normoglycemia than recipients transplanted with mock infected islets. Furthermore, histological analysis indicated that the infected grafts with local overexpression of SOCS1 showed decreased apoptosis in the early post-transplant period.

Significance: These results demonstrate that overexpression of SOCS1 in islet grafts prior to transplantation can significantly protect them from apoptotic loss and prolong their survival. This approach might find a clinical counterpart.
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http://dx.doi.org/10.1016/j.lfs.2009.03.010DOI Listing
June 2009
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