| 11. |
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| 12. |
- Johard, Helena, et al.
(författare)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Tidskriftsartikel (refereegranskat)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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| 13. |
- Jörnsten, Rebecka, 1971, et al.
(författare)
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Network modeling of the transcriptional effects of copy number aberrations in glioblastoma
- 2011
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- DNA copy number aberrations (CNAs) are a hallmark of cancer genomes. However, little is known about how such changes affect global gene expression. We develop a modeling framework, EPoC (Endogenous Perturbation analysis of Cancer), to (1) detect disease-driving CNAs and their effect on target mRNA expression, and to (2) stratify cancer patients into long- and short-term survivors. Our method constructs causal network models of gene expression by combining genome-wide DNA- and RNA-level data. Prognostic scores are obtained from a singular value decomposition of the networks. By applying EPoC to glioblastoma data from The Cancer Genome Atlas consortium, we demonstrate that the resulting network models contain known disease-relevant hub genes, reveal interesting candidate hubs, and uncover predictors of patient survival. Targeted validations in four glioblastoma cell lines support selected predictions, and implicate the p53-interacting protein Necdin in suppressing glioblastoma cell growth. We conclude that large-scale network modeling of the effects of CNAs on gene expression may provide insights into the biology of human cancer. Free software in MATLAB and R is provided.
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| 14. |
- Karlsson-Lindahl, Linda, 1972, et al.
(författare)
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Heparanase affects food intake and regulates energy balance in mice.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.
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| 15. |
- Niklasson, Mia, et al.
(författare)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
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Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 16. |
- Nissling, Linnea, 1991, et al.
(författare)
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Effectiveness of and processes related to internet-delivered acceptance and commitment therapy for adolescents with anxiety disorders : a randomized controlled trial
- 2023
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Ingår i: RESEARCH IN PSYCHOTHERAPY-PSYCHOPATHOLOGY PROCESS AND OUTCOME. - : PAGEPress Publications. - 2499-7552 .- 2239-8031. ; 26:2
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Tidskriftsartikel (refereegranskat)abstract
- Early access to evidence-based help is crucial for adolescents with anxiety disorders. Internet-delivered acceptance and commitment therapy (iACT) may offer adolescents increased access to care and more flexibility in engaging with treatment when and how they prefer. Process-based therapies, such as ACT, focus on the-oretically derived and empirically tested key mechanisms in treat-ment that enable change. This study aimed to investigate the effectiveness of iACT for adolescents with anxiety disorders. The study also assessed the relationship between psychological flexi-bility and treatment outcomes and the relationship between par-ticipating adolescents' and therapists' perceived alliance and treatment outcomes. This was a randomized controlled trial com-paring a 10-week intervention group with a wait-list control group. The 52 participants, aged 15 to 19, were recruited from all over Sweden. The treatment was effective in increasing quality of life and psychological flexibility, with moderate between-group effect sizes based on observed values. Changes in psychological flexibility was associated with changes in anxiety symptoms. The results further showed a statistically significant between-group difference in post-treatment diagnoses. No significant time per group interaction was found for anxiety symptoms, as both groups improved. Working alliance was rated as high by both participat-ing adolescents and therapists but showed no significant relation-ship with treatment outcomes. Participants found the treatment an acceptable intervention. This study shows promising results for iACT in treating adolescents with anxiety disorders. The results suggest the model of psychological flexibility as an important process of change in treatment outcomes. Future research should validate these findings in larger samples and clinical contexts.
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| 17. |
- Nissling, Linnea, 1991, et al.
(författare)
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Internet-delivered Acceptance and Commitment Therapy for adolescents with anxiety disorders
- 2023
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Ingår i: SweSRII – The 12th Swedish Congress on Internet Interventions..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background Anxiety disorders are common causes of mental illness in adolescents. Acceptance and Commitment Therapy delivered through internet (iACT) shows promising results for adults with anxiety disorders, but few studies exist on internet-delivered ACT programs for adolescents. Aims investigate the effectiveness of internet-delivered ACT for adolescents with anxiety disorders assess the relationship between psychological flexibility and treatment outcomes assess the relationship between adolescents and therapists perceived alliance and treatment outcomes. Population 52 adolescents aged 15 to 19 and from all over Sweden were recruited through advertisements on social media, in schools, primary health care centers and outpatient psychiatric clinics and were assessed by the diagnostic interview M.I.N.I Kid as meeting criteria for one or several anxiety diagnosis. Intervention An internet-delivered ACT treatment, “Ångesthjälpen UNG”, was developed (Psykologpartners, 2017). Outcomes The treatment increased the adolescents’ self-rated quality of life and psychological flexibillity (moderate between-group effect sizes, d=.65 and d=.51) Post treatment assessment with M.I.N.I Kid showed diminished anxiety diagnoses No significant group difference was found for anxiety symptoms, as both groups improved Changes in psychological flexibility were associated with changes in anxiety symptoms Working alliance was rated as high by both adolescents and therapists but showed no significant relationship with treatment outcomes Take-home message This study shows promising results for internet-delivered ACT in treating adolescents with anxiety disorders. The results suggest the model of psychological flexibility as an important process of change in treatment outcomes. Future research should validate these findings in larger samples and in clinical contexts.
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| 18. |
- Schmidt, Linnéa, et al.
(författare)
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Case-specific potentiation of glioblastoma drugs by pterostilbene
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 73200-73215
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
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| 19. |
- Stjärngrim, Jessica, et al.
(författare)
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Post-endoscopy colorectal cancer after colectomy in inflammatory bowel disease patients : a population-based register study
- 2023
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Ingår i: European Journal of Gastroenterology and Hepathology. - : Lippincott Williams & Wilkins. - 0954-691X .- 1473-5687. ; 35:3, s. 288-293
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Long-standing inflammatory bowel disease (IBD) colitis is an indication for endoscopic surveillance. Postcolonoscopy colorectal cancer (PCCRC), cancer detected after a negative colonoscopy, is a quality indicator for colonoscopy. In analogy with PCCRC, we aimed to assess postendoscopy CRC (PECRC) in individuals with IBD who had undergone colectomy.Methods: This register study included Swedish adults with an IBD diagnosis who had undergone colectomy and later were examined by either colonoscopy or sigmoidoscopy during 2001-2012. The final study population had a CRC diagnosis within 36 months of the index examination. Poisson regression was used to assess the relative risks (RR) of PECRC.Results: A total of 33 individuals, 12 with an ileorectal anastomosis and 21 with a rectal remnant, had a CRC diagnosis within 36 months of the index endoscopy. Eleven cancers were detected as CRCs, and 22 (67%) were PECRCs. Compared with individuals aged >70 years, individuals aged <30 years had an RR of 3.1 (P = 0.054) and individuals aged 30-50 years had a RR of 2.6 (P = 0.030). A longer interval between colectomy and index endoscopy (>10 vs. <10 years) was associated with a lower risk of PCCRC (RR = 0.5; P = 0.007). There was no significant difference between the risk for Crohn's disease vs. ulcerative colitis, or between ileorectal anastomosis and rectal remnant risks.Conclusions: Continuous surveillance of IBD patients after colectomy is important. In the postcolectomy context, PECRC may be used as a quality indicator.
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| 20. |
- Thorén, Matilda Munksgaard, et al.
(författare)
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Integrin α10, a novel therapeutic target in glioblastoma, regulates cell migration, proliferation, and survival
- 2019
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10Β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10Β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin a10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10Β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10Β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
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