Aims
It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to ...predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status.
Methods
MGMT protein expression was quantified in tumour cells in 171 GBMs from the population‐based Region of Southern Denmark (RSD)‐cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM‐patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules.
Results
When divided at the median, patients with low expression of MGMT protein (AF‐low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS‐cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF‐low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF‐low had the best outcome; median OS 23.1 and 20.0 months, respectively.
Conclusion
Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour‐specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.
During adolescence, biological, psychological, and social changes naturally propel youth to confront religious matters and form outlooks, moral beliefs, and religious attitudes. However, it is not ...uncommon for them to manifest changes of affiliation with a religious group or a total removal of all religious expressions within their lives. In Poland, a decline in the level of religiosity of young people has been reported for years. This study aimed to analyze how processes of deconversion affect adolescents' quality of life. In total, 272 respondents aged between 14 and 18 (M = 15.74, SD = 1.14) participated in the research. The Adolescent Deconversion Scale, Multidimensional Scale of Perceived Social Support, and Quality of Life Questionnaire for Children and Adolescents were applied. The results showed that existential emptiness and faith abandonment predicted lower adolescent satisfaction, since they weakened the sense of family support. However, moral criticism predicted higher social integration, because adolescents who criticize moral rules taught by religion had a stronger sense of peer support.
The aim of the study was to investigate the role of temporal dialogues and self-compassion in coping with emotions connected to difficult past situations. In this study, we used the dialogical chair ...procedure, where we asked participants to narrate a difficult, past negative experience by moving from "here and now" to that time and place (Suffering-I/past-I), and to narrate the same past event from a current perspective (Distanced-I/current-I). Additionally, fifty seven participants completed three measures: The Positive and Negative Affect Schedule (PANAS); the Self-Compassion Scale (SCS); and the rating scales for functions of dialogue (criticism, support, instruction, and evaluation). The study showed that self-compassion predicts lower negative affect after an internal dialogue about difficult past events, but this effect is not mediated by functions of dialogue. On the other hand, dialogue functions are associated with higher levels of positive affect after dialogue, while self-compassion does not appear to be significant here.
Patients with glioblastoma (GBM) have a poor outcome, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long ...survival. From the Nordic trial, which randomized GBM patients of 60 years or older between two radiotherapy arms (60 Gy or 34 Gy) or temozolomide (TMZ), we selected 59 with good prognostic factors. These selected GBM patients were equally distributed according to treatment and MGMT promoter methylation status but had long or short survival. Methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays was performed and utilized for methylation-based CNS tumor classification, and pathway enrichment analysis of differentially methylated CpG sites (DMCs), as well as calculation of epigenetic age acceleration with three different algorithms, to compare the long and short survival groups. Samples identified by the classifier as non-GBM
IDH
wildtype were excluded. DMCs between long- and short-term survivors were found in patients with methylated
MGMT
promoter treated with TMZ (123,510), those with unmethylated
MGMT
treated with 60Gy radiotherapy (4,086), and with methylated
MGMT
promoter treated with 34Gy radiotherapy (39,649). Long-term survivors with methylated
MGMT
promoter treated with TMZ exhibited hypermethylation of the Wnt signaling and the platelet activation, signaling, and aggregation pathways. The joint analysis of radiotherapy arms revealed 319 DMCs between long- and short-term survivors with unmethylated
MGMT
and none for samples with methylated
MGMT
promoter. An analysis comparing epigenetic age acceleration between patients with long- and short-term survival across all treatment arms showed a decreased epigenetic age acceleration for the latter. We identified DMCs for both TMZ and RT-treated patients and epigenetic age acceleration as a potential prognostic marker, but further systematic analysis of larger patient cohorts is necessary for confirmation of their prognostic and/or predictive properties.
Introduction
Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the ...human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with
NF1
being the most common mutated gene (20–25%). In many sporadic tumors, however, a genetic explanation is still lacking.
Materials and methods
We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas.
Results
We discovered on average 33 non-silent somatic variants 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 pediatric brain tumors. 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.
Conclusion
Besides
RET
and
HRAS
,
FGFR1
is only the third protooncogene found to be recurrently mutated in pheochromocytomas. The results advance our biological understanding of pheochromocytoma and suggest that somatic
FGFR1
activation is an important event in a subset of sporadic pheochromocytomas.
Functions of internal temporal dialogues Lysiak, Malgorzata; Puchalska-Wasyl, Malgorzata
British journal of guidance & counselling,
03/2019, Letnik:
47, Številka:
2
Journal Article
Recenzirano
Psychological literature in the field of internal dialogical activity assumes that internal temporal dialogues perform several important functions, namely: support, redefining the past, balancing, ...distancing, advising, making decisions, acquiring wisdom and managing the future. The article is an attempt to verify this proposal through qualitative analyses of temporal dialogues conducted by three persons, who participate in the wider research project on functions of internal temporal dialogues (N = 200). Dialogical Temporal Chair Technique was used. Presented qualitative analyses of internal temporal dialogues seem to confirm most of the functions listed in the theoretical proposition. The results are also discussed with reference to well-being and happiness as well as the theory of the dialogical self (the role of metaposition) and time perspective.
We sought to analyse the androgen receptor (AR) in glioblastoma (GBM) due to the location of the AR gene on chromosome X, often reported with shorter survival and higher prevalence of GBM among ...males. Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 91 fresh‐frozen GBM samples and 170 formalin‐fixed, paraffin‐embedded samples collected at Linköping University Hospital. The fresh‐frozen cohort was also subjected to pyrosequencing methylation analysis of 17 CpG sites in the AR promoter. Additionally, the gene expression of AR was analysed in the fresh‐frozen cohort and The Cancer Genome Atlas (TCGA) cohort of isocitrate dehydrogenase wild‐type primary GBM (135 females and 219 males). The association of AR expression and overall survival (OS) was tested with Kaplan–Meier log rank analysis after dichotomisation by maximally selected rank statistics. We found that AR CN alterations were more common in female GBM. AR gene expression correlated with methylation levels of different CpG sites in males and females but there was no difference in expression between sexes. Survival analysis of TCGA cohort revealed the opposite effect of AR overexpression on OS of males and females, with high AR expression correlating with shorter OS in females and longer OS in males. Additional gene set enrichment analysis showed that AR expression correlated with DNA repair response, especially in the male group. In summary, we found that high AR gene expression in GBM exhibits sex‐dependent effects on patient survival, which, for males, is linked to DNA repair response.
Glioblastoma (GBM) is more common among males; however, the reason for sex differences remains largely unknown. Through molecular analyses of androgen receptor (AR) in GBM samples, we found that AR is commonly expressed in tumours of both sexes, but copy number alterations of the gene coding for AR are more frequent in females. Additionally, high AR expression correlates with worse survival among females but better survival among males.
The phenomenon of abandonment of faith, which in psychology is referred to as deconversion, is observed today. Deconversion is particularly widespread in young people. In this paper we examine the ...parents’ religiosity, parents’ care, and social support as potential predictors of deconversion in adolescents. Specifically, we aimed to analyse whether or not parents’ religiousness, individual differences in childrens’ attachment to their parents, and received support from family, friends, and significant others differentiate adolescents in deconversion processes. The hypotheses were tested on a sample of 232 adolescents in a cross-sectional study, which applied three scales. The Adolescent Deconversion Scale, Parental Bonding Instrument, and Multidimensional Scale of Perceived Social Support. The results showed that adolescents having both caring and religious parents are less prone to abandon faith and to moral criticism than those having caring but not religious parents or those having religious but not caring parents. The low social support group was more likely to abandon faith and moral criticism than moderate or high social support groups. Regression analyses revealed that deconversion in adolescence is negatively predicted by the mother’s care and friends’ support.
Adolescence is a period of exceptional sensitivity to the ideals that are subject to verification. Therefore, a phenomenon of deconversion (i.e. abandonment of religion) is observed among ...adolescents. The paper aims to analyze deconversion and its connections with the identity formation as well as mediators and moderators of these relationships. Participants were 272 adolescents aged between 14 and 18. Three scales were used: the Circumplex Identity Modes Questionnaire, the Internal Dialogical Activity Scale-Revised, and the Adolescent Deconversion Scale. We found that identity modes such as moratorivity, diffusion, and defiance are positively related to deconversion, whereas socialization and normativity are negatively related to deconversion. The negative relationships between normativity and deconversion exist if the parent (especially mother) is assessed as religious or very religious. Moreover, internal dialogs moderate and mediate links between different identity modes and dimensions of deconversion.
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