Alexandre Ferreira Ramos
I have been working with symmetries and stochastic modeling applied to biological systems since my Master of Sciences. Currently I am coordinating a group dedicated to the application of quantitative and computational techniques for the analysis of cancer related phenomena. Our research on RKIP consists on the proposition of a stochastic binary model for the transcription of RKIP. A second goal is to design an experiment to validate our model such that it will become a tool to investigate randomness on the expression of RKIP gene. That investigation has a potential translational impact as it enables the design of treatment strategies aiming at predicting how it will affect the average and standard deviation values of RKIP transcripts levels. Hence, one may even try to control heterogenenity in tumor cells when it is measured in terms of the expression levels of RKIP.
Apostolos is an Associate Professor of Genetics in the Department of Basic Medical Sciences of the College of Medicine at Qatar University. He received his B.Sc. in Molecular Biology from the Department of Biology of the University of Crete (2004) and his Ph.D. in Medicine from the Medical School of the same University (2008). He worked as Research Scientist at the Harris Birthright Research Center for Fetal Medicine at King’s College Hospital (2009-2010) and performed postdoctoral research in Cancer Genetics at the Molecular Medicine Research Center of the University of Cyprus (2011-2013). He completed his postdoctoral training in Immunogenetics and Cancer Genetics at the Department of Laboratory Medicine of the Karolinska Institute (2013-2015). From September 2015 to 2019 he worked as Assistant Professor in Cancer Genetics at the Department of Life Sciences at the European University Cyprus and was then promoted in the rank of Associate Professor. He holds two Specialisations, one in “Systems Biology” from the Systems Biology Center at Icahn School of Medicine, Mount Sinai (2015) and another in “Genomic Data Science” from the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University (2018). Apostolos’ research focuses on the advance understanding of carcinogenesis through the investigation of interactions between genes and the analysis of Big Data in Genomics. Apostolos has worked as a Guest Editor for several Special Issues in scientific journals and as Associate Faculty Member of the F1000Prime (2013-2015). He is the recipient of the Science Award (2017) from the Youth Board of Cyprus, and the first Young Investigator Award from the Bank Of Cyprus Oncology Centre (2017). He is also a member of the EACR, FEBS, the Swedish Society for Biochemistry and the ECCO, and has authored in >70 original research articles, 10 review articles, and 4 book chapters. Apostolos has investigated the role of RKIP as an independent prognostic factor for patient survival, using normalized TCGA gene expression data for all cancer types.
Apostolos' research has shown that RKIP is reversely expressed with BRAFwt in nasal polyposis (Cancer Lett. 2008) and that RKIP and BRAF are significantly decreased in squamous cell carcinoma (Cell Cycle. 2009) and urinary bladder cancer (Pathol Oncol Res. 2011). His group has also highlighted the relationships of the NF-κB/Snail/YY1/RKIP circuitry with specific cancer-related gene sets in multiple myeloma (Tumour Biol. 2014). Furthermore, he recently reviewed the contribution of RKIP in the regulation of early metastatic steps, as well as in tumor sensitivity to conventional therapeutics and immuno-mediated cytotoxicity (Cancers. 2018). He currently uses multi-omics approaches to highlight the putative associations of RKIP promoter methylation with its deregulated expression levels, as well as the correlation of increased RKIP expression with high copy number levels, across human malignancies (2nd International Symposium on prognostic and therapeutic implications of RKIP in cancer).
Distinguished Research Professor
I am currently a Distinguished Research Professor, Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA). My research career, thus far, has focused on basic immunochemistry and cancer immunobiology. My research investigations have ranged from the mechanisms of cell-mediated killing and sensitization of resistant tumor cells to chemo/immunotherapies, characterization of resistant factors in cancer cells, cell-signaling pathways mediated by therapeutic anti-cancer antibodies, and characterization of each of the gene products in the dysregulated NF-κB/Snail/YY1/RKIP/PTEN loop in many cancers that regulate cell survival, proliferation, invasion, metastasis, and resistance. I have also investigated the role of nitric oxide in cancer and its potential anti-tumor activity. Many of the above studies are centered on the clinical challenging features of cancer patients’ failure to respond to both conventional and targeted therapies. I have published extensively on the above research topics.
My primary focus at the present time on RKIP research investigations comprises the role of both active and inactive RKIP expressions on the regulation of tumor cells’ chemo and immuno resistance as well as means to override resistance. In addition, the role of RKIP expression in both the development and differentiation of naïve human T lymphocytes into activated cytotoxic CD8+ T lymphocytes. In addition, I have currently been examining the role of RKIP in the regulation of the expression in both activating and inhibitory receptors on human natural killer cells.
I am currently Editor-in-Chief of Critical Reviews in Oncogenesis, the Series Editor for Resistance to Targeted Anti-Cancer Therapeutics published by Springer, and the Series Editor of the following three series: Chemotherapy-Sensitizing Agents for Cancer, Breaking Cancer Resistance to Therapeutic Antibodies, and Breaking Tolerance to Anti-Cancer Immunotherapy, published by Elsevier/Academic Press.
Chief Scientific Officer
I am a professor of Genomic Medicine and have a special interest in metastasis suppressors such as RKIP (PEBP1). Metastasis suppressors are not born with this function in mind. They most likely control major processes. We have shown for example how RKIP modulates cell-cycle kinetics. Our lab was the first to show a strong correlation between RKIP expression and survival in colorectal and breast cancers. Moreover, we have shown that RKIP can be utilized as a biomarker in breast cancer classification, using a robust method, which is much more cost-effective than OncotypeDx or PAM 50. We have established a clear interactome for RKIP and have shown that it binds and activates GSK3-Beta in vivo and in vitro. Updated 2023
Here are some publications from my laboratory.
Luca Falzone is a Ph.D. student within the Ph.D. Program in Basic & Applied Biomedical Sciences at the University of Catania (Catania, Italy). He received the MSc in Medical Biotechnologies with full marks at the University of Catania in 2018. At the same University, he obtained a Bachelor Degree in Biomedical Laboratory Techniques in 2014. His research activity is focused on the molecular mechanisms of tumor development and progression with particular reference to the study of cancer cells and tumor microenvironment interactions, the study of the activation of the NGA/MMP-9, and the functional role of the hyper-activation of the RAF-MAPK-ERK and PI3K-AKT signal transduction pathways. The study of these mechanisms may allow identifying new markers that can be used for new diagnosis and therapeutic strategies. Furthermore, he is developing computational biology skills to be used for the study of epigenetic alteration predisposing neoplastic transformation. Among these epigenetic alterations, he found strong associations between DNA methylation hotspots and oncogene over-expression and between microRNAs and patients' prognosis.
About the RKIP expertise, he is carrying out computational studies on the epigenetic modulation of RKIP in colorectal cancer. In particular, several miRNAs able to significantly alter the RKIP gene expression have been identified and, currently, validation studies are being performed
Marta Smeda (maiden: Wojewoda)
From November 2011 works at the Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland headed by Professor Stefan Chlopicki position: adjunct scope of interest: adaptation of endothelium to exercise in mouse models of endothelial dysfunction (atherosclerosis, NO deficiency), antiplatelet therapy in prevention of cancer metastasis, role of endothelial barrier in cancer progression and spreading, INTERESTED TO INVESTIGATE ROLE OF RKIP IN MAINTENANCE OF ENDOTHELIAL FUNCTION
In September 2011 obtained PhD at the Nencki Institute of Experimental Biology, Warsaw, Poland in the field of Biochemistry/Cell biology dissertation title: Effects of selenite on adaptive changes in osteosarcoma cells induced by mitochondrial stress
Blat A, Wiercigroch E, Smeda M, Wislocka A, Chlopicki S, Malek K, Fourier transform infrared spectroscopic signature of blood plasma in the progression of breast cancer with simultaneous metastasis to lungs, J Biophotonics. 2019 Oct;12(10):e201900067. doi: 10.1002/jbio.201900067
Kij A, Kus K, Smeda M, Zakrzewska A, Proniewski B, Matyjaszczyk K, Jasztal A, Stojak M, Walczak M, Chlopicki S, Differential effects of nitric oxide deficiency on primary tumour growth, pulmonary metastasis and prostacyclin/thromboxane A2 balance in orthotopic and intravenous murine models of 4T1 breast cancer, J Physiol Pharmacol. 2018 Dec;69(6)
Augustyniak K, Chrabaszcz K, Jasztal A, Smeda M, Quintas G, Kuligowski J, Marzec KM, Malek K, High and ultra-high definition of infrared spectral histopathology gives an insight into chemical environment of lung metastases in breast cancer, J Biophotonics. 2018 Dec 12:e201800345
Chrabaszcz K, Jasztal A, Smęda M, Zieliński B, Blat A, Diem M, Chlopicki S, Malek K, Marzec KM, Label-free FTIR spectroscopy detects and visualizes the early stage of pulmonary micrometastasis seeded from breast carcinoma, Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3574-3584
Smeda M, Kieronska A, Adamski MG, Proniewski B, Sternak M, Mohaissen T, Przyborowski K, Derszniak K, Kaczor D, Stojak M, Buczek E, Jasztal A, Wietrzyk J, Chlopicki S, Nitric oxide deficiency and endothelial-mesenchymal transition of pulmonary endothelium in the progression of 4T1 metastatic breast cancer in mice, Breast Cancer Res. 2018 Aug 3;20(1):86
Smeda M, Kieronska A, Proniewski B, Jasztal A, Selmi A, Wandzel K, Zakrzewska A, Wojcik T, Przyborowski K, Derszniak K, Stojak M, Kaczor D, Buczek E, Watala C, Wietrzyk J, Chlopicki S, Dual antiplatelet therapy with clopidogrel and aspirin increases mortality in 4T1 metastatic breast cancer-bearing mice by inducing vascular mimicry in primary tumour, Oncotarget. 2018; 9:17810-17824
Przyborowski K, Proniewski B, Czarny J, Smeda M, Sitek B, Zakrzewska A, Zoladz JA, Chlopicki S, Vascular Nitric Oxide-Superoxide Balance and Thrombus Formation after Acute Exercise, Med Sci Sports Exerc. 2018, doi: 10.1249/MSS.0000000000001589
Senior Research Assistant
I am a Senior Research Assistant based in Kuwait and working on a funded research project at Kuwait University. I am a member of Prof. Fahd AL-Mulla's research team. I am currently focusing on the identification and characterization of RKIP networking in breast cancer metastasis. We are looking at the mechanisms through which RKIP promotes tumor invasion and metastasis. I am utilizing a variety of experimental techniques including, cell culture, immunohistochemistry (IHC), western blot, RT-PCR and Elisa. I use siRNA to silence RKIP in cell lines such as MDA-MB-231. Further, we will be interrogating matrix metalloproteinases as downstream effector molecules for the RKIP mode of action. Other investigative techniques will include gene expression microarray and RNA-Seq. My first work on RKIP goes back to my M.Sc. thesis as a student at Professor Fahd Al-Mulla's laboratory, where I was investigating the presence or absence of RKIP copy number changes using quantitative real-time PCR, sequencing, array-CGH and Human SNP Array 6.0 on DNA samples extracted from FFPE sections.
Degree in Applied Biology by University of Minho, Portugal (2006). PhD in Health Sciences by University of Minho, Portugal (2011). Developed my PhD thesis at Life and Health Sciences Research Institute (ICVS) in the oncobiology field. In 2012 did a postdoctoral research in the Molecular Oncology Research Center, Barretos, Brazil where I’m currently a collaborating investigator. I was Professor of the Faculty of Health Sciences Dr. Paulo Prata Barretos, Brazil in 2012 and I’m currently professor of the post-graduation program in oncology of the PIOXII Foundation - Barretos Cancer Hospital, Brazil.
Actually, I’m an Auxiliary Researcher at Life and Health Sciences Research Institute (ICVS) of the Medicine School of University of Minho, Portugal, and works mainly in the areas of molecular and cellular biology of tumors; tumor signaling pathways and molecular targeted therapy in oncology.
Regarding my expertise on RKIP protein, I was focused for several years in exploiting RKIP’s role as a prognostic marker in solid tumors, having also dissected its biological and chemotherapy resistance role in gliomas and cervical tumors. Recently, we have optimized the CRISPR/CAS9 technology and knocked out RKIP in several tumor cell lines. Thus, we have a powerful tool and a good collection of cell lines that can be used as models to study the effect of RKIP absence in the cancer field. Actually, my research group is focused in understanding the role of RKIP as a predictive marker for oncogene targeted therapies response.
Raquel-Cunha A, Cardoso-Carneiro D, Reis RM, Martinho O. Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling. Cells. 2019;8(5).
Martinho O, Campos M, Ribeiro G, Penna V, Curcelli EC, Olivieri MV, et al. Raf Kinase Inhibitor Protein Expression and Prognostic Value in Soft Tissue Sarcomas. Pathobiology. 2016;83(1):41-6.
Martinho O, Pinto F, Granja S, Miranda-Goncalves V, Moreira MA, Ribeiro LF, et al. RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy. PloS one. 2013;8(3):e59104.
Afonso J, Longatto-Filho A, Martinho O, Lobo F, Amaro T, Reis RM, et al. Low RKIP expression associates with poor prognosis in bladder cancer patients.Virchows Archiv: an international journal of pathology. 2013;462(4):445-53.
Martinho O, Simoes K, Longatto-Filho A, Jacob CE, Zilberstein B, Bresciani C, et al. Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients. Oncology reports. 2013;29(2):690-6.
Valadão M, Braggio D, Santos AF, Pimenta-Inada HK, Linhares E, Gonçalves R, Romano S, Vilhena B, Small I, Cubero D, Cruz F, Oliveira AT, Martinho O, Reis RM, Guimarães DP, Ferreira CG. Involvement of signaling molecules in the prediction of response to imatinib treatment in metastatic GIST patients. J Surg Res. 2012;178(1):288-93.
Martinho O, Granja S, Jaraquemada T, Caeiro C, Miranda-Goncalves V, Honavar M, et al. Downregulation of RKIP is associated with poor outcome and malignant progression in gliomas. PloS one. 2012;7(1):e30769.
Martinho O, Faloppa CC, Neto CS, Longatto-Filho A, Baiocchi G, da Cunha IW, et al. Loss of RKIP expression during the carcinogenic evolution of endometrial cancer. Journal of clinical pathology. 2012;65(2):122-8.
Martinho O, Gouveia A, Silva P, Pimenta A, Reis RM, Lopes JM. Loss of RKIP expression is associated with poor survival in GISTs. Virchows Archiv : an international journal of pathology. 2009;455(3):277-84.
Pasquapina Ciarmela is an Associate Professor of Human Anatomy in the Department of Experimental and Clinical Medicine, at Università Politecnica delle Marche, Italy.
She graduated on 1998 in Biological Sciences at University of Urbino, Italy. Dr. Ciarmela received her Ph.D. in Prenatal Medicine at University of Siena. From March 2004 to March 2007 she was Research Associate at The Salk Institute, Peptide Biology Laboratories, La Jolla, California. In 2007, she was hired as staff scientist at Università Politecnica della Marche.
She focused her research investigation in uterine physiology and pathophysiology and explored the role of growth factors and signalling modulators of proliferation and differentiation and the underlying molecular mechanisms.
I am the Administrative Assistant of Prof. Fahd Al-Mulla and here I will do my best to organize and coordinate the RKIP CONSORTIUM
Dr. Baritaki is currently an Assistant Professor of Experimental Oncology in the Division of Surgery at the University of Crete Medical School. She earned a B.A in Biology from University of Crete Biology Department and her M.sc and PhD in Molecular Biology and Biomedicine from the same university. She had long pre-doctoral training in the Institute of Molecular Biology and Biotechnology (IMBB) at FORTH and the University of Heidelberg, Germany (1998-2002). She completed her postdoctoral fellowship in Tumor Immunobiology in the Department of Microbiology, Immunology and Molecular Genetics (MIMG) at the University of California, Los Angeles (UCLA) Medical School, USA (2004-2010). In 2011, Dr Baritaki joined the UCLA Junior Faculty as an Assistant Researcher at Melanoma/Immunotherapy Group in the Department of Surgical Oncology at UCLA Medical School, while from 2012 until 2015 she served as an Adjunct Assistant Professor in the UCLA Division of Digestive Diseases. Since 2016, Dr. Baritaki has been leading the group of Experimental Oncology at the University of Crete Medical School.
She is a recipient of multiple fellowships and awards, including among others a European Molecular Biology Organization (EMBO) fellowship, an EACR traineeship in cancer research in USA, a UICC ICRETT award, a Young Investigator Career Award from Bodosaki Foundation, as well as research awards from the American Association of Cancer research (AACR), the American Society in Hematology and the American Gastroenterology Association. She has received multiple competitive national and international extramural funding, while her published work has been recognized by the scientific community with more than 3500 citations
Her research interests mainly focus on:
1) understanding the underlying molecular mechanisms of tumor resistance to conventional chemo/immunotherapies and immuno-mediated cytotoxicity, as well as exploring the molecular basis of the early metastatic steps (EMT), using Systems Biomedicine approaches
2) identifying novel gene signatures, including lncRNA biomarkers, with prognostic and therapeutic significance in οncology and cancer stem cell biology,
3) characterizing novel chemo/immuno-therapeutics with sensitizing activities against solid and hematological malignancies resistant to conventional therapies, using highthroughput drug screening platforms.
4) identifying molecular links among stress, inflammation and cancer onset and progression in gastrointestinal malignancies.
Dr. Baritaki has a long contribution in the field of RKIP implication in cancer, evidenced by multiple relevant publications. Among others, she first identified the role of RKIP as a suppressor of tumor cell chemo/immuno-resistance and EMT and characterized novel agents, including proteasome inhibitors and Nitric Oxide Donors that are able to upregulate RKIP expression both in vitro and in vivo in different types of solid and hematologic malignancies. Dr. Baritaki co-organized with Prof. Bonavida from UCLA the ‘’2nd International Symposium on prognostic and therapeutic implications of RKIP in cancer’’ that took place in 2019 in Heraklion, Greece.
Dr. Baritaki’s full academic profile and bibliography are available at: https://scholar.google.com/citations?user=3g2D6iIAAAAJ and https://www.ncbi.nlm.nih.gov/pubmed/?term=baritaki+s+or+baritakis+s.