Publications by authors named "Dionysios J Papachristou"

65 Publications

A Custom Ultra-Low-Cost 3D Bioprinter Supports Cell Growth and Differentiation.

Front Bioeng Biotechnol 2020 4;8:580889. Epub 2020 Nov 4.

Department of Physiology, School of Medicine, University of Patras, Patras, Greece.

Advances in 3D bioprinting have allowed the use of stem cells along with biomaterials and growth factors toward novel tissue engineering approaches. However, the cost of these systems along with their consumables is currently extremely high, limiting their applicability. To address this, we converted a 3D printer into an open source 3D bioprinter and produced a customized bioink based on accessible alginate/gelatin precursors, leading to a cost-effective solution. The bioprinter's resolution, including line width, spreading ratio and extrusion uniformity measurements, along with the rheological properties of the bioinks were analyzed, revealing high bioprinting accuracy within the printability window. Following the bioprinting process, cell survival and proliferation were validated on HeLa Kyoto and HEK293T cell lines. In addition, we isolated and 3D bioprinted postnatal neural stem cell progenitors derived from the mouse subventricular zone as well as mesenchymal stem cells derived from mouse bone marrow. Our results suggest that our low-cost 3D bioprinter can support cell proliferation and differentiation of two different types of primary stem cell populations, indicating that it can be used as a reliable tool for developing efficient research models for stem cell research and tissue engineering.
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http://dx.doi.org/10.3389/fbioe.2020.580889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676439PMC
November 2020

Inhibition of Adipogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by a Phytoestrogen Diarylheptanoid from .

J Agric Food Chem 2020 Sep 4;68(37):9993-10002. Epub 2020 Sep 4.

The Pittsburgh Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15261, United States.

We investigated the effect of a phytoestrogen, (3)-1,7-diphenyl-(4,6)-4,6-heptadien-3-ol (DPHD), from Roxb. (Zingiberaceae family) on the adipogenic differentiation of mesenchymal progenitors, human bone marrow-derived mesenchymal stem cells (hBMSCs). DPHD inhibited adipocyte differentiation of hBMSCs by suppressing the expression of genes involved in adipogenesis. DPHD at concentrations of 0.1, 1, and 10 μM significantly decreased triglyceride accumulation in hBMSCs to 7.1 ± 0.2, 6.3 ± 0.4, and 4.9 ± 0.2 mg/dL, respectively, compared to the nontreated control (10.1 ± 0.9 mg/dL) ( < 0.01). Based on gene expression profiling, DPHD increased the expression of several genes involved in the Wnt/β-catenin signaling pathway, a negative regulator of adipocyte differentiation in hBMSCs. DPHD also increased the levels of essential signaling proteins which are extracellular signal-regulated kinases 1 and 2 (ERK1/2) and glycogen synthase kinase 3 beta (GSK-3β) that link estrogen receptor (ER) signaling to Wnt/β-catenin signaling. In conclusion, DPHD exhibited the anti-adipogenic effect in hBMSCs by suppression of adipogenic markers in hBMSCs through the activation of ER and Wnt/β catenin signaling pathways. This finding suggests the potential role of DPHD in preventing bone marrow adiposity which is one of the major factors that exacerbates osteoporosis in postmenopause.
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http://dx.doi.org/10.1021/acs.jafc.0c04063DOI Listing
September 2020

Platelet-rich Plasma and Mesenchymal Stem Cells Local Infiltration Promote Functional Recovery and Histological Repair of Experimentally Transected Sciatic Nerves in Rats.

Cureus 2020 May 24;12(5):e8262. Epub 2020 May 24.

Orthopaedics, HYGEIA Private Hospital, Athens, GRC.

Introduction Platelet-rich plasma (PRP) products and mesenchymal stem cells (MSCs) seem to have a significant potential as neurogenic therapeutic modulator systems. This study aimed to investigate such biological blood derivatives that could enhance nerve regeneration when applied locally in the primary repair of peripheral nerve transection of an experimental rat model. Methods A total of 42 two-month-old male Wistar rats were divided into three "treatment" groups (control, PRP, and MSCs). All the subjects were operated under anesthesia, and the surgical site was infiltrated with either normal saline, PRP derived from the animal's peripheral blood, or MSCs derived from the animal's femoral bone marrow. All three groups were also sub-divided into two sub-groups based on the post-operative administration of Non-steroidal anti-inflammatory drugs (NSAIDs) or not in order to evaluate the effect of NSAIDs on the final outcome. Three months post-surgery, electromyography evaluation of both hind limbs (right operated and left non-operated) was performed. The animals were euthanized, and nerve repair specimens were prepared for histology. Results PRP group had a significant effect (p<0.05) on the sciatic nerve repair when compared with the control group, whereas the MSC group had a positive effect but was not statistically significant (p=0.2). The number of counted neural axons at the area distal to the nerve repair site were significantly repetitive (p<0.05) in both the PRP and MSC groups when compared with the control group. Conclusions Both PRP and MSCs appear to play an essential role in the enhancement of nerve repair in terms of functionality and histology. MSCs group demonstrated a positive effect, whereas the PRP group showed statistically significant better results.
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http://dx.doi.org/10.7759/cureus.8262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313431PMC
May 2020

An MRI study of immune checkpoint inhibitor-induced musculoskeletal manifestations myofasciitis is the prominent imaging finding.

Rheumatology (Oxford) 2020 05;59(5):1041-1050

Department of Rheumatology, University of Patras Medical School, Patras, Greece.

Objective: To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs.

Methods: All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed.

Results: During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation.

Conclusion: In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.
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http://dx.doi.org/10.1093/rheumatology/kez361DOI Listing
May 2020

Correction: The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro.

Lab Invest 2020 May;100(5):790

Veteran's Affairs Medical Center, Pittsburgh, PA, 15206, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41374-020-0374-yDOI Listing
May 2020

The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro.

Lab Invest 2019 12 29;99(12):1850-1860. Epub 2019 Aug 29.

Veteran's Affairs Medical Center, Pittsburgh, PA, 15206, USA.

We examined bone formation and turnover in high-density lipoprotein (HDL) receptor, scavenger receptor type I (Scarb1), knockout animals relative to wild-type (WT) controls. Scarb1 animals have elevated serum adrenocorticotropic hormone (ACTH) due to the role of Scarb1 in glucocorticoid production, which might cause increased bone mass. However, this was not observed: Scarb1 mice, with ACTH, over 1000 pg/ml relative to wild-type ACTH ~ 25 pg/ml, bone of the knockout animals was osteopenic relative to the wild type at 16 weeks, including bone volume/total volume and trabecular thickness. Other serum parameters of WT and Scarb1 animals in cortisol or calcium were unaffected, although Scarb1 animals had significantly elevated PTH and decreased phosphate. Osteoblast and osteoclast-related mRNAs extracted from bone were greatly decreased at 8 or 16 weeks. Importantly, in normal ACTH, osteogenic differentiation in vitro from mesenchymal stem cells showed reduced alkaline phosphatase and mineralization. In Scarb1 cells relative to WT, mRNAs for RunX2, alkaline phosphatase, type I collagen, and osteocalcin were reduced 40-90%, all p < 0.01, indicating a role of Scarb1 in osteoblast differentiation independent of ACTH. Additionally, in vitro osteoblast differentiation at variable ACTH in WT cells confirmed ACTH increasing bone differentiation, mineralization, alkaline phosphatase, and osteocalcin mRNA at 0-10 nM ACTH, but reduced bone differentiation at 100-1000 nM ACTH. Overall Scarb1 animals show inhibited bone formation with age. This may be a mixed effect on direct bone formation and of very high ACTH. Further, this work shows that both ACTH concentration and the HDL receptor Scarb1 play important independent roles in osteoblast differentiation.
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http://dx.doi.org/10.1038/s41374-019-0311-0DOI Listing
December 2019

Immunophenotypic expression of UCP1 in hibernoma and other adipose/non adipose soft tissue tumours.

Clin Sarcoma Res 2019 13;9. Epub 2019 May 13.

1Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Sciences, University of Oxford, Nuffield Orthopaedic Centre, Oxford, OX7 HE UK.

Background: Uncoupling protein 1 (UCP1) is a mitochondral protein transporter that uncouples electron transport from ATP production. UCP1 is highly expressed in brown adipose tissue (BAT), including hibernomas, but its expression in other adipose tumours is uncertain. UCP1 has also been found in other tissues (e.g. smooth muscle) but whether it is expressed in non-adipose benign and malignant soft tissue tumours is unknown.

Methods: Immunohistochemical staining of normal (axillary) BAT and subcutaneous/abdominal white adipose tissue (WAT) as well as a wide range of benign and malignant primary soft tissue tumours (n = 171) was performed using a rabbit polyclonal antibody to UCP1. BAT and hibernomas were also stained by immunohistochemistry with monoclonal and polyclonal antibodies to adipose/non-adipose tumour markers in order to characterise the immunophenotype of BAT cells.

Results: UCP1 was strongly expressed in the cytoplasm of brown fat cells in BAT and hibernomas, both of which also expressed aP2, S100, CD31, vimentin and calponin. UCP1 was not expressed in WAT or other adipose tumours with the exception a few tumour cells in pleomorphic liposarcoma. UCP1 was variably expressed by tumour cells in a few non-adipose sarcomas including leiomyosarcoma, rhabdomyosarcoma, alveolar soft part sarcoma, synovial sarcoma and clear cell sarcoma.

Conclusions: UCP1 is strongly expressed in BAT but not WAT and is found in all hibernomas and a few pleomorphic liposarcomas but not in other adipose tumours. UCP1 expression in a few non-adipose soft tissue sarcomas may possibly reflect origin of tumour cells from a common mesenchymal stem cell precursor and/or developmental pathway.
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http://dx.doi.org/10.1186/s13569-019-0118-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515671PMC
May 2019

The Impact of Anti-tumor Agents on ER-Positive MCF-7 and HER2-Positive SKBR-3 Breast Cancer Cells Biomechanics.

Ann Biomed Eng 2019 Aug 16;47(8):1711-1724. Epub 2019 May 16.

Laboratory of Biomechanics and Biomedical Engineering, Department of Mechanical Engineering and Aeronautics, University of Patras, Rion, 26504, Patra, Greece.

Studying human cancer from a biomechanical perspective may contribute to pathogenesis understanding which leads to the malignancy. In this study, biomechanics of suspended and adhered breast cancer cells were investigated via the micropipette aspiration method with special emphasis on comparing the cell stiffness and viscoelastic parameters of estrogen receptor positive, ER+, MCF-7 and human epidermal growth factor receptor 2 positive, HER2 +, SKBR-3 cancer cell lines prior to and post treatment with tamoxifen and trastuzumab, respectively. Alterations of mechanical parameters included significant increase in cell stiffness, especially after treatment with trastuzumab and changes in viscoelastic parameters, in both cancer cell lines post treatment. According to immunofluorescence analysis, the raised cell stiffness was corresponded to remodeling of F-actin, which peripherally located in tamoxifen treated and perinuclear accumulated in trastuzumab treated cancer cell cytoskeleton, implying a reduced potential for cell deformation and motility. Additionally, these results were in line with the study of single and collective cell migration through Boyden chamber and wound healing assays respectively, where the potential for migration was significantly decreased after treatment. Consequently, these findings lead to an increased interest in biomechanics of cancer progression after treatment with anti-tumor agents, importantly in understanding the effect of the alterations of mechanical properties upon the possibility for change in metastatic potential.
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http://dx.doi.org/10.1007/s10439-019-02284-3DOI Listing
August 2019

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis.

Front Oncol 2018 23;8:470. Epub 2018 Oct 23.

Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.

Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth ( ≤ 0.001). IGF-I was shown to increase biglycan expression ( ≤ 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells ≤ 0.001; ≤ 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated ( ≤ 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/β-catenin pathway, was demonstrated to induce a significant increase in β-catenin protein expression evident at cytoplasmic ( ≤ 0.01), membrane ( ≤ 0.01), and nucleus fractions in MG63 cells ( ≤ 0.05). As demonstrated by immunofluorescence, increase in β-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated β-catenin degradation. Furthermore, applying anti-β-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, ( ≤ 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/β-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth.
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http://dx.doi.org/10.3389/fonc.2018.00470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206209PMC
October 2018

Dickkopf-1 is downregulated early and universally in the skin of patients with systemic sclerosis despite normal circulating levels.

Clin Exp Rheumatol 2018 Jul-Aug;36 Suppl 113(4):45-49. Epub 2018 Sep 28.

Department of Rheumatology, Patras University Hospital, University of Patras Medical School, Greece.

Objectives: The activity of the Wnt pathway, a critical mediator of fibrosis, is regulated by Dickkopf-1 (Dkk-1). Dkk-1 is absent from scleroderma skin in contrast to skin from healthy subjects where it is clearly expressed. There are no data on circulating levels and function of Dkk-1 in patients with systemic sclerosis (SSc). Our objectives are to assess: i) circulating and functional levels of Dkk-1 in patients with SSc and ii) whether the striking lack of Dkk-1 skin expression is also evident in a) clinically uninvolved skin from patients with SSc and b) very early disease prior to skin thickening.

Methods: Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 controls. Skin biopsies were obtained from SSc patients from a) clinically involved skin b) clinically uninvolved skin, c) oedematous skin prior to skin thickening.

Results: Circulating and functional Dkk-1 levels were similar in patients with SSc and controls. Healthy skin displayed a high Dkk-1 immuno-expression in the epidermis and dermal fibroblasts in contrast to clinically involved scleroderma skin where Dkk-1 was totally absent. In all biopsies of clinically uninvolved skin Dkk-1 was only moderately expressed whereas skin from very early disease displayed only a weak Dkk-1 immunoreactivity.

Conclusions: The downregulation of Dkk-1 at the oedematous phase of the disease indicates that the Wnt pathway is involved early in the disease process and may play a role in driving fibrosis. The decrease in Dkk-1 expression in clinically uninvolved scleroderma skin indicates that skin in SSc is universally affected.
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January 2019

Western-type diet differentially modulates osteoblast, osteoclast, and lipoblast differentiation and activation in a background of APOE deficiency.

Lab Invest 2018 12 11;98(12):1516-1526. Epub 2018 Sep 11.

Laboratory of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University Patras Medical School, Patras, Greece.

During the past few years, considerable evidence has uncovered a strong relationship between fat and bone metabolism. Consequently, alterations in plasma lipid metabolic pathways strongly affect bone mass and quality. We recently showed that the deficiency of apolipoprotein A-1 (APOA1), a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, results in reduced bone mass in C57BL/6 mice. It is documented that apolipoprotein E (APOE), a lipoprotein know for its atheroprotective functions and de novo biogenesis of HDL-C, is associated with the accumulation of fat in the liver and other organs and regulates bone mass in mice. We further studied the mechanism of APOE in bone metabolism using well-characterized APOE knockout mice. We found that bone mass was remarkably reduced in APOE deficient mice fed Western-type diet (WTD) compared to wild type counterparts. Static (microCT-based) and dynamic histomorphometry showed that the reduced bone mass in APOΕ mice is attributed to both decreased osteoblastic bone synthesis and elevated osteoclastic bone resorption. Interestingly, histologic analysis of femoral sections revealed a significant reduction in the number of bone marrow lipoblasts in APOΕ compared to wild type mice under WTD. Analyses of whole bone marrow cells obtained from femora of both animal groups showed that APOE null mice had significantly reduced levels of the osteoblastic (RUNX2 and Osterix) and lipoblastic (PPARγ and CEBPα) cardinal regulators. Additionally, the modulators of bone remodeling RANK, RANKL, and cathepsin K were greatly increased, while OPG and the OPG/RANKL ratio were remarkably decreased in APOΕ mice fed WTD, compared to their wild-type counterparts. These findings suggest that APOE deficiency challenged with WTD reduces osteoblastic and lipoblastic differentiation and activity, whereas it enhances osteoclastic function, ultimately resulting in reduced bone mass, in mice.
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http://dx.doi.org/10.1038/s41374-018-0107-7DOI Listing
December 2018

Evidence for the efficacy of disulfiram and copper combination in glioblastoma multiforme - A propos of a case.

J BUON 2017 Sep-Oct;22(5):1227-1232

Department of Neurosurgery, Olympion General Hospital and Rehabilitation Center, Patras, Greece.

Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates. One of the most promising drugs to repurpose for treating GBM is disulfiram (DSF). DSF is a relatively nontoxic drug used for more than sixty years in the treatment of chronic alcoholism with the ability to readily cross the blood-brain barrier. Repurposing DSF for use as an anticancer drug in general has recently become of interest because of its preclinically described anticancer effects against various human cancers. Interestingly, a number of these effects were shown to be copper (Cu)-dependent. The purpose of this paper was to review the existing literature surrounding preclinical and clinical data on the effects of DSF -alone or in combination with Cu- in GBM. In addition, we present the first case of a GBM patient safely treated with DSF/Cu combination along with standard therapy exhibiting remarkably increased progression-free (PFS) and overall survival (OS).
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August 2019

IGF-I regulates HT1080 fibrosarcoma cell migration through a syndecan-2/Erk/ezrin signaling axis.

Exp Cell Res 2017 12 28;361(1):9-18. Epub 2017 Sep 28.

Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece. Electronic address:

Fibrosarcoma is a tumor of mesenchymal origin, originating from fibroblasts. IGF-I is an anabolic growth factor which exhibits significant involvement in cancer progression. In this study, we investigated the possible participation of syndecan-2 (SDC-2), a cell membrane heparan sulfate (HS) proteoglycan on IGF-I dependent fibrosarcoma cell motility. Our results demonstrate that SDC-2-deficient HT1080 cells exhibit attenuated IGF-I-dependent chemotactic migration (p < 0.001). SDC-2 was found to co-localize to IGF-I receptor (IGF-IR) in a manner dependent on IGF-I activity (P ≤ 0.01). In parallel, the downregulation of SDC-2 significantly inhibited both basal and due to IGF-I action ERK1/2 activation, (p < 0.001). The phosphorylation levels of ezrin (Thr567), which is suggested to act as a signaling bridge between the cellular membrane receptors and actin cytoskeleton, were strongly enhanced by IGF-I at both 1h and 24h (p < 0.05; p < 0.01). The formation of an immunoprecipitative complex revealed an association between SDC2 and ezrin which was enhanced through IGF-I action (p < 0.05). Immunoflourescence demonstrated a co-localization of IGF-IR, SDC2 and ezrin upregulated by IGF-I action. IGF-I enhanced actin polymerization and ezrin/actin specific localization to cell membranes. Finally, treatment with IGF-I strongly increased SDC2 expression at both the mRNA and protein level (p < 0.001). Therefore, we propose a novel SDC2-dependent mechanism, where SDC2 is co-localized with IGF-IR and enhances its' IGFI-dependent downstream signaling. SDC2 mediates directly IGFI-induced ERK1/2 activation, it recruits ezrin, contributes to actin polymerization and ezrin/actin specific localization to cell membranes, ultimately facilitating the progression of IGFI-dependent fibrosarcoma cell migration.
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http://dx.doi.org/10.1016/j.yexcr.2017.09.035DOI Listing
December 2017

High-density lipoprotein (HDL) metabolism and bone mass.

J Endocrinol 2017 05 17;233(2):R95-R107. Epub 2017 Mar 17.

Department of Anatomy-Histology-EmbryologyUnit of Bone and Soft Tissue Studies, University of Patras Medical School, Patras, Greece

It is well appreciated that high-density lipoprotein (HDL) and bone physiology and pathology are tightly linked. Studies, primarily in mouse models, have shown that dysfunctional and/or disturbed HDL can affect bone mass through many different ways. Specifically, reduced HDL levels have been associated with the development of an inflammatory microenvironment that affects the differentiation and function of osteoblasts. In addition, perturbation in metabolic pathways of HDL favors adipoblastic differentiation and restrains osteoblastic differentiation through, among others, the modification of specific bone-related chemokines and signaling cascades. Increased bone marrow adiposity also deteriorates bone osteoblastic function and thus bone synthesis, leading to reduced bone mass. In this review, we present the current knowledge and the future directions with regard to the HDL-bone mass connection. Unraveling the molecular phenomena that underline this connection will promote the deeper understanding of the pathophysiology of bone-related pathologies, such as osteoporosis or bone metastasis, and pave the way toward the development of novel and more effective therapies against these conditions.
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http://dx.doi.org/10.1530/JOE-16-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598779PMC
May 2017

Heparin regulates B6FS cell motility through a FAK/actin cytoskeleton axis.

Oncol Rep 2016 Nov 30;36(5):2471-2480. Epub 2016 Aug 30.

Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece.

Soft tissue sarcomas are rare, heterogeneous tumors of mesenchymal origin with an aggressive behavior. Heparin is a mixture of heavily sulfated, linear glycosaminoglycan (GAG) chains, which participate in the regulation of various cell biological functions. Heparin is considered to have significant anticancer capabilities, although the mechanisms involved have not been fully defined. In the present study, the effects of unfractionated heparin (UFH) and low‑molecular‑weight heparin (LMWH) on B6FS fibrosarcoma cell motility were examined. Both preparations of heparin were shown to both enhance B6FS cell adhesion (p<0.01 and p<0.05), and migration (p<0.05), the maximal effect being evident at the concentration of 10 µg/ml. The utilization of FAK‑deficient cells demonstrated that the participation of FAK was obligatory for heparin‑dependent fibrosarcoma cell adhesion (p<0.05). The results of confocal microscopy indicated that heparin was taken up by the B6FS cells, and that UFH and LMWH induced F‑actin polymerization. Heparitinase digestion demonstrated that the endogenous heparan sulfate (HS) chains did not affect the motility of the B6FS cells (p>0.05, not significant). In conclusion, both UFH and LMWH, through a FAK/actin cytoskeleton axis, promoted the adhesion and migration of B6FS fibrosarcoma cells. Thus, our findings indicate that the responsiveness of fibrosarcoma cells to the exogenous heparin/HS content of the cancer microenvironment may play a role in their ability to become mobile and metastasize.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055209PMC
http://dx.doi.org/10.3892/or.2016.5057DOI Listing
November 2016

Mammalian PNLDC1 is a novel poly(A) specific exonuclease with discrete expression during early development.

Nucleic Acids Res 2016 Oct 11;44(18):8908-8920. Epub 2016 Aug 11.

Department of Biochemistry, School of Medicine, University of Patras, 26504 Rio Achaia, Greece

PNLDC1 is a homologue of poly(A) specific ribonuclease (PARN), a known deadenylase with additional role in processing of non-coding RNAs. Both enzymes were reported recently to participate in piRNA biogenesis in silkworm and C. elegans, respectively. To get insights on the role of mammalian PNLDC1, we characterized the human and mouse enzymes. PNLDC1 shows limited conservation compared to PARN and represents an evolutionary related but distinct group of enzymes. It is expressed specifically in mouse embryonic stem cells, human and mouse testes and during early mouse embryo development, while it fades during differentiation. Its expression in differentiated cells, is suppressed through methylation of its promoter by the de novo methyltransferase DNMT3B. Both enzymes are localized mainly in the ER and exhibit in vitro specificity restricted solely to 3' RNA or DNA polyadenylates. Knockdown of Pnldc1 in mESCs and subsequent NGS analysis showed that although the expression of the remaining deadenylases remains unaffected, it affects genes involved mainly in reprogramming, cell cycle and translational regulation. Mammalian PNLDC1 is a novel deadenylase expressed specifically in cell types which share regulatory mechanisms required for multipotency maintenance. Moreover, it could be involved both in posttranscriptional regulation through deadenylation and genome surveillance during early development.
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http://dx.doi.org/10.1093/nar/gkw709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062988PMC
October 2016

Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review).

Oncol Rep 2016 Oct 1;36(4):1787-92. Epub 2016 Aug 1.

Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece.

Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non‑mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N‑terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling.
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http://dx.doi.org/10.3892/or.2016.4986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022866PMC
October 2016

Fibro-Osseous Pseudotumor of the Hand.

J Hand Surg Asian Pac Vol 2016 06;21(2):269-72

3 Department of Orthopaedic Surgery, School of Health Sciences, University Hospital of Thessalia, Larissa, Greece.

Fibro-osseous pseudotumor of digits (FOPD) is an uncommon histological diagnosis. Clinical and imaging findings may resemble high-grade sarcoma or infection. We describe a patient with progressive pain and swelling at the dorsal surface of the first web space. MRI and CT imaging revealed an intramuscular heterogenous soft tissue mass defined by a mineralized peripheral ring. Core needle biopsy diagnosed FOPD. Eight months later a matured ossified nodule that was quite smaller than the initial soft tissue mass was excised. The patient is symptom free without local recurrence at 1 year follow up. Soft tissue masses of the hand pose a challenging diagnostic and therapeutic issue. An in depth interpretation of clinical, imaging and histology findings is important to avoid erroneous diagnosis and treatment.
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http://dx.doi.org/10.1142/S2424835516720127DOI Listing
June 2016

B cell depletion therapy upregulates Dkk-1 skin expression in patients with systemic sclerosis: association with enhanced resolution of skin fibrosis.

Arthritis Res Ther 2016 05 21;18(1):118. Epub 2016 May 21.

Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, Rion, Patras, 26504, Greece.

Background: Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway.

Methods: Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration.

Results: In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFβ expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFβ in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFβ was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022).

Conclusions: This is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFβ-Dkk-1 axis in improving skin fibrosis.
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http://dx.doi.org/10.1186/s13075-016-1017-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875588PMC
May 2016

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice.

Lab Invest 2016 07 18;96(7):763-72. Epub 2016 Apr 18.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.

Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1(-/-) mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1(-/-) femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1(-/-) mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1(-/-) mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1(-/-) mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1(-/-) animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1(-/-) phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.
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http://dx.doi.org/10.1038/labinvest.2016.51DOI Listing
July 2016

Bone and high-density lipoprotein: The beginning of a beautiful friendship.

World J Orthop 2016 Feb 18;7(2):74-7. Epub 2016 Feb 18.

Dionysios J Papachristou, Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras, School of Medicine, 26504 Rion-Patras, Greece.

There is a tight link between bone and lipid metabolic pathways. In this vein, several studies focused on the exploration of high-density lipoprotein (HDL) in the pathobiology of bone diseases, with emphasis to the osteoarthritis (OA) and osteoporosis, the most common bone pathologies. Indeed, epidemiological and in vitro data have connected reduced HDL levels or dysfunctional HDL with cartilage destruction and OA development. Recent studies uncovered functional links between HDL and OA fueling the interesting hypothesis that OA could be a chronic element of the metabolic syndrome. Other studies have linked HDL to bone mineral density. Even though at epidemiological levels the results are conflicting, studies in animals as well as in vitro experiments have shown that HDL facilitates osteoblastogensis and bone synthesis and most probably affects osteoclastogenesis and osteoclast bone resorption. Notably, reduced HDL levels result in increased bone marrow adiposity affecting bone cells function. Unveiling the mechanisms that connect HDL and bone/cartilage homeostasis may contribute to the design of novel therapeutic agents for the improvement of bone and cartilage quality and thus for the treatment of related pathological conditions.
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http://dx.doi.org/10.5312/wjo.v7.i2.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757660PMC
February 2016

Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines.

Biomed Res Int 2015 25;2015:690721. Epub 2015 Oct 25.

Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.

In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression.
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http://dx.doi.org/10.1155/2015/690721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637082PMC
September 2016

Decreased Serotonin Levels and Serotonin-Mediated Osteoblastic Inhibitory Signaling in Patients With Ankylosing Spondylitis.

J Bone Miner Res 2016 Mar 13;31(3):630-9. Epub 2015 Oct 13.

Division of Rheumatology, University of Patras Medical School, Patras University Hospital, Patras, Greece.

Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFα blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean ± SEM ng/mL 122.9 ± 11.6 versus 177.4 ± 24.58, p = 0.038) and patients with RA (mean ± SEM ng/mL 244.8 ± 37.5, p = 0.0004). Patients with AS receiving TNFα blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean ± SEM ng/mL 95.8 ± 14.9 versus 149.2 ± 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFα treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS.
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http://dx.doi.org/10.1002/jbmr.2724DOI Listing
March 2016

Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition.

Eur J Pharmacol 2015 Nov 28;766:76-85. Epub 2015 Sep 28.

Pharmacology Department, University of Patras Medical School, Rio, Achaias TK 26500, Greece. Electronic address:

Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1(-/-)) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1(-/-) mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [(3)H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1(-/-) mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1016/j.ejphar.2015.09.040DOI Listing
November 2015

Scavenger Receptor Class B Type I Regulates Plasma Apolipoprotein E Levels and Dietary Lipid Deposition to the Liver.

Biochemistry 2015 Sep 3;54(36):5605-16. Epub 2015 Sep 3.

Pharmacology Department, ‡Anatomy Histology and Embryology Department, §Medical Physics Department, and ∥Endocrinology Department, University of Patras Medical School , Rio Achaias, TK 26500, Greece.

Scavenger receptor class B type I (SR-BI) is primarily responsible for the selective uptake of cholesteryl esters (CE) of high-density lipoprotein (HDL) by the liver and other tissues. In the present study, we show that SR-BI-deficient (scarb1(-/-)) mice are resistant to diet-induced obesity, hepatic lipid deposition, and glucose intolerance after 24 weeks of being fed a western-type diet. No differences in energy expenditure or mitochondrial function could account for the observed phenotype. Kinetic and gene expression analyses suggested reduced de novo fatty acid synthesis in scarb1(-/-) mice. Furthermore, adenosine monophosphate-activated protein kinase (AMPK)-stimulated hepatic FFA catabolism was reduced in these mice, leaving direct dietary lipid uptake from plasma as the major modulator of hepatic lipid content. Analysis of the apolipoprotein composition of plasma lipoproteins revealed a significant accumulation of apolipoprotein E (ApoE)-containing HDL and TG-rich lipoproteins in scarb1(-/-) mice that correlated with reduced plasma LpL activity. Our data suggest that scarb1(-/-) mice fed a western-type diet for 24 weeks accumulate CE- and ApoE-rich HDL of abnormal density and size. The elevated HDL-ApoE levels inhibit plasma LpL activity, blocking the clearance of triglyceride-rich lipoproteins and preventing the shuttling of dietary lipids to the liver.
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http://dx.doi.org/10.1021/acs.biochem.5b00700DOI Listing
September 2015

Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates.

Vascul Pharmacol 2016 Mar 30;78:17-23. Epub 2015 Jun 30.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras Medical School, Patras, Greece. Electronic address:

Macrophages recycle components of dead cells, including cell membranes. When quantities of lipids from cell membranes of dead cells exceed processing capacity, phospholipid and cholesterol debris accumulate as atheromas. Plasma lipid profiles, particularly HDL and LDL cholesterol, are important tools to monitor atherosclerosis risk. Membrane lipids are exported, as triglycerides or phospholipids, or as cholesterol or cholesterol esters, via lipoproteins for disposal, for re-use in cell membranes, or for fat storage. Alternative assays evaluate other aspects of lipid pathology. A key process underlying atherosclerosis is backup of macrophage fatty acid catabolism. This can be quantified by accumulation of acylcarnitine intermediates in extracellular fluid, a direct assay of adequacy of β-oxidation to deal with membrane fatty acid recycling. Further, membranes of somatic cells, such as red blood cells (RBC), incorporate fatty acids that reflect dietary intake. Changes in RBC lipid composition occur within days of ingesting modified fats. Since diets with high saturated fat content or artificial trans-fatty acids promote atherosclerosis, RBC lipid content shifts occur with atherosclerosis, and can show cellular adaptation to pathologically stiff membranes by increased long-chain doubly unsaturated fatty acid production. Additional metabolic changes with atherosclerosis of potential utility include inflammatory cytokine production, modified macrophage signaling pathways, and altered lipid-handling enzymes. Even after atherosclerotic lesions appear, approaches to minimize macrophage overload by reducing rate of fat metabolism are promising. These include preventive measures, and drugs including statins and the newer PCSK9 inhibitors. New cell-based biochemical and cytokine assays provide data to prevent or monitor atherosclerosis progression.
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http://dx.doi.org/10.1016/j.vph.2015.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696919PMC
March 2016

ADAMTS expression in colorectal cancer.

PLoS One 2015 18;10(3):e0121209. Epub 2015 Mar 18.

Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.

ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). By acting on a large panel of extracellular substrates, they control several cell functions such as fusion, adhesion, proliferation and migration. Through their thrombospondin motifs they also possess anti-angiogenic properties. We investigated whether ADAMTSs participate in colorectal cancer progression and invasion. Their expression was investigated at both mRNA and protein levels. Using RT-PCR, the expression of ADAMTS-1, -4, -5 and ADAMTS-20 was estimated in colorectal tumors of different cancer stage and anatomic site and 3 cell lines of different aggressiveness. An overexpression of ADAMTS-4 and -5 was observed, especially in tissue samples, whereas ADAMTS-1 and -20 were found to be down-regulated. Western blot analysis further supported the RT-PCR findings, revealing in addition the degradation of ADAMTS-1 and -20 in cancer. In situ expression and localization of ADAMTS-1, -4, -5 and -20 was also investigated by immunohistochemical analysis. Our data suggest a positive correlation between ADAMTS-4 and -5 expression and cancer progression, in contrast with the anti-angiogenic members of the family, ADAMTS-1 and -20, which were found to be down-regulated. Our findings support the notion that overexpression of ADAMTS-4 and ADAMTS-5 in colorectal cancer might be a possible invasive mechanism of cancer cells in order to degrade proteoglycans of ECM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364768PMC
February 2016

Eosinophilic granuloma of the sternum in a child treated with closed biopsy.

Pediatr Int 2014 Jun;56(3):417-9

Department of Orthopaedic Surgery and Musculoskeletal Trauma, University Hospital of Thessaly, Larissa, Greece.

Langerhans cell histiocytosis is a rare neoplastic proliferative disorder of the Langerhans cells. The clinical course is variable, ranging from a low symptomatic single bone lesion to fatal multiple organ involvement. Rarely, the sternum can be the first and single location of the disease. We report on a 12-year-old boy who presented with an aggressive lytic lesion of the proximal sternum associated with local pain and afternoon fever. Histopathological analysis of the closed biopsy specimen indicated eosinophilic granuloma of bone/Langerhans cell histiocytosis. Soon after the biopsy procedure the pain and fever subsided. Computed tomography at 2 months showed healing of the lytic lesion. The patient received no other type of treatment. At 2 year follow up he was symptom and disease free.
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http://dx.doi.org/10.1111/ped.12263DOI Listing
June 2014

Nrf2 is commonly activated in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells.

J Clin Endocrinol Metab 2013 Aug 13;98(8):E1422-7. Epub 2013 Jun 13.

Department of Internal Medicine, Division of Endocrinology, University of Patras Medical School, 26500 Patras, Greece.

Context: The antioxidant transcription factor NFE2-related factor 2 (Nrf2), encoded by NFE2L2, has been implicated as mediator of thyroid cancer cell line resistance to proteasome inhibitors. However, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown.

Objective: The aims of this study were assessment of the activity status of the Nrf2 pathway in papillary thyroid carcinoma (PTC) and investigation of its role(s) in antioxidant transcriptional responses and viability of cancer cells.

Design And Setting: We conducted retrospective immunohistochemical analyses of PTC specimens, adjacent normal tissue, and benign lesions; assays of viability and gene expression in the PTC cell lines K1 and TPC-1 after genetic/pharmacological manipulation of Nrf2; and DNA sequencing at an academic medical center.

Patients: The study included 42 PTC and 42 benign lesions (24 adenomas and 18 nodular hyperplasias).

Main Outcome Measures: We assessed the abundance of Nrf2, Nqo1, Keap1, and 4HNE; cell line viability and mRNA expression of Nrf2, Nqo1, and Trdx1; and the sequence of NFE2L2, KEAP1, and BRAF.

Results: Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions (P < .0001 and P = .024, respectively). The Nrf2 inhibitor Keap1 was variably abundant in PTC, and its levels did not correlate with Nrf2 (P = .37), arguing against decreased levels as the mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue (P < .001), indicating oxidative stress. Nrf2 mediated transcriptional antioxidant responses in both the PTC cell lines K1 and TPC-1 and in the nontransformed cell line TAD2, but it conferred a viability advantage specifically in the PTC cell lines.

Conclusions: The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.
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http://dx.doi.org/10.1210/jc.2013-1510DOI Listing
August 2013

Cell-surface serglycin promotes adhesion of myeloma cells to collagen type I and affects the expression of matrix metalloproteinases.

FEBS J 2013 May 1;280(10):2342-52. Epub 2013 Mar 1.

Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece.

Serglycin (SG) is mainly expressed by hematopoetic cells as an intracellular proteoglycan. Multiple myeloma cells constitutively secrete SG, which is also localized on the cell surface in some cell lines. In this study, SG isolated from myeloma cells was found to interact with collagen type I (Col I), which is a major bone matrix component. Notably, myeloma cells positive for cell-surface SG (csSG) adhered significantly to Col I, compared to cells lacking csSG. Removal of csSG by treatment of the cells with chondroitinase ABC or blocking of csSG by an SG-specific polyclonal antibody significantly reduced the adhesion of myeloma cells to Col I. Significant up-regulation of expression of the matrix metalloproteinases MMP-2 and MMP-9 at both the mRNA and protein levels was observed when culturing csSG-positive myeloma cells on Col I-coated dishes or in the presence of soluble Col I. MMP-9 and MMP-2 were also expressed in increased amounts by myeloma cells in the bone marrow of patients with multiple myeloma. Our data indicate that csSG of myeloma cells affects key functional properties, such as adhesion to Col I and the expression of MMPs, and imply that csSG may serve as a potential prognostic factor and/or target for pharmacological interventions in multiple myeloma.
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http://dx.doi.org/10.1111/febs.12179DOI Listing
May 2013