| 1. |
- Dolatabadi, Soheila, et al.
(författare)
-
JAK–STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma
- 2019
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:2, s. 435-449
-
Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcoma (MLS) shows extensive intratumoural heterogeneity with distinct subpopulations of tumour cells. Despite improved survival of MLS patients, existing therapies have shortcomings as they fail to target all tumour cells. The nature of chemotherapy-resistant cells in MLS remains unknown. Here, we show that MLS cell lines contained subpopulations of cells that can form spheres, efflux Hoechst dye and resist doxorubicin, all properties attributed to cancer stem cells (CSCs). By single-cell gene expression, western blot, phospho-kinase array, immunoprecipitation, immunohistochemistry, flow cytometry and microarray analysis we showed that a subset of MLS cells expressed JAK–STAT genes with active signalling. JAK1/2 inhibition via ruxolitinib decreased, while stimulation with LIF increased, phosphorylation of STAT3 and the number of cells with CSC properties indicating that JAK–STAT signalling controlled the number of cells with CSC features. We also show that phosphorylated STAT3 interacted with the SWI/SNF complex. We conclude that MLS contains JAK–STAT-regulated subpopulations of cells with CSC features. Combined doxorubicin and ruxolitinib treatment targeted both proliferating cells as well as cells with CSC features, providing new means to circumvent chemotherapy resistance in treatment of MLS patients. © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC
|
|
| 2. |
- Dolatabadi, Soheila, et al.
(författare)
-
FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma
- 2022
-
Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.
|
|
| 3. |
- Käll, Anton, et al.
(författare)
-
Therapist-Guided Internet-Based Treatments for Loneliness : A Randomized Controlled Three-Arm Trial Comparing Cognitive Behavioral Therapy and Interpersonal Psychotherapy
- 2021
-
Ingår i: Psychotherapy and Psychosomatics. - : Karger. - 0033-3190 .- 1423-0348. ; 90:5, s. 351-358
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Chronic loneliness has been linked to many adverse outcomes, including mental health problems. Psychological treatment of loneliness can be effective, but the evidence base is limited. Objective: To investigate the efficacy of 2 internet-based interventions based on cognitive behavioral therapy (ICBT) and interpersonal psychotherapy (IIPT) relative to a wait-list control group and each other. Methods: A total of 170 participants were recruited and randomized to either 9 weeks of ICBT (n = 68), IIPT (n = 68), or a wait-list condition (n = 34). The primary outcome was loneliness, measured using the UCLA Loneliness Scale before, during, and after treatment. Secondary measures of psychiatric disorders and quality of life were administered before and after treatment. Follow-up was conducted 4 months after the treatment had ended. Primary outcome data were analyzed using growth curve modeling. Secondary outcomes were analyzed using robust regression models. The trial was preregistered (ClinicalTrials.gov ID: NCT03807154). Results: The ICBT condition had a significantly greater impact on loneliness compared to the wait-list and IIPT conditions. Effect sizes were moderate to large (Cohen d = 0.71) compared to the wait-list and moderate (d = 0.53) compared to IIPT. The IIPT condition did not differ significantly from the wait-list. Both active treatments led to significant increases in quality of life. Only the ICBT group had significantly lower symptoms of depression and generalized anxiety compared to the wait-list group. Treatment gains were maintained but not improved at follow-up. Conclusions: ICBT can be an efficacious option for alleviating loneliness. The IIPT intervention was not as effective.
|
|
| 4. |
- Lindén, Malin, et al.
(författare)
-
FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex
- 2019
-
Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor-coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy. © 2019 The Authors. Published under the terms of the CC BY 4.0 license
|
|
| 5. |
- Lindén, Malin, et al.
(författare)
-
FET fusion oncoproteins interact with BRD4 and SWI/SNF chromatin remodelling complex subtypes in sarcoma
- 2022
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 16:13, s. 2470-2495
-
Tidskriftsartikel (refereegranskat)abstract
- FET fusion oncoproteins containing one of the FET (FUS, EWSR1, TAF15) family proteins juxtaposed to alternative transcription-factor partners are characteristic of more than 20 types of sarcoma and leukaemia. FET oncoproteins bind to the SWI/SNF chromatin remodelling complex, which exists in three subtypes: cBAF, PBAF and GBAF/ncBAF. We used comprehensive biochemical analysis to characterize the interactions between FET oncoproteins, SWI/SNF complexes and the transcriptional coactivator BRD4. Here, we report that FET oncoproteins bind all three main SWI/SNF subtypes cBAF, PBAF and GBAF, and that FET oncoproteins interact indirectly with BRD4 via their shared interaction partner SWI/SNF. Furthermore, chromatin immunoprecipitation sequencing and proteomic analysis showed that FET oncoproteins, SWI/SNF components and BRD4 co-localize on chromatin and interact with mediator and RNA Polymerase II. Our results provide a possible molecular mechanism for the FET-fusion-induced oncogenic transcriptional profiles and may lead to novel therapies targeting aberrant SWI/SNF complexes and/or BRD4 in FET-fusion-caused malignancies.
|
|
| 6. |
- Osman, Ayman, et al.
(författare)
-
Identification of genomic binding sites and direct target genes for the transcription factor DDIT3/CHOP
- 2023
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 422:1
-
Tidskriftsartikel (refereegranskat)abstract
- DDIT3 is a tightly regulated basic leucine zipper (bZIP) transcription factor and key regulator in cellular stress responses. It is involved in a variety of pathological conditions and may cause cell cycle block and apoptosis. It is also implicated in differentiation of some specialized cell types and as an oncogene in several types of cancer. DDIT3 was originally believed to act as a dominant-negative inhibitor by forming heterodimers with other bZIP transcription factors, preventing their DNA binding and transactivating functions. DDIT3 has, however, been reported to bind DNA and regulate target genes. Here, we employed ChIP sequencing combined with microarray-based expression analysis to identify direct binding motifs and target genes of DDIT3. The results reveal DDIT3 binding to motifs similar to other bZIP transcription factors, known to form heterodimers with DDIT3. Binding to a class III satellite DNA repeat sequence was also detected. DDIT3 acted as a DNA-binding transcription factor and bound mainly to the promotor region of regulated genes. ChIP sequencing analysis of histone H3K27 methylation and acetylation showed a strong overlap between H3K27-acetylated marks and DDIT3 binding. These results support a role for DDIT3 as a transcriptional regulator of H3K27ac-marked genes in transcriptionally active chromatin.
|
|
| 7. |
- Stigson, Helena, 1979, et al.
(författare)
-
Incidence of Acute Injuries among Licensed and Non-Licensed Cyclists using Insurance Registry Data
- 2019
-
Ingår i: 2019 IRCOBI Conference Proceedings. - : International Research Council on the Biomechanics of Injury.
-
Konferensbidrag (refereegranskat)abstract
- Few previous studies have examined acute injuries in competitive cycling or training as compared to other sports. By using nationwide insurance data including all injured cyclist registered in the Swedish Cycling Federation and all reported injuries during exercise race in Sweden, the objective was to examine acute injuries during competitive cycling or training for different types of cyclists. The injury incidence and injuries leading to permanent medical impairment were examined. All cyclists that were injured during 2008-2017 were included (n=1937).Among the 2666 licensed cyclists the incidence of cyclists injured during training or competition was 44 per 1000 licensed cyclists per year. Focusing on participants in exercise races, the incidence was annually 1.5 injured cyclists per 1000 participants per year. The most commonly injured body region was the upper extremity (41%), followed by head and neck (18%). In total 9.4% of all injured cyclists sustained a permanent medical impairment. Given an injury, non-licensed participants in exercise races were slightly older, and the proportion of females were higher (30% vs. 16%), than among licensed cyclists. The injury incidence among the cyclists was high, and to maintain a healthy and physically active population it is important to make efforts to prevent injuries.
|
|
| 8. |
- Vannas, Christoffer, et al.
(författare)
-
Different HSP90 Inhibitors Exert Divergent Effect on Myxoid Liposarcoma In Vitro and In Vivo
- 2022
-
Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:3
-
Tidskriftsartikel (refereegranskat)abstract
- The therapeutic options for patients with relapsed or metastatic myxoid liposarcoma (MLS) remain scarce and there is currently no targeted therapy available. Inhibition of the HSP90 family of chaperones has been suggested as a possible therapeutic option for patients with MLS. However, the clinical effect of different HSP90 inhibitors vary considerably and no comparative study in MLS has been performed. Here, we evaluated the effects of the HSP90 inhibitors 17-DMAG, AUY922 and STA-9090 on MLS cell lines and in an MLS patient-derived xenograft (PDX) model. Albeit all drugs inhibited in vitro growth of MLS cell lines, the in vivo responses were discrepant. Whereas 17-DMAG inhibited tumor growth, AUY922 surprisingly led to increased tumor growth and a more aggressive morphological phenotype. In vitro, 17-DMAG and STA-9090 reduced the activity of the MAPK and PI3K/AKT signaling pathways, whereas AUY922 led to a compensatory upregulation of downstream ERK. Furthermore, all three tested HSP90 inhibitors displayed a synergistic combination effect with trabectidin, but not with doxorubicin. In conclusion, our results indicate that different HSP90 inhibitors, albeit having the same target, can vary significantly in downstream effects and treatment outcomes. These results should be considered before proceeding into clinical trials against MLS or other malignancies.
|
|
| 9. |
|
|
| 10. |
- Åman, Malin, et al.
(författare)
-
A Nationwide Follow-up Survey on the Effectiveness of an Implemented Neuromuscular Training Program to Reduce Acute Knee Injuries in Soccer Players
- 2018
-
Ingår i: The Orthopaedic Journal of Sports Medicine. - : Sage Publications. - 2325-9671. ; 6:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A cruciate ligament (CL) injury is a severe injury in soccer. Neuromuscular training programs have a well-documented preventive effect, but there are few studies on the effectiveness of such a program at a national level. The Swedish Knee Control Program (KCP) was found to be effective in preventing CL injuries in youth female soccer players. The KCP was implemented nationwide in Sweden in 2010.Purpose: To evaluate the effectiveness of the Swedish KCP in reducing acute knee injuries in soccer players at a nationwide level.Study Design: Descriptive epidemiology study.Methods: All licensed soccer players in Sweden are covered by the same insurance company. Using this insurance database, around 17,500 acute knee injuries that were reported to the insurance company between 2006 and 2015 were included in the study. By matching the number of licensed soccer players with the number of reported injuries each year, the annual incidence of knee and CL injuries was able to be calculated. To evaluate the spread of the KCP nationally, a questionnaire was sent to all 24 Swedish district football associations (FAs) with questions regarding KCP education. The number of downloads of the KCP mobile application (app) was obtained.Results: The incidence of CL injuries decreased during the study period for both male (from 2.9 to 2.4 per 1000 player-years) and female players (from 4.9 to 3.9 per 1000 player-years). The overall incidence of knee injuries decreased in both male (from 5.6 to 4.6 per 1000 player-years) and female players (from 8.7 to 6.4 per 1000 player-years). Comparing before and after the nationwide implementation of the KCP, there was a decrease in the incidence of CL injuries by 6% (rate ratio [RR], 0.94 [95% CI, 0.89-0.98]) in male players and 13% (RR, 0.87 [95% CI, 0.81-0.92]) in female players and a decrease in the incidence of knee injuries by 8% (RR, 0.92 [95% CI, 0.89-0.96]) and 21% (RR, 0.79 [95% CI, 0.75-0.83]), respectively (P < .01 for all). This trend corresponded to a reduction of approximately 100 CL injuries each year in Sweden. A total of 21 of 24 district FAs held organized KCP educational courses during the study period. The percentage of district FAs holding KCP courses was between 46% and 79% each year. There were 101,236 downloads of the KCP app.Conclusion: The KCP can be considered partially implemented nationwide, and the incidence of knee and CL injuries has decreased in both sexes at a nationwide level.
|
|
