| 1. |
- Fritzell, Sara, et al.
(författare)
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Does non-employment contribute to the health disadvantage among lone mothers in Britain, Italy and Sweden? Family policy and synergy effects
- 2012
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Ingår i: Health and Place. - : Elsevier BV. - 1353-8292 .- 1873-2054. ; 18:2, s. 199-208
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Tidskriftsartikel (refereegranskat)abstract
- This study analyses self-rated health and non-employment and potential synergy effects among lone and couple mothers aged 25–59 in Britain, Sweden and Italy, representing different family policy categories using data from national surveys (2000–2005). Synergy effects on health were calculated by synergy index. Non-employment only marginally contributed to the excess risk of poor health among lone mothers but there were synergy effects between lone motherhood and non-employment in all three countries, producing a higher risk of poor health than would be expected from a simple addition of these exposures. Results are discussed in relation to the different family policy and living contexts.
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| 2. |
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| 3. |
- Eberstål, Sofia, et al.
(författare)
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Immunizations with unmodified tumor cells and simultaneous COX-2 inhibition eradicate malignant rat brain tumors and induce a long-lasting CD8(+) T cell memory.
- 2014
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 274:1-2, s. 161-167
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Tidskriftsartikel (refereegranskat)abstract
- Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8(+) T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors.
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| 4. |
- Eberstål, Sofia, et al.
(författare)
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Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors.
- 2012
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Ingår i: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 61:8, s. 1191-1199
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme is the most common and aggressive malignant brain tumor in humans, and the prognosis is very poor despite conventional therapy. Immunotherapy represents a novel treatment approach, but the effect is often weakened by release of immune-suppressive molecules such as prostaglandins. In the current study, we investigated the effect of immunotherapy with irradiated interferon-γ (IFN-γ)-secreting tumor cells and administration of the selective cyclooxygease-2 (COX-2) inhibitor parecoxib as treatment of established rat brain tumors. COX-2 inhibition and immunotherapy significantly enhanced the long-term cure rate (81% survival) compared with immunotherapy alone (19% survival), and there was a significant increase in plasma IFN-γ levels in animals treated with the combined therapy, suggesting a systemic T helper 1 immune response. COX-2 inhibition alone, however, did neither induce cure nor prolonged survival. The tumor cells were identified as the major source of COX-2 both in vivo and in vitro, and unmodified tumor cells produced prostaglandin E(2) in vitro, while the IFN-γ expressing tumor cells secreted significantly lower levels. In conclusion, we show that immunotherapy of experimental brain tumors is greatly potentiated when combined with COX-2 inhibition. Based on our results, the clinically available drug parecoxib may be added to immunotherapy against human brain tumors. Furthermore, the discovery that IFN-γ plasma levels can be used to determine the ongoing in vivo immune response has translational potential.
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| 5. |
- Eberstål, Sofia, et al.
(författare)
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Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors.
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 134:11, s. 2748-2753
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate). Both combined therapies induced a systemic anti-tumor response of proliferating CD4(+) and CD8(+) T cells and further analysis revealed T helper 1 (Th 1) cell supremacy. The GL261 tumor cell line produced very low levels of PGE2 in vitro and co-staining at the tumor site demonstrated that a large fraction of the COX-2(+) cells were derived from CD45(+) immune cells and more specifically macrophages (F4/80(+) ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target. © 2013 Wiley Periodicals, Inc.
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| 6. |
- Enell Smith, Karin, et al.
(författare)
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ATOR-1017 (evunzekibart), an Fc-gamma receptor conditional 4-1BB agonist designed for optimal safety and efficacy, activates exhausted T cells in combination with anti-PD-1
- 2023
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Ingår i: Cancer Immunology, Immunotherapy. - 0340-7004. ; 72:12, s. 4145-4159
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Tidskriftsartikel (refereegranskat)abstract
- Background: 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity. Methods: ATOR-1017 (evunzekibart), a second-generation Fc-gamma receptor conditional 4-1BB agonist in IgG4 format, was designed to overcome the limitations of the first generation of 4-1BB agonists, providing strong agonistic effect while minimizing systemic immune activation and risk of hepatoxicity. The epitope of ATOR-1017 was determined by X-ray crystallography, and the functional activity was assessed in vitro and in vivo as monotherapy or in combination with anti-PD1. Results: ATOR-1017 binds to a unique epitope on 4-1BB enabling ATOR-1017 to activate T cells, including cells with an exhausted phenotype, and NK cells, in a cross-linking dependent, FcγR-conditional, manner. This translated into a tumor-directed and potent anti-tumor therapeutic effect in vivo, which was further enhanced with anti-PD-1 treatment. Conclusions: These preclinical data demonstrate a strong safety profile of ATOR-1017, together with its potent therapeutic effect as monotherapy and in combination with anti-PD1, supporting further clinical development of ATOR-1017.
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| 7. |
- Enell Smith, Karin, et al.
(författare)
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Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNgamma is mediated by both CD8(+) and CD4(+) T-cells.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:3, s. 630-637
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Tidskriftsartikel (refereegranskat)abstract
- We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNgamma of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNgamma systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFNgamma-producing T-cells, were augmented after immunizations with GM-CSF and IFNgamma. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.c.) rechallenges. Depletion of T-cells showed that both CD4(+) and CD8(+) T-cells were essential for the combined GM-CSF and IFNgamma effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFNgamma survived. We conclude that the addition of recombinant IFNgamma to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors. (c) 2008 Wiley-Liss, Inc.
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| 8. |
- Enríquez Pérez, Julio, et al.
(författare)
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The effect of locally delivered cisplatin is dependent on an intact immune function in an experimental glioma model
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Several chemotherapeutic drugs are now considered to exert anti-tumour effects, by inducing an immune-promoting inflammatory response. Cisplatin is a potent chemotherapeutic agent used in standard medulloblastoma but not glioblastoma protocols. There is no clear explanation for the differences in clinical efficacy of cisplatin between medulloblastomas and glioblastomas, despite the fact that cisplatin is effective in vitro against the latter. Systemic toxicity is often dose limiting but could tentatively be reduced by intratumoral administration. We found that intratumoral cisplatin can cure GL261 glioma-bearing C57BL/6 mice and this effect was abolished in GL261-bearing NOD-scid IL2rγ null (NSG) mice. Contrary to previous results with intratumoral temozolomide cisplatin had no additive or synergistic effect with whole cell either GL261 wild-type or GM-CSF-transfected GL261 cells whole cell vaccine-based immunotherapy. While whole tumour cell immunizations increased CD8 + T-cells and decreased F4/80 + macrophages intratumorally, cisplatin had no effect on these cell populations. Taken together, our results demonstrate that intratumoral cisplatin treatment was effective with a narrow therapeutic window and may be an efficient approach for glioma or other brain tumour treatment.
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| 9. |
- Fritzell, Sara C., et al.
(författare)
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Family Structure, Child Living Arrangement and Mothers’ Self-rated Health in Sweden — A Cross-Sectional Study
- 2017
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Ingår i: International Journal of Health Services. - : SAGE Publications. - 0020-7314 .- 1541-4469. ; 47:2, s. 298-311
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Tidskriftsartikel (refereegranskat)abstract
- Alternate living, i.e. children living 50-50 with their parents following separation is emerging as a new family form. This study is the first to differentiate separated mothers with sole/main custody from mothers with alternately living children, analysing health outcomes and using a sample representative of the population. The association between the self-rated health (SRH) of mothers and different family structures are examined. Parental cooperation is included in the analyses as a potential mediator. Data on 755 mothers from the 2010 Swedish Level of Living Survey were analyzed by multivariate logistic regression. Single mothers with sole/main custody reported poorer SRH than couple mothers in intact families while the difference was not significant for single mothers with children living alternately and mothers in stepfamilies. Controlling for potential confounders, probabilities for poor SRH for single mothers were reduced. The excess risk among mothers with sole/main custody may be due to poorer socioeconomic conditions. Employment was significantly more common among mothers with alternate living and an important explanatory factor for their better health compared to single mothers with sole/main custody. Adjusting for parental cooperation lowered the increased probability for poor SRH among single mothers with sole/main custody compared to single mothers with alternate living.
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| 10. |
- Fritzell, Sara, et al.
(författare)
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Child living arrangements following separation and mental health of parents in Sweden
- 2020
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Ingår i: SSM - Population Health. - : Elsevier BV. - 2352-8273. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Father involvement and joint physical custody in post-separation families are increasingly common. In Sweden, 35 percent of the children of separated parents live equally much with both parents. Since parenthood is gendered, the associations between child living arrangement and parental health may vary between women and men. This study analyzes the association between children's living arrangement and mental health of parents, and how this interacts with material and social circumstances. Drawing on The Swedish Survey of Living Conditions (ULF) 2008-2013, the association between child living arrangements and mental health (worry/anxiety) of parents in five family structures: two biological parents, reconstituted with joint or main/sole custody arrangements, single with joint physical custody, and single with main or sole custody, were analyzed. Data on 9,225 mothers and fathers with resident children aged 0-17 were analyzed by logistic regressions for average marginal effects adjusting for socio-demographic, socio-economic and social factors. Analyses of interaction effects were made using the synergy index. Substantial family type differences were found in mental health between two biological parent family and all other family types for mothers, and two biological parent family and single parents for fathers. For the single mothers, the higher risk for worry and anxiety was still found following controls for socioeconomic factors. For fathers, the only differences that remained following control for socioeconomic factors was that of single fathers with children in joint physical custody. Interaction effects were found for the combination of single motherhood and non-employment, indicating a higher risk of mental health problems for single mothers (both with joint and sole custody), than would be expected from a simple addition of these exposures, suggesting that this is a vulnerable group. The results indicate that joint custody is associated with higher risk for worry and anxiety for the parents, especially for mothers both re-partnered and single, but also for single fathers.
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