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  1. Article ; Online: The sex-dependent role of the androgen receptor in glioblastoma: results of molecular analyses.

    Łysiak, Małgorzata / Trybuła, Małgorzata / Mudaisi, Munila / Bratthäll, Charlotte / Strandeus, Michael / Milos, Peter / Hallbeck, Martin / Malmström, Annika

    Molecular oncology

    2022  Volume 16, Issue 19, Page(s) 3436–3451

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Brain Neoplasms/genetics ; DNA Methylation/genetics ; Female ; Formaldehyde ; Glioblastoma/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Male ; RNA, Messenger ; Receptors, Androgen/genetics
    Chemical Substances RNA, Messenger ; Receptors, Androgen ; Formaldehyde (1HG84L3525) ; Isocitrate Dehydrogenase (EC 1.1.1.41)
    Language English
    Publishing date 2022-06-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2415106-3
    ISSN 1878-0261 ; 1574-7891
    ISSN (online) 1878-0261
    ISSN 1574-7891
    DOI 10.1002/1878-0261.13262
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6637: Show issues Location:
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  2. Article ; Online: "Do I want to know it all?" A qualitative study of glioma patients' perspectives on receiving information about their diagnosis and prognosis.

    Malmström, Annika / Åkesson, Lisa / Milos, Peter / Mudaisi, Munila / Bruhn, Helena / Strandeus, Michael / Karlsson, Marit

    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer

    2020  Volume 29, Issue 6, Page(s) 3339–3346

    Abstract: Purpose: Glioma patients have poor prognosis. The amount of detail of disease-related information patients wish to receive is not known. The aim of this study was to explore glioma patients' experiences and preferences regarding receiving information on ...

    Abstract Purpose: Glioma patients have poor prognosis. The amount of detail of disease-related information patients wish to receive is not known. The aim of this study was to explore glioma patients' experiences and preferences regarding receiving information on diagnosis and prognosis.
    Methods: Semi-structured interviews were performed with patients diagnosed with glioma. The interviews were analysed by qualitative content analysis without predefined categories by two independent coders.
    Results: Ten women and 15 men, with newly diagnosed grade II-IV glioma, age 25-76 years, were interviewed. Participants' experience on diagnosis communication was either indirect, meaning they found out their diagnosis unintentionally, e.g., from their electronic health record (EHR) instead of from their doctor, this causing anxiety and feelings of abandonment, insufficiently tailored: lacking in many aspects or individualised and compassionate. Participants generally wanted to know "the truth" about diagnosis and prognosis, but what they meant varied; some desired full honest information to allow for autonomous choices, others preferred general information without details, and some wanted no bad news at all, only positive information. Participants disclosed vulnerability after receiving their diagnosis, being cast into the unknown. They expressed a need for better everyday practical information to help create some control. Supportive staff could reduce participants' distress.
    Conclusion: There is a need to further develop and implement individually tailored information to glioma patients, both in consultations and patient-accessed EHR systems, which should have safe guards for sensitive information. Not all patients want to know it all, one size does not fit all.
    MeSH term(s) Adult ; Aged ; Female ; Glioma/diagnosis ; Glioma/mortality ; Humans ; Male ; Middle Aged ; Prognosis ; Qualitative Research ; Survival Analysis
    Language English
    Publishing date 2020-10-30
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1134446-5
    ISSN 1433-7339 ; 0941-4355
    ISSN (online) 1433-7339
    ISSN 0941-4355
    DOI 10.1007/s00520-020-05846-7
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  3. Article ; Online: Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma: A Randomized Clinical Trial.

    Werlenius, Katja / Kinhult, Sara / Solheim, Tora Skeidsvoll / Magelssen, Henriette / Löfgren, David / Mudaisi, Munila / Hylin, Sofia / Bartek, Jiri / Strandéus, Michael / Lindskog, Magnus / Rashid, Havyan Bahroz / Carstam, Louise / Gulati, Sasha / Solheim, Ole / Salvesen, Øyvind / Jakola, Asgeir Store

    JAMA network open

    2023  Volume 6, Issue 3, Page(s) e234149

    Abstract: Importance: Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.: Objective: To evaluate the efficacy and safety of disulfiram and copper as add-on ... ...

    Abstract Importance: Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.
    Objective: To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.
    Design, setting, and participants: This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.
    Interventions: Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).
    Main outcomes and measures: The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.
    Results: Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.
    Conclusions and relevance: This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.
    Trial registration: ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.
    MeSH term(s) Humans ; Male ; Middle Aged ; Female ; Glioblastoma/drug therapy ; Copper/therapeutic use ; Disulfiram/therapeutic use ; Quality of Life ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use
    Chemical Substances Copper (789U1901C5) ; Disulfiram (TR3MLJ1UAI)
    Language English
    Publishing date 2023-03-01
    Publishing country United States
    Document type Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2023.4149
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  4. Article: Deletions on Chromosome Y and Downregulation of the

    Łysiak, Małgorzata / Smits, Anja / Roodakker, Kenney Roy / Sandberg, Elisabeth / Dimberg, Anna / Mudaisi, Munila / Bratthäll, Charlotte / Strandeus, Michael / Milos, Peter / Hallbeck, Martin / Söderkvist, Peter / Malmström, Annika

    Cancers

    2021  Volume 13, Issue 7

    Abstract: Background: 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).: ... ...

    Abstract Background: 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).
    Methods: 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.
    Results: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months,
    Conclusion: 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.
    Language English
    Publishing date 2021-03-31
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13071619
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  5. Article ; Online: Assessment of genetic and non-genetic risk factors for venous thromboembolism in glioblastoma - The predictive significance of B blood group.

    Heenkenda, Menikae K / Malmström, Annika / Lysiak, Malgorzata / Mudaisi, Munila / Bratthäll, Charlotte / Milos, Peter / Strandeus, Michael / Åkesson, Lisa / Söderkvist, Peter / Uppugunduri, Srinivas / Osman, Abdimajid

    Thrombosis research

    2019  Volume 183, Page(s) 136–142

    Abstract: Introduction: 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.: Materials and ... ...

    Abstract Introduction: 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.
    Materials and methods: 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.
    Results: 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.
    Conclusion: 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.
    MeSH term(s) Aged ; Blood Group Antigens/adverse effects ; Disease Progression ; Female ; Glioblastoma/blood ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; Male ; Middle Aged ; Risk Factors ; Venous Thromboembolism/blood ; Venous Thromboembolism/genetics ; Venous Thromboembolism/pathology
    Chemical Substances Blood Group Antigens
    Language English
    Publishing date 2019-10-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 121852-9
    ISSN 1879-2472 ; 0049-3848
    ISSN (online) 1879-2472
    ISSN 0049-3848
    DOI 10.1016/j.thromres.2019.10.009
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    Zs.A 863: Show issues Location:
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  6. Article ; Online: ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide.

    Malmström, Annika / Łysiak, Malgorzata / Åkesson, Lisa / Jakobsen, Ingrid / Mudaisi, Munila / Milos, Peter / Hallbeck, Martin / Fomichov, Victoria / Broholm, Helle / Grunnet, Kirsten / Poulsen, Hans Skovgaard / Bratthäll, Charlotte / Strandeus, Michael / Papagiannopoulou, Angeliki / Stenmark-Askmalm, Marie / Green, Henrik / Söderkvist, Peter

    The pharmacogenomics journal

    2019  Volume 20, Issue 2, Page(s) 213–219

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; Adult ; Aged ; Antineoplastic Agents, Alkylating/administration & dosage ; Brain Neoplasms/genetics ; Brain Neoplasms/mortality ; Brain Neoplasms/therapy ; Chemoradiotherapy/methods ; Cohort Studies ; Female ; Genetic Variation/genetics ; Glioblastoma/genetics ; Glioblastoma/mortality ; Glioblastoma/therapy ; Humans ; Male ; Middle Aged ; Pilot Projects ; Polymorphism, Single Nucleotide/genetics ; Survival Rate/trends ; Sweden/epidemiology ; Temozolomide/administration & dosage ; Treatment Outcome
    Chemical Substances ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; Antineoplastic Agents, Alkylating ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2019-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2106831-8
    ISSN 1473-1150 ; 1470-269X
    ISSN (online) 1473-1150
    ISSN 1470-269X
    DOI 10.1038/s41397-019-0107-z
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    Zs.A 5806: Show issues Location:
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  7. Article ; Online: Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial.

    Jakola, Asgeir Store / Werlenius, Katja / Mudaisi, Munila / Hylin, Sofia / Kinhult, Sara / Bartek, Jiri / Salvesen, Øyvind / Carlsen, Sven Magnus / Strandéus, Michael / Lindskog, Magnus / Löfgren, David / Rydenhag, Bertil / Carstam, Louise / Gulati, Sasha / Solheim, Ole / Solheim, Tora

    F1000Research

    2018  Volume 7, Page(s) 1797

    Abstract: Background: ...

    Abstract Background:
    MeSH term(s) Humans ; Brain Neoplasms/drug therapy ; Copper/therapeutic use ; Dietary Supplements ; Disulfiram/therapeutic use ; Drug Repositioning ; Glioblastoma/drug therapy ; Neoplasm Recurrence, Local/drug therapy ; Research Report ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Clinical Trials, Phase II as Topic
    Chemical Substances Copper (789U1901C5) ; Disulfiram (TR3MLJ1UAI)
    Language English
    Publishing date 2018-11-15
    Publishing country England
    Document type Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2699932-8
    ISSN 2046-1402 ; 2046-1402
    ISSN (online) 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.16786.1
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