Publications by authors named "George N Goulielmos"

73 Publications

[Corrigendum] Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece.

Following the publication of the above article on modeling variants of adenosine deaminase 2 (ADA2), previously identified by Gibson [Kristen M. Gibson, Kimberly A. Morishita, Paul Dancey, Paul Moorehead, Britt Drögemöller, Xiaohua Han, Jinko Graham, Robert E. W. Hancock, Dirk Foell, Susanne Benseler, Rashid Luqmani, Rae S. M.Yeung, Susan Shenoi, Marek Bohm, Alan M. Rosenberg, Colin J. Ross, David A. Cabral and Kelly L. Brown: Identification of novel adenosine deaminase 2 gene variants and varied clinical phenotype in pediatric vasculitis. Arthritis Rheumatol 71: 1747‑1755, 2019], (reference 18 in the article), Dr. Kelly L. Brown, corresponding author of the Gibson article, drew to the authors' attention possible discrepancies identified therein. Upon examining the matters raised by Dr. K. Brown, the authors wish to publish a corrigendum for this article, and the following textual changes are required to the main text. The authors noted that it was not accurate to have referred to the p.Gly47Arg mutation as being 'novel' when this mutation was being specifically referred to, so the word 'novel' should have been omitted from the sentence in the abstract starting on line 17: 'This led to suggestions that the mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme (15)'. However, Gibson  in their paper stated that ADA2 variant with the mutation Gly47Arg in sera from homozygous individuals was a dimer (18). Also, the word 'novel' should not have been included in the title of Fig. 3, and this should have appeared as follows: 'Figure 3. The DADA2‑associated mutation G47R in the ADA2 structure', and also, for consistency, the titles of Figs. 4 and 5 should have been written as 'Figure 4. The DADA2‑associated novel mutation R34W in the ADA2 structure' and 'Figure 5. The DADA2‑associated novel mutation A357T in the ADA2 structure'. The authors would like to add that the p.Arg34Trp variant's association with DADA2 has been previously identified in a paper by Kaljas : Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Kaijas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I and Zavialow AV: Cell Mol Life Sci 74: 550‑570, 2017. In addition, the novel rare mutation identified by Gibson  as Arg9Trp associated with DADA2 lies in the signal peptide [stated by the authors as Arg8Trp because Met#1 (ATG start codon) is not included in the protein numbering] and is not obviously included in the three‑dimensional structure, and therefore the authors did not deal with it. So, the sentence in the Abstract starting on line 19 should have been written as follows: 'It was thus concluded that the Gly47Arg mutation affects the position and interaction of the dimer‑associated HN1 helical structure'. All references of Arg8Trp in the text, when referred to the Gibson article, should be changed to Arg9Trp as referred therein so as not to cause confusion. Finally, in the legend for Fig. 2, 'His358' should have been written as 'His356' (line 3), and for the purposes of clarification, where 'at the next Asn352 (2)' was written at the end of the same sentence, this text should be changed to 'at the neighboring glycosylated Asn378 [Asn352 in (2)]'. Similarly, on p. 880, the sentence at the end of the penultimate paragraph of the Results section should have been written as follows: 'This disruption could be transmitted to the neighboring His356 coordinated to the metal ion or affect the confirmed glycosylation at the neighboring glycosylated Asn378 [Asn352 in (2)]'. The authors thank Dr. K. L. Brown for drawing these matters to their attention, and emphasize that the resultant corrections and clarifications do not alter either the results or the main conclusions reported in the paper. [the original article was published in 21: 876‑882, 2020; DOI: 10.3892/mmr.2019.10862].
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http://dx.doi.org/10.3892/mmr.2021.12128DOI Listing
July 2021

Demetra Application: An integrated genotype analysis web server for clinical genomics in endometriosis.

Int J Mol Med 2021 Jun 28;47(6). Epub 2021 Apr 28.

Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece.

Demetra Application is a holistic integrated and scalable bioinformatics web‑based tool designed to assist medical experts and researchers in the process of diagnosing endometriosis. The application identifies the most prominent gene variants and single nucleotide polymorphisms (SNPs) causing endometriosis using the genomic data provided for the patient by a medical expert. The present study analyzed >28.000 endometriosis‑related publications using data mining and semantic techniques aimed towards extracting the endometriosis‑related genes and SNPs. The extracted knowledge was filtered, evaluated, annotated, classified, and stored in the Demetra Application Database (DAD). Moreover, an updated gene regulatory network with the genes implements in endometriosis was established. This was followed by the design and development of the Demetra Application, in which the generated datasets and results were included. The application was tested and presented herein with whole‑exome sequencing data from seven related patients with endometriosis. Endometriosis‑related SNPs and variants identified in genome‑wide association studies (GWAS), whole‑genome (WGS), whole‑exome (WES), or targeted sequencing information were classified, annotated and analyzed in a consolidated patient profile with clinical significance information. Probable genes associated with the patient's genomic profile were visualized using several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, in an effort to obtain a representative number of the most credible candidate genes and biological pathways associated with endometriosis. An evaluation analysis was performed on seven patients from a three‑generation family with endometriosis. All the recognized gene variants that were previously considered to be associated with endometriosis were properly identified in the output profile per patient, and by comparing the results, novel findings emerged. This novel and accessible webserver tool of endometriosis to assist medical experts in the clinical genomics and precision medicine procedure is available at http://geneticslab.aua.gr/.
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http://dx.doi.org/10.3892/ijmm.2021.4948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083807PMC
June 2021

Comment on "Risk of systemic lupus erythematosus in patients with endometriosis: a nationwide population‑based cohort study".

Arch Gynecol Obstet 2021 Mar 23. Epub 2021 Mar 23.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1007/s00404-021-06037-3DOI Listing
March 2021

Comment on: The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study.

Rheumatology (Oxford) 2021 Feb 22. Epub 2021 Feb 22.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1093/rheumatology/keab182DOI Listing
February 2021

Comment on: Obstetric antiphospholipid syndrome is not associated with an increased risk of subclinical atherosclerosis.

Rheumatology (Oxford) 2021 Feb 8. Epub 2021 Feb 8.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1093/rheumatology/keab110DOI Listing
February 2021

Correspondence on 'Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden'.

Ann Rheum Dis 2021 Feb 1. Epub 2021 Feb 1.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece

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http://dx.doi.org/10.1136/annrheumdis-2021-219894DOI Listing
February 2021

Comment on: Association of systemic lupus erythematosus with peripheral arterial disease: a meta-analysis of literature studies.

Rheumatology (Oxford) 2021 May;60(5):e187-e188

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete.

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http://dx.doi.org/10.1093/rheumatology/keaa869DOI Listing
May 2021

Correspondence on 'Increased risk of systemic lupus erythematosus in patients with autoimmune haemolytic anaemia: a nationwide population-based cohort study'.

Ann Rheum Dis 2020 Nov 20. Epub 2020 Nov 20.

Laboratory of Molecular Medicine and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1136/annrheumdis-2020-219321DOI Listing
November 2020

High risk of systemic lupus erythematosus and antiphospholipic syndrome in patients with idiopathic thrombocytopenic purpura: Genetic aspects.

Lupus 2021 01 11;30(1):175-176. Epub 2020 Nov 11.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1177/0961203320972797DOI Listing
January 2021

Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: Structural biological insights.

Mol Med Rep 2020 Dec 29;22(6):4492-4498. Epub 2020 Sep 29.

Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece.

Although genome‑wide association studies (GWAS) have identified hundreds of autoimmune disease‑associated loci, much of the genetics underlying these diseases remains unknown. In an attempt to identify potential causal variants, previous studies have determined that the rs35677470 missense variant of the Deoxyribonuclease I‑like 3 (DNASE1L3) gene was associated with the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SSc). DNase1L3 is a member of the human DNase I family, representing a nuclease that cleaves double‑stranded DNA during apoptosis and serving a role in the development of autoimmune diseases. The present study aimed to determine the role of the rs35677470 variant at the DNASE1L3 gene leading to the R206C mutation in SLE, RA and SSc. The underlying mechanism potentially affecting protein structure loss of function was also assessed. DNASE1L3 evolution was investigated to define conservation elements in the protein sequence. Additionally, 3D homology modeling and in silico mutagenesis was performed to localize the polymorphism under investigation. Evolutionary analysis revealed heavily conserved sequence elements among species, indicating structural/functional importance. In silico mutagenesis and 3D protein structural analysis also demonstrated the potentially varied impact of the DNASE1L3 (rs35677470) single nucleotide polymorphism (SNP), providing an explanation for its effect on the R206C variant. Structural analysis demonstrated that the rs35677470 SNP encodes a non‑conservative amino acid variation, R206C, which disrupted the conserved electrostatic network holding secondary protein structure elements in position. Specifically, the R206 to E170 interaction forming part of a salt bridge network stabilizing two α‑helices was interrupted, thereby affecting the molecular architecture. Previous studies on the effect of this SNP in Caucasian populations demonstrated lower DNAse1L3 activity levels, which is consistent with the current results. The present study comprehensively evaluated the shared autoimmune locus of DNASE1L3 (rs35677470), which produced an inactive form of DNaseIL3. Furthermore, structural analysis explained the potential role of the produced mutation by modifying the placement of structural elements and consequently introducing disorder in protein folding, affecting biological function.
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http://dx.doi.org/10.3892/mmr.2020.11547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646740PMC
December 2020

Identification and characterization of a rare variant in apolipoprotein A-IV, p.(V336M), and evaluation of HDL functionality in a Greek cohort with extreme HDL cholesterol levels.

Arch Biochem Biophys 2020 12 29;696:108655. Epub 2020 Oct 29.

Department of Basic Medical Sciences, University of Crete Medical School, Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece. Electronic address:

High-Density Lipoprotein cholesterol (HDL-C) levels do not correlate well with Coronary Artery Disease (CAD) risk, while HDL functionality affects atherogenesis and is a better prognostic marker for CAD. Often, the extreme HDL-C levels have a multigenic origin. Here, we searched for single-nucleotide polymorphisms (SNPs) in ten genes of HDL metabolism in a Greek cohort with very low (<10th percentile, n = 13) or very high (>90th percentile, n = 21) HDL-C. We also evaluated the association between HDL-C levels, HDL functionality (anti-oxidant capacity) and CAD in the subjects of this cohort. Individuals with low HDL-C levels had higher triglyceride levels, lower apoA-I levels, decreased HDL anti-oxidant capacity and higher incidence of CAD compared with individuals with control or high HDL-C levels. With next generation sequencing we identified 18 exonic SNPs in 6 genes of HDL metabolism and for selected amino acid changes we performed computer-aided structural analysis and modeling. A previously uncharacterized rare apolipoprotein A-IV variant, apoA-IV [V336M], present in a subject with low HDL-C (14 mg/dL) and CAD, was expressed in recombinant form and structurally and functionally characterized. ApoA-IV [V336M] had similar α-helical content to WT apoA-IV but displayed a small thermodynamic stabilization by chemical unfolding analysis. ApoA-IV [V336M] was able to associate with phospholipids but presented reduced kinetics compared to WT apoA-IV. Overall, we identified a rare apoA-IV variant in a subject with low HDL levels and CAD with altered biophysical and phospholipid binding properties and showed that subjects with very low HDL-C presented with HDL dysfunction and higher incidence of CAD in a Greek cohort.
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http://dx.doi.org/10.1016/j.abb.2020.108655DOI Listing
December 2020

Risk of systemic lupus erythematosus in patients with idiopathic thrombocytopenic purpura: population-based cohort study.

Ann Rheum Dis 2020 Jul 22. Epub 2020 Jul 22.

Department of Internal Medicine, Laboratory of Molecular Medicine and Human Genetics, University of Crete, Heraklion, Greece.

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http://dx.doi.org/10.1136/annrheumdis-2020-218128DOI Listing
July 2020

Primary open angle glaucoma genetics: The common variants and their clinical associations (Review).

Mol Med Rep 2020 Aug 9;22(2):1103-1110. Epub 2020 Jun 9.

Department of Ophthalmology, University Hospital of Heraklion, 71110 Heraklion, Greece.

Glaucoma is a group of progressive optic neuropathies that have in common characteristic optic nerve head changes, loss of retinal ganglion cells and visual field defects. Among the large family of glaucomas, primary open‑angle glaucoma (POAG) is the most common type, a complex and heterogeneous disorder with environmental and genetic factors contributing to its pathogenesis. Approximately 5% of POAG is currently attributed to single‑gene or Mendelian forms of glaucoma. Genetic linkage analysis and genome‑wide association studies have identified various genomic loci, paving the path to understanding the pathogenesis of this enigmatic, blinding disease. In this review we summarize the most common variants reported thus far and their possible clinical correlations.
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http://dx.doi.org/10.3892/mmr.2020.11215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339808PMC
August 2020

Abdominal and perineal scar endometriosis: Retrospective study on 40 cases.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 26;252:225-227. Epub 2020 Jun 26.

Third Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Greece.

Objective(s): Abdominal and perineal scar endometriosis usually develop in association with a prior surgical scar. The purpose of the study was to detect and review patients' characteristics of these women over a long period.

Study Design: We retrospectively review the clinical records of 860 women with endometriosis between 1989 and 2019. Data were collected and analyzed from medical and pathological reports of 40 patients with abdominal and perineal scar endometriosis.

Results: 26 patients (3,0 %) were detected in the abdominal wall endometriosis group (AWE) (mean age 36,5 ± 3,4 years) and 14(1,6 %) cases in the perineal endometriosis (PE) group (32,5 ± 2,4 years), respectively. We observed that 92,3 % of women with AWE had undergone at least 1 cesarean section. Moreover, the majority of patients presented with abdominal pain (77, 0 %) and sensation of a mass (96,2 %). 15,4 % of cases had concurrent pelvic endometriosis and the recurrent rate of the disease was 15,4 %. All cases with perineal scar endometriosis were multiparous and delivered vaginally with episiotomy. 92,8 % of patients presented with cyclical pain and swelling. 3 cases suffered from perineal endometriosis combined with pelvic endometriosis. There was a recurrence of perineal endometriosis in 2 women (14,2 %). Surgical excision was the standard treatment of this condition and tissue biopsy confirmed the diagnosis.

Conclusions: Abdominal wall and perineal scar endometriosis are rare, multifactorial entities which are associated mainly with cesarean section and vaginal episiotomy. Clinicians should be aware of these conditions among all women of reproductive age presenting with cyclic or non-cyclic pain and swelling at the incision sites.
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http://dx.doi.org/10.1016/j.ejogrb.2020.06.054DOI Listing
September 2020

Endometriosis research in the -omics era.

Gene 2020 May 9;741:144545. Epub 2020 Mar 9.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine School of Medicine, University of Crete, Heraklion, Greece. Electronic address:

Endometriosis is a pathological condition extensively studied, but its pathogenesis is not completely understood, since its pathophysiology stems from a broad spectrum of environmental influences and genetic factors. Moreover, the nature of this condition is heterogeneous and includes different anatomical entities. Scientists actively pursue discovery of novel biomarkers in the hope of better identifying susceptible individuals in early stages of the disease. High-throughput technologies have substantially revolutionized medical research and, as a first step, the advent of genotyping arrays led to large-scale genome-wide association studies (GWAS) and enabled the assessment of global transcript levels, thus giving rise to integrative genetics. In this framework, comprehensive studies have been conducted at multiple biological levels by using the "omics" platforms, thus allowing to re-examine endometriosis at a greater degree of molecular resolution. -Omics technologies can detect and analyze hundreds of markers in the same experiment and their increasing use in the field of gynecology comes from an urgent need to find new diagnostic and therapeutic tools that improve the diagnosis of endometriosis and the efficacy of assisted reproductive techniques. Proteomics and metabolomics have been introduced recently into the every day methodology of researchers collaborating with gynecologists and, importantly, multi-omics approach is advantageous to gain insight of the total information that underlies endometriosis, compared to studies of any single -omics type. In this review, we expect to present multiple studies based on the high-throughput-omics technologies and to shed light in all considerable advantages that they may confer to a proper management of endometriosis.
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http://dx.doi.org/10.1016/j.gene.2020.144545DOI Listing
May 2020

Epidemiological aspects of the outcomes from the treatment of endometriosis: Experience from two different geographical areas.

Exp Ther Med 2020 Feb 5;19(2):1079-1083. Epub 2019 Dec 5.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece.

The purpose of the present study was two-fold: First to review the epidemiological aspects of the experience on the surgical outcomes via laparotomy or laparoscopy, as regards endometriosis from two different academic institutions and, second, to illustrate potential differences in two different geographical areas, New Haven (US) and Greece. This retrospective study included 1,200 patients (15-80 years of age) treated via laparotomy or laparoscopy, at two different institutions, for endometriosis, between 1990 and 2017. Data were collected and analyzed from medical and pathological reports. The statistical methods used included the Student's t-test and χ test, as well as the Mann-Whitney U test. A total of 600 women from Yale University and 600 women from Greece participated in this study. Endometrioma was confirmed in 359 (29.9%) cases. Women were compatible in terms of the site of endometriomas. Left-sided cysts were observed (P<0.001) significantly more often compared with right-sided cysts in both groups. The two groups of patients had similar rates of endometriosis stages. A statistically significant positive association (P<0.001) was found for the co-existence of benign gynecological tumors (apart from endometrioma), endometriosis-associated ovarian cancer and for post-menopausal endometriosis in women with endometriosis from Greece. Moreover, similar results were observed as regards endometriosis following exposure to diethylstilbestrol (DES), non-Hodgkin's lymphoma, endometriosis-associated Lyme disease, human immuno-deficiency virus (HIV), melanoma and endometriosis in adolescents, between the two groups. To conclude, the two populations exhibited similar results as regards the surgical outcomes of endometriosis laparoscopic or open surgery. Endometriosis represents a multifactorial entity that depends on complex interactions of hormonal, genetic, immunological and environmental factors. Gynecologists should be aware that there is an association between endometriosis and cancerous diseases. It is thus suggested that the presence of comorbidities in women with endometriosis.
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http://dx.doi.org/10.3892/etm.2019.8296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966115PMC
February 2020

Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach.

Mol Med Rep 2020 Feb 5;21(2):876-882. Epub 2019 Dec 5.

Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece.

Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel and already known variants in ADA2, this study aimed to further investigate the functional significance of the rare variants detected, namely p.Gly47Arg, p.Gly47Ala, p.Arg8Trp, p.Leu351Gln and p.Ala357Thr, by using a structural biological approach. Three‑dimensional models of the mutants were developed and their three‑dimensional (3D) structures were subjected to detailed interaction and conformational analyses. This led to suggestions that the novel mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme. It was thus concluded that the Arg8Trp and Gly47Arg mutations affect the position and interaction of the dimer‑associated HN1 helical structure and therefore, dimer formation and stabilization, while Leu351Gln and Ala357Thr influence the metal coordination in the active site. These findings shed further light onto the structural consequences of the mutations under investigation.
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http://dx.doi.org/10.3892/mmr.2019.10862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947897PMC
February 2020

Functional Significance of the C324R Mutation Examined Using a Structural Biological Approach.

J Rheumatol 2019 06;46(6):654-655

Professor of Biochemistry, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.

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http://dx.doi.org/10.3899/jrheum.181346DOI Listing
June 2019

Role of FN1 and GREB1 gene polymorphisms in endometriosis.

Mol Med Rep 2019 Jul 15;20(1):111-116. Epub 2019 May 15.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece.

Endometriosis is a complex gynecological disorder, affecting up to 10% of women of childbearing age, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic, epigenetic and environmental factors, with an overall heritability estimated at approximately 50%. The aim of the present study was to evaluate the association of rs1250248 and rs11674184 single nucleotide polymorphisms (SNPs), mapping to fibronectin 1 (FN1) and growth regulation by estrogen in breast cancer 1 (GREB1) genetic loci, respectively, with the risk of endometriosis. A total of 166 women with endometriosis (stages I-IV) who were hospitalized for the condition, diagnosed by laparoscopic intervention and histologically confirmed, and 168 normal controls were recruited and genotyped. Genotyping of the rs1250248 and rs11674184 SNPs was performed with TaqMan primer/probe sets. A significant association was detected with the A allele, as well as the AA and AG genotypes of rs1250248 (FN1) in patients with endometriosis, as well as in patients with stage I and II of the disease only. The rs11674184 SNP of the GREB1 gene was not found to be associated with an increased susceptibility to endometriosis either for all patients (stages I-IV) or for subgroups of stage I and II or III and IV of the disease only. Our results demonstrated a genetic association between the rs1250248 (FN1) SNP and endometriosis at both the genotypic and allelic level. However, although rs11674184 of GREB1 constitutes one of the most consistently associated SNPs with endometriosis in European ancestry populations, it was not found to be associated with endometriosis in this study.
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http://dx.doi.org/10.3892/mmr.2019.10247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580018PMC
July 2019

Retrospective evaluation of pathological results among women with ovarian endometriomas versus teratomas.

Mol Clin Oncol 2019 Jun 15;10(6):592-596. Epub 2019 Apr 15.

Department of Obstetrics and Gynecology, Venizeleio and Pananio General Hospital of Heraklion, Heraklion 71409, Greece.

The coexistence of endometrioma with dermoid cyst of the ovaries is an unusual entity, although they are both common and benign gynecological tumors. The present study aimed to investigate the association between ovarian dermoid cyst (teratoma) and endometrioma. We retrospectively, included 315 women with endometrioma and 172 with ovarian teratoma. Data were collected from medical and pathological reports from two different areas between 1995 and 2018. The mean age of cases with endometrioma was similar (35.8±7.2 years) to patients with ovarian teratoma (34.2±6.8 years). Considering the types of dermoid cysts, the observed proportion of mature type was 168/172 (98%), the immature type was 4/172 (2%) and struma ovarii was14/172 (8.1%) respectively. Endometrioma was significantly more frequent in the left ovary [174/266 (65.4%)] than in the right ovary [92/266 (34.6%)], P<0.001. By contrast, ovarian teratoma were predominant in the right ovary, 98/172 (60.6%), compared to the left side, 56/172 (32.5%), P<0.001. Regarding the size of the masses, we detected an inverse distribution between the two groups. Thirteen women were detected with ovarian teratoma and endometriosis, with 6 cases being in the same ovary. Our results indicate a left lateral predispostion of endometrioma and a right of ovarian teratoma and suggest that the pathogenesis between these conditions is different. The coexistence of endometriosis with dermoid cyst of the ovary, presents a challenge to the physicians and the investigators. Further research is required to establish the relationship between endometriosis and ovarian teratoma.
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http://dx.doi.org/10.3892/mco.2019.1844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488942PMC
June 2019

Defining the genetic profile of endometriosis.

Exp Ther Med 2019 May 6;17(5):3267-3281. Epub 2019 Mar 6.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion 71003, Greece.

Endometriosis is a pathological condition which has been extensively studied, since its pathophysiology stems from a broad spectrum of environmental influences and genetic factors. Familial studies aim at defining inheritance trends, while linkage analysis studies focus on the identification of genetic sites related to endometriosis susceptibility. Genetic association studies take into account candidate genes and single nucleotide polymorphisms, and hence target at unraveling the association between disease severity and genetic variation. The common goal of various types of studies is, through genetic mapping methods, the timely identification of therapeutic strategies for disease symptoms, including pelvic pain and infertility, as well as efficient counselling. While genome-wide association studies (GWAS) play a primary role in depicting genetic contributions to disease development, they entail a certain bias as regards the case-control nature of their design and the reproducibility of the results. Nevertheless, genetic-oriented studies and the implementation of the results through clinical tests, hold a considerable advantage in proper disease management. In this review article, we present information about gene-gene and gene-environment interactions involved in endometriosis and discuss the effectiveness of GWAS in identitying novel potential therapeutic targets in an attempt to develop novel therapeutic strategies for a better management and treatment of patients with endometriosis.
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http://dx.doi.org/10.3892/etm.2019.7346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447774PMC
May 2019

Keeping an Eye on Perimenopausal and Postmenopausal Endometriosis.

Diseases 2019 Mar 12;7(1). Epub 2019 Mar 12.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece.

: We aimed to describe and review the epidemiological aspect of the disease pattern of a series of perimenopausal and postmenopausal women with a histology confirmation of endometriosis. : We retrospectively examined the clinical records of 184 perimenopausal and 46 postmenopausal women with endometriosis. Data were collected and analyzed from 1100 patients' charts with confirmed endometriosis and involved cases from two different geographical areas, New Haven (US) and Greece. The statistical methods included ײ and the Mann-Whitney U test. In the perimenopausal group (age 45⁻54 years), there were 184 patients (16.7%) and the postmenopausal group (55⁻80 years) had 46 (4.2%). The average age of diagnosis was (49 ± 2.3) and (61.2 ± 5.1), respectively ( < 0.01). : Advanced endometriosis was more aggressive in the perimenopausal group ( < 0.05); in the same group, we observed a higher left-sided predisposition of endometriosis in comparison with the right side ( < 0.01). Endometrioma was the most common gynecological condition among patients with perimenopausal endometriosis in relation to the postmenopausal group ( < 0.001). Additionally, we found uterine leiomyomata more prominent in the perimenopausal group ( < 0.05). In contrast, adenomyosis was found higher in postmenopausal patients ( < 0.05); further, 24 cases with dry eye we observed. : Postmenopausal endometriosis is an important underestimated condition. Although the reported situation is not common, various clinicopathological characteristics were observed in both groups. Clinicians should be aware that there is a correlation between endometriosis and endometriosis-associated ovarian cancer in perimenopausal and postmenopausal age.
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http://dx.doi.org/10.3390/diseases7010029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473414PMC
March 2019

Normal-tension glaucoma: Pathogenesis and genetics.

Exp Ther Med 2019 Jan 26;17(1):563-574. Epub 2018 Nov 26.

Department of Ophthalmology, University Hospital of Heraklion, 71110 Heraklion, Greece.

Normal-tension glaucoma (NTG) is a multifactorial optic neuropathy which, similar to open-angle glaucomas, is characterized by progressive retinal ganglion cell death and glaucomatous visual field loss. The major distinction of NTG from open-angle glaucomas is that the intraocular pressure (IOP) does not exceed the normal range. Missing the major risk factor and target of therapy, the elevated IOP, NTG poses a clinical challenge. Several insightful reviews have been published on the pathophysiology of NTG describing the possible underlying mechanisms. The current literature available also suggests that a significant percentage of patients with NTG (as high as 21%) have a family history of glaucoma, indicating a genetic predisposition to the disease. These facts strengthen the indication that NTG remains an enigmatic process. The aim of this review was to summarize the vascular, mechanical and genetic components considered to be responsible for NTG development and to discuss the mechanisms through which they are involved in the pathogenesis of NTG.
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http://dx.doi.org/10.3892/etm.2018.7011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307418PMC
January 2019

Whole exome sequencing identifies hemizygous deletions in the UGT2B28 and USP17L2 genes in a three‑generation family with endometriosis.

Mol Med Rep 2019 Mar 3;19(3):1716-1720. Epub 2019 Jan 3.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, University of Crete, Heraklion 710 03, Crete, Greece.

Endometriosis is an enigmatic condition with an unknown etiology and a poorly understood pathogenesis. It is considered to appear from the interplay of many genetic and environmental factors, affecting up to 10% of women and represents a major cause of pain and infertility. The familial association of endometriosis, as demonstrated through monozygotic twin and family studies suggests a genetic contribution to the disease, with further case‑control and genome‑wide association studies (GWAS) detecting various endometriosis risk factors. In a recent study, we described a unique, three‑generation family of Cretan origin (Greece) with 7 females with surgically confirmed endometriosis (grandmother, 3 daughters and 3 granddaughters). All the affected members of this family displayed a variety of clinical manifestations and complications. In the present study, to further analyze the genetic variants conferring the risk of developing endometriosis, whole exome sequencing (WES) was performed, using the AmpliSeq technology on the Ion Proton platform. An initial analysis of 64 variants that were detected across the 14 genes previously confirmed to be associated with endometriosis, did not identify any deleterious exonic variants in these genes. However, further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis of endometriosis, apart from those already identified by GWAS.
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http://dx.doi.org/10.3892/mmr.2019.9818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390005PMC
March 2019

Insights on the alteration of functionality of a tyrosine kinase 2 variant: a molecular dynamics study.

Bioinformatics 2018 09;34(17):i781-i786

Laboratory of Protein Structure & Molecular Modeling, Institute of Biosciences & Applications, National Center for Scientific Research "DEMOKRITOS", Athens, Greece.

Motivation: The tyrosine kinase 2 protein (Tyk2), encoded by the TYK2 gene, has a crucial role in signal transduction and the pathogenesis of many diseases. A single nucleotide polymorphism of the TYK2 gene, SNP rs34536443, is of major importance, since it has been shown to confer protection against various, mainly, autoimmune diseases. This polymorphism results in a Pro to Ala change at amino acid position 1104 of the encoded Tyk2 protein that affects its enzymatic activity. However, the details of the underlined mechanism are unknown. To address this issue, in this study, we used molecular dynamics simulations on the kinase domains of both wild type and variant Tyk2 protein.

Results: Our MD results provided information, at atomic level, on the consequences of the Pro1104 to Ala substitution on the structure and dynamics of the kinase domain of Tyk2 and suggested reduced enzymatic activity of the resulting protein variant due to stabilization of inactive conformations, thus adding to knowledge towards the elucidation of the protection mechanism against autoimmune diseases associated with this point mutation.
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http://dx.doi.org/10.1093/bioinformatics/bty556DOI Listing
September 2018

Co-existence of endometriosis with 13 non-gynecological co-morbidities: Mutation analysis by whole exome sequencing.

Mol Med Rep 2018 Dec 1;18(6):5053-5057. Epub 2018 Oct 1.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion 71003, Greece.

Endometriosis is an enigmatic condition with an unknown etiology and poorly understood pathogenesis and women with endometriosis represent a high-risk population group for a large category of chronic conditions. The study focused on a 67-year-old woman who presented with a 40-year history of familial endometriosis associated with various non-gynecological co-morbidities, thus representing a unique case from a cohort of 1,000 patients with endometriosis. Her family history included infertile members suffering from endometriosis. Thirteen non-gynecological co-morbidities were documented throughout the years, including five autoimmune diseases (i.e., systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis, bronchial asthma and Crohn's disease), urinary bladder diverticulum, osteoporosis, multinodular goiter, cardiovascular diseases, gastroesophageal reflux disease, malignant tumor of urinary bladder, Barrett's esophagus and bilateral cataract. In order to understand the potential role of gene mutations in the development of all those co-morbidities, whole exome sequencing was performed and the presence of various disease-associated, potentially causal missense variants, were observed. These findings are in accordance with the previously suggested common underlying etiologic pathway for some, but not all, autoimmune disorders. This unusual case provides novel insights demonstrating that endometriosis can coexist with various chronic autoimmune diseases and other conditions, including non-gynecological malignancies, which possibly share a common genetic cause, a fact that should be taken into consideration seriously by clinicians.
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http://dx.doi.org/10.3892/mmr.2018.9521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236265PMC
December 2018

Endometriosis and fertilisation.

Exp Ther Med 2018 Aug 13;16(2):1043-1051. Epub 2018 Jun 13.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece.

The aim of the present review was to discuss a matter of concern in the clinical field of obstetrics/gynecology, namely the potency of fertilization (IVF) in the management of endometriosis-associated infertility. Endometriosis is a medical condition affecting one tenth of women in their fertile years, and accounts for up to 50% of infertile women. Thus, such high prevalence has established the necessity for investigating the effectiveness of available techniques in eradicating the disease and constraining infertility as well as the accompanying pain symptoms of endometriosis. The underlying mechanisms connecting endometriosis with low fecundity have been extensively studied, both in terms of genetic alterations and epigenetic events that contribute to the manifestation of an infertility phenotype in women with the disease. Several studies have dealt with the impact of IVF in pregnancy rates (PRs) on patients with endometriosis, particularly regarding women who wish to conceive. Results retrieved from studies and meta-analyses depict a diverse pattern of IVF success, underlining the involvement of individual parameters in the configuration of the final outcome. The ultimate decision on undergoing IVF treatment should be based on objective criteria and clinicians' experience, customized according to patients' individual needs.
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http://dx.doi.org/10.3892/etm.2018.6307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090275PMC
August 2018

Association of the Interleukin-6 rs1800795 Polymorphism with Type 2 Diabetes Mellitus in the Population of the Island of Crete, Greece.

Genet Test Mol Biomarkers 2018 Jul 29;22(7):448-452. Epub 2018 Jun 29.

1 Department of Internal Medicine, University Hospital of Heraklion and Laboratory of Internal Medicine-Host Defense Unit , School of Medicine, University of Crete, Heraklion, Crete, Greece .

Background: Interleukin 6 (IL-6), a proinflammatory cytokine, is elevated in patients with type 2 diabetes (T2D), and is considered an independent predictor of T2D. IL-6 single-nucleotide polymorphisms (SNPs) have been associated with higher levels of IL-6. This study investigated the role of an IL-6 gene polymorphism and its possible association to T2D in the genetically homogeneous Greek population of the island of Crete.

Materials And Methods: A total of 144 patients with T2D and 180 controls, all Cretans, selected from the Diabetes Clinic and the Department of Internal Medicine at the University Hospital of Heraklion, Crete, Greece, were genotyped for the IL-6 -174G>C (rs1800795) SNP by the restriction fragment length polymorphism method.

Results: The G/C genotype and the minor allele C of the IL-6 rs1800795 SNP were more common in individuals with T2D than controls (p = 0.004, odds ratio [OR] = 1.98, 95% confidence interval [CI]: 1.24-3.18 and p = 0.011, OR = 1.59, 95% CI: 1.11-2.26, respectively).

Conclusion: An association of the rs1800795 SNP of the IL-6 gene with T2D has been detected for the first time in Cretans. The present results, in combination with those presented previously from different ethnic/racial populations, highlight the necessity of comparative studies among different ethnic/racial populations to detect genetic characteristics and associations with T2D.
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http://dx.doi.org/10.1089/gtmb.2017.0220DOI Listing
July 2018

Advanced choroidal melanoma with a desirable aesthetic outcome after enucleation: A case report.

Oncol Lett 2018 Jul 8;16(1):511-514. Epub 2018 May 8.

Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece.

Choroidal melanoma is a rare ocular tumor. The present study reports the case of a 66-year-old male who presented with chronic headache and progressive visual loss. Physical eye examination and combined A- and B-mode ultrasonography detected choroidal melanoma. Due to tumor characteristics the eye was enucleated restoring the orbital volume with a 22 mm intraorbital bioceramic sphere implant. The eye was subjected to histopathological examination that confirmed the choroidal melanoma, 2 cm in diameter and 0.8 cm in elevation, occupying almost half of the globe. Microscopically, the neoplasm comprises mostly of epithelioid cells and fewer Type B spindle cells, with intense pigmentation. AJCC staging for the melanoma was T4b. The patient was fitted with an artificial eye after enucleation. Thirteen months after initial diagnosis, liver metastases were confirmed during his scheduled follow-up.
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http://dx.doi.org/10.3892/ol.2018.8661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006346PMC
July 2018