Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for ...single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multiforme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for ...VTE among GBM patients.
A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk.
In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio OR = 6.91; confidence interval CI = 2.19–24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1–10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk.
In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.
•Thrombosis is a major problem in patients with high grade glioblastoma tumors (GBM).•We investigated several potential thrombosis risk factors in 139 GBM patients.•B blood group but not A or O blood groups significantly increased thrombosis risk.•GBM patients with B blood group could benefit from thrombosis prophylaxis.
Recent studies suggest an overrepresentation of
promoter methylated tumors in females with
wt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment.
To ...reveal sex-bound associations that may have gone unnoticed in the original analysis, we re-analyzed two previously published clinical cohorts. One was the multicenter Nordic trial of elderly patients with GBM, randomizing patients into three different treatment arms, including 203 cases with known
promoter methylation status. The other was a population-based study of 179 patients with
wt GBM, receiving concomittant radiotherapy and chemotherapy with temozolomide. Cohorts were stratified by sex to test the hypothesis that female sex in combination with
promoter methylation constitutes a subgroup with more favorable outcome.
There was a significantly larger proportion of
promoter methylation and better outcome for female patients with
promoter methylated tumors. Results were confirmed in 257 TCGA-derived
wt GBM with known sex and
status.
These results confirm that patient sex in combination with
promoter methylation is a key determinant in GBM to be considered prior to treatment decisions. Our study also illustrates the need for stratification to identify such sex-bound associations.
Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, ...especially loss of chromosome Y (LOY).
Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination.
LOY was associated with significantly shorter overall survival (7 vs. 14.6 months,
= 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months,
= 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression.
Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.
Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been ...suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.
The primary brain tumors, gliomas, are not very common but they are deadly. Each year in Sweden around 500 patients will be diagnosed with a glioma and unfortunately most of them will have the most ...aggressive type, glioblastoma (GBM). Median survival, even if treated, is poor (14-17 months). Males are diagnosed up to 60% more often than females and they often have a worse prognosis. GBM affects mainly older patients and treatment includes radiochemotherapy with temozolomide (TMZ). The only known predictive biomarker for TMZ treatment is methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter and patients with methylated MGMT have better outcomes. There is a great need for biomarkers to decipher existing sex differences and others that identify patients that will benefit from radiotherapy (RT) or TMZ despite of unmethylated MGMT. Papers I-III are focused on investigating sex differences in GBM and in Paper IV we examined the methylation-based biomarkers used in diagnostics, on patients from the Nordic trial with exceptionally good and poor survival when treated with TMZ or RT. Loss of the Y chromosome (LOY) in male’s blood cells is associated with aging and, among other diseases, with cancer. We looked at 10 genes located on chromosome Y in 105 males with GBM treated with TMZ concomitant with RT and found that they are often deleted. Detected LOY, as well as deletion of the sex determining region Y (SRY) gene were associated with shorter overall survival. Low SRY gene expression analyzed in an additional cohort of 219 samples from The Cancer Genome Atlas (TCGA) was also associated with a shorter survival. In Paper II we re-analyzed data from three cohorts to compare the frequency of MGMT methylated tumors in males and females and investigated whether sex is an important factor associated with patient’s survival. This was done in a GBM cohort from the randomized, phase 3 Nordic trial, which included patients 60 years or older, treated with standard RT (60Gy) vs. hypofractionated RT vs. TMZ given in up to six 4 weekly cycles; in a population-based cohort, treated with TMZ concomitant with RT and an excerpt of the TCGA cohort of patients treated with different modalities. In all three cohorts there was a higher fraction of MGMT methylated tumors in females and MGMT methylation was predictive of longer survival for those treated with an alkylating agent, such as TMZ. The third study investigated the androgen receptor (AR), located on chromosome X as a potential sex susceptibility factor for GBM. We found that the gene encoding for AR can be amplified or deleted in GBM, and these changes are more common in females. The AR gene expression was enhanced in GBM but did not differ between sexes. At the same time, in a separate analysis for males and females, we found that high AR expression is associated with shorter survival in females and longer survival in males Also, the methylation sites in the AR promoter that correlated with gene expression are sex specific. In Paper IV we included 59 patients from the Nordic trial, equally divided by the treatment arms and MGMT methylation status, with good prognostic factors and with long or short survival. We performed genome-wide methylation analysis and identified differentially methylated sites between those with long and short survival for the TMZ treated, MGMT methylated samples, as well as the 60Gy, MGMT unmethylated and 34Gy MGMT methylated samples. This small pilot study was unable to discern any differentially methylated sites in TMZ treated samples with unmethylated MGMT, associated with long or short survival. By using a methylation-based diagnostic classifier, we were able to detect a misclassified sample that was not a GBM. Lastly, we calculated so called ‘epigenetic age’ of the tumor tissue based on the methylation data and using three different algorithms and found that in all treatment groups short-term survivors tended to have lower epigenetic age, though these results were not significant and need verification in a larger cohort. In summary, this thesis advances our knowledge on the molecular differences between male and female GBM and the association between these alterations and patients’ survival. Our results also suggest that there are potential methylation-based biomarkers apart from the MGMT promoter methylation, that can be used to distinguish between patients with good and poor prognosis, for instance, the epigenetic age.
Dialogical Temporal Chair Technique Lysiak, Malgorzata
British journal of guidance & counselling,
01/2020, Letnik:
48, Številka:
1
Journal Article
Recenzirano
The Dialogical Temporal Chair Technique (DTCT) is a method based on Hermans's dialogical self theory combined with Gestalt and cognitive-behavioural therapeutic techniques. The Dialogical Temporal ...Chair Technique is a method of activating temporal voices. Three chairs symbolising the past, present and future are used to help subjects create a temporal dialogue. Participants are asked to take a specific I-position and to construct a temporal self-dialogue by changing chair (and hence I-position). The DTCT can be used to solve undefined problems or to explore new ways of thinking, but it may also be used to review important life decisions or enable integration of, or detachment from, ambivalent feelings and attitudes.
The world of people imprisoned in penitentiary institutions may never be understood by those who enjoy their freedom. The present study investigated the narratives about close relations, produced by ...inmates, with the analyses focusing specifically on the motive of power and the motive of intimacy, as described by McAdams. It was hypothesized that, depending on the length of prison sentence, the inmates would differ significantly regarding these motives and secondly that the motive of intimacy and the subjects’ age would be significant predictors for the duration of the prison sentence. The study involved 356 male inmates (M = 28.80; SD = 10.91) who were asked to write stories about close relations with their partners. The findings show that individuals with longer prison sentence present a higher level of the power motive focused on building a stronger self, compared to the inmates sentenced to prison for a shorter duration. A multivariate regression analysis showed that the duration of imprisonment is positively predicted by the subjects’ age and negatively by the motive of intimacy.
Dialogicality and its relation to personality traits have been extensively explored since the evolution of dialogical self theory. However, the latest edition of the Diagnostic and Statistical Manual ...of Mental Disorders (DSM-5) proposes a new hybrid personality disorder system and, thereby, a new model of pathological personality traits. As of now, there are no studies which show the relationships between self-talk, internal dialogicality, and pathological traits. Thus, the aim of this study was twofold: (a) to investigate the relationship between self-talk and pathological personality traits and (b) to explore the possible affinity between pathological structure of personality and dialogicality. A representative sample of 458 individuals from the non-clinical population, aged 18-67 (
= 30.99,
= 10.27), including 52% women, completed three questionnaires: the Self-Talk Scale by Brinthaupt et al. (2009), the Internal Dialogical Activity Scale by Oleś (2009), and the Personality Inventory for DSM-5 by Krueger et al. (2012). To verify the correspondence between self-talk, internal dialogues, and pathological personality traits, the Pearson product-moment correlation coefficients (Pearson's
) and canonical correlation analysis were used. The results supported the hypotheses about the specific relationship between internal dialogical activity and five crucial dysfunctional personality traits related to the hybrid DSM-5 system of diagnosis. People characterized as having emotional lability, anxiousness, and separation insecurity (high negative affectivity), with unusual beliefs and experiences, as well as eccentricity (high psychoticism), are prone to having ruminative and confronting dialogues. The correlation between pathological personality traits and self-talk were statistically significant, but the relationships are very small.
Pheochromocytomas are neuroendocrine tumors of the adrenal glands that cause hypertension. More than a third of the cases are associated with hereditary mutations in a growing list of susceptibility ...genes, some of which are also somatically altered in sporadic pheochromocytomas. However, for the majority of sporadic pheochromocytomas, a genetic explanation is still lacking. Here we investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples, and discovered on average 33 non-silent somatic mutations per tumor. One of the recurrently mutated genes was FGFR1 , encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pilocytic astrocytoma and childhood glioblastoma. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1- RET- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of these tumors.
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