Publications by authors named "Peter J Nelson"

162 Publications

Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation.

Redox Biol 2021 May 13;41:101942. Epub 2021 Mar 13.

Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China. Electronic address:

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), but its clinical effects are still limited. In this study we identify Quiescin sulfhydryl oxidase 1 (QSOX1) acting as a cellular pro-oxidant, specifically in the context of sorafenib treatment of HCC. QSOX1 disrupts redox homoeostasis and sensitizes HCC cells to oxidative stress by inhibiting activation of the master antioxidant transcription factor NRF2. A negative correlation between QSOX1 and NRF2 expression was validated in tumor tissues from 151 HCC patients. Mechanistically, QSOX1 restrains EGF-induced EGFR activation by promoting ubiquitination-mediated degradation of EGFR and accelerating its intracellular endosomal trafficking, leading to suppression of NRF2 activity. Additionally, QSOX1 potentiates sorafenib-induced ferroptosis by suppressing NRF2 in vitro and in vivo. In conclusion, the data presented identify QSOX1 as a novel candidate target for sorafenib-based combination therapeutic strategies in HCC or other EGFR-dependent tumor types.
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http://dx.doi.org/10.1016/j.redox.2021.101942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024711PMC
May 2021

Integrin αvβ3-dependent thyroid hormone effects on tumour proliferation and vascularisation.

Endocr Relat Cancer 2020 12;27(12):685-697

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

Thyroid hormones are emerging as critical regulators of tumour growth and progression. To assess the contribution of thyroid hormone signalling via integrin αvβ3, expressed on many tumour cells, endothelial cells, and stromal cells, to tumour growth, we compared the effects of thyroid hormones vs tetrac, a specific inhibitor of thyroid hormone action at integrin αvβ3, in two murine xenograft tumour models with and without integrin αvβ3 expression. Integrin αvβ3-positive human anaplastic thyroid cancer cells SW1736 and integrin αvβ3-negative human hepatocellular carcinoma cells HuH7 were injected into the flanks of nude mice. Tumour growth was monitored in euthyroid, hyperthyroid, hypothyroid, and euthyroid tetrac-treated mice. In SW1736 xenografts, hyperthyroidism led to a significantly increased tumour growth resulting in a decreased survival compared to euthyroid mice, while tumour growth was significantly reduced and, hence, survival prolonged in hypothyroid and tetrac-treated mice. Both proliferation and vascularisation, as determined by Ki67 and CD31 immunofluorescence staining, respectively, were significantly increased in tumours from hyperthyroid mice as compared to hypothyroid and tetrac-treated mice. No differences in tumour growth, survival, or Ki67 staining were observed between the different groups in integrin αvβ3-negative HuH7 xenografts. Vascularisation, however, was significantly decreased in hypothyroid and tetrac-treated mice compared to euthyroid and hyperthyroid mice. Apoptosis was not affected in either tumour model, nor were cell proliferation or apoptosis in vitro. Tumour growth regulation by thyroid hormones in αvβ3-positive tumours has important implications for cancer patients, especially those with thyroid dysfunctions and thyroid cancer patients treated with thyrotropin-suppressive L-thyroxine doses.
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http://dx.doi.org/10.1530/ERC-20-0353DOI Listing
December 2020

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy.

Mol Ther 2021 02 15;29(2):788-803. Epub 2020 Oct 15.

Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany; Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA. Electronic address:

The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.
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http://dx.doi.org/10.1016/j.ymthe.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854278PMC
February 2021

Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer.

Theranostics 2020 1;10(16):7178-7192. Epub 2020 Jun 1.

Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and effective therapy remains a challenge. IFIT3 is an interferon-stimulated gene with antiviral and pro-inflammatory functions. Our previous work has shown that high expression of IFIT3 is correlated with poor survival in PDAC patients who receive chemotherapy suggesting a link between IFIT3 and chemotherapy resistance in PDAC. However, the exact role and molecular mechanism of IFIT3 in chemotherapy resistance in PDAC has been unclear. A group of transcriptome datasets were downloaded and analyzed for the characterization of IFIT3 in PDAC. Highly metastatic PDAC cell line L3.6pl and patient-derived primary cell TBO368 were used and IFIT3 knockdown and the corresponding knockin cells were established for studies. Chemotherapy-induced apoptosis, ROS production, confocal immunofluorescence, subcellular fractionation, chromatin-immunoprecipitation, co-immunoprecipitation and mass spectrometry analysis were determined to further explore the biological role of IFIT3 in chemotherapy resistance of PDAC. Based on PDAC transcriptome data, we show that IFIT3 expression is associated with the squamous molecular subtype of PDAC and an increase in inflammatory response and apoptosis pathways. We further identify a crucial role for IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuates the chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments, independent of individual chemotherapy regimens. While IFIT3 overexpression was found to promote drug resistance. Co-immunoprecipitation identified a direct interaction between IFIT3 and the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. It was subsequently found that IFIT3 regulates the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with O-GlcNAc transferase. Increased O-GlcNAcylation of VDAC2 protected PDAC cells from chemotherapy induced apoptosis. These results effectively demonstrate a central mechanism by which IFIT3 expression can affect chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 may represent a novel strategy to sensitize aggressive forms of pancreatic cancer to conventional chemotherapy regimens.
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http://dx.doi.org/10.7150/thno.43093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330856PMC
May 2021

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer.

Signal Transduct Target Ther 2020 05 13;5(1):53. Epub 2020 May 13.

Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200040, China.

Enolase 2 (ENO2) is a key glycolytic enzyme in the metabolic process of glycolysis, but its potential function in pancreatic ductal adenocarcinoma (PDAC) is unclear. In this study, we observed a significant overexpression of ENO2 in PDAC tissues, and its expression was correlated with metastasis and poor prognosis in PDAC patients. K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity, cell metabolism and PDAC progression. Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC. Re-expression of wild-type (WT) ENO2, but not the K394 acetylation mimetic mutant, could reverse the decreased tumor malignancy. We further characterized histone deacetylase 3 (HDAC3) and P300/CBP-associated factor (PCAF) as the potential deacetylase and acetyltransferase for ENO2, respectively. HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis. Importantly, insulin-like growth factor-1 (IGF-1) was found to decrease K394 acetylation and stimulate ENO2 activity in a dose- and time-dependent manner. The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424, which promoted K394 deacetylation and activation of ENO2. Linsitinib, an oral small-molecule inhibitor of IGF-1R, could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway. Furthermore, linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2. Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis. Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.
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http://dx.doi.org/10.1038/s41392-020-0146-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217878PMC
May 2020

Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter () gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells.

Theranostics 2020 15;10(10):4490-4506. Epub 2020 Mar 15.

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs). : NIS induction in heat-treated HSP70B-NIS-MSCs was verified by I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by I-scintigraphy. The most effective uptake regime was then selected for I therapy. : The HSP70B promoter showed low basal activity and was significantly induced in response to heat. , the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups. : The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.
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http://dx.doi.org/10.7150/thno.41489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150485PMC
April 2021

Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5.

J Clin Med 2020 Apr 2;9(4). Epub 2020 Apr 2.

Department of Plastic and Hand Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.

The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts. Decellularization of this co-culture after seven days reveals an extracellular matrix that is linear in fashion, high in pro-oncogenic collagen type VI, and able to promote invasion of reseeded cells. Further investigation revealed linear collagen VI is produced by fibroblasts in response to a paracrine co-culture of adipose derived stem cells and MDA-MB-231, which together secrete high levels of the chemokine CCL5. The addition of monoclonal antibody against CCL5 to the co-culture results in an unorganized matrix with dramatically decreased collagen VI. Importantly, reseeded cells do not exhibit pro-oncogenic behavior. These data illustrate a cellular mechanism, which creates linear extracellular matrix (ECM) in vitro, and highlight a potential role of CCL5 for building striated tumor collagen in vivo.
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http://dx.doi.org/10.3390/jcm9040991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230614PMC
April 2020

Integrin αvβ3-Mediated Effects of Thyroid Hormones on Mesenchymal Stem Cells in Tumor Angiogenesis.

Thyroid 2019 12 9;29(12):1843-1857. Epub 2019 Dec 9.

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

Several clinical and experimental studies have implicated thyroid hormones in cancer progression. Cancer-relevant effects, including stimulation of tumor growth and new blood vessel formation by angiogenesis, are thought to be mediated by a nonclassical signaling pathway initiated through integrin αvβ3 expressed on cancer cells and proliferating endothelium. In an earlier study, we established mesenchymal stem cells (MSCs), important contributors to the fibrovascular network of tumors, as new thyroid hormone-dependent targets. Here, we evaluated the effects of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) versus Tetrac, an integrin-specific inhibitor of thyroid hormone action, on MSCs in tumor angiogenesis. Modulation of the expression and secretion of angiogenesis-relevant factors by thyroid hormones in primary human MSCs and their effect on endothelial cell tube formation were tested . We further engineered MSCs to express the sodium iodide symporter () reporter gene under control of a hypoxia-responsive promoter and the vascular endothelial growth factor (VEGF) promoter to test effects on these pathways and, for VEGF, in an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model by positron emission tomography imaging. T3 and T4 increased the expression of pro-angiogenic genes in MSCs and NIS-mediated radioiodide uptake in both NIS reporter MSC lines in the presence of HCC cell-conditioned medium. Supernatant from thyroid hormone-treated MSCs significantly enhanced endothelial cell tube formation. Tetrac and/or inhibitors of signaling pathways downstream of the integrin reversed all these effects. Tumoral radioiodide uptake demonstrated successful recruitment of MSCs to tumors and VEGF promoter-driven NIS expression. Hyperthyroid mice showed an increased radioiodide uptake compared with euthyroid mice, while tracer uptake was markedly reduced in hypothyroid and Tetrac-treated mice. Our data suggest that thyroid hormones influence angiogenic signaling in MSCs via integrin αvβ3 and further substantiate the anti-angiogenic activity of Tetrac in the tumor microenvironment.
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http://dx.doi.org/10.1089/thy.2019.0413DOI Listing
December 2019

Therapeutic Strategies Targeting Cancer Stem Cells and Their Microenvironment.

Front Oncol 2019 24;9:1104. Epub 2019 Oct 24.

Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai, China.

Cancer stem cells (CSCs) have been demonstrated in a variety of tumors and are thought to act as a clonogenic core for the genesis of new tumor growth. This small subpopulation of cancer cells has been proposed to help drive tumorigenesis, metastasis, recurrence and conventional therapy resistance. CSCs show self-renewal and flexible clonogenic properties and help define specific tumor microenvironments (TME). The interaction between CSCs and TME is thought to function as a dynamic support system that fosters the generation and maintenance of CSCs. Investigation of the interaction between CSCs and the TME is shedding light on the biologic mechanisms underlying the process of tumor malignancy, metastasis, and therapy resistance. We summarize recent advances in CSC biology and their environment, and discuss the challenges and future strategies for targeting this biology as a new therapeutic approach.
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http://dx.doi.org/10.3389/fonc.2019.01104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821685PMC
October 2019

Tumor biology and multidisciplinary strategies of oligometastasis in gastrointestinal cancers.

Semin Cancer Biol 2020 02 21;60:334-343. Epub 2019 Aug 21.

Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany; Center for Integrated Oncology (CIO) Achen, Bonn, Cologne and Düsseldorf, Cologne, Germany. Electronic address:

More than 70% of gastrointestinal (GI) cancers are diagnosed with metastases, leading to poor prognosis. For some cancer patients with limited sites of metastatic tumors, the term oligometastatic disease (OMD) has been coined as opposed to systemic polymetastasis (PMD) disease. Stephan Paget first described an organ-specific pattern of metastasis in 1889, now known as the "seed and soil" theory where distinct cancer types are found to metastasize to different tumor-specific sites. Our understanding of the biology of tumor metastasis and specifically the molecular mechanisms driving their formation are still limited, in particular, as it relates to the genesis of oligometastasis. In the following review, we discuss recent advances in general understanding of this metastatic behavior including the role of specific signaling pathways, various molecular features and biomarkers, as well as the interaction of carcinoma cells with their tissue microenvironments (both primary and metastatic niches). The unique features that underlie OMD provide potential targets for localized therapy. As it relates to clinical practice, OMD is emerging as treatable with surgical resection and/or other local therapy options. Strategies currently being applied in the clinical management of OMD will be discussed including surgical, radiation-based therapy, ablation procedures, and the results of emerging clinical trials involving immunotherapy.
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http://dx.doi.org/10.1016/j.semcancer.2019.08.026DOI Listing
February 2020

Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell-Mediated Sodium Iodide Symporter () Gene I Therapy.

Clin Cancer Res 2019 10 13;25(19):5997-6008. Epub 2019 Jun 13.

Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.

Purpose: The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter () transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT.

Experimental Design: We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using I-scintigraphy followed by I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7).

Results: Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored by I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications.

Conclusions: MSC-based NIS-mediated I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based expression within the tumor milieu.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4092DOI Listing
October 2019

Tetrac as an anti-angiogenic agent in cancer.

Endocr Relat Cancer 2019 06;26(6):R287-R304

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

The thyroid hormones T3 and T4 have emerged as pro-angiogenic hormones with important implications for cancer management. Endogenous circulating hormone levels may help stimulate cancer progression and limit the effectiveness of anticancer therapy, though clinical data remain inconclusive. The capacity of thyroid hormones to modulate angiogenesis is mediated through non-canonical mechanisms initiated at the cell surface receptor integrin αvβ3. This integrin is predominantly expressed on tumour cells, proliferating endothelial cells and tumour stroma-associated cells, emphasising its potential relevance in angiogenesis and tumour biology. Thyroid hormone/integrin αvβ3 signalling results in the activation of intracellular pathways that are commonly associated with angiogenesis and are mediated through classical pro-angiogenic molecules such as vascular endothelial growth factor. The naturally occurring T4 analogue tetrac blocks the pro-angiogenic actions of thyroid hormones at the integrin receptor, in addition to agonist-independent anti-angiogenic effects. Tetrac reduces endothelial cell proliferation, migration and tube formation through a reduction in the transcription of vascular growth factors/growth factor receptors, hypoxia-inducible factor-1α, pro-angiogenic cytokines and a number of other pro-angiogenic genes, while at the same time stimulating the expression of endogenous angiogenesis inhibitors. It further modulates vascular growth factor activity by disrupting the crosstalk between integrin αvβ3 and adjacent growth factor receptors. Moreover, tetrac disrupts thyroid hormone-stimulated tumour recruitment, differentiation and the pro-angiogenic signalling of tumour stroma-associated mesenchymal stem cells. Tetrac affects tumour-associated angiogenesis via multiple mechanisms and interferes with other cancer cell survival pathways. In conjunction with its low toxicity and high tissue selectivity, tetrac is a promising candidate for clinical application.
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http://dx.doi.org/10.1530/ERC-19-0058DOI Listing
June 2019

Core fucosylated glycan-dependent inhibitory effect of QSOX1-S on invasion and metastasis of hepatocellular carcinoma.

Cell Death Discov 2019 3;5:84. Epub 2019 Apr 3.

1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China.

The goal of the present study was to identify glycoproteins associated with the postoperative relapse of hepatocellular carcinoma (HCC) and to investigate their potential role in HCC metastasis. A method for quantitating N-glycoproteome was used to screen for, and identify, recurrence-related N-linked glycoproteins from 100 serum samples taken from patients with early-stage HCC. The prognostic significance of candidate glycoproteins was then validated in 193 HCC tissues using immunohistochemical staining. Serum core fucosylated quiescin sulfhydryl oxidase 1 (cf-QSOX1) was identified as a leading prognostic glycoprotein that significantly correlated with HCC recurrence. Patients with high serum cf-QSOX1 levels had a significantly longer time to recurrence (TTR) as compared with those with low serum cf-QSOX1. As was seen with serum cf-QSOX1, QSOX1 in HCC tissues was further shown to be significantly associated with good patient outcome. Gain-functional and loss-functional analyses of QSOX1-S were performed in vitro and in vivo. QSOX1-S overexpression significantly increased in vitro apoptosis, but decreased the invasive capacity of HCC cells, and reduced lung metastasis in nude mice models bearing human HCC. Furthermore, overexpression of a mutant version of QSOX1-S, which had eliminated the core-fucosylated glycan at Asn-130, showed no demonstrable effect on invasion or metastasis of HCC cells. Our study suggests that serum cf-QSOX1-S and tumor QSOX1 levels are helpful for predicting recurrence in HCC patients, and its core-fucosylated glycan at Asn-130 is critical for the inhibitory effects of QSOX1-S on invasion and metastasis of HCC.
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http://dx.doi.org/10.1038/s41420-019-0164-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447561PMC
April 2019

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial.

Int J Cancer 2019 09 13;145(6):1538-1546. Epub 2019 Mar 13.

Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany.

TREAT-ME-1, a Phase 1/2 open-label multicenter, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC), MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Immunological and inflammatory markers were also assessed. All patients (3 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 at one dose level on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer's instructions for 48─72 h after MSC_apceth_101 injection. Ten patients were treated with a total dose of 3.0 x 10 cells/kg MSC_apceth_101. 36 adverse events and six serious adverse events were reported. Five patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.8 months (95% CI: 0.5, 3.9 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (1 year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease.
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http://dx.doi.org/10.1002/ijc.32230DOI Listing
September 2019

A Novel Approach for Image-Guided I Therapy of Pancreatic Ductal Adenocarcinoma Using Mesenchymal Stem Cell-Mediated NIS Gene Delivery.

Mol Cancer Res 2019 01 17;17(1):310-320. Epub 2018 Sep 17.

Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.

The sodium iodide symporter () as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a -expressing plasmid driven by the -promoter (NIS-MSC). I-scintigraphy and I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated delivery, followed by I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of α-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive I therapeutic effect. IMPLICATIONS: These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0185DOI Listing
January 2019

TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer.

Endocr Relat Cancer 2019 01;26(1):89-101

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

Based on their excellent tumor-homing capacity, genetically engineered mesenchymal stem cells (MSCs) are under investigation as tumor-selective gene delivery vehicles. Transgenic expression of the sodium iodide symporter (NIS) in genetically engineered MSCs allows noninvasive tracking of MSC homing by imaging of functional NIS expression as well as therapeutic application of 131I. The use of tumor stroma-activated promoters can improve tumor-specific MSC-mediated transgene delivery. The essential role of transforming growth factor B1 (TGFB1) and the SMAD downstream target in the signaling between tumor and the surrounding stroma makes the biology of this pathway a potential option to better control NIS expression within the tumor milieu. Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by a synthetic SMAD-responsive promoter (SMAD-NIS-MSCs). Radioiodide uptake assays revealed a 4.9-fold increase in NIS-mediated perchlorate-sensitive iodide uptake in SMAD-NIS-MSCs after TGFB1 stimulation compared to unstimulated cells demonstrating the successful establishment of MSCs, which induce NIS expression in response to activation of TGFB1 signaling using a SMAD-responsive promoter. 123I-scintigraphy revealed significant tumor-specific radioiodide accumulation and thus NIS expression after systemic application of SMAD-NIS-MSCs into mice harboring subcutaneous tumors derived from the human hepatocellular carcinoma (HCC) cell line HuH7, which express TGFB1. 131I therapy in SMAD-NIS-MSCs-treated mice demonstrated a significant delay in tumor growth and prolonged survival. Making use of the tumoral TGFB1 signaling network in the context of MSC-mediated NIS gene delivery is a promising approach to foster tumor stroma-selectivity of NIS transgene expression and tailor NIS-based gene therapy to TGFB1-rich tumor environments.
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http://dx.doi.org/10.1530/ERC-18-0173DOI Listing
January 2019

Synthesis of next generation dual-responsive cross-linked nanoparticles and their application to anti-cancer drug delivery.

Nanoscale 2018 Aug;10(34):16062-16068

WACKER Lehrstuhl für Makromolekulare Chemie, Technische Universität München, Lichtenbergstraße 4, 85748 Garching bei München, Germany.

Rare earth metal-mediated group transfer polymerisation enables the synthesis of previously inaccessible block copolymers of 2-vinylpyridine, diethyl vinylphosphonate and the new diallyl vinylphosphonate monomer. This precision polymerisation and the selective cross-linking of allyl side groups via thiol-ene click chemistry leads to the formation of well-defined dual-responsive nanoparticles. We demonstrate that these next generation nanocarriers are pH- and temperature-responsive and are capable of efficiently delivering doxorubicin into the nucleus of cancer cells. High anti-cancer activity could be demonstrated via cytotoxicity tests on breast cancer (MCF-7) and cervical cancer (HeLa) cells. These results validate this modular synthesis route as an ideal platform for the development of sophisticated nanocarriers for future drug delivery applications.
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http://dx.doi.org/10.1039/c8nr04760jDOI Listing
August 2018

Targeting cancer stem cells and their niche: perspectives for future therapeutic targets and strategies.

Semin Cancer Biol 2018 12 3;53:139-155. Epub 2018 Aug 3.

General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany. Electronic address:

A small subpopulation of cells within the bulk of tumors share features with somatic stem cells, in that, they are capable of self-renewal, they differentiate, and are highly resistant to conventional therapy. These cells have been referred to as cancer stem cells (CSCs). Recent reports support the central importance of a cancer stem cell-like niche that appears to help foster the generation and maintenance of CSCs. In response to signals provided by this microenvironment, CSCs express the tumorigenic characteristics that can drive tumor metastasis by the induction of epithelial-mesenchymal-transition (EMT) that in turn fosters the migration and recolonization of the cells as secondary tumors within metastatic niches. We summarize here recent advances in cancer stem cell research including the characterization of their genetic and epigenetic features, metabolic specialities, and crosstalk with aging-associated processes. Potential strategies for targeting CSCs, and their niche, by regulating CSCs plasticity, or therapeutic sensitivity is discussed. Finally, it is hoped that new strategies and related therapeutic approaches as outlined here may help prevent the formation of the metastatic niche, as well as counter tumor progression and metastatic growth.
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http://dx.doi.org/10.1016/j.semcancer.2018.08.002DOI Listing
December 2018

Studies on the Biocompatibility of Poly(diethyl vinyl-phosphonate) with a New Fluorescent Marker.

Macromol Rapid Commun 2018 Aug 11;39(15):e1800259. Epub 2018 Jun 11.

Wacker Chair of Macromolecular Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany.

Utilization of group transfer polymerization for the synthesis of poly(diethyl vinylphosphonate) (PDEVP) allows its controlled end-group functionalization. Thus, a new fluorescent chromophore/PDEVP conjugate is prepared and subjected to biocompatibility tests on two different human cell lines. In contrast to the previous studies, the tagged polymer is not absorbed by cells from the solution and has nearly no impact on cell mortality rate.
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http://dx.doi.org/10.1002/marc.201800259DOI Listing
August 2018

External Beam Radiation Therapy Enhances Mesenchymal Stem Cell-Mediated Sodium-Iodide Symporter Gene Delivery.

Hum Gene Ther 2018 11 3;29(11):1287-1300. Epub 2018 May 3.

1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany .

The tumor-homing properties of mesenchymal stem cells (MSC) have led to their development as delivery vehicles for the targeted delivery of therapeutic genes such as the sodium-iodide symporter (NIS) to solid tumors. External beam radiation therapy may represent an ideal setting for the application of engineered MSC-based gene therapy, as tumor irradiation may enhance MSC recruitment into irradiated tumors through the increased production of select factors linked to MSC migration. In the present study, the irradiation of human liver cancer cells (HuH7; 1-10 Gy) showed a strong dose-dependent increase in steady-state mRNA levels of CXCL8, CXCL12, FGF2, PDGFB, TGFB1, THBS1, and VEGF (0-48 h), which was verified for most factors at the protein level (after 48 h). Radiation effects on directed MSC migration were tested in vitro using a live cell tracking migration assay and supernatants from control and irradiated HuH7 cells. A robust increase in mean forward migration index, mean center of mass, and mean directionality of MSCs toward supernatants was seen from irradiated as compared to non-irradiated tumor cells. Transferability of this effect to other tumor sources was demonstrated using the human breast adenocarcinoma cell line (MDA-MB-231), which showed a similar behavior to radiation as seen with HuH7 cells in quantitative polymerase chain reaction and migration assay. To evaluate this in a more physiologic in vivo setting, subcutaneously growing HuH7 xenograft tumors were irradiated with 0, 2, or 5 Gy followed by CMV-NIS-MSC application 24 h later. Tumoral iodide uptake was monitored using I-scintigraphy. The results showed increased tumor-specific dose-dependent accumulation of radioiodide in irradiated tumors. The results demonstrate that external beam radiation therapy enhances the migratory capacity of MSCs and may thus increase the therapeutic efficacy of MSC-mediated NIS radionuclide therapy.
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http://dx.doi.org/10.1089/hum.2018.025DOI Listing
November 2018

Fluorescent Polyvinylphosphonate Bioconjugates for Selective Cellular Delivery.

Chemistry 2018 Feb 25;24(11):2584-2587. Epub 2018 Jan 25.

WACKER-Lehrstuhl für Makromolekulare Chemie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching bei München, Germany.

To date, many poly(ethylene glycol) (PEG) and poly(N-isopropylacrylamide) (PNIPAAm) biomolecule conjugates have been described, but they often show long response times, are not bio-inert, or lose function in biological fluids. Herein, we present a modular synthetic approach to generate polyvinylphosphonate biomolecule conjugates. These conjugates exhibit a sharp phase transition temperature even under physiological conditions where few other examples with this property have been described to date. Furthermore, it was feasible to add biological functions to the polymers via the conjugation step. The polyvinylphosphonate cholesterol constructs are attached to the cellular membrane and the folic acid anchored polymers are shuttled into the cells. This is an exceptional finding through a straightforward synthetic approach.
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http://dx.doi.org/10.1002/chem.201706034DOI Listing
February 2018

Lymphotoxin expression in human and murine renal allografts.

PLoS One 2018 4;13(1):e0189396. Epub 2018 Jan 4.

Division of Nephrology, University Hospital, Zuerich, Switzerland.

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTβ, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTβ receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTβ and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTβ in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754061PMC
January 2018

Current diagnostics and treatment of fibrosarcoma -perspectives for future therapeutic targets and strategies.

Oncotarget 2017 Nov 10;8(61):104638-104653. Epub 2017 Aug 10.

Department of General, Visceral und Vascular Surgery, Otto-von-Guericke University, Magdeburg, Germany.

Adult-type fibrosarcoma is a rare and highly aggressive subtype of soft tissue sarcomas. Due to the existence of other spindle-cell shaped sarcomas, its diagnosis is always one of exclusion. The likelihood of misdiagnoses between similar tumour entities is high, and often leads to inappropriate tumour treatment. We summarize here the main features of fibrosarcoma. When fibrosarcoma is appropriately diagnosed, the patient`s overall prognosis is generally quite poor. Fibrosarcoma is characterized by its low sensitivity towards radio- and chemotherapy as well as by its high rate of tumour recurrences. Thus it is important to identify new methods to improve treatment of this tumour entity. We discuss some promising new directions in fibrosarcoma research, specifically focusing on more effective targeting of the tumour microenvironment. Communication between tumour cells and their surrounding stromal tissue play a crucial role in cancer progression, invasion, metastasis and chemosensitivity. The therapeutic potential of targeting the tumour microenvironment is addressed.
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http://dx.doi.org/10.18632/oncotarget.20136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732833PMC
November 2017

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells - TREAT-ME-1 - a phase I, first in human, first in class trial.

Oncotarget 2017 Oct 16;8(46):80156-80166. Epub 2017 Sep 16.

Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany.

Purpose: This phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma.

Experimental Design: The study design consisted of a dose-escalation 3 + 3 design. All patients ( = 6) were treated with up to three applications of MSC_apceth_101, followed by GCV infusions given on three consecutive days starting 48 hours after injection of MSC_apceth_101. Three of six patients received a total dose of 1.5 × 10 cells/kg. Two patients received three doses of 1 × 10 cells/kg, while one patient received only two doses of 1 × 10 cells/kg due to a SADR.

Results: Six patients received MSC_apceth_101. No IMP-related serious adverse events occurred. Adverse-events related to IMP-injection were increased creatinine, cough, fever, and night sweat. TNF, IL-6, IL-8, IL-10 and sE-Selectin, showed that repeated application is immunologically safe, but induces a switch of the functional properties of monocytes to an inflammatory phenotype. Treatment induced stable disease in 4/6 patients, and progressive disease in 2/6 patients.

Conclusion: Treatment with MSC_apceth_101 in combination with GCV demonstrated acceptable safety and tolerability in patients with advanced gastrointestinal adenocarcinoma.
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http://dx.doi.org/10.18632/oncotarget.20964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655186PMC
October 2017

A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome.

Kidney Int 2018 02 18;93(2):439-449. Epub 2017 Oct 18.

Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Diabetic kidney disease is the leading cause of kidney failure. However, studies of molecular mechanisms of early kidney damage are lacking. Here we examined for possible linkage between transcriptional regulation and quantitative structural damage in early diabetic kidney disease in Pima Indians with type 2 diabetes. Tissue obtained from protocol kidney biopsies underwent genome-wide compartment-specific gene expression profiling and quantitative morphometric analysis. The ultrastructural lesion most strongly associated with transcriptional regulation was cortical interstitial fractional volume (VvInt), an index of tubule-interstitial damage. Transcriptional co-expression network analysis identified 1843 transcripts that correlated significantly with VvInt. These transcripts were enriched for pathways associated with mitochondrial dysfunction, inflammation, migratory mechanisms, and tubular metabolic functions. Pathway network analysis identified IL-1β as a key upstream regulator of the inflammatory response and five transcription factors cooperating with p53 to regulate metabolic functions. VvInt-associated transcripts showed significant correlation with the urine albumin to creatinine ratio and measured glomerular filtration rate 10 years after biopsy, establishing a link between the early molecular events and long-term disease progression. Thus, molecular mechanisms active early in diabetic kidney disease were revealed by correlating intrarenal transcripts with quantitative morphometry and long-term outcomes. This provides a starting point for identification of urgently needed therapeutic targets and non-invasive biomarkers of early diabetic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2017.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794609PMC
February 2018

Reintroducing the Sodium-Iodide Symporter to Anaplastic Thyroid Carcinoma.

Thyroid 2017 12 10;27(12):1534-1543. Epub 2017 Nov 10.

1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany .

Background: Anaplastic thyroid carcinoma (ATC), the most aggressive form of thyroid cancer, is unresponsive to radioiodine therapy. The current study aimed to extend the diagnostic and therapeutic application of radioiodine beyond the treatment of differentiated thyroid cancer by targeting the functional sodium-iodide symporter (NIS) to ATC.

Methods: The study employed nanoparticle vectors (polyplexes) based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG) and coupled to the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand in order to target a NIS-expressing plasmid (LPEI-PEG-GE11/NIS) to EGFR overexpressing human thyroid carcinoma cell lines. Using ATC xenograft mouse models, transfection efficiency by I scintigraphy and potential for systemic radioiodine therapy after systemic polyplex application were evaluated.

Results: In vitro iodide uptake studies in SW1736 and Hth74 ATC cells, and, for comparison, in more differentiated follicular (FTC-133) and papillary (BCPAP) thyroid carcinoma cells demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS that correlated well with EGFR expression levels. After systemic polyplex injection, in vivo I gamma camera imaging revealed significant tumor-specific accumulation of radioiodine in an SW1736 and an Hth74 xenograft mouse model. Radioiodine accumulation was found to be higher in SW1736 tumors, reflecting in vitro results, EGFR expression levels, and results from ex vivo analysis of NIS staining. Administration of I in LPEI-PEG-GE11/NIS-treated SW1736 xenograft mice resulted in significantly reduced tumor growth associated with prolonged survival compared to control animals.

Conclusions: The data open the exciting prospect of NIS-mediated radionuclide imaging and therapy of ATC after non-viral reintroduction of the NIS gene. The high tumor specificity after systemic application makes the strategy an attractive alternative for the treatment of highly metastatic ATC.
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http://dx.doi.org/10.1089/thy.2017.0290DOI Listing
December 2017

Defining Renal Neoplastic Disease, One Cell at a Time: Mass Cytometry, a New Tool for the Study of Kidney Biology and Disease.

Am J Kidney Dis 2017 12 12;70(6):758-761. Epub 2017 Oct 12.

University of Michigan, Ann Arbor, Michigan.

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http://dx.doi.org/10.1053/j.ajkd.2017.08.009DOI Listing
December 2017

Successive Release of Tissue Inhibitors of Metalloproteinase-1 Through Graphene Oxide-Based Delivery System Can Promote Skin Regeneration.

Nanoscale Res Lett 2017 Sep 15;12(1):533. Epub 2017 Sep 15.

Department of Plastic and Reconstructive Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The purpose of this study was to testify the hypothesis that graphene oxide (GO) could act as an appropriate vehicle for the release of tissue inhibitors of metalloproteinase-1 (TIMP-1) protein in the context of skin repair. GO characteristics were observed by scanning electron microscopy, atomic force microscopy, and thermal gravimetric analysis. After TIMP-1 absorbing GO, the release profiles of various concentrations of TIMP-1 from GO were compared. GO biocompatibility with fibroblast viability was assessed by measuring cell cycle and apoptosis. In vivo wound healing assays were used to determine the effect of TIMP-1-GO on skin regeneration. The greatest intensity of GO was 1140 nm, and the most intensity volume was 10,674.1 nm (nanometer). TIMP-1 was shown to be continuously released for at least 40 days from GO. The proliferation and viability of rat fibroblasts cultured with TIMP-1-GO were not significantly different as compared with the cells grown in GO or TIMP-1 alone (p > 0.05). Skin defect of rats treated with TIMP-1 and TIMP-1-GO showed significant differences in histological and immunohistochemical scores (p < 0.05). GO can be controlled to release carrier materials. The combination of TIMP-1 and GO promoted the progression of skin tissue regeneration in skin defect.
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http://dx.doi.org/10.1186/s11671-017-2305-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602890PMC
September 2017

The hormetic functions of Wnt pathways in tubular injury.

Pflugers Arch 2017 Aug 6;469(7-8):899-906. Epub 2017 Jul 6.

Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Chronic tubulointerstitial damage with tubular epithelial atrophy and interstitial fibrosis is the hallmark of chronic kidney disease (CKD) and a predictor for progression of CKD.Several experiments have now provided evidence that the Wnt signaling pathways are significantly contributing to atrophy and fibrosis; in contrast, it also has been shown that the Wnt system fosters regenerative processes in acute tubular injury.We now have demonstrated that Dickkopf 3 (DKK3) is an agonist for canonical Wnt signaling in CKD and fosters chronic fibrosing inflammation of the tubulointerstitial compartment. Genetic- and antibody-mediated inhibition of DKK3 leads to a pronounced improvement of tubular differentiation and a reduction in fibrosis.In addition, the secreted glycoprotein DKK3 can be used as a non-invasive urinary marker for the extent of CKD in man.
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http://dx.doi.org/10.1007/s00424-017-2018-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541077PMC
August 2017