National/international scientific publications and participations -2016
A. Book chapters
1. Irinel Popescu, Sorin Alexandrescu. Book title: Liver Cancer, Chapter title: “Onco-surgical Management of Liver Metastases from Colorectal Cancer”, ISBN 978-953-51-4910-1, 2016
2. Simona Olimpia Dima, Dana Cucu, Nicolae Bacalbasa, Valeria Tica and Irinel Popescu. Book title: Stem cells between regeneration and tumorigenesis, Chapter title: “Cancer stem cells in pancreatic and hepatocellular carcinoma: similarities and differences”, pg. 187-201, 2016.
http://www.eurekaselect.com/145577/chapter/cancer-stem-cells-in-pancreatic-and-hepatocellular-carcinoma%3A-similarities-and-difference
3. Cristiana Pistol Tanase, Elena Condrici, Ionela Daniela Popescu, Simona Mihai, Laura Necula and Radu Albulescu. Book title: Stem cells between regeneration and tumorigenesis, Chapter title: “Current proteomic studies for new concept in stem cell biology”, Bentham Sciences Publishers, ISBN 978-1-68108-332-2 pg. 235-280, 2016
https://ebooks.benthamscience.com/book/9781681083315/chapter/145579/
B. Articles
1. Rusu E., Necula L.G., Neagu A.I., Alecu M., Stan C., Albulescu R., Tanase C. Current status on stem cell therapy: opportunities and limitations. Turk J Biol 40: 955-967, 2016, FI= 1,183
http://journals.tubitak.gov.tr/biology/issues/biy-16-40-5/biy-40-5-1-1506-95.pdf
2. Tanase C, Necula LG, Neagu AI, Albulescu R. The Association between Inflammation and Angiogenesis in Human Pancreatic Adenocarcinoma. Journal of Translational Medicine and Research, Review 2, 2016
http://www.jtmr.ro/article/the-association-between-inflammation-and-angiogenesis-in-human-pancreatic-adenocarcinoma_full-text
3. Razvan Iacob · Vlad Herlea · Codruta Popa, Irinel Popescu, et. al. “Prognostic Significance of CD44 Expression in Hepatocellular Carcinoma Following a Potentially Curative Treatment”, J.Transl.Res. 21 (4):267-273, 2016
http://www.jtmr.ro/pdfs/2016-4-267.pdf
4. Yunching Chen, Ya-Chi Liu, Yun-Chieh Sung, Rakesh R. Ramjiawan, Ts-Ting Lin, Chih-Chun Chang, Kuo-Shyang Jeng, Chiung-Fang Chang, Chun-Hung Liu, Dong-Yu Gao, Fu-Fei Hsu, Annique M. Duyverman, Shuji Kitahara, Peigen Huang, Simona Dima, Irinel Popescu, Keith T. Flaherty, Andrew X. Zhu, Nabeel Bardeesy, Rakesh K. Jain, Cyril H. Benes, and Dan G. Duda. “Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors”, Scientific Reports 2017
5. Simona Dima, Anca Nastase, Andrei Sorop, Valeria Tica, Raluca Florea, Veronica Ilie, Nicolae Bacalbasa, Sorin Alexandrescu, Dana Cucu, Vlad Herlea, Irinel Popescu, Dan Duda “Circulating Plasma VEGF and VEGF-C are Potential Prognostic Biomarkers for Hepatocellular Carcinoma Patients Undergoing Surgical Treatments” (in press)
6. Anca Nastase, Irinel Popescu, et. al., “Genomic and proteomic characterization of ARID1A chromatin remodeler”, 2017 (in press)
C. Communications at national/international congress
I. International Conference – Education and creativity for a knowledge based society (10th ed.) Workshop “4 SEE Romania-Norway”, 17-19 November 2016, “Titu Maiorescu” University – “Nicolae Cajal” Institute, Moderators: CS I Dr Simona Olimpia Dima; Prof. Dr. Cristiana Tănase
http://www.utm.ro/conferinta/files/program_conferinta_2016.pdf
1. Radu Albulescu, Laura Georgiana Necula, Ana Iulia Neagu, Catalin Pecheanu, Elena Stoica Mustafa, Vlad Herlea, Simona Dima, Cristiana Tanase, Irinel Popescu. “Advantaje of xMAP array proteomic technology (mesoscale) in evaluation of patients with hepatocellular carcinoma”
2. Cristiana Tanase, Radu Albulescu, Laura Georgiana Necula, Ana Iulia Neagu, Catalin Pecheanu, Elena Stoica Mustafa, Vlad Herlea, Simona Dima, Irinel Popescu. „Genomic and proteomic interdisciplinarity within the project – “Hepatocellular carcinoma stratification based on noninvasive markers”
3. Simona Dima, Andrei Sorop, Valeria Tica, Raluca Florea, Veronica Ilie, Nicolae Bacalbasa, Anca Nastase, Razvan Grigorie, Sorin Alexandrescu, Dana Cucu, Vlad Herlea, Irinel Popescu. “Exosomes isolation by size exclusion chromatography for patients with hepatocellular carcinoma”
4. Simona Dima, Andrei Sorop, Valeria Tica, Raluca Florea, Veronica Ilie, Nicolae Bacalbasa, Razvan Grigorie, Sorin Alexandrescu, Dana Cucu, Vlad Herlea, Irinel Popescu. “The analysis of expression levels of miRNA species by microarray technology in hepatic tumors”
II. Poster presentation ILTS 22nd Annual Congress, Seoul, Korea, 4-7 May 2016
Circulating Il-6 Is Differentially Associated with Survival in Resected versus Transplanted Hepatocellular Carcinoma Patients
Dan G. Duda1, Simona Dima2, Tai Hato1, Shuji Kitahara1, Raluca Florea2, Daniela Cucu2,
Dana Tomescu2, Cristiana Tanase3, Vlad Herlea2,3, Irinel Popescu2
1-E.L.Steele Laboratory for Tumor Biology, Department of Radiation Oncology,
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA;
2- Fundeni Clinical Institute, Bucharest, Romania; Fundeni Clinical Institute, Bucharest, Romania;
3- Faculty of Medicine , Titu Maiorescu University, Bucharest, Romania
Currently, liver transplantation (LT) and surgical resection (LR) are the main treatment options for hepatocellular carcinoma (HCC). Previous studies have shown that circulating interleukin 6 (IL-6) levels are associated with poor prognosis in advanced HCC. This retrospective study aimed to examine the role of circulating IL-6 and other inflammatory factors in LR and LT HCC patients. The study included 110 patients with HCC who underwent LR and 56 who underwent LT in one center (Fundeni Clinical Institute, Bucharest, Romania) between 2003 and 2013. Circulating concentrations of IL-6 as well as other inflammatory markers, such as IL-10, IL-2, IL-4, IL-8 were measured using a multiplex protein array from Meso-Scale Discovery in a CLIA-certified lab at Harvard Medical School, Boston. Biomarker levels were tested for associations with disease-free survival (DFS) and overall survival (OS). IL-6 levels were detectable (>1,6 ng/ml) in 64 patients with LR and 46 with LT. Circulating IL-6 is correlated with DFS and OS both in LR and LT HCC patients. Strikingly, an undetectable level of IL-6 was significantly correlated with improved survival in LR patients (P<0.01, 48-month OS 55% vs 39%) but with more unfavorable survival in transplanted patients (P=0.035, 48-month OS 50% vs 66%). We identify pretreatment blood circulating IL-6 as a prognostic biomarker in HCC patients treated by surgery. Interestingly, the analysis showed a differential prognostic value for IL-6 in resected versus transplanted patients, supporting a differential role of this cytokine in these settings. Complete biomarker analysis will be presented at the meeting. This study has been supported by the EEA-JRP-RO-NO-2013-1-0363. https://www.researchgate.net/profile/Simona_Dima/publication/302895361_Circulating_Il6_Is_Differentially_Associated_with_Survival_in_Resected_versus_Transplanted_Hepatocellular_Carcinoma_Patient/links/5732b33a08aea45ee8364b48.pdf
III. Fundeni Clinical Institute Days Conference, Poiana-Brasov 29 September – 02 October 2016
1. S. Dima, P. Saetrom, V. Tica, R. Florea, V. Ilie, A. Sorop, A. Nastase, N. Bacalbasa, R. Grigorie, S. Alexandrescu, D. Cucu, V. Herlea, I. Popescu. “Identification of a microRNA panel by next generation sequencing, correlated with hepatocellular carcinoma patients survival”– (oral presentation)
IV. The XI th Symposium Academician Nicolae Cajal (with international participation), Bucharest, 17-19 March 2016
http://trima-events.ro/wp-content/uploads/2016/03/PROGRAM-FINALCAJAL_2016_WEBSITE.pdf
1. Necula LG, Neagu AI, Albulescu R, Pecheanu C, Mustafa ES, Herlea V, Dima SO, Tanase C, Popescu I. “Evaluation of tisular tumor angiogenesis in human hepatocellular carcinoma” – (poster)
2. Cristiana Tanase, Radu Albulescu, Mihail E Hinescu. “Precision Medicine – Multiomic Approaches” – (poster)
3. Pål Sætrom. “microRNA signatures of hepatocellular carcinoma in serum and tissue” – (oral presentation)
V. Romanian Medical Association Annual Congress – AMR, Bucharest, 24-26 April 2016
1. A. Şorop, D. Cucu, R. Florea, V. Ilie, V. Tica, L. Mardare, A. Dinischiotu, S. Dima, I. Popescu. “Plasma exosomes extraction from patients with hepatocellular carcinoma” – (poster)
VI. “European Association for Cancer Research Congress – (EACR)”, Manchester, UK, 2016
1. Albulescu R., Necula L.G., Neagu A.I., Herlea V., Dima S.O., Tanase C., Popescu I. Angiogenic markers in hepatocellular carcinoma. European Journal of Cancer, Vol. 61, Supl 1, pg. 373, S75. FI 6.163, 2016
http://www.ejcancer.com/article/S0959-8049(16)61261-3/abstract
VII. The 12th IHPBA International Congress-“International Hepato-Pancreato-Biliary Association”, Sao Paulo, Brazil, 20-23 april, 2016
S. Dima, D. Cucu, N. Bacalbasa, D. Tomescu, R. Florea, V. Herlea, V. Tica, C. Tanase, D. Duda and Popescu. “Prognostic role of circulating angiogenic markers in patients with hepatocellular carcinoma undergoing liver transplantation and liver resection”, HPB Vol.18, Suppl.1, Pages e58–e59, 2016
http://www.hpbonline.org/article/S1365-182X(16)30160-5/fulltext
National/international scientific publications and participations -2015
A. Book chapters
1. C. Tanase, E. Codrici, I.D. Popescu, S. Mihai, L. Necula, R. Albulescu, Stem Cells between Regeneration and Tumorigenesis, 2015, 1-39, Chapter 9
Current Proteomic Studies For New Concept In Stem Cell Biology
2. S.O. Dima, D. Cucu, N. Bacalbasa, V. Tica, I. Popescu, Stem Cells between Regeneration and Tumorigenesis, 2015, Chapter 7, Cancer stem cells in pancreatic and hepatocellular carcinoma: similarities and differences
B. Articles
1. Necula LG, Mambet C, Albulescu R, Diaconu CC., Epigenetics in gastric carcinogenesis: TET genes as important players., J Immunoassay Immunochem, 2015; 36(5): 445-55. Doi:10.1080/15321819.2015.1017402
http://www.tandfonline.com/doi/abs/10.1080/15321819.2015.1017402
C. Communications at national/international congress
1. Poster presentation Academician Nicolae Cajal Symposium X-th edition, Bucharest, April 1 – 4, 2015
CITOSTATIC DOSE DEPENDENT EMT TRANSITION AS A RESULT OF FOXC1 OVEREXPRESSION IN HUMAN HEPATOCELLULAR CARCINOMA CELL LINES
Raluca Florea1, Veronica Madalina Ilie1, Andrei Sorop1, Valeria Tica1, Liliana Livia Paslaru1,2,Nicolae Bacalbasa2, Razvan Iacob1, Simona Dima1, Irinel Popescu1
1 Fundeni Clinical Institute, Bucharest, Romania
2 University of Farmacy and Medicine “Carol Davila”, Bucharest, Romania
Introduction: Human hepatocellular carcinoma is one of the most common liver diseases worldwide and is the third cause of death, responsible for 13% of deaths. High mortality rate is related primarily with the
recurrence rate after therapeutic interventions. Epithelial-mesenchymal transition is a morphogenetic process in several steps during which epithelial cells downregulate their epithelial proprieties and overexpress
their mesenchymal features. This mechanism can be induced in vitro by doxorubicin, where is observed an increased ability of cancer cells migration, changing the culture morphological phenotype mimicking a fibroblast-like aspect.
Aim: In this study we performed in vitro analysis of the effects of different doses of doxorubicin on human hepatocellular carcinoma cell lines in terms of EMT promotion.
Methods and materials: For the analysis of EMT we analyzed by Real Time PCR the gene expression of the transcriptional factors Snail, Slug, FOXC1 and proteins Vimentin, E-cadherin following treatment of Huh7 and HepG2 cell lines with different doses of doxorubicin at 24 and 48 hours.
Results and discussion: In HCC cell lines, doxorubicin at doses greater than 0.0025 µg/µl, induces apoptosis and cell necrosis.The results showed that low doses of doxorubicin (between 0.0003125µg/µl and 0.0025 µg/µl) promote EMT marked by overexpression of transcription factors FOXC1, Slug, Snail, promotion of vimentin expression and decreasing the expression of E-cadherin.
Conclusions: At various points in time cytostatic action at low doses induce morphological changes and also
changes in the cellular mechanisms. These morphological changes lead to EMT process activated by the effect of doxorubicin as a result of overexpression of transcription factors Snail, Slug and FOXC1, of Vimentin
and E-cadherin downregulation. Thus, we can recommend the adjustment of doxorubicin concentration used in TACE procedures based on tumor volume.
This study was financially supported by 125/2011 (PN-II-ID-PCE- 2011-3-0605), PD 23/ 2011 (PN-II-RU-PD-
2011-3-0137), EEA-JRP-Romania-Norvegia nr.4SEE/30.06.2014.
The findings were published as a summary in the Journal of Translational Medicine and Research, Supplement II / Vol. 20/2015
http://www.trima-events.ro/wp-content/uploads/2015/04/Supliment-II-JTMR.pdf
2. Poster presentation ILTS 21st Annual International Congress, Chicago, IL, USA, July 8-11 2015
Angiogenic Markers in Patients With Liver Transplantation for Hepatocellular Carcinoma
Simona Dima1, Dan Duda2, Dana Cucu1, Mihai Eftimie1, Valeria Tica1, Nicolae Bacalbasa1, Adina Croitoru1, Vlad Herlea1, Cristiana Tanase3, Irinel Popescu1
1 General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Bucuresti – Ilfov, Romania;
2 Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA;
3 Titu Maiorescu Univesity, Bucharest, Ilfov, Romania.
Background/aims: The aim of the present study was to investigate the profile of angiogenic and inflammatory biomarkers in peripheral blood of patients with liver transplantation (LT) for hepatocellular carcinoma (HCC) compared to patients who underwent liver resection (LR) or to healthy volunteers.
Methodology: The study included 77 patients with resection for HCC, 18 patients with LT and 51 healthy volunteers from Center of Liver Transplantation and General Surgery Dan Setlacec, Fundeni Clinical Institute, Bucharest, Romania. Measured biomarkers included members of the vascular endothelial growth factor (VEGF) protein family (VEGF-A, VEGF-C and VEGF-D), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), soluble VEGF receptor 1 (sFLT1) and soluble TIE2 and inflammatory markers such us Il-10, IL-2, IL-4, IL-6, IL-8. We analyzed disease-free survival (DFS) and overall survival (OS) after LT in patients with HCC in correlation with invetigated biomarkers.
Informed consent was obtained for all patients included in the present study.
Results: Circulating bFGF, sFLT-1, TIE2, levels were significantly higher in LT patients versus LR patients (p=0.064, p=0.097 and p=0.025) and VEGF-C level is higher in LR versus LT group (p=0.027). OS and DFS in patients with a higher level of VEGF-D and IL-6 were significantly worse.
Conclusions: This hypothesis generating data on HCC biomarkers for angiogenesis in LT patients should be confirmed in larger studies, but preliminary results of ours study demonstrated the prognostic significance.
Aknowledgments: this study has been supported by the Romanian – EEA Research Programme EEA-JRP-RO-NO-2013-1-0363.
The abstract was published in Transplantation, Supplement 7S / Vol. 99 /pag. 282/ 2015
http://journals.lww.com/transplantjournal/Citation/2015/07001/Abstracts_.3.aspx
3. Poster presentation ILTS 21st Annual International Congress, Chicago, IL, USA, July 8-11 2015
Significance of Liver Enriched Transcription Factors as Molecular Markers for Hepatocellular Carcinoma Recurrence After a Potentially Curative Treatment
Razvan Iacob1,2, Codruta Vagu1, Anca Nastase1, Speranta Iacob1, Florin Botea1, Razvan Grigorie1, Luminita Stoica1, Vlad Herlea1, Adina Croitoru1, Simona Dima1, Liana Gheorghe1,2, Cristian Gheorghe1,2, Michael Ott3, Irinel Popescu1,2
1 Fundeni Clinical Institute, Bucharest, Romania;
2 CarolDavila University of Medicine and Pharmacy, Bucharest, Romania;
3 Hannover Medical School, Hannover, Germany
Background: The liver enriched transcription factors (LETF) are critical in inducing and maintaining hepatic phenotype during liver organogenesis and their expression level in HCC could have prognostic implications.
The aim of our study was to investigate the prognostic significance for early HCC recurrence (within 24 months following a potentially curative treatment) for LETF expression in HCC specimens, in comparison to paired non-tumoral liver tissue.
Methods: The study group included 40 patients, 23 with liver resection and 17 with liver transplantation for HCC, with a mean follow-up after treatment of 29 months. Gene expression has been quantified by qRT-PCR, using beta-actin as reference gene for eight transcription factors: FoxA2, HNF6 (ONECUT1), HNF1-alpha, HNF1-beta, HNF4-alpha, C/Ebp-alpha, Gata4, Gata6. Multivariate survival analysis has been conducted by Cox proportional hazards model. Clinical variables have also been included in the multivariate survival analysis: Milan Criteria, Child-Pugh C class, poorly differentiated tumor grading, type of treatment (liver resection vs. liver transplantation).
Results: During follow-up, tumor recurrence has been detected in 42.5% of patients who underwent LT and 57.5% of patients after liver resection. As independent predictors for tumor recurrence have been identified: down regulation of HNF4alpha, up-regulation of Gata4 and up-regulation of HNF6. Clinical variables were not independent predictors according to our multivariate survival analysis. Based on survival analysis data, a statistical model to predict recurrence after curative treatment has been generated. The model has a C-statistic of 0.83, suggesting an excellent clinical utility. A cut-off level of 0.64 of the prognostic score has a 76.5% sensitivity and a 83.3% specificity in predicting recurrence of HCC after a potentially curative treatment.
Conclusions: Down regulation of HNF4alpha, and upregulation of Gata4 and HNF6 in tumoral tissue are significant independent molecular prognostic factors for tumor recurrence following a potentially curative treatment for HCC.
The abstract was published in Transplantation, Supplement 7S / Vol. 99 /pag. 224/ 2015
http://journals.lww.com/transplantjournal/Citation/2015/07001/Abstracts_.3.aspx
4. Oral presentation 25th IASGO World Congress, Fuzhou, China, September 4-6, 2015
Angiogenic markers in patients with hepatocellular carcinoma
Simona Dima
Fundeni Clinical Institute, Bucharest, Romania
http://www.cmacss.org/2015/program_en.asp?flag=vp&meeting_hall_name=406%BB%E1%D2%E9%CA%D2
5. Presentation Academician Nicolae Cajal Symposium X-th edition, Bucharest, April 1 – 4, 2015
Personalized/Precision Medicine – Transdisciplinary And Translational Approach; Omics Technology
Cristiana Tanase1,2, C. Stan1 , R. Albulescu1,2,3
1 ”Titu Maiorescu” University, Faculty of Medicine, Bucharest, Romania
2 ”Victor Babes” National Institute of Pathology, Bucharest, Romania
3 National Institute for Chemical Pharmaceutical Research and Development, Bucharest, Romania
Personalized/precision medicine will focus on an individual approach and its nature will be proactive. Personalized medicine promotes the concept of the right therapy for the right group of patients, at the right moment, with the right cost. Systems biology and systems medicine has led to a “P4 medicine” that is predictive, preventive, personalized and participatory. The future of medicine relies on such personalization. Personalized medicine is designed medicine based on “Omics” contribution. The need to apply molecular screening in order to improve the diagnosis is crucial in most of the pathologies. The incorporation of proteomics in the further development of the personalized medicine concept is a more recent phenomenon and it has given rise to a complete image of the health/disease status of an individual, especially at functional level. In order to identify new circulating biomarkers, high throughput proteomic technologies, such as mass spectrometry (SELDI-ToF, MALDI-ToF), 2D-DIGE, multiplexed and protein microarray are being used. Proteomics can generate new and useful information by identifying and establishing protein-protein interactions at intra- and intercellular level. The most recent tendency in personalized/precision medicine approach relies on the “P4/P5 medicine”, which constitutes a health concept focused on each individual patient.
Acknowledgment: The present work was supported by project PN 09.33-03.10 and 4SEE/2014.
The findings were published as a summary in the Journal of Translational Medicine and Research, Supplement I / Vol. 20/2015
http://www.jtmr.ro/pdfs/supplements/2015-supplement-1.pdf
6. The International Conference “Education And Creativity For A Knowledge-Based Society”, Universitatea Titu Maiorescu, IX-th edition, ISBN 978-3-9503145, ISSN 2248-0064, Bucharest, 2015
Tissular Angiogenic Markers In Hepatocellular Carcinoma.
Laura Georgiana Necula, Ana Iulia Neagu, Radu Albulescu, Catalin Pecheanu, Elena Stoica Mustafa, Vlad Herlea, Simona Dima, Cristiana Tanase.