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- Abolhalaj, Milad, et al.
(författare)
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Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia
- 2022
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:15, s. 3023-3032
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute myeloid leukemia (AML) patients have limited effect from T-cell-based therapies, such as PD-1 and CTLA-4 blockade. However, recent data indicate that AML patients with TP53 mutation have higher immune infiltration and other immunomodulatory therapies could thus potentially be effective. Here, we performed the transcriptional analysis of distinct T-cell subpopulations from TP53-mutated AML to identify gene expression signatures suggestive of altered functional properties.Methods: CD8+ cytotoxic T lymphocytes (CTLs), conventional helper T cells (Th), and regulatory T cells (Tregs) were sorted from peripheral blood of AML patients with TP53 mutation (n = 5) and healthy donors (n = 3), using FACS, and the different subpopulations were subsequently subjected to RNA-sequencing. Differentially expressed genes were identified and gene set enrichment analysis (GSEA) was performed to outline altered pathways and exhaustion status. Also, expression levels for a set of genes encoding established and emerging immuno-oncological targets were defined.Results: The results showed altered transcriptional profiles for each of the T-cell subpopulations from TP53-mutated AML as compared to control subjects. IFN-α and IFN-γ signaling were stronger in TP53-mutated AML for both CTLs and Tregs. Furthermore, in TP53-mutated AML as compared to healthy controls, Tregs showed gene expression signatures suggestive of metabolic adaptation to their environment, whereas CTLs exhibited features of exhaustion/dysfunction with a stronger expression of TIM3 as well as enrichment of a gene set related to exhaustion.Conclusions: The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.
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| 3. |
- Metsä-Simola, Niina S., et al.
(författare)
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Changes in parents' psychotropic medication use following child's cancer diagnosis : A fixed-effects register-study in Finland
- 2022
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:16, s. 3145-3155
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Tidskriftsartikel (refereegranskat)abstract
- Background: Symptoms of depression and anxiety are elevated among parents of children with cancer. However, knowledge of parents' psychotropic medication use following child's cancer diagnosis is scarce.Methods: We use longitudinal Finnish register data on 3266 mothers and 2687 fathers whose child (aged 0–19) was diagnosed with cancer during 2000–2016. We record mothers' and fathers' psychotropic medication use (at least one annual purchase of anxiolytics, hypnotics, sedatives, or antidepressants) 5 years before and after the child's diagnosis and assess within-individual changes in medication use by time since diagnosis, cancer type, child's age, presence of siblings, and parent's living arrangements and education using linear probability models with the individual fixed-effects estimator. The fixed-effects models compare each parent's annual probability of psychotropic medication use after diagnosis to their annual probability of medication use during the 5-year period before the diagnosis.Results: Psychotropic medication use was more common among mothers than fathers already before the child's diagnosis, 11.2% versus 7.3%. Immediately after diagnosis, psychotropic medication use increased by 6.0 (95% CI 4.8–7.2) percentage points among mothers and by 3.2 (CI 2.1–4.2) percentage points among fathers. Among fathers, medication use returned to pre-diagnosis level by the second year, except among those whose child was diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma. Among mothers of children with a central nervous system cancer, medication use remained persistently elevated during the 5-year follow-up. For mothers with other under-aged children or whose diagnosed child was younger than 10 years, the return to pre-diagnosis level was also slow.Conclusions: Having a child with cancer clearly increases parents' psychotropic medication use. The increase is smaller and more short-lived among fathers, but among mothers its duration depends on both cancer type and family characteristics. Our results suggest that an increased care burden poses particular strain to the long-term mental well-being of mothers.
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| 7. |
- Teleka, Stanley, et al.
(författare)
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The interaction between smoking and bladder cancer genetic variants on urothelial cancer risk by disease aggressiveness
- 2022
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 11:15, s. 2896-2905
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSmoking has shown interactions with bladder cancer (BC) genetic variants, especially N-acetyltransferase-2 (NAT2), a tobacco smoke metabolism gene, on BC risk. The interactions by disease aggressiveness are unknown.MethodsWe investigated the interaction between smoking and 18 single nucleotide polymorphisms (SNPs) for BC, individually and in a genetic risk score (GRS), on urothelial cancer (UC) risk including BC. We analysed data from 25,453 individuals with 520 incident UCs during follow-up, 339 non-aggressive (non-fatal, non-muscle invasive) and 163 aggressive (all other) UCs. Hazard ratios (HRs), absolute risks and additive and multiplicative interactions for two-by-two combinations of never/ever smoking with low/high genetic risk were calculated.ResultsSmoking and NAT2 rs1495741 interacted strongly, positively on aggressive UC on both the multiplicative (p = 0.004) and additive (p = 0.0002) scale, which was not observed for non-aggressive UC (pinteractions ≥ 0.6). This manifested in a higher HR of aggressive UC by ever smoking for the slow acetylation NAT2 genotype (HR, 5.00 [95% confidence interval, 2.67–9.38]) than for intermediate/fast acetylation NAT2 (HR, 1.50 [0.83–2.71]), and in differences in absolute risks by smoking and NAT2 genotype. Smoking also interacted additively and positively with the GRS on any UC (p = 0.01) and non-aggressive UC (p = 0.02), but not on aggressive UC (p = 0.1). Gene-smoking interactions of lesser magnitude than for NAT2 were found for SNPs in APOBEC3A, SLC14A1 and MYNN.ConclusionsThis study suggests that smoking increases UC risk more than expected when combined with certain genetic risks. Individuals with the slow acetylation NAT2 variant might particularly benefit from smoking intervention to prevent lethal UC; however, replication in larger studies is needed.
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| 8. |
- Wikman, Anna, et al.
(författare)
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Psychotropic medication use in parents of survivors of adolescent cancer : A register-based cohort study
- 2022
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:22, s. 4341-4353
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim was to investigate psychotropic medication use in parents of survivors of adolescent cancer from the acute post-diagnostic phase and up to 2 years following the cancer diagnosis.METHODS: This study had a nationwide register-based cohort design comparing psychotropic medication use in parents of adolescent survivors of cancer (n = 2323) to use in parents of cancer-free controls (n = 20,868). Cox proportional hazards models, adjusted for cancer diagnostic group, parents' age, country of birth, education level, marital status and previous mental health problems estimated the risk of use from the time of the cancer diagnosis up to 2 years later.RESULTS: During the first 6 months after the cancer diagnosis, both mothers and fathers had an increased risk of use of anxiolytics (mothers: HRadj 1.71, 95% CI 1.30-2.25; fathers: HRadj 1.57, 95% CI 1.10-2.45) and hypnotics/sedatives (mothers: HRadj 1.53, 95% CI 1.23-1.90; fathers: HRadj 1.32, 95% CI 1.00-1.75). For fathers with a prescription of psychotropic medication during the first 6 months after the cancer diagnosis, the risk remained increased after 6 months (HRadj 1.66, 95% CI 1.04-2.65). From 6 months after the cancer diagnosis, only the risk of antidepressant use among mothers was increased (HRadj 1.38, 95% CI 1.08-1.76). Risk factors included being divorced/widowed, born in a non-Nordic country, older age and having had previous mental health problems.CONCLUSION: Our study results show that during the immediate post-diagnostic phase, mothers and fathers of survivors of adolescent cancer are at increased risk of use of anxiolytics and sedatives, whereas only mothers are at increased risk of antidepressant use from 6 months until 2 years after the diagnosis. Further, previous mental health problems were shown to be the strongest risk factor for psychotropic medication use in both mothers and fathers, pointing to the particular vulnerability of these parents.
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| 9. |
- Wu, Wendy Yi-Ying, et al.
(författare)
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Pre-diagnostic levels of sVEGFR2, sTNFR2, sIL-2Rα and sIL-6R are associated with glioma risk : A nested case–control study of repeated samples
- 2022
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 11:4, s. 1016-1025
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Tidskriftsartikel (refereegranskat)abstract
- No strong aetiological factors have been established for glioma aside from genetic mutations and variants, ionising radiation and an inverse relationship with asthmas and allergies. Our aim was to investigate the association between pre-diagnostic immune protein levels and glioma risk. We conducted a case–control study nested in the Northern Sweden Health and Disease Study cohort. We analysed 133 glioma cases and 133 control subjects matched by age, sex and date of blood donation. ELISA or Luminex bead-based multiplex assays were used to measure plasma levels of 19 proteins. Conditional logistic regression models were used to estimate the odds ratios and 95% CIs. To further model the protein trajectories over time, the linear mixed-effects models were conducted. We found that the levels of sVEGFR2, sTNFR2, sIL-2Rα and sIL-6R were associated with glioma risk. After adjusting for the time between blood sample collection and glioma diagnosis, the odds ratios were 1.72 (95% CI = 1.01–2.93), 1.48 (95% CI = 1.01–2.16) and 1.90 (95% CI = 1.14–3.17) for sTNFR2, sIL-2Rα and sIL-6R, respectively. The trajectory of sVEGFR2 concentrations over time was different between cases and controls (p-value = 0.031), increasing for cases (0.8% per year) and constant for controls. Our findings suggest these proteins play important roles in gliomagenesis.
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