326 results on '"Athanasios G. Papavassiliou"'
Search Results
2. Histone Mark Profiling in Pediatric Astrocytomas Reveals Prognostic Significance of H3K9 Trimethylation and Histone Methyltransferase SUV39H1
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Alexia Klonou, Penelope Korkolopoulou, Athanasios G. Papavassiliou, Spyros Sgouros, Christina Piperi, Andreas Mitsios, Marios Themistocleous, Hector Katifelis, Dimitrios S. Kanakoglou, Kostas A. Papavassiliou, George Stranjalis, Sarantis Chlamydas, Maria Gazouli, Theodosis Kalamatianos, and Antonios N. Gargalionis
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Male ,Adolescent ,Astrocytoma ,Methylation ,Cohort Studies ,SETD2 ,Cell Line, Tumor ,Histone methylation ,Humans ,Histone code ,Pharmacology (medical) ,Epigenetics ,Child ,Pharmacology ,biology ,Brain Neoplasms ,Gene Expression Profiling ,EZH2 ,Infant ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,Prognosis ,Histone Code ,Repressor Proteins ,Histone ,Child, Preschool ,Histone methyltransferase ,biology.protein ,Cancer research ,H3K4me3 ,Original Article ,Female ,Neurology (clinical) - Abstract
Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01090-x.
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- 2021
3. Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability
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Narjes Nasiri-Ansari, Eliana Spilioti, Ioannis Kyrou, Vassiliki Kalotychou, Antonios Chatzigeorgiou, Despina Sanoudou, Karin Dahlman-Wright, Harpal S. Randeva, Athanasios G. Papavassiliou, Paraskevi Moutsatsou, and Eva Kassi
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Catalysis ,Inorganic Chemistry ,Protein-Lysine 6-Oxidase ,Estrogen Receptor beta ,Humans ,RNA, Messenger ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Tissue Inhibitor of Metalloproteinase-2 ,Tissue Inhibitor of Metalloproteinase-1 ,Estradiol ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,atherosclerosis ,plaque vulnerability ,estrogen ,estrogen receptors ,GPR-30 ,endothelial cells ,matrix metalloproteinases MMPs ,MCP-1 ,p21 ,Estrogen Receptor alpha ,Endothelial Cells ,Estrogens ,General Medicine ,Atherosclerosis ,Plaque, Atherosclerotic ,Computer Science Applications ,Matrix Metalloproteinase 9 ,Receptors, Estrogen ,Matrix Metalloproteinase 2 ,Transcriptome - Abstract
In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.
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- 2022
4. Mechanobiology of solid tumors
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Antonios N. Gargalionis, Kostas A. Papavassiliou, and Athanasios G. Papavassiliou
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Neoplasms ,Biophysics ,Tumor Microenvironment ,Molecular Medicine ,Humans ,Stress, Mechanical ,Molecular Biology ,Extracellular Matrix - Abstract
Mechanical features of cancer cells emerge as a distinct trait during development and progression of solid tumors. Herein, we discuss recent key findings regarding the impact of various types of mechanical stresses on cancer cell properties. Data suggest that different mechanical forces, alterations of matrix rigidity and tumor microenvironment facilitate cancer hallmarks, especially invasion and metastasis. Moreover, a subset of mechanosensory proteins are responsible for mediating mechanically induced oncogenic signaling and response to chemotherapy. Delineating cancer dynamics and decoding of respective signal transduction mechanisms will provide new therapeutic strategies against solid tumors in the future.
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- 2022
5. Polycystin‐1 modulates RUNX2 activation and osteocalcin gene expression via ERK signalling in a human craniosynostosis cell model
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Efthimia K. Basdra, Marios Themistocleous, Ilianna Zoi, Antonios N. Gargalionis, Kostas A. Papavassiliou, Maira Katsianou, Christina Piperi, Athanasios G. Papavassiliou, and Dimitrios Panagopoulos
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0301 basic medicine ,Male ,Dolichocephaly ,TRPP Cation Channels ,MAP Kinase Signaling System ,RUNX2 ,Osteocalcin ,Trigonocephaly ,Core Binding Factor Alpha 1 Subunit ,Mechanotransduction, Cellular ,Craniosynostosis ,03 medical and health sciences ,PC1 ,Craniosynostoses ,0302 clinical medicine ,medicine ,Humans ,mechanosensation ,Mechanotransduction ,Child ,Cells, Cultured ,mechanotransduction ,Fibrous joint ,Osteoblasts ,Mechanosensation ,biology ,trigonocephaly ,Cell Biology ,Original Articles ,Fibroblasts ,medicine.disease ,dolichocephaly ,Cell biology ,craniosynostosis ,ERK ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,osteoblast differentiation ,biology.protein ,Molecular Medicine ,Original Article ,Female - Abstract
Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology‐related mechanisms of craniosynostosis still remain unknown. Understanding how aberrant mechanosensation and mechanotransduction drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage and prevent premature suture fusion. Herein, we provide evidence for the first time on the role of polycystin‐1 (PC1), a key protein in cellular mechanosensitivity, in craniosynostosis, using primary cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, two common types of craniosynostosis. Initially, we showed that PC1 is expressed at the mRNA and protein level in both trigonocephaly and dolichocephaly cranial suture cells. Followingly, by utilizing an antibody against the mechanosensing extracellular N‐terminal domain of PC1, we demonstrated that PC1 regulates runt‐related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via extracellular signal–regulated kinase (ERK) signalling in our human craniosynostosis cell model. Altogether, our study reveals a novel mechanotransduction signalling axis, PC1‐ERK‐RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients.
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- 2021
6. Polycystin-1 induces activation of the PI3K/AKT/mTOR pathway and promotes angiogenesis in renal cell carcinoma
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Christina Piperi, Constantinos Constantinides, Aristotelis Bamias, Antonios N. Gargalionis, Konstantinos Stravodimos, Christos Adamopoulos, Anastasios Stofas, Athanasios G. Papavassiliou, Eleni Boutati, Eleni Sarlani, Lina S. Malakou, and Penelope Korkolopoulou
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Adult ,Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,endocrine system ,Cancer Research ,TRPP Cation Channels ,Angiogenesis ,urologic and male genital diseases ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Polycystic kidney disease ,medicine ,Humans ,Carcinoma, Renal Cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aged ,Cell Proliferation ,Retrospective Studies ,Neovascularization, Pathologic ,Chemistry ,Cell growth ,TOR Serine-Threonine Kinases ,Cell migration ,Middle Aged ,medicine.disease ,Kidney Neoplasms ,female genital diseases and pregnancy complications ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Phosphorylation ,Female ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
In the present study we investigated the expression and the functional role of mechanosensitive polycystins in renal cell carcinoma (RCC). In 115 RCC patients we evaluated the protein expression of polycystin-1 (PC1), polycystin-2 (PC2), VEGF and protein components of the PI3K/Akt/mTOR pathway, which have been implicated both in RCC and polycystic kidney disease. PC1 and PC2 demonstrated reduced expression throughout the RCC tissue compared to the adjacent normal tissue. PC1 and PC2 revealed high expression when they were associated with higher grade and decreased 5-year survival respectively. PC1 and PC2 were positively correlated with p110γ subunit of PI3K and high PC1 expressing cells tended to display activation/phosphorylation of Akt. There was also a positive association between PC1 and VEGF expression, whereas PC1 augmented the tumor's microvascular network in stage IV carcinomas. In human RCC cells, functional inhibition of PC1 resulted in upregulation of the PI3K/Akt/mTOR pathway, enhanced cell proliferation and led to inhibition of cell migration. Conclusively, aberrant PC1 regulation is associated with increased angiogenesis and features of advanced disease in RCC tissues.
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- 2020
7. Polycystin-1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model
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Maria A. Katsianou, Kostas A. Papavassiliou, Antonios N. Gargalionis, George Agrogiannis, Penelope Korkolopoulou, Dimitrios Panagopoulos, Marios S. Themistocleous, Christina Piperi, Efthimia K. Basdra, and Athanasios G. Papavassiliou
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Craniosynostoses ,Phosphatidylinositol 3-Kinases ,TRPP Cation Channels ,Molecular Medicine ,Humans ,Cell Biology ,Mechanistic Target of Rapamycin Complex 2 ,Child ,Proto-Oncogene Proteins c-akt ,Cell Proliferation - Abstract
Craniosynostosis is the premature fusion of skull sutures and has a severe pathological impact on childrens' life. Mechanical forces are capable of triggering biological responses in bone cells and regulate osteoblastogenesis in cranial sutures, leading to premature closure. The mechanosensitive proteins polycystin-1 (PC1) and polycystin-2 (PC2) have been documented to play an important role in craniofacial proliferation and development. Herein, we investigated the contribution of PC1 to the pathogenesis of non-syndromic craniosynostosis and the associated molecular mechanisms. Protein expression of PC1 and PC2 was detected in bone fragments derived from craniosynostosis patients via immunohistochemistry. To explore the modulatory role of PC1 in primary cranial suture cells, we further abrogated the function of PC1 extracellular mechanosensing domain using a specific anti-PC1 IgPKD1 antibody. Effect of IgPKD1 treatment was evaluated with cell proliferation and migration assays. Activation of PI3K/AKT/mTOR pathway components was further detected via Western blot in primary cranial suture cells following IgPKD1 treatment. PC1 and PC2 are expressed in human tissues of craniosynostosis. PC1 functional inhibition resulted in elevated proliferation and migration of primary cranial suture cells. PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis.
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- 2022
8. mTOR Signaling Components in Tumor Mechanobiology
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Antonios N. Gargalionis, Kostas A. Papavassiliou, Efthimia K. Basdra, and Athanasios G. Papavassiliou
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integrin ,QH301-705.5 ,Mechanotransduction, Cellular ,PI3K ,Catalysis ,Inorganic Chemistry ,Neoplasms ,Tumor Microenvironment ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,tumor mechanobiology ,Molecular Biology ,QD1-999 ,Spectroscopy ,Cell Proliferation ,mechanotransduction ,TOR Serine-Threonine Kinases ,Akt ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Chemistry ,mTOR ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mechanistic target of rapamycin (mTOR) is a central signaling hub that integrates networks of nutrient availability, cellular metabolism, and autophagy in eukaryotic cells. mTOR kinase, along with its upstream regulators and downstream substrates, is upregulated in most human malignancies. At the same time, mechanical forces from the tumor microenvironment and mechanotransduction promote cancer cells’ proliferation, motility, and invasion. mTOR signaling pathway has been recently found on the crossroads of mechanoresponsive-induced signaling cascades to regulate cell growth, invasion, and metastasis in cancer cells. In this review, we examine the emerging association of mTOR signaling components with certain protein tools of tumor mechanobiology. Thereby, we highlight novel mechanisms of mechanotransduction, which regulate tumor progression and invasion, as well as mechanisms related to the therapeutic efficacy of antitumor drugs.
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- 2022
9. Polycystin-1 and hydrostatic pressure are implicated in glioblastoma pathogenesis in vitro
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Ilianna Zoi, Antonios N. Gargalionis, Kostas A. Papavassiliou, Narjes Nasiri‐Ansari, Christina Piperi, Efthimia K. Basdra, and Athanasios G. Papavassiliou
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Epithelial-Mesenchymal Transition ,TRPP Cation Channels ,Cell Line, Tumor ,Hydrostatic Pressure ,Tumor Microenvironment ,Molecular Medicine ,Humans ,Cell Biology ,Glioblastoma ,Cell Proliferation ,Transcription Factors - Abstract
The mechanobiological aspects of glioblastoma (GBM) pathogenesis are largely unknown. Polycystin-1 (PC1) is a key mechanosensitive protein which perceives extracellular mechanical cues and transforms them into intracellular biochemical signals that elicit a change in cell behaviour. The aim of the present study was to investigate if and how PC1 participates in GBM pathogenesis under a mechanically induced microenvironment. Therefore, we subjected T98G GBM cells to continuous hydrostatic pressure (HP) and/or PC1 blockade and evaluated their effect on cell behaviour, the activity of signalling pathways and the expression of mechano-induced transcriptional regulators and markers associated with properties of cancer cells. According to our data, PC1 and HP affect GBM cell proliferation, clonogenicity and migration; the diameter of GBM spheroids; the phosphorylation of mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK); the protein expression of transcription cofactors YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ); and the mRNA expression of markers related to anti-apoptosis, apoptosis, angiogenesis, epithelial to mesenchymal transition (EMT) and proliferation. Together, our in vitro results suggest that PC1 plays an important role in GBM mechanobiology.
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- 2022
10. Inhibition of c‐MET increases the antitumour activity of PARP inhibitors in gastric cancer models
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Evangelos Koustas, Dimitrios Schizas, Athanasios G. Papavassiliou, Michalis V. Karamouzis, and Panagiotis Sarantis
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0301 basic medicine ,Indoles ,C-Met ,Poly ADP ribose polymerase ,Antineoplastic Agents ,Apoptosis ,Poly(ADP-ribose) Polymerase Inhibitors ,Models, Biological ,Piperazines ,Histones ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Sulfonamides ,Gene knockdown ,business.industry ,Cancer ,Cell Biology ,DNA Repair Pathway ,Proto-Oncogene Proteins c-met ,medicine.disease ,Xenograft Model Antitumor Assays ,Clone Cells ,Neoplasm Proteins ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,Cancer cell ,Quinazolines ,Cancer research ,Molecular Medicine ,business ,DNA Damage - Abstract
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Activation of c-MET increases tumour cell survival through the initiation of the DNA damage repair pathway. PARP is an essential key in the DNA damage repair pathway. The primary role of PARP is to detect and initiate an immediate cellular response to single-strand DNA breaks. Tumours suppressor genes such as BRCA1/2 are closely associated with the DNA repair pathway. In BRCA1/2 mutations or deficiency status, cells are more likely to develop additional genetic alterations and chromosomal instability and can lead to cancer. In this study, we investigate the role of c-MET and PARP inhibition in a gastric cancer model. We exploited functional in vitro and in vivo experiments to assess the antitumour potential of co-inhibition of c-MET (SU11274) and PARP (NU1025). This leads to a reduction of gastric cancer cells viability, especially after knockdown of BRCA1/2 through apoptosis and induction of γ-Η2ΑΧ. Moreover, in AGS xenograft models, the combinatorial treatment of NU1025 plus SU11274 reduced tumour growth and triggers apoptosis. Collectively, our data may represent a new therapeutic approach for GC thought co-inhibition of c-MET and PARP, especially for patients with BRCA1/2 deficiency tumours.
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- 2020
11. Coronary Artery Disease and Endothelial Dysfunction: Novel Diagnostic and Therapeutic Approaches
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Iris Niovi Oikonomou, Ilias Simanidis, Manolis Vavuranakis, Christodoulos Stefanadis, Maria-Evi Panoilia, Evanthia Bletsa, Marina Zaromitidou, Marianna Spinou, Michail Spartalis, Angeliki Papastavrou, Georgios Kokosias, Vasiliki Tsigkou, Gerasimos Siasos, Athanasios G. Papavassiliou, Dimitris Tousoulis, Panagiota K. Stampouloglou, and Evangelos Oikonomou
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medicine.medical_specialty ,Endothelium ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Nitric Oxide ,01 natural sciences ,Biochemistry ,Nitric oxide ,Coronary artery disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Endothelial dysfunction ,Pharmacology ,business.industry ,Organic Chemistry ,Coronary vasculature ,Cardiovascular Agents ,Atherosclerosis ,medicine.disease ,Coronary Vessels ,Pathophysiology ,0104 chemical sciences ,Review article ,Vasodilation ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,chemistry ,Cardiology ,Molecular Medicine ,Endothelium, Vascular ,business ,Artery - Abstract
Coronary artery disease is the leading cause of morbidity and mortality worldwide. The most common pathophysiologic substrate is atherosclerosis which is an inflammatory procedure that starts at childhood and develops throughout life. Endothelial dysfunction is associated with the initiation and progression of atherosclerosis and is characterized by the impaired production of nitric oxide. In general, endothelial dysfunction is linked to poor cardiovascular prognosis and different methods, both invasive and non-invasive, have been developed for its evaluation. Ultrasound evaluation of flow mediated dilatation of the branchial artery is the most commonly used method to assessed endothelial function while intracoronary administration of vasoactive agents may be also be used to test directly endothelial properties of the coronary vasculature. Endothelial dysfunction has also been the subject of therapeutic interventions. This review article summarizes the knowledge about evaluation of endothelial function in acute coronary syndromes and stable coronary artery disease and demonstrates the current therapeutic approaches against endothelial dysfunction.
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- 2020
12. Expression of clock-related genes in benign and malignant adrenal tumors
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Georgios Kyriakopoulos, Athanasios G. Papavassiliou, Giorgos Zografos, Eva Kassi, Christos Parianos, Narjes Nasiri-Ansari, Anna Angelousi, Angeliki Karapanagioti, Krystallenia I Alexandraki, Harpal S. Randeva, Theodora Kounadi, Gregory Kaltsas, Chrysanthi Aggeli, and Theodosia Choreftaki
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endocrine system ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasms ,030209 endocrinology & metabolism ,Biology ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Downregulation and upregulation ,Adrenal Glands ,medicine ,Humans ,Adrenocortical carcinoma ,RNA, Messenger ,Pathological ,Messenger RNA ,Aldosterone ,medicine.disease ,Circadian Rhythm ,CLOCK ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Carcinogenesis ,PER1 - Abstract
Although the effect of the central clock system on adrenal function has been extensively studied, the role of the peripheral clock system in adrenal tumorigenesis remains largely unexplored. In this study we investigated the expression of clock-related genes in normal adrenocortical tissue and adrenocortical tumors. Twenty-seven fresh frozen human adrenal tissues including 13 cortisol secreting adenomas (CSA), seven aldosterone producing adenomas (APA), and seven adrenocortical carcinomas (ACC) were collected. CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα mRNA and protein expression were determined by qPCR and immunoblotting in pathological tissues and compared with the adjacent normal adrenal tissues. A significant downregulation of PER1, CRY1, and Rev-ERB compared with their normal tissue was demonstrated in CSA. All clock-related genes were overexpressed in APA compared with their normal tissue, albeit not significantly. A significant upregulation of CRY1 and PER1 and downregulation of BMAL1, RORα, and Rev-ERB compared with normal adrenal tissue was observed in ACC. BMAL1 and PER1 were significantly downregulated in APA compared with CSA. CLOCK, CRY1, and PER1 were upregulated, whereas BMAL1, RORα, and Rev-ERB were downregulated in ACC compared with CSA. Our study demonstrated the expression of CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα in normal and pathological human adrenal tissues. Adrenal tumors exhibited altered expression of these genes compared with normal tissue, with specific differences between benign and malignant lesions and between benign tumors arising from glomerulosa vs fasciculata zone. Further studies should clarify whether these alterations could be implicated in adrenocortical tumorigenesis.
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- 2020
13. Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes
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Gregory Kaltsas, Ioannis D. Kostakis, Athanasios G. Papavassiliou, George N Zografos, Eva Kassi, Anastasia Dimitriadi, Christos Parianos, Narjes Nasiri-Ansari, Georgios Kyriakopoulos, Chrysanthi Aggeli, and Anna Angelousi
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Disease ,Malignancy ,Biochemistry ,Endocrinology ,Median follow-up ,Internal medicine ,medicine ,Adrenocortical Carcinoma ,Biomarkers, Tumor ,Adrenocortical carcinoma ,Endocrine system ,Humans ,Stage (cooking) ,Aged ,Retrospective Studies ,business.industry ,Biochemistry (medical) ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Adrenal Cortex Neoplasms ,Immunohistochemistry ,Histopathology ,Female ,business ,Follow-Up Studies - Abstract
Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19–77). The median size of ACCs was 9 cm (IQR 3.5–22 cm) and the median weight 127 g (IQR 18–1400 g). The median follow up period was 18 months (IQR 1–96). Ki67 varied from400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.
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- 2021
14. Circulating Omentin-1 as a Biomarker at the Intersection of Postmenopausal Breast Cancer Occurrence and Cardiometabolic Risk: An Observational Cross-Sectional Study
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Gerasimos Socrates Christodoulatos, Sotiria Psallida, Georgios Antonakos, Theodora Stratigou, Maria Dalamaga, Irene Karampela, Styliani I. Kokoris, Ioanna Marinou, Athanasios G. Papavassiliou, Antigoni Lekka, Evaggelos Vogiatzakis, and Natalia G. Vallianou
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medicine.medical_specialty ,obesity ,Waist ,Cross-sectional study ,intelectin ,Adipokine ,Blood lipids ,Breast Neoplasms ,Microbiology ,Biochemistry ,Gastroenterology ,Article ,Breast cancer ,breast cancer ,cardiovascular disease ,Internal medicine ,cardiometabolic risk ,Mediterranean diet ,medicine ,cancer ,Humans ,Molecular Biology ,omentin ,postmenopausal ,Adiponectin ,adipokine ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,QR1-502 ,Postmenopause ,Cross-Sectional Studies ,Biomarker (medicine) ,Female ,business - Abstract
Aberrant circulating omentin-1, which is an anti-inflammatory and pro-apoptotic adipokine, has been reported in various solid tumors. Therefore, we investigated whether or not circulating omentin-1 could be associated with postmenopausal BC (PBC) and could be used as a potential diagnostic and clinical tool taking into consideration clinicopathologic features, tumor markers, as well as anthropometric, metabolic, and inflammatory parameters. Serum omentin-1, tumor markers (CA15-3 and CEA), metabolic (insulin, glucose, HOMA index, and serum lipids), anthropometric (BMI, waist circumference, and fat mass), and inflammatory (TNF-α, IL-6, hsCRP) parameters, classic adipokines (leptin and adiponectin), the Mediterranean diet (MedDiet) score, and cardiovascular (CVD) risk were determined in 103 postmenopausal women with pathologically confirmed incident invasive BC, 103 controls matched on age, 51 patients with benign breast lesions (BBL), and 50 obese postmenopausal women of similar age. The mean serum omentin-1 was significantly lower in cases than in controls and patients with BBL (p <, 0.001). In the patients, omentin-1 was inversely associated with tumor, metabolic and inflammatory biomarkers, cancer stage, and the number of infiltrated lymph nodes (p <, 0.05). In all study participants, omentin-1 was negatively correlated with CVD risk and positively correlated with MedDiet score. Lower circulating omentin-1 was independently associated with PBC occurrence above and beyond known risk factors. According to the ROC curve analysis, the overall diagnostic performance of omentin-1 (0.84, 95% CI 0.79–0.89) is similar to CA15-3. Circulating omentin-1 may be a biomarker at the intersection of PBC and cardiometabolic risk in postmenopausal women, and could be modulated by the adoption of a MedDiet. Further mechanistic and large multicentric prospective and longitudinal studies are required to elucidate the ontological role of omentin-1 in BC and CVD risks, as well as its diagnostic and prognostic ability and its therapeutic potential.
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- 2021
15. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors
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Panagiotis Sarantis, Eleni-Myrto Trifylli, Evangelos Koustas, Kostas A. Papavassiliou, Michalis V. Karamouzis, and Athanasios G. Papavassiliou
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Carcinogenesis ,Papillomavirus Infections ,Organic Chemistry ,Endothelial Cells ,General Medicine ,Hepatitis C ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Cell Transformation, Neoplastic ,Cytomegalovirus Infections ,Tumor Microenvironment ,Humans ,Immunotherapy ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Gastrointestinal Neoplasms - Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
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- 2022
16. Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options
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Dimitrios Strepkos, Kostas A. Papavassiliou, Mariam Markouli, Athanasios G. Papavassiliou, and Christina Piperi
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Histology ,Kinase ,Angiogenesis ,Brain Neoplasms ,Brain ,YAP-Signaling Proteins ,Biology ,Pathology and Forensic Medicine ,Cell biology ,Neurology ,Physiology (medical) ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Disease Progression ,Animals ,Humans ,Neurology (clinical) ,Stem cell ,Progenitor cell ,Receptor ,Transcription factor ,Tissue homeostasis ,G protein-coupled receptor - Abstract
The transcriptional co-activators Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif (YAP/TAZ) have emerged as significant regulators of a wide variety of cellular and organ functions with impact in early embryonic development, especially during the expansion of the neural progenitor cell pool. YAP/TAZ signalling regulates organ size development, tissue homeostasis, wound healing, and angiogenesis by participating in a complex network of various pathways. However, recent evidence suggests an association of these physiologic regulatory effects of YAP/TAZ with pro-oncogenic activities. Herein, we discuss the physiological functions of YAP/TAZ as well as the extensive network of signalling pathways that control their expression and activity, leading to brain tumour development and progression. Furthermore, we describe current targeting approaches and drug options including direct YAP/TAZ and YAP-TEA Domain Transcription Factor (TEAD) interaction inhibitors, G-protein coupled receptors (GPCR) signalling modulators and kinase inhibitors, which may be used to successfully attack YAP/TAZ-dependent tumours.
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- 2021
17. Insights into the multi-faceted role of Pioneer transcription factors in glioma formation and progression with targeting options
- Author
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Angeliki-Ioanna Giannopoulou, Dimitrios S. Kanakoglou, Athanasios G. Papavassiliou, and Christina Piperi
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Cancer Research ,Oncology ,Genetics ,Humans ,DNA ,Glioma ,Oleanolic Acid ,Chromatin ,Transcription Factors - Abstract
Pioneer transcription factors (TFs) present an important subtype of transcription factors which are vital for cell programming during embryonic development and cellular memory during mitotic growth, as well as cell fate reprogramming. Pioneer TFs can engage specific target binding sites on nucleosomal DNA to attract chromatin remodeling complexes, cofactors, and other transcription factors, ultimately controlling gene expression by shaping locally the epigenome. The priority of binding that they exhibit in contrast to other transcription factors and their involvement in crucial events regarding cell fate, has implicated their aberrant function in the pathogenesis of several disorders including carcinogenesis. Emerging experimental data indicate that certain Pioneer TFs are highly implicated in gliomas development, in neoplastic cell proliferation, angiogenic processes, resistance to therapy, and patient survival. Herein, we describe the main structural characteristics and functional mechanisms of pioneer TFs, focusing on their central role in the pathogenesis and progression of gliomas. We further highlight the current treatment options ranging from natural agents (oleanolic acid) to a variety of chemical compounds (APR-246, COTI-2) and discuss potential delivery systems, including nanoparticles, viral vectors, and intracellular protein delivery techniques.
- Published
- 2022
18. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review
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Narjes Nasiri-Ansari, Theodoros Androutsakos, Christina-Maria Flessa, Ioannis Kyrou, Gerasimos Siasos, Harpal S. Randeva, Eva Kassi, and Athanasios G. Papavassiliou
- Subjects
Diabetes Mellitus, Type 2 ,Non-alcoholic Fatty Liver Disease ,Endothelial Cells ,Humans ,Obesity ,General Medicine ,Atherosclerosis - Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a “golden target” for the development of new treatment strategies for NAFLD and its comorbid CVD.
- Published
- 2022
19. Low IL-23 levels in peripheral blood and bone marrow at diagnosis of acute leukemia in children increased with the elimination of leukemic burden
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Athanasios G. Papavassiliou, Christina Piperi, Maria Moschovi, Iliana Zoi, Margarita Baka, and Archontis Zampogiannis
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Male ,Adolescent ,medicine.medical_treatment ,acute lymphoblastic leukemia ,acute myeloid leukemia ,Interleukin-23 ,children ,Bone Marrow ,hemic and lymphatic diseases ,Interleukin 23 ,medicine ,Humans ,acute leukemia ,Child ,Acute leukemia ,business.industry ,Myeloid leukemia ,Cancer ,Infant ,IL‐23 ,Cell Biology ,Induction Chemotherapy ,Original Articles ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Peripheral blood ,Leukemia ,medicine.anatomical_structure ,Cytokine ,Child, Preschool ,Immunology ,Molecular Medicine ,Female ,Original Article ,Bone marrow ,business - Abstract
IL‐23 is an IL‐12 cytokine family member with pleiotropic functions that regulates tumour growth in various cancer types, exhibiting both anti‐tumorigenic and pro‐tumorigenic properties. Preclinical studies have shown a potential anti‐leukemic action on childhood B‐ALL cells. The study involved 65 children with acute leukemia [59 patients with acute lymphoblastic leukemia (ALL) and 6 patients with acute myeloid leukemia (AML)] and 27 healthy controls. Using an enzyme‐linked immunosorbent assay, we aimed to determine the IL‐23 levels in the peripheral blood (PB) and bone marrow (BM) of patients at diagnosis and at the end of the induction therapy (EIT). PB IL‐23 levels were lower in leukemia patients compared to the healthy controls. In all acute leukemia patients, IL‐23 levels were significantly lower at diagnosis both in PB (P = .015) and in BM (P = .037) compared to the PB and BM concentrations at the EIT. The same pattern was present in both subgroups of ALL and AML patients. The high leukemic burden at diagnosis was related with lower IL‐23 levels, which were increased with the disease remission. Considering the anti‐leukemic potential of this cytokine, the elevation of the IL‐23 concentration at the disease remission indicates a beneficial role of IL‐23 in paediatric acute leukemia.
- Published
- 2021
20. Autophagy-related Proteins as a Prognostic Factor of Patients With Colorectal Cancer
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Panagiotis Sarantis, Maria Michelli, Dimitrios Schizas, Michalis V. Karamouzis, Stamatios Theoharis, Georgia Kyriakopoulou, Athanasios G. Papavassiliou, Ioanna Giannopoulou, Ilenia Chatziandreou, Evangelos Koustas, and Angelica A. Saetta
- Subjects
Male ,Cancer Research ,Colorectal cancer ,Autophagy-Related Proteins ,Kaplan-Meier Estimate ,medicine.disease_cause ,chemotherapy ,Cohort Studies ,0302 clinical medicine ,030212 general & internal medicine ,Aged, 80 and over ,Biopsy, Needle ,Middle Aged ,Original Articles: Gastrointestinal ,Prognosis ,Combined Modality Therapy ,Immunohistochemistry ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Beclin-1 ,Female ,Colorectal Neoplasms ,medicine.drug ,Adult ,autophagy ,colorectal cancer ,Disease-Free Survival ,Statistics, Nonparametric ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,neoplasms ,Survival analysis ,Aged ,Retrospective Studies ,business.industry ,Autophagy ,Hydroxychloroquine ,medicine.disease ,Survival Analysis ,digestive system diseases ,Oxaliplatin ,Irinotecan ,Cancer cell ,Mutation ,Cancer research ,Carcinogenesis ,business - Abstract
Supplemental Digital Content is available in the text., Objectives: Autophagy plays a dual role in tumorigenesis. In the initial stages, it promotes cell survival and suppresses carcinogenesis, whereas in cancer development, it induces cancer cell survival. In this study, we investigate the role of autophagy as a protective or tumor suppressor mechanism in colorectal cancer (CRC) cell lines and evaluate its role as a potential biomarker in human tumor samples. Materials and Methods: The data of 68 patients with CRC treated at our Department from January 1 to December 31, 2016 were analyzed. Immunohistochemistry evaluation of p62, LC3B, Beclin-1, and Rab-7 in formalin-fixed paraffin-embedded tissue samples was performed and their expression was correlated with clinicopathologic characteristics, mutation status, and therapeutic approach. The χ2 was used to test an association among categorical variables. Survival curves were estimated using the Kaplan-Meier method and differences were assessed using the log-rank test. Colo-205, HT29, SW-480, and Caco-2 cell lines were also used so as to test the autophagy markers with oxaliplatin, irinotecan, hydroxychloroquine, and 3-methyladenine. Results: Overexpression of Beclin-1 is associated with poor survival (P=0.001) in patients with CRC treated with chemotherapy, irrespective of the stage and mutational status. Rab-7 is also correlated with progression-free survival (PFS) (P=0.088). Oxaliplatin (10 and 20 μΜ) and irinotecan (10 and 20 μΜ) inhibit autophagy in microsatellite stable (MSS) CRC cell lines. The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through monodancylcadaverine staining. Moreover, inhibition of autophagy with molecules such as hydroxychloroquine (20 μΜ) and 3-methyladenine (5 mM) was identified by the accumulation of p62 and LC3B. Conclusions: Beclin-1 is an independent prognostic factor of overall survival and PFS. Also, Rab-7 is identified as an independent prognostic factor of PFS. Besides, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like hydroxychloroquine and 3-methyladenine. Thus, in MSS patients who develop chemoresistance, a combination of other therapies that include an autophagy inhibitor could be more beneficial. Further clinical trials are needed to investigate these therapeutic strategies.
- Published
- 2019
21. Regulation of matrix metalloproteinase-1 by Filifactor alocis in human gingival and monocytic cells
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Athanasios G. Papavassiliou, Christina Piperi, James Deschner, Anna Damanaki, Efthimia K. Basdra, Sigrun Eick, Marjan Nokhbehsaim, Georgia Dalagiorgou, Andressa Vilas Boas Nogueira, and Christos Adamopoulos
- Subjects
Gingiva ,Matrix metalloproteinase ,Chronic inflammatory disease ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Humans ,Periodontitis ,610 Medicine & health ,Receptor ,General Dentistry ,Clostridiales ,biology ,business.industry ,030206 dentistry ,Fibroblasts ,medicine.disease ,Filifactor alocis ,TLR2 ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Matrix Metalloproteinase 1 ,Antibody ,business - Abstract
OBJECTIVES Periodontitis is a highly prevalent chronic inflammatory disease caused by periodontopathogens, such as Filifactor alocis. This study sought to examine the matrix metalloproteinase (MMP)-1 synthesis by monocytic and fibroblastic cells in response to F. alocis and to unravel the underlying cellular mechanisms. MATERIAL AND METHODS Gingival biopsies from periodontally healthy and periodontitis individuals were analyzed for the presence of F. alocis and MMP-1 by RT-PCR. Human gingival fibroblastic (HGF-1) and monocytic (THP-1) cells were stimulated with F. alocis in the presence and absence of a blocking toll-like receptor (TLR)2 antibody or specific inhibitors against MAPKs. MMP-1 expression and protein levels were studied by RT-PCR and ELISA, respectively. RESULTS F. alocis was highly prevalent in biopsies from periodontitis patients but barely present in the healthy gingiva. Significantly higher MMP-1 expression levels were found in the inflamed gingiva as compared with healthy biopsies. F. alocis caused a significant and dose-dependent MMP-1 upregulation in both cells. The stimulatory effect of F. alocis on MMP-1 was TLR2- and MAPK-dependent and more pronounced on THP-1 cells as compared with HGF-1 cells. CONCLUSIONS Our results demonstrate that F. alocis and MMP-1 are more prevalent at periodontitis sites. Additionally, our study provides original evidence that F. alocis can stimulate MMP-1 production by fibroblastic and monocytic cells, suggesting that F. alocis may contribute to periodontal breakdown through MMP-1. CLINICAL RELEVANCE F. alocis and MMP-1 are linked to each other and key players in periodontitis, which may have significant implications for future diagnostic and treatment strategies.
- Published
- 2019
22. Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword
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Marina Boziki, Athanasios G. Papavassiliou, Alexios-Fotios A. Mentis, and Nikolaos Grigoriadis
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Carcinogenesis ,Context (language use) ,Inflammation ,medicine.disease_cause ,Helicobacter Infections ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Stomach Neoplasms ,medicine ,Humans ,Molecular Biology ,Pharmacology ,0303 health sciences ,Helicobacter pylori ,biology ,Stomach ,030302 biochemistry & molecular biology ,Cancer ,Cell Biology ,biology.organism_classification ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,Immunology ,Molecular Medicine ,medicine.symptom ,Stem cell - Abstract
Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.
- Published
- 2019
23. Associations between Adiponectin Gene Variability, Proinflammatory and Angiogenetic Markers: Implications for Microvascular Disease Development in Type 2 Diabetes Mellitus?
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Nikolaos Gouliopoulos, Evangelos Oikonomou, Christina Kollia, Theodosia Konsola, Nicholas Tentolouris, Alexios S. Antonopoulos, Vasiliki Tsigkou, Athanasios G. Papavassiliou, Aggeliki Papapanagiotou, Gerasimos Siasos, Niki Katsiki, Manolis Vavuranakis, Dimitris Tousoulis, and Eva Kassi
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Neovascularization, Physiologic ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,030204 cardiovascular system & hematology ,ADIPOQ Gene ,Polymorphism, Single Nucleotide ,Risk Assessment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Genetic variability ,Allele ,Aged ,Pharmacology ,Adiponectin ,Interleukin-6 ,business.industry ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Intercellular Adhesion Molecule-1 ,medicine.disease ,Vascular endothelial growth factor ,C-Reactive Protein ,Cross-Sectional Studies ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Female ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Diabetic Angiopathies - Abstract
Background: Adiponectin gene (ADIPOQ) variability may affect the risk for type 2 diabetes mellitus (T2DM) but it remains unclear whether it is involved in microvascular complications. Objective: To explore the impact of ADIPOQ variability on markers of inflammation and angiogenesis in T2DM. Methods: Overall, 220 consecutive T2DM patients from our outpatient diabetic clinic were genotyped for G276T (rs1501299) and T45G (rs2241766) single nucleotide polymorphisms of ADIPOQ gene. Serum levels of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay and high sensitivity Creactive protein (hsCRP) by immunonephelometry. Results: Homozygosity for the G allele on rs2241766 was associated with significantly lower serum VEGF and ICAM-1 levels compared with other genotype groups, but had no effect on IL-6. Genetic variability on rs1501299 was not associated with either VEGF or ICAM-1 levels, but T homozygotes for rs1501299 had significantly lower IL-6 concentrations compared with G carriers. Furthermore, the presence of the G allele on rs2241766 was associated with significantly lower HbA1c, whereas no associations were observed for both body mass index and hsCRP with either rs2241766 or rs1501299. Conclusion: Genetic variability on adiponectin gene was associated with serum levels of inflammatory and angiogenetic markers. Further research is required to elucidate the role of adiponectin in the development and/or progression of microvascular disease in T2DM patients.
- Published
- 2019
24. Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer—Current Treatment Options and Future Perspectives
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Evangelos Koustas, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos Papadopoulos, Eleni Karapedi, Georgios Aloizos, Christos Damaskos, Nikolaos Garmpis, Anna Garmpi, Kostas A. Papavassiliou, Michalis V. Karamouzis, and Athanasios G. Papavassiliou
- Subjects
Organic Chemistry ,General Medicine ,Cancer Vaccines ,Immunotherapy, Adoptive ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Tumor Microenvironment ,Humans ,Immunologic Factors ,Immunotherapy ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Gastrointestinal Neoplasms - Abstract
Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.
- Published
- 2022
25. Chemerin as a biomarker at the intersection of inflammation, chemotaxis, coagulation, fibrinolysis and metabolism in resectable non-small cell lung cancer
- Author
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Irene Karampela, Gerasimos Socrates Christodoulatos, Ioanna Marinou, Georgios Antonakos, Evaggelos Vogiatzakis, Maria Dalamaga, George P. Sotiropoulos, Marianna Kotopouli, Athanasios G. Papavassiliou, and Antigoni Lekka
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Adipokine ,Inflammation ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Fibrinolysis ,Biomarkers, Tumor ,Humans ,Chemerin ,Medicine ,Lung cancer ,Blood Coagulation ,Aged ,biology ,Adiponectin ,business.industry ,Chemotaxis ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Case-Control Studies ,030220 oncology & carcinogenesis ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Biomarker (medicine) ,Female ,Chemokines ,Insulin Resistance ,medicine.symptom ,business - Abstract
Chemerin is an emerging adipocytokine at the intersection of inflammation, chemotaxis, thrombosis, fibrinolysis and metabolism. Our aims were 1) to explore circulating chemerin in resectable non-small cell lung cancer (NSCLC) taking into account its several interfaces; 2) to study its diagnostic potential; and 3) to assess its associations with clinicopathological features of NSCLC.In a large case-control study, serum chemerin, insulin resistance and lipid parameters, classic adipocytokines, inflammatory, coagulation, fibrinolysis and tumor biomarkers were determined in 110 consecutive patients with resectable NSCLC and 110 healthy controls matched on age (± 5 years), gender and date of blood draw (± 1 month).NSCLC cases exhibited significantly elevated circulating chemerin compared to controls (p 0.001). In NSCLC cases, chemerin was positively associated with Homeostasis model assessment score of insulin resistance (HOMA-IR), fibrinogen, plasminogen activity, tumor and inflammatory biomarkers, adiponectin, number of infiltrated lymph nodes and NSCLC stage. In control participants, circulating chemerin was positively correlated with somatometric, metabolic, lipid, hemostatic and inflammatory biomarkers, and leptin. Serum chemerin was independently associated with NSCLC, above and beyond NSCLC risk factors (OR: 2.20, 95% CI: 1.09-4.40, p = 0.03). In cases, hemostatic parameters (platelet count and plasminogen activity), HOMA-IR, CYFRA 21-1, creatinine and plant food consumption emerged as independent predictors of circulating chemerin (p 0.05). Serum chemerin greater than 220 μg/L (cut-off point) yielded a sensitivity and a specificity of 63% and 91.8% respectively with a modest discriminative ability (AUC = 0.72, 95% C.I. 0.64-0.79) for the diagnosis of NSCLC.Chemerin may represent a potentially useful biomarker in NSCLC integrating tumor-promoting networks, inflammatory and hemostatic mechanisms, and cancer-related metabolic pathways. More preclinical, prospective and longitudinal studies highlighting the pathogenetic role of chemerin in NSCLC are needed to corroborate and extend these data.
- Published
- 2018
26. Polycystin-1 downregulation induces ERK-dependent mTOR pathway activation in a cellular model of psoriasis
- Author
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Marjan Nokhbehsaim, Penelope Korkolopoulou, Irene Theohari, James Deschner, Efthimia K. Basdra, Antonios N. Gargalionis, Christos Adamopoulos, Christina Piperi, Evangelia Papadavid, Georgios Kokkalis, Lina S. Malakou, and Athanasios G. Papavassiliou
- Subjects
Genetic Markers ,0301 basic medicine ,MAPK/ERK pathway ,endocrine system ,TRPP Cation Channels ,MAP Kinase Signaling System ,Down-Regulation ,Models, Biological ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Psoriasis ,medicine ,Humans ,Mechanotransduction ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Gene knockdown ,Cell growth ,Chemistry ,TOR Serine-Threonine Kinases ,medicine.disease ,Cell biology ,HaCaT ,030104 developmental biology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Molecular Medicine - Abstract
Psoriatic plaques tend to localize to the knees and elbows, areas that are particularly subject to mechanical stress resulting from bending and friction. Moreover, plaques often develop at sites of mechanical trauma or injury (Koebner phenomenon). Nevertheless, mechanotransduction has never been linked to psoriasis. Polycystins (polycystin-1, PC1; polycystin-2, PC2) are mechanosensitive molecules that function as key regulators of cellular mechanosensitivity and mechanotransduction. The aim of this in vitro study was to investigate the role of polycystins in the development of psoriasis. We showed that PC1 knockdown in HaCaT cells led to an elevated mRNA expression of psoriasis-related biomarkers Ki-67, IL-6, TNF-α, VEGF and Bcl-2, while PC1 functional inhibition was accompanied by increased cell proliferation and migration of HaCaT cells. In addition, PC1 knockdown via siRNA in HaCaT cells was followed by activation of critical molecules of the mTOR and MAPK pathways and this mTOR pathway activation was ERK-dependent. Furthermore, loss of PC1 protein expression and elevated levels of activated mTOR substrates were also observed in human samples of psoriatic plaques. Overall, our study suggests that the PC1/ERK/mTOR signaling axis represents a novel potential mechanism in psoriasis pathogenesis.
- Published
- 2018
27. Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis
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Athanasios G. Papavassiliou, Efthimia K. Basdra, Dimitrios Strepkos, Mariam Markouli, and Christina Piperi
- Subjects
Epithelial-Mesenchymal Transition ,Review ,Catalysis ,Histones ,lcsh:Chemistry ,Inorganic Chemistry ,Neoplasms ,novel therapies ,Transcriptional regulation ,Animals ,Humans ,metastasis ,Epigenetics ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Physical and Theoretical Chemistry ,anoikis resistance ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,acetylation ,biology ,epigenetics ,histone modifications ,intravasation ,Organic Chemistry ,Intravasation ,EMT ,drug targeting ,General Medicine ,Neoplasm Proteins ,Computer Science Applications ,Chromatin ,Gene Expression Regulation, Neoplastic ,Histone ,lcsh:Biology (General) ,lcsh:QD1-999 ,Tumor progression ,DNA methylation ,Cancer research ,biology.protein ,methylation ,Protein Processing, Post-Translational - Abstract
Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate in the widespread changes of gene expression that characterize the metastatic phenotype. At the chromatin level, active and repressive histone post-translational modifications (PTM) in association with pleiotropic transcription factors regulate pivotal genes involved in the initiation of the EMT process as well as in intravasation and anoikis resistance, playing a central role in the progression of tumors. Herein, we discuss the main epigenetic mechanisms associated with the different steps of metastatic process, focusing in particular on the prominent role of histone modifications and the modifying enzymes that mediate transcriptional regulation of genes associated with tumor progression. We further discuss the development of novel treatment strategies targeting the reversibility of histone modifications and highlight their importance in the future of cancer therapy.
- Published
- 2021
28. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives
- Author
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Christina-Maria, Flessa, Ioannis, Kyrou, Narjes, Nasiri-Ansari, Gregory, Kaltsas, Athanasios G, Papavassiliou, Eva, Kassi, and Harpal S, Randeva
- Subjects
Liver ,Non-alcoholic Fatty Liver Disease ,Autophagy ,Unfolded Protein Response ,Animals ,Humans ,Obesity ,Endoplasmic Reticulum Stress - Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment.The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression.
- Published
- 2021
29. Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity
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Christina Piperi, Kostas A. Papavassiliou, Dimitrios Strepkos, Mariam Markouli, and Athanasios G. Papavassiliou
- Subjects
Cellular differentiation ,Review ,medicine.disease_cause ,Catalysis ,Epigenesis, Genetic ,Inorganic Chemistry ,lcsh:Chemistry ,histones ,glioma ,medicine ,Humans ,cancer ,Hedgehog Proteins ,Epigenetics ,Physical and Theoretical Chemistry ,Promoter Regions, Genetic ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,bivalent genes ,Cell Proliferation ,Regulation of gene expression ,epigenetics ,biology ,Organic Chemistry ,glioblastoma ,Cell Differentiation ,General Medicine ,HOX genes ,Chromatin ,Computer Science Applications ,Cell biology ,Solute carrier family ,Gene Expression Regulation, Neoplastic ,glioma therapy ,Histone ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Homeobox ,bivalency ,Carcinogenesis - Abstract
Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.
- Published
- 2021
30. Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules
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Christos Vallilas, Anastasios Kyriazoglou, Stamatios Theocharis, Panagiotis Sarantis, Michalis V. Karamouzis, Evangelos Koustas, and Athanasios G. Papavassiliou
- Subjects
0301 basic medicine ,Receptor, Platelet-Derived Growth Factor alpha ,Cabozantinib ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,PDGFRA ,Review ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Regorafenib ,Medicine ,Humans ,Gastrointestinal stromal tumors (GISTs) ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Immune Checkpoint Inhibitors ,Protein Kinase Inhibitors ,Spectroscopy ,Gastrointestinal Neoplasms ,GiST ,business.industry ,Sunitinib ,Organic Chemistry ,Cancer ,Imatinib ,General Medicine ,medicine.disease ,Computer Science Applications ,Proto-Oncogene Proteins c-kit ,small molecules ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,imatinib ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,immunotherapy ,business ,medicine.drug ,GIST - Abstract
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).
- Published
- 2020
31. The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL
- Author
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Evangelos Koustas, Panagiotis Sarantis, Aristofania Simatou, Michalis V. Karamouzis, and Athanasios G. Papavassiliou
- Subjects
musculoskeletal diseases ,Receptor, ErbB-2 ,EGFR ,Breast Neoplasms ,Review ,medicine.disease_cause ,RANK ,Catalysis ,Inorganic Chemistry ,immune checkpoint inhibitors ,lcsh:Chemistry ,Immune system ,Osteoclast ,Animals ,Humans ,Medicine ,Epidermal growth factor receptor ,Physical and Theoretical Chemistry ,ERBB2 ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Receptor Activator of Nuclear Factor-kappa B ,biology ,business.industry ,RANK Ligand ,Organic Chemistry ,RANKL ,denosumab ,General Medicine ,Computer Science Applications ,Denosumab ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Cancer research ,Female ,Signal transduction ,business ,Carcinogenesis ,Signal Transduction ,medicine.drug - Abstract
The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging.
- Published
- 2020
32. Are cystic fibrosis mutation carriers a potentially highly vulnerable group to COVID‐19?
- Author
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Evangelos Koustas, Athanasios G. Papavassiliou, Panagiotis Sarantis, and Michalis V. Karamouzis
- Subjects
0301 basic medicine ,Coronavirus disease 2019 (COVID-19) ,Cystic Fibrosis ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Inflammatory response ,Short Communication ,Population ,Short Communications ,Cystic Fibrosis Transmembrane Conductance Regulator ,Disease ,medicine.disease_cause ,Cystic fibrosis ,Vulnerable Populations ,Virus ,SARS‐CoV‐2 ,03 medical and health sciences ,0302 clinical medicine ,COVID‐19 ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Inflammation ,Mutation ,education.field_of_study ,business.industry ,SARS-CoV-2 ,COVID-19 ,Cell Biology ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,CTFR ,Molecular Medicine ,ACE‐2 ,Angiotensin-Converting Enzyme 2 ,business - Abstract
Undoubtedly, the new SARS‐CoV‐2 virus poses a grave health threat, plaguing the health and socio‐economic sectors. COVID‐19 disease must be treated quickly and effectively as soon as possible. The main axes in this direction are establishing vaccines, drugs, diagnostic tests, as well as identifying the most vulnerable groups. Probably, there is a correlation between COVID‐19 and cystic fibrosis. Our interest is focused on cystic fibrosis carriers that, due to limited tests, remain undetectable. There is an activation of the inflammatory response in the carriers, as well as in cystic fibrosis patients. First of all, a striking similarity lies between the inflammatory response in COVID‐19 and cystic fibrosis carriers. Notably, ACE‐2 plays the same role in both cases and a similar geographical distribution is observed in both diseases. In conclusion, we suggest that cystic fibrosis mutation carriers are potential members of a certain vulnerable group and the detection of such mutations in the population might be vital for the prevention of SARS‐CoV‐2 virus, and more specifically to limit its serious complications.
- Published
- 2020
33. Transcription factors in glioblastoma – Molecular pathogenesis and clinical implications
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Kostas A, Papavassiliou and Athanasios G, Papavassiliou
- Subjects
Cancer Research ,Oncology ,Brain Neoplasms ,Genetics ,Humans ,Glioblastoma ,Cell Proliferation ,Signal Transduction ,Transcription Factors - Abstract
Glioblastoma, also known as glioblastoma multiforme (GBM), is one of the most lethal human cancers, however, the molecular mechanisms driving GBM remain largely elusive. Recent studies have revealed that transcription factors are significantly involved in GBM biology. Transcription factors (TFs), which are proteins that bind DNA to regulate gene expression, have critical roles at focal points in signaling pathways, orchestrating many cellular processes, such as cell growth and proliferation, differentiation, apoptosis, immune responses, and metabolism. Dysregulated or mutated TFs are common in GBM, resulting in aberrant gene expression that promotes tumor initiation, progression, and resistance to conventional therapies. In the present Review, we focus on TFs that are implicated in GBM pathogenesis, highlighting their oncogenic or tumor suppressive functions and describing the molecular mechanisms underlying their effect on GBM cells. We also discuss their use as biomarkers for GBM prognosis and therapeutic response, as well as their targeting with drugs for GBM treatment. Deciphering the role of TFs in the biology of GBM will provide new insights into the pathological mechanisms and reveal novel biomarkers and therapeutic targets.
- Published
- 2022
34. Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential
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Mariam Markouli, Christina Piperi, Dimitrios Strepkos, Athanasios G. Papavassiliou, and Alexia Klonou
- Subjects
0301 basic medicine ,Cancer Research ,Methyltransferase ,Transcription, Genetic ,Carcinogenesis ,Down-Regulation ,Biology ,medicine.disease_cause ,Methylation ,Histones ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Neoplasms ,medicine ,Humans ,Genes, Tumor Suppressor ,Epigenetics ,Regulation of gene expression ,Lysine ,Cancer ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,030104 developmental biology ,Histone ,Oncology ,030220 oncology & carcinogenesis ,Histone methyltransferase ,biology.protein ,Cancer research ,Protein Processing, Post-Translational - Abstract
Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents.
- Published
- 2020
35. Investigating correlation between self-reported clinical manifestation and synovial fluid and blood levels of Dickkopf-1 and sclerostin in patients with primary knee osteoarthritis
- Author
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T. P. Theologis, Narjes Nasiri-Ansari, L. Benakis, Panagiotis T. Masouros, Vasileios S. Nikolaou, Athanasios G. Papavassiliou, and Eva Kassi
- Subjects
medicine.medical_specialty ,Knee Joint ,business.industry ,Diagnostic Tests, Routine ,MEDLINE ,General Medicine ,Clinical manifestation ,Osteoarthritis ,Osteoarthritis, Knee ,medicine.disease ,Rheumatology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Synovial Fluid ,Medicine ,Sclerostin ,Synovial fluid ,Humans ,In patient ,Self Report ,business ,Self report - Published
- 2020
36. Defective Anti-oxidant System: An Aggravating Factor for COVID-19 Patients Outcome?
- Author
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Kostas A. Papavassiliou, Athanasios G. Papavassiliou, and Eva Kassi
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,COVID-19 ,General Medicine ,Anti oxidant ,Article ,Antioxidants ,Oxidative Stress ,Immunology ,Medicine ,Anti-oxidants ,Humans ,Aggravating Factor ,business - Published
- 2020
37. Pancreatic Cancer and Cachexia—Metabolic Mechanisms and Novel Insights
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Panagiotis Sarantis, Michalis V. Karamouzis, K.A. Poulia, Dimitra Antoniadou, Adriana Papadimitropoulou, Evangelos Koustas, and Athanasios G. Papavassiliou
- Subjects
0301 basic medicine ,pancreatic cancer ,Anti-Inflammatory Agents ,Appetite ,Review ,systemic inflammatory response ,Bioinformatics ,0302 clinical medicine ,Adrenal Cortex Hormones ,Insulin ,Progesterone ,media_common ,Nutrition and Dietetics ,digestive, oral, and skin physiology ,Pathophysiology ,Anorexia ,Zinc ,medicine.anatomical_structure ,Adipose Tissue ,030220 oncology & carcinogenesis ,Body Composition ,Hypermetabolism ,Cytokines ,medicine.symptom ,Pancreas ,lcsh:Nutrition. Foods and food supply ,media_common.quotation_subject ,Hypothalamus ,Nutritional Status ,lcsh:TX341-641 ,cachexia ,Cachexia ,03 medical and health sciences ,Pancreatic cancer ,medicine ,Animals ,Humans ,Adverse effect ,Inflammation ,business.industry ,Lipid Metabolism ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Quality of Life ,Insulin Resistance ,Energy Metabolism ,business ,Food Science - Abstract
Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70%–80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with lower effectiveness of treatment, compromised quality of life, and higher mortality. Understanding the complex pathways underlying the pathophysiology of cancer cachexia, new therapeutic targets will be unraveled. The interplay between tumor and host factors, such as cytokines, holds a central role in cachexia pathophysiology. Cytokines are possibly responsible for anorexia, hypermetabolism, muscle proteolysis, and apoptosis. In particular, cachexia in pancreatic cancer might be the result of the surgical removal of pancreas parts. In recent years, many studies have been carried out to identify an effective treatment algorithm for cachexia. Choosing the most appropriate treatment, the clinical effect and the risk of adverse effects should be taken under consideration. The purpose of this review is to highlight the pathophysiological mechanisms as well as the current ways of cachexia treatment in the pharmaceutical and the nutrition field.
- Published
- 2020
38. G6PD and chloroquine: Selecting the treatment against SARS‐CoV‐2?
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Eva Kassi, Athanasios G. Papavassiliou, and Kostas A. Papavassiliou
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,oxidative injury ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Glucosephosphate Dehydrogenase ,Betacoronavirus ,Chloroquine ,retinopathy ,Pandemic ,medicine ,Humans ,Oxidative injury ,biology ,SARS-CoV-2 ,business.industry ,pandemic ,Editorial Foreword ,Cell Biology ,Haemolysis ,biology.organism_classification ,Virology ,COVID-19 Drug Treatment ,Editorial ,Glucosephosphate Dehydrogenase Deficiency ,Molecular Medicine ,haemolysis ,Coronavirus Infections ,business ,COVID‐19 (SARS‐CoV‐2) ,G6PD ,medicine.drug - Published
- 2020
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39. Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia
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Loukia Psaridi, Andromachi Vryonidou, Ismene Dontas, Eva Kassi, George Mastorakos, Narjes Nasiri-Ansari, Symeon Tournis, Dimitrios Stefanopoulos, Antonis Galanos, Athanasios G. Papavassiliou, and Ioannis G. Fatouros
- Subjects
Fibroblast growth factor 23 ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Thalassemia ,Iron ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Hemosiderosis ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Iron Chelating Agents ,Biochemistry ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Medicine ,Humans ,Klotho ,Klotho Proteins ,Glucuronidase ,Calcium metabolism ,biology ,business.industry ,Biochemistry (medical) ,beta-Thalassemia ,Beta thalassemia ,General Medicine ,Middle Aged ,medicine.disease ,Ferritin ,Fibroblast Growth Factors ,stomatognathic diseases ,Fibroblast Growth Factor-23 ,Ferritins ,biology.protein ,Female ,business ,Hormone - Abstract
Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=–0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in βTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.
- Published
- 2020
40. Androgen Receptor in Breast Cancer—Clinical and Preclinical Research Insights
- Author
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Aristomenis Anestis, Michalis V. Karamouzis, Ilianna Zoi, and Athanasios G. Papavassiliou
- Subjects
Oncology ,antiandrogens ,medicine.medical_specialty ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Estrogen receptor ,Antineoplastic Agents ,Breast Neoplasms ,Review ,Malignancy ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Breast cancer ,breast cancer ,lcsh:Organic chemistry ,Internal medicine ,androgen receptor ,Drug Discovery ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Physical and Theoretical Chemistry ,Triple-negative breast cancer ,030304 developmental biology ,0303 health sciences ,business.industry ,Organic Chemistry ,androgens ,medicine.disease ,3. Good health ,Clinical trial ,Androgen receptor ,Clinical research ,Receptors, Androgen ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,triple negative breast cancer ,Molecular Medicine ,Female ,business ,Signal Transduction ,estrogen receptor - Abstract
The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.
- Published
- 2020
41. Orexin-A Exerts Equivocal Role in Atherosclerosis Process Depending on the Duration of Exposure: In Vitro Study
- Author
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Angeliki Karapanagioti, Narjes Nasiri Ansari, Evi Lianidou, Gerasimos Siasos, Athanasios G. Papavassiliou, Harpal S. Randeva, Aphrodite Daskalopoulou, Flora Spentza, Eva Kassi, and Georgios K Dimitriadis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,RJ ,Cell Survival ,lcsh:TX341-641 ,Peptide hormone ,Article ,Drug Administration Schedule ,Cell Line ,03 medical and health sciences ,Orexin-A ,0302 clinical medicine ,Western blot ,Internal medicine ,Intermittent fasting ,medicine ,orexin-α ,Humans ,Receptor ,Incubation ,Chemokine CCL2 ,Cell Proliferation ,Orexins ,Nutrition and Dietetics ,Tissue Inhibitor of Metalloproteinase-1 ,medicine.diagnostic_test ,Chemistry ,Monocyte ,QP ,R1 ,endothelial cells ,3. Good health ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,breast feeding ,Matrix Metalloproteinase 2 ,MMPs ,atherosclerosis ,Breast feeding ,lcsh:Nutrition. Foods and food supply ,RC ,030215 immunology ,Food Science ,MCP-1 ,diurnal intermittent fasting - Abstract
Orexin-A is a peptide hormone that plays a crucial role in feeding regulation and energy homeostasis. Diurnal intermittent fasting (DIF) has been found to increase orexin-A plasma levels during fasting hours, while Ramadan fasting which resembles DIF, has led to beneficial effects on endothelial function. Herein, we aimed to investigate the effects of orexin-A on the expression of molecules involved in the atherogenesis process: Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), in human aortic endothelial cells (HAECs). HAECs were incubated with orexin-A at concentrations of 40 ng/mL, 200 ng/mL and 400 ng/mL for 6, 12 and 24 h. The mRNA levels of MCP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 and orexin-1 receptor were measured by real-time qPCR. We also evaluated the MMP-2, p38, phospho-p38, NF-&kappa, &Beta, /p65 as well as TIMP-1 protein levels by Western blot and ELISA, respectively. MMP-2 activity was measured by gelatin zymography. Short-term 6-h incubation of HAECs with orexin-A at a high concentration (400 ng/mL) decreased MCP-1, MMP-2 expression, MMP-2/TIMP-1 ratio (p <, 0.05), and MMP-2 activity, while incubation for 24 h increased MCP-1, MMP-2 expression (p <, 0.05), MMP-2/TIMP-1 and MMP-2/TIMP-2 ratio (p <, 0.01 and p <, 0.05, respectively) as well as MMP-2 activity. The dual effects of orexin-A are mediated, at least in part, via regulation of p38 and NF-&kappa, pathway. Orexin-A may have an equivocal role in atherosclerosis process with its effects depending on the duration of exposure.
- Published
- 2019
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42. Combination of checkpoint inhibitors with other agents as a strategy to improve anti-cancer effect – a glimpse to the future
- Author
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Michalis V. Karamouzis and Athanasios G. Papavassiliou
- Subjects
0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,Immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Pharmacology ,Chemotherapy ,business.industry ,Cancer ,Immunosuppression ,General Medicine ,Immunotherapy ,medicine.disease ,Combined Modality Therapy ,Blockade ,Radiation therapy ,030104 developmental biology ,Drug Design ,030220 oncology & carcinogenesis ,Cancer research ,Immunogenic cell death ,business - Abstract
In the last years, a remarkable progress has been made in the clinical application of novel immunotherapy agents, the so called 'checkpoint inhibitors,' that has revolutionized the treatment of many malignant tumors. Their design has been based on the immune-mediated mechanisms of antitumor activity circle, such as antigen release and presentation, activation and trafficking of T-cells into tumors, depletion of immunosuppression, and immunogenic cell death. Various combinations of checkpoint inhibitors are being designed and/or tested, such as double checkpoint blockade, combination with chemotherapy, radiotherapy, molecularly targeted agents, and other immune-directed strategies.
- Published
- 2018
43. Impact of Aldehyde Dehydrogenase Activity on Gliomas
- Author
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Theodora Vasilogiannakopoulou, Athanasios G. Papavassiliou, and Christina Piperi
- Subjects
Bioenergetics ,Aldehyde dehydrogenase ,Toxicology ,03 medical and health sciences ,Therapeutic approach ,0302 clinical medicine ,Cell Line, Tumor ,Glioma ,Animals ,Humans ,Medicine ,Neoplasm Invasiveness ,Primary Brain Tumors ,neoplasms ,Cell Proliferation ,Pharmacology ,biology ,Brain Neoplasms ,business.industry ,Aldehyde dehydrogenase isoenzyme ,Cancer ,Aldehyde Dehydrogenase ,medicine.disease ,Isoenzymes ,Cell metabolism ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,business ,030217 neurology & neurosurgery - Abstract
High-grade gliomas are primary brain tumors with a highly aggressive, invasive phenotype and dismal outcome. Targeting cell metabolism and cancer bioenergetics has emerged as a potential effective therapeutic approach. Selective aldehyde dehydrogenase isoenzyme activity regulates glioma tumor growth, invasiveness, and resistance to current treatments, and has potential as a therapeutic target.
- Published
- 2018
44. Osteonectin as a screening marker for pancreatic cancer: A prospective study
- Author
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Edward T. Parkin, Dimitris Raptis, Sanjay Panchal, Athanasios G. Papavassiliou, George Sgourakis, Angeliki Papapanagiotou, P. Brotzakis, and K. Karkoulias
- Subjects
0301 basic medicine ,Male ,Medicine (General) ,Clinical Research Reports ,pancreatic cancer ,Pilot Projects ,Biochemistry ,Gastroenterology ,0302 clinical medicine ,Interquartile range ,Reference Values ,Osteonectin ,Prospective Studies ,Prospective cohort study ,Early Detection of Cancer ,biology ,Area under the curve ,General Medicine ,Middle Aged ,musculoskeletal system ,3. Good health ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,prospective study ,medicine.medical_specialty ,Enzyme-Linked Immunosorbent Assay ,03 medical and health sciences ,R5-920 ,Predictive Value of Tests ,Internal medicine ,Pancreatic cancer ,screening marker ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,adenocarcinoma ,Receiver operating characteristic ,business.industry ,Biochemistry (medical) ,Significant difference ,biomarkers ,Cell Biology ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Case-Control Studies ,biology.protein ,business - Abstract
Objective Osteonectin plays a central role in various processes during the development of pancreatic adenocarcinoma. This prospective pilot study was performed to determine the feasibility of serum osteonectin as a screening tool for pancreatic cancer. Methods Blood samples were collected from 15 consecutive patients with newly diagnosed pancreatic cancer and 30 matched healthy controls. Serum osteonectin was measured using an osteonectin enzyme-linked immunosorbent assay kit. The primary outcomes were the diagnostic performance of serum osteonectin and the threshold value for differentiation of patients from controls. Results The median/quartile range of serum osteonectin in patients and controls were 306.8/288.5 ng/mL and 67.5/39.8 ng/mL, respectively. Osteonectin concentrations significantly differed among the study groups. A plasma osteonectin concentration of >100.18 ng/mL as selected by the receiver operating characteristic curves demonstrated an estimated area under the curve of 86% for prediction of pancreatic cancer. Tumour size was a significant predictor of serum osteonectin. A statistically significant difference in serum osteonectin between T1/T2 and T3/T4 tumours was found. Post-hoc comparisons revealed statistically significant differences in the serum osteonectin among the control, T1/T2, and T3/T4 groups. Conclusion Osteonectin may be used as a screening tool for pancreatic cancer, although this must be validated in prospective studies.
- Published
- 2018
45. Malignant circuits: Novel therapeutic opportunities in neuro‐oncology
- Author
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Kostas A. Papavassiliou and Athanasios G. Papavassiliou
- Subjects
medicine.medical_specialty ,business.industry ,Brain Neoplasms ,Neuro oncology ,Editorial Foreword ,Nervous System Neoplasms ,MEDLINE ,Disease Management ,Cell Biology ,Molecular Medicine ,Medicine ,Humans ,Medical physics ,business - Published
- 2021
46. Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer
- Author
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Panagiotis Sarantis, Adriana Papadimitropoulou, Michalis V. Karamouzis, Alexandros Papalampros, Athanasios G. Papavassiliou, Pavlos Papakotoulas, Alexandros Bokas, Stamatios Theocharis, Dimitrios Schizas, Evangelos Koustas, and Evangelos Felekouras
- Subjects
0301 basic medicine ,Angiogenesis ,medicine.medical_treatment ,pancreatic cancer ,Mice, SCID ,chemotherapy ,Deoxycytidine ,Mice ,nab-paclitaxel ,0302 clinical medicine ,Mice, Inbred NOD ,Antineoplastic Combined Chemotherapy Protocols ,Biology (General) ,Spectroscopy ,Caspase 3 ,gemcitabine ,General Medicine ,Heparin ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Chemistry ,xenografts ,030220 oncology & carcinogenesis ,medicine.drug ,Paclitaxel ,QH301-705.5 ,Cell Survival ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,In vivo ,Albumins ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Cell Proliferation ,Chemotherapy ,Dose-Response Relationship, Drug ,tinzaparin ,business.industry ,Organic Chemistry ,Tinzaparin ,medicine.disease ,Xenograft Model Antitumor Assays ,Gemcitabine ,Pancreatic Neoplasms ,Regimen ,030104 developmental biology ,Cancer research ,business - Abstract
Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor, thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis, hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.
- Published
- 2021
47. A step-by-step microRNA guide to cancer development and metastasis
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Eugenia Roupakia, Georgios S. Markopoulos, Christos Polytarchou, Raphael Sandaltzopoulos, Maria Hatziapostolou, Evangelos Kolettas, Evangelia Chavdoula, Athanasios G. Papavassiliou, Maria Tokamani, and Kenneth B. Marcu
- Subjects
0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Carcinogenesis ,Biology ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Neoplasms ,microRNA ,medicine ,Humans ,Genes, Tumor Suppressor ,Neoplastic transformation ,Epigenetics ,Regulation of gene expression ,General Medicine ,Prognosis ,medicine.disease ,Microvesicles ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,Cancer cell ,Disease Progression ,Molecular Medicine - Abstract
Cancer is one of the leading causes of mortality. The neoplastic transformation of normal cells to cancer cells is caused by a progressive accumulation of genetic and epigenetic alterations in oncogenes, tumor suppressor genes and epigenetic regulators, providing cells with new properties, collectively known as the hallmarks of cancer. During the process of neoplastic transformation cells progressively acquire novel characteristics such as unlimited growth potential, increased motility and the ability to migrate and invade adjacent tissues, the ability to spread from the tumor of origin to distant sites, and increased resistance to various types of stresses, mostly attributed to the activation of genetic stress-response programs. Accumulating evidence indicates a crucial role of microRNAs (miRNAs or miRs) in the initiation and progression of cancer, acting either as oncogenes (oncomirs) or as tumor suppressors via several molecular mechanisms. MiRNAs comprise a class of small ~22 bp long noncoding RNAs that play a key role in the regulation of gene expression at the post-transcriptional level, acting as negative regulators of mRNA translation and/or stability. MiRNAs are involved in the regulation of a variety of biological processes including cell cycle progression, DNA damage responses and apoptosis, epithelial-to-mesenchymal cell transitions, cell motility and stemness through complex and interactive transcription factor-miRNA regulatory networks. The impact and the dynamic potential of miRNAs with oncogenic or tumor suppressor properties in each stage of the multistep process of tumorigenesis, and in the adaptation of cancer cells to stress, are discussed. We propose that the balance between oncogenic versus tumor suppressive miRNAs acting within transcription factor-miRNA regulatory networks, influences both the multistage process of neoplastic transformation, whereby normal cells become cancerous, and their stress responses. The role of specific tumor-derived exosomes containing miRNAs and their use as biomarkers in diagnosis and prognosis, and as therapeutic targets, are also discussed.
- Published
- 2017
48. Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer
- Author
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Michalis V. Karamouzis, Dimitrios Schizas, Chrysovalantou Mihailidou, Athanasios G. Papavassiliou, and Evangelos Koustas
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Oncology ,Cancer Research ,Programmed cell death ,medicine.medical_specialty ,Cetuximab ,Antineoplastic Agents ,Biology ,Transfection ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Autophagy ,medicine ,Humans ,Panitumumab ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,Neoplasm Metastasis ,PI3K/AKT/mTOR pathway ,Antibodies, Monoclonal ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Colorectal Neoplasms ,Signal Transduction ,medicine.drug - Abstract
The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways. Recent data also suggest that acquired-resistance to anti-EGFR MoAbs is accompanied by inhibition of EGFR internalization, ubiqutinization, degradation and prolonged downregulation. It is well established that autophagy, a self-cannibalization process, is considered to be associated with resistance to the anti-EGFR MoAbs therapy. Additionally, autophagy induced by anti-EGFR MoAbs acts as a protective response in cancer cells. Thus, inhibition of autophagy after treatment with EGFR MoAbs can result in autophagic cell death. A combination therapy comprising of anti-EGFR MoAbs and autophagy inhibitors would represent a multi-pronged approach that could be evolved into an active therapeutic strategy in mCRC patients.
- Published
- 2017
49. Potential of glycative stress targeting for cancer prevention
- Author
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Christos Adamopoulos, Athanasios G. Papavassiliou, and Christina Piperi
- Subjects
0301 basic medicine ,Genome instability ,Cancer Research ,Receptor for Advanced Glycation End Products ,Biology ,medicine.disease_cause ,RAGE (receptor) ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,Glycation ,Neoplasms ,medicine ,Humans ,Enzyme Inhibitors ,chemistry.chemical_classification ,Reactive oxygen species ,Autophagy ,Lactoylglutathione Lyase ,Cancer ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Oncology ,Biochemistry ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Carcinogenesis ,Oxidative stress - Abstract
Glycative stress from endogenous and exogenous advanced glycation end-products (AGEs) has been implicated to cancer development and progression. Dicarbonyl compounds, the main AGE precursors and crosslinked AGE forms may directly react with proteins, lipids and nucleic acids, modify their structure and affect tissue microenvironment. They may also induce elevation of reactive oxygen species (ROS) and enhance cellular oxidative stress, an important regulator of cancer hallmarks. Moreover, the activation of AGE-receptor for AGE (RAGE) signalling pathways mediates inflammation, oxidative stress, autophagy and apoptosis leading to genomic instability and cancer initiation. Here, we provide evidence on the impact of glycative stress in promoting human tumorigenesis and we discuss the potential application of anti-glycating agents, RAGE and glyoxalase-1 inhibitors in cancer prevention.
- Published
- 2017
50. PIWI family proteins as prognostic markers in cancer: a systematic review and meta-analysis
- Author
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Alexios-Fotios A. Mentis, Nicholas A Romas, Athanasios G. Papavassiliou, and Efthimios Dardiotis
- Subjects
Oncology ,medicine.medical_specialty ,Piwi-interacting RNA ,Metastasis ,Cellular and Molecular Neuroscience ,Internal medicine ,Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,RNA, Messenger ,Molecular Biology ,Survival analysis ,Proportional Hazards Models ,Pharmacology ,business.industry ,Hazard ratio ,Cancer ,Cell Biology ,Publication bias ,medicine.disease ,Prognosis ,Confidence interval ,Meta-analysis ,Argonaute Proteins ,Disease Progression ,Molecular Medicine ,business - Abstract
P-element-induced-wimpy-testis-(PIWI)-like proteins are implicated in germ cells’ regulation and detected in numerous cancer types. In this meta-analysis, we aimed to associate, for the first time, the prognosis in cancer patients with intratumoral expression of PIWI family proteins. PubMed, Embase, and Web of Knowledge databases were searched, and studies investigating the association between intratumoral mRNA or protein expression of different PIWI family proteins and survival, metastasis, or recurrence of various cancer types were reviewed. Study qualities were assessed using the REMARK criteria. Studies’ heterogeneity was evaluated using I2 index and Cochran Q test. Publication bias was assessed by funnel plots and Egger’s regression. Pooled hazard ratios (HR) with 95% confidence intervals (95% CIs) were calculated for different PIWI family proteins separately. Specifically, log of calculated HR was pooled using random-effects model. Twenty-six studies (4299 participants) were included. The pooled HR of mortality in high versus low expression of PIWIL1, PIWIL2, and PIWIL4 was 1.87 (95% CI: 1.31–2.66, p
- Published
- 2019
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