Iuliu Hatieganu Medical University

Cluj-Napoca, Romania

Iuliu Hatieganu Medical University

Cluj-Napoca, Romania
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Frede J.,Imperial College London | Frede J.,University of Heidelberg | Fraser S.P.,Imperial College London | Oskay-Ozcelik G.,Medical University of Berlin | And 7 more authors.
European Journal of Cancer | Year: 2013

Ovarian cancer is associated with limited overall survival, due to problems in early detection and therapy. Membrane ion channels have been proposed to play a significant, concerted role in the cancer process, from initial proliferation to metastasis, and promise to be early, functional biomarkers. We review the evidence for ion channel and aquaporin expression and functioning in human ovarian cancer cells and tissues. In vitro, K+ channels, mainly voltage-gated, including Ca2+-activated channels, have been found to control the cell cycle, as in other cancers. Voltage-gated, volume-regulated and intracellular Cl- channels have been detected in vitro and in vivo and shown to be involved in proliferation, adhesion and invasion. Evidence for 'transient receptor potential', voltage-gated sodium and calcium channels, which have been shown to contribute to pathogenesis of other carcinomas, is also emerging in ovarian cancer. Aquaporins may be involved in cell growth, migration and formation of ascites via increased water permeability of micro-vessels. It is concluded that functional expression of ion channels and their regulation by steroid hormones and growth factors are an integral part of ovarian cancer development and progression. Furthermore, ion channels may be involved in multidrug resistance, commonly associated with treatment of ovarian cancer. We propose that ion channel studies can facilitate our understanding of the pathobiology of ovarian cancer and, ultimately, can serve as viable novel targets for its clinical management. © 2013 Elsevier Ltd. All rights reserved.

Bujor A.M.,Boston University | Haines P.,Boston University | Padilla C.,Boston University | Christmann R.B.,Boston University | And 4 more authors.
International Journal of Molecular Medicine | Year: 2012

Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. The present study was undertaken to examine the effects of ciprofloxacin, a fluoroquinolone antibiotic implicated in matrix remodeling, on dermal and lung fibroblasts obtained from SSc patients. Dermal and lung fibroblasts from SSc patients and healthy subjects were treated with ciprofloxacin. Western blotting was used to analyze protein levels and RT-PCR was used to measure mRNA expression. The pharmacologic inhibitor UO126 was used to block Erk1/2 signaling. SSc dermal fibroblasts demonstrated a significant decrease in collagen type I mRNA and protein levels after antibiotic treatment, while healthy dermal fibroblasts were less sensitive to ciprofloxacin, downregulating collagen only at the protein levels. Connective tissue growth factor (CCN2) gene expression was significantly reduced and matrix metalloproteinase 1 (MMP1) levels were enhanced after ciprofloxacin treatment to a similar extent in healthy and SSc fibroblasts. Ciprofloxacin induced Erk1/2 phosphorylation, and Erk1/2 blockade completely prevented MMP1 upregulation. However, Smad1 and Smad3 activation in response to TGFβ was not affected. The expression of friend leukemia integration factor 1 (Fli1), a transcriptional repressor of collagen, was increased after treatment with ciprofloxacin only in SSc fibroblasts, and this was accompanied by a decrease in the levels of DNA methyltransferase 1 (Dnmt1). Similar effects were observed in SSc-interstitial lung disease (ILD) lung fibroblasts. In summary, our study demonstrates that ciprofloxacin has antifibrotic actions in SSc dermal and lung fibroblasts via the downregulation of Dnmt1, the upregulation of Fli1 and induction of MMP1 gene expression via an Erk1/2-dependent mechanism. Thus, our data suggest that ciprofloxacin may be an attractive therapy for SSc skin and lung fibrosis.

Nassir M.,Charité - Medical University of Berlin | Darb-Esfahani S.,Charité - Medical University of Berlin | Richter R.,Charité - Medical University of Berlin | Chekerov R.,Charité - Medical University of Berlin | And 7 more authors.
Anticancer Research | Year: 2013

Aim: Our purpose was to analyze the tissue expression of human epididymis protein-4 (HE4) in borderline tumors of the ovary (BOT) and to correlate it with histological subtypes and clinical features. Patients and Methods: Tumor tissue samples from 25 patients with BOT were stained on tissue microarrays. The percentage of stained tumor cells was represented by grouped immunoreactivity scores (IRS) 0 to 4. Results: The median patient age was 47 (range=22-73) years. Tumors in most patients (19/25) were staged-FIGO I and presented serous (52%) or mucinous (40%) histology. HE4 immunoreactivity occurred exclusively within the tumor cells. No association between grouped IRS and histological type, age, CA125 and FIGO stage was found. Correlation between HE4 positivity cells and HE4 IRS was significant (p<0.001). Conclusion: The role of HE4 in BOT remains unclear. Multicenter surveys are needed to more profoundly help in the understanding of the biological and clinical features of BOT.

Braicu E.I.,Charité - Medical University of Berlin | Gasimli K.,Charité - Medical University of Berlin | Richter R.,Charité - Medical University of Berlin | Nassir M.,Charité - Medical University of Berlin | And 13 more authors.
Anticancer Research | Year: 2014

Aim: The aim of the current study was to analyze the type of variations in expression profiles of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 2 (TIMP2), and vascular endothelial growth factor A (VEGFA) before and after radiochemotherapy in patients with locally advanced FIGO stage Ib-IIb cervical cancer. We analyzed the role of these biomarkers in monitoring response to treatment. Patients and Methods: Serum from 72 patients with cervical cancer treated within a phase III trial with either simultaneous radiochemotherapy (S-RC) with cisplatin, or systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R) was analyzed by ELISA. Sera were obtained during surgery and after the end of adjuvant treatment. Results: The median age at time of diagnosis was 46 years (range=30-71 years). The most common histological types were squamous cell (73.6%) and adenocarcinoma (25%). Thirty-five (48.6%) patients underwent surgery followed by S-RC and 37 (51.4%) patients were treated with surgery followed by PC-R. Five patients developed recurrence within six months after radiochemotherapy. VEGFA levels were significantly higher before and after adjuvant treatment in patients who developed early recurrence (p=0.001). An increase of more than 500 pg/ml VEGFA and a decrease of more than 9% of the pre-therapeutic value of TIMP2 were significantly associated with a higher risk of early recurrence (RR=8.5, 95% CI=1.8-39.8 and RR=11.0, 95% CI=2.5-48.2, respectively). TIMP2 expression and risk score for early relapse (which is calculated using values of VEGFA and TIMP2) were independent prognostic factors for overall survival (p=0.043, HR=0.96, 95% CI=0.93-0.99 and p=0.002, HR=1.09, 95% CI=1.03-1.15, respectively). Conclusion: Our results indicate a predictive value of VEGFA and TIMP2 in monitoring cervical cancer patients undergoing radiochemotherapy. © 2014, International Institute of Anticancer Research. All rights reserved.

Braicu E.I.,Charité - Medical University of Berlin | Braicu E.I.,Iuliu Hatieganu Medical University | Fotopoulou C.,Charité - Medical University of Berlin | Chekerov R.,Charité - Medical University of Berlin | And 8 more authors.
Cytokine | Year: 2013

Objective: Aim of the present study was to analyze the expression-profile of IGF1, IGFBP3, sICAM1, sVCAM1, MMP2, MMP9, TIMP2, VEGFA, VEGFD, VEGFC and VEGFR1 in patients with high-risk FIGO-stage Ib-IIb cervical cancer. Methods: Serum from 68 cervical cancer patients treated within a phase-III-trial with either simultaneous cisplatin radiochemotherapy or sequential systemic carboplatin and paclitaxel followed by percutaneous irradiation was analyzed by ELISA. Both target expression and correlation with important clinicopathological factors were analyzed following standard statistic procedures. Results: All 68 patients underwent a primary radical hysterectomy with pelvic and/or paraaortic lymphadenectomy. 85.3% of the extirpated tumors had clear surgical margins (R0). Increased levels of VEGFR1, TIMP2 and MMP2 were significantly associated with positive surgical margins (p= 0.004, p= 0.018 and p= 0.004, respectively). High concentration of MMP2 and TIMP2 correlated additionally with an advanced age at time of diagnosis (p= 0.001 and p= 0.007, respectively). For the cut-off value of 100. pg/ml, an increased VEGFR1 was significantly associated with poor overall (OS) and progression-free (PFS) survival (p= 0.017 and p= 0.015, respectively). A TIMP2 concentration of lower than 90. ng/ml was significantly associated with poorer OS and PFS (p= 0.009 and p= 0.043, respectively). In the multivariate analysis, TIMP2 expression in serum was the only independent prognostic factor for OS (p= 0.032, HR = 6.51, 95% CI = 1.17-36.01). Conclusions: Expression-profile of specific biomarkers associated with tumor invasion, cell migration and angiogenesis seems to be of prognostic value for both OS and PFS in patients undergoing surgery due to primary cervical cancer. Further analyses are warranted to allow an implementation of such markers into clinical practice. © 2013 Elsevier Ltd.

Braicu E.I.,Charite Medizinische University Berlin | Chekerov R.,Charite Medizinische University Berlin | Richter R.,Charite Medizinische University Berlin | Pop C.,Charite Medizinische University Berlin | And 8 more authors.
Annals of Surgical Oncology | Year: 2014

Background: Epithelial ovarian cancer (EOC) remains the main cause of mortality due to gynecological malignancies. Optimal tumor debulking and platinum response are the most important prognostic factors for overall survival (OS) in primary EOC. In the setting of recurrence, the role of cytoreduction is not clear. A critical point is to predict preoperatively the subgroup of patients with optimal surgical outcome. The aim of the study was to analyze the predictive role of HE4 for surgical outcome and platinum response in EOC patients experiencing a first relapse. Secondary aims were the prognostic role of HE4 for OS and progression-free survival (PFS). Methods: Plasma was obtained before secondary cytoreduction from 73 EOC patients. A total of 66.7 % underwent a total macroscopic tumor clearance; 86.3 % of the patients had disease that responded to platinum therapy. HE4 was detected by enzyme-linked immunosorbent assay. For statistical analysis, the chi-square test, Fisher's exact test, Kendall's tau b, and Mann-Whitney U test were used. OS, PFS rates, and respective 95 % confidence intervals (CI) were estimated according to the Kaplan-Meier method. Results: At a HE4 cutoff value of 250 pMk, a sensitivity of 52 % and a specificity of 93.8 % (p = 0.001, 95 % CI 0.601-0.861) were reached in predicting total macroscopic tumor clearance. Plasma HE4 concentrations together with platinum response were the only independent prognostic factors for OS (p < 0.001, hazard ratio [HR] 18.77, 95 % CI 4.68-75.25; and p = 0.044, HR 3.33, 95 % CI 1.03-10.7, respectively). Together with ascites, HE4 was the only independent predictive factor for surgical outcome (p = 0.029, odds ratio [OR] 7.2, 95 % CI 1.22-42.19 and p = 0.036, OR 10.18, 95 % CI 1.16-88.69, respectively). Conclusions: HE4 is an independent predictive marker for surgical outcome and OS in patients with recurrent EOC. Larger population studies are needed to validate these results. © 2013 Society of Surgical Oncology.

Nemes A.,Institute Of Oncology Prof Dr Ion Chiricuta Cluj | Tomuleasa C.,Institute Of Oncology Prof Dr Ion Chiricuta Cluj | Tomuleasa C.,Iuliu Hatieganu Medical University | Kacso G.,Institute Of Oncology Prof Dr Ion Chiricuta Cluj | Kacso G.,Iuliu Hatieganu Medical University
Journal of B.U.ON. | Year: 2014

Metastatic castration-resistant prostate cancer (mCRPC) shows a number of adaptive mechanisms that facilitate continued androgen receptor (AR) dependent tumor growth. In this article we reviewed the subsequent hormonal manipulation in mCRPC, including the recently approved new drugs, in relation to the AR dependent and independent growth mechanisms. Maintaining castrate levels of testosterone is mandatory. The AR amplification, a process that can occur within the hypersensitive AR escape route, can be fought by using high dose antiandrogen (bicalutamide 150mg), change in antiandrogen preparation or the use of enzalutamide. Switch to another antiandrogen, the use of LHRH antagonists, change to another LHRH agonist, bilateral orchidectomy, adrenals' inhibition and the blockade of intratumor testosterone synthesis are several ways to counter the increased AR sensitivity. Increased androgen levels can be reduced by the use of ketoconazole, dexamethasone, abiraterone acetate or 5a-reductase inhibitors. Antiandrogen withdrawal and enzalutamide can be used to counter the promiscuous AR escape route. The use of metformin, cetuximab or cabozantinib could represent ways to overcome the outlaw pathway, but further studies are needed to show the efficacy of these drugs in mCRPC. Bcl-2 inhibitors, emerging drugs still in experimental phase, show great potential in counteracting the bypass pathway. Docetaxel and cabazitaxel, the standard chemotherapy of mCRPC, are the treatment of choice when androgen-independent prostate cancer cells are selected (as supported by the lurker cell pathway). The correct and rational use of all these drugs may delay by months or even years the need to administer chemotherapy in patients with mCRPC but some AR targeted therapies may impair the subsequent response to chemotherapy.

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