Apostolos Zaravinos | Karolinska Institutet (original) (raw)

Papers by Apostolos Zaravinos

Oncoscience, Jan 3, 2014

. It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to rad... more . It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a metaanalysis of 5 publicly available gene expression datasets and identified a list of coderegulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/ gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease.

Medical Advancements in Aging and Regenerative …, 2013

Biomedical …, 2011

Page 1. Abstract—Cancer is one of the leading fatal diseases in the western world and many approa... more Page 1. Abstract—Cancer is one of the leading fatal diseases in the western world and many approaches have been proposed for both its treatment and prevention. Several of these approaches are dealing with the use of chemicals ...

Biological systems are characterized by their potential for dynamic adaptation. Such systems, who... more Biological systems are characterized by their potential for dynamic adaptation. Such systems, whose properties depend on their initial conditions and response over time, are expected to manifest non-linear behaviour. In a previous work we examined the oscillatory pattern exhibited by leukemic cells under in vitro growth conditions, where the system was simulating the dynamics of growth with disease progression. Our question in a previous study evolved around the nature of the dynamics of a cell population that grows, or even struggles to grow, under treatment with chemotherapeutic agents. We mentioned several tools that could become useful in answering that question, as for example the in vitro models which provide information over the spatio-temporal nature of such dynamics, but in vivo models could prove useful too.

The Journal of …, 2012

Purpose: miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered e... more Purpose: miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined. Materials and Methods: Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296-5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined. Results: miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly downregulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p ϭ 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p ϭ 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p ϭ 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets. Conclusions: Most miRNAs analyzed are down-regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future.

British Journal of Dermatology, 2010

Background Actinic keratosis (AK) is a well-established precancerous skin lesion that has the po... more Background Actinic keratosis (AK) is a well-established precancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). Basal cell carcinoma (BCC) is a locally aggressive slowly growing tumour that rarely metastasizes. A number of viruses have been proposed to play a role in the development of nonmelanoma skin cancers (NMSC), but the most plausible evidence to date suggests that cutaneous human papillomavirus (HPV) is the key instigating factor.Objectives To evaluate the prevalence of HPV, cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein–Barr virus (EBV) and investigate their relationship with the presence of RAS gene mutations in cutaneous lesions obtained from nonimmunosuppressed patients.Methods HPV, CMV, HSV and EBV detection was performed using polymerase chain reaction (PCR) in skin biopsies (26 AK, 12 SCC and 15 BCC samples) that were collected from immunocompetent patients. The RAS mutation incidence was also investigated in all cutaneous lesions by use of PCR/restriction fragment length polymorphism and direct DNA sequencing.Results Seventeen out of 53 (32%) skin lesions were found to be positive for HPV DNA. The highest incidences of HPV infection were five of 15 (33%) in BCC and four of 12 (33%) in SCC specimens. The HPV incidence was eight of 26 (31%) in AK and eight of 53 (15%) in normal skin tissue. Twelve out of 53 (23%) skin lesions were CMV-positive. The highest incidence of CMV infection was six of 15 (40%), observed in BCC specimens. The CMV incidence was two of 26 (8%) in AK and four of 12 (33%) in SCC. No normal skin biopsy was found to be positive for CMV. All cutaneous samples were negative for HSV and EBV DNA, as assessed by our PCR-based assays. Only three samples, one AK (4%), one BCC (6%) and one SCC (8%), were found to carry a G>T transversion at the second position of HRAS codon 12. Both HRAS mutant SCC and BCC biopsies were HPV- and CMV-positive, as well.Conclusions HPV DNA is detected in NMSC, AK and normal skin biopsies. Our results also indicate that CMV is involved in NMSC at higher levels than in premalignant lesions, whereas the virus was not detected in normal skin biopsies. HSV and EBV do not appear to be involved in the pathogenesis of cutaneous lesions. Moreover, we suggest that the HRAS codon 12 mutation is not a very common event in AK or NMSC. Finally, both viral infection and HRAS activation appear to represent independent factors in the aetiology of NMSC, samples of which were obtained from immunocompetent patients.

Urology, 2011

perature is much increased and sustains high temperature longer in an intracorporeal setting than... more perature is much increased and sustains high temperature longer in an intracorporeal setting than that in an extracorporeal setting, suggesting that thermal damage is more significant in laparoscopic surgery than that in open surgery.

American Journal of …, 2009

ances in a single cell can be detected by oligo-based array CGH when there is enough high-density... more ances in a single cell can be detected by oligo-based array CGH when there is enough high-density coverage in the targeted regions.

British Journal of Dermatology, 2009

The Journal of …, 2009

of bladder cancer requires further investigation. The diverse genetic background of this panel of... more of bladder cancer requires further investigation. The diverse genetic background of this panel of cell lines with respect to p53, p21, and PTEN makes them useful in determining the efficacy of chemotherapeutic and immunotherapeutic agents.

Placenta, 2011

The expression of imprinted genes is regulated by epigenetic modifications, such as DNA methylati... more The expression of imprinted genes is regulated by epigenetic modifications, such as DNA methylation. Many imprinted genes are expressed in the placenta and affect nutrient transfer capacity of the placental exchange barrier. The H19 gene is abundantly expressed by the human placenta and is implicated in the pathogenesis of congenital growth disorders such as Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes. The aim of this study was to investigate the role of DNA methylation on H19 transcription and imprinting, in the pathophysiology of fetal growth restriction (FGR). Thirty one and 17 placentas from FGR-complicated and normal pregnancies were collected, respectively. We studied gene transcription, genotyping and methylation analysis of the AluI H19 on exon 5 polymorphism. Placental expression levels of H19 were significantly increased in the FGR group. The H19 mRNA levels were similar between normal placental samples that demonstrated loss and maintenance of imprinting. Placentas from growth-restricted pregnancies had lower methylation levels compared to normals, in the H19 promoter region. We have demonstrated an increased H19 transcription in the FGR group of placentas. The hypomethylation of the H19 promoters is compatible with the aberrant expression. The association of these two findings is reported for the first time in placental tissues, however, its significance remains unknown. Whether the results of this study represent an adaptation of the placenta to hypoperfusion, or they are part of FGR pathophysiology has to be further investigated.

Journal of Urology, 2009

Bladder cancer is the fifth most common malignancy in men in Western society. We determined RAS c... more Bladder cancer is the fifth most common malignancy in men in Western society. We determined RAS codon 12 and 13 point mutations and evaluated mRNA expression levels in transitional cell carcinoma cases.Samples from 30 human bladder cancers and 30 normal tissues were analyzed by polymerase chain reaction/restriction fragment length polymorphism and direct sequencing to determine the occurrence of mutations in codons 12 and 13 of RAS family genes. Moreover, we used real-time reverse transcriptase-polymerase chain reaction to evaluate the expression profile of RAS genes in bladder cancer specimens compared to that in adjacent normal tissues.Overall H-RAS mutations in codon 12 were observed in 9 tumor samples (30%). Two of the 9 patients (22%) had invasive bladder cancer and 7 (77%) had noninvasive bladder cancer. One H-RAS mutation (11%) was homozygous and the remaining 89% were heterozygous. All samples were WT for K and N-RAS oncogenes. Moreover, 23 of 30 samples (77%) showed over expression in at least 1 RAS family gene compared to adjacent normal tissue. K and N-RAS had the highest levels of over expression in bladder cancer specimens (50%), whereas 27% of transitional cell carcinomas demonstrated H-RAS over expression relative to paired normal tissues.Our results underline the importance of H-RAS activation in human bladder cancer by codon 12 mutations. Moreover, they provide evidence that increased expression of all 3 RAS genes is a common event in bladder cancer that is associated with disease development.

International journal of oncology, Jan 1, 2007

Although it is well established that ras genes contribute to tumourigenesis either through the ac... more Although it is well established that ras genes contribute to tumourigenesis either through the accumulation of mutations or by aberrant expression in a wide range of human cancers, little is known regarding their involvement in human nasal polyps (NPs). In the present study, the occurrence of mutations in codons 11 and 12 of the ras family genes was examined by PCR/RFLP and direct sequencing in 23 human NPs and their adjacent turbinates, as well as in turbinates from 13 control subjects. Moreover, the expression pattern of ras mRNA levels was assessed in NP specimens and compared to adjacent and control tissues. K-ras codon 11 and 12 mutations were detected in 17 and 35% of NPs, respectively, and were found in the adjacent inferior turbinate (AIT) (22 and 16%, respectively) and adjacent middle turbinates (AMT) (16 and 26%, respectively). K-and H-ras expression levels were elevated, whereas N-ras mRNA levels were lower in NPs and adjacent turbinates as compared to the control tissues. K-ras mRNA levels were up-regulated in advanced-stage polyps (P=0.037), while N-ras levels were found elevated in small polyps (P=0.046). Statistically significant negative correlations between K-and N-ras expression profiles arose in NPs and AITs (P=0.009 and 0.003, respectively). This, to our knowledge, is the first report on ras mutations and expression analysis in NPs. Our findings suggest a potential key role for activated members of ras family genes in terms of their contribution to the development of NPs as well as to the hypertrophy of adjacent turbinates.

Oncology reports, Jan 1, 2008

The user has requested enhancement of the downloaded file. All in-text references underlined in b... more The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately.

Cancer letters, Jan 1, 2008

Little is known about the implication of BRAF and RKIP expression, or about the incidence of BRAF... more Little is known about the implication of BRAF and RKIP expression, or about the incidence of BRAF mutations in the formation of nasal polyposis.

Thrombosis research, Jan 1, 2009

Regulated on activation, normal T cell expressed and secreted (RANTES) gene promoter is a regulat... more Regulated on activation, normal T cell expressed and secreted (RANTES) gene promoter is a regulatory region and a site of notable genetic diversity. In order to explore a possible interaction between RANTES promoter genetic diversity and susceptibility to coronary artery disease (CAD) and in stent restenosis (ISR), we initially sequenced a locus extending from - 516 to 40 covering the entire region of the RANTES promoter in 100 subjects randomly selected from our cohort. Four single nucleotide polymorphisms (SNPs) were identified: - 403G/A, - 256G/A, - 109C/T and - 28C/G. The frequency of the - 109C/T and - 256G/A variations was < 0.01, and was considered to be of limited significance. The frequency of the - 403G/A and - 28C/G polymorphisms was evaluated in the entire sample, which consisted of 118 patients subjected to percutaneous coronary intervention (PCI) without ISR on angiographic re-evaluation (no IRS group), 74 CAD patients with ISR on angiographic re-evaluation (IRS group) and 146 controls without angiographic evidence of CAD (no CAD group). No association was established between the RANTES promoter genotype and ISR. A genotype-phenotype interaction was observed between the - 403G/A polymorphism and CAD. The - 403A homozygotes were significantly more common in the CAD group than in the controls. The severity of CAD among case subjects, expressed as the mean number of diseased vessels, was significantly higher among - 403A homozygotes as compared to wild-type homozygotes and heterozygotes. In conclusion, the RANTES - 403A allele was associated with the presence and severity of CAD independently of conventional cardiovascular risk factors. The RANTES promoter genotype did not influence susceptibility to ISR in patients subjected to PCI.

Cell cycle (Georgetown, Tex.), Jan 1, 2009

pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). Ho... more pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). However, little is known about the implication of BRAF and RKIP expression, or about the incidence of BRAF mutations in the formation of these cutaneous diseases. The RAS oncogene has been proposed to significantly contribute to skin cancer development. Moreover, numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines.