| 1. |
- Tomic, Tajana Tesan, et al.
(författare)
-
MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
-
Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
-
Tidskriftsartikel (refereegranskat)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
|
|
| 2. |
- Wahlund, Martina, et al.
(författare)
-
The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia
- 2020
-
Ingår i: The Journal of Pediatrics. - : MOSBY-ELSEVIER. - 0022-3476 .- 1097-6833. ; 216, s. 150-
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL). Study design The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing. Results TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P = .019 and P amp;lt; .0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P = .0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia. Conclusions White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.
|
|
| 3. |
- Östling, Johan, et al.
(författare)
-
Developing the History of Knowledge
- 2020
-
Ingår i: Forms of Knowledge : Developing the History of Knowledge - Developing the History of Knowledge. - 9789188909381 ; , s. 9-26
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 4. |
- Ali, Zaheer, et al.
(författare)
-
Abstract 6124 : Translation of zebrafish tumor-derived xenograft-models for improved diagnosis and treatment planning in urinary bladder cancer patients
- 2020
-
Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 80:6 Supplement, s. 6124-6124
-
Tidskriftsartikel (refereegranskat)abstract
- Precision medicine in oncology aims to identify the most effective treatment for any given patient based on individualized analyses of patient material. Currently, precision medicine relies on sequencing of DNA or RNA to identify patient tumor-specific mutational profiles that may be coupled to drug response. These techniques, however, fail to reveal actionable mutations in approximately 85% of the cancer patients, and have not been established at all for many commonly used drugs including cisplatin-based treatments used in urinary bladder cancer. While mouse-PDX models can determine drug response rates with high accuracy in most patients and for most drugs, such techniques are too slow and expensive to be relevant for first line treatment planning. Urinary bladder cancer patients are often treated with cisplatin-containing combination therapy, with the hope of down-staging tumors before surgery. 60%, however, do not respond or even progress on this treatment, and these patients would benefit from immediate surgery upon diagnosis. To help identify non-responding patients, we show here that patient-derived tumor xenograft models can be established in zebrafish larvae (ZTX models) and that the resulting tumors exhibit differential responses to the two main cisplatin-containing treatments GC and MVAC.Preliminary results from the first 19 patients are presented. Two tumor biopsies were destroyed during transport and two did not allow isolation of sufficient viable cells for implantation. From the remaining 15 samples an average of 2,6 million cells with average viability of 53% were isolated and used to implant at least 60 2-days old larvae. All 15 samples implanted in the larvae and survived and/or grew exhibiting varying degrees of metastatic dissemination (average between 2 and 13 metastasized cells per embryo and model) within only three days from implantation. Four ZTX models exhibited different responses to GC and MVAC demonstrating that these treatments are not equally effective in all patients. Non-response in ZTX models was associated with tumors having re-appeared in the bladder upon radical cystectomy in all patients undergoing surgery prior to Dec. 5th 2019 (n=3). GC inhibited metastasis in all models (average 69% inhibition), whereas MVAC inhibited metastasis in 40% of the models (average 36% inhibition).In conclusion: The ZTX urinary bladder cancer platform presented here overcome limitations associated with long assay time and high cost of other functional models within precision medicine as well as the low hit-rate of actionable mutations associated with genomic techniques. ZTX models will therefore likely become a powerful method for functional precision medicine within oncology, in the near future.
|
|
| 5. |
- Bennet, Tova, et al.
(författare)
-
Den rättspsykiatriska vården är inte rättssäker – agera nu
- 2020
-
Ingår i: Göteborgs-Posten. - Göteborg : Göteborgposten. - 1103-9345. ; :Oktober 19
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Det svenska rättssystemet som tillåter att vi dömer psykiskt sjuka för brott och att personer som saknar vårdbehov kan hållas frihetsberövade inom rättspsykiatrin under mycket lång tid med oklart vårdinnehåll, är unikt och har fått rättmätig kritik under lång tid. Ändå händer ingenting.
|
|
| 6. |
- Benrick, Anna, 1979, et al.
(författare)
-
Electroacupuncture mimics exercise-induced changes in skeletal muscle gene expression in polycystic ovary syndrome women.
- 2020
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:6, s. 2027-2041
-
Tidskriftsartikel (refereegranskat)abstract
- Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown.To identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS).Participants: In a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays.A single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q<0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q<0.20), and these changes correlated with altered expression of 101 genes (p<0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these two genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis.Our findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.
|
|
| 7. |
- Benrick, Anna, 1979-, et al.
(författare)
-
Electroacupuncture mimics exercise-induced changes in skeletal muscle gene expression in women with polycystic ovary syndrome
- 2020
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 105:6, s. 2027-2041
-
Tidskriftsartikel (refereegranskat)abstract
- ContextAutonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown.ObjectiveTo identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS).Design/ParticipantsIn a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays.ResultsA single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q < 0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q < 0.20), and these changes correlated with altered expression of 101 genes (P < 0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these 2 genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis.ConclusionOur findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.
|
|
| 8. |
- Bergström, Lena, et al.
(författare)
-
Klimatförändringar och biologisk mångfald : Slutsatser från IPCC och IPBES i ett svenskt perspektiv.
- 2020
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- De stora miljö- och samhällsproblemen kommer inte ensamma. De är sammankopplade på olika sätt. Detta innebär utmaningar men ger också möjligheter att utveckla åtgärder och lösningar. Det gäller både för klimatfrågan och frågan om att motverka förlusten av biologisk mångfald och ekosystem. Kunskapens betydelse för att hantera dessa och andra aspekter är ovärderlig, såväl kring specifika frågeställningar som kring omständigheter och förutsättningar för åtgärdsarbetet.Den här kunskapssammanställningen har gjorts av forskare från Lunds universitet och Sveriges lantbruksuniversitet på uppdrag av Naturvårdsverket och SMHI. Forskarna har tagit avstamp i de omfattande kunskapsutvärderingar som gjorts av den mellanstatliga klimatpanelen (IPCC) och den mellanstatliga plattformen för biologisk mångfald (IPBES). Slutsatserna från IPCC och IPBES sätts i ett svenskt perspektiv, bland annat genom utvalda exempel vilka fungerar som aktuella illustrationer av hur klimatförändringar påverkar biologisk mångfald och ekosystem i Sverige.
|
|
| 9. |
- Chen, Yihong, et al.
(författare)
-
Evidence for a protective role of placental growth factor in cardiovascular disease
- 2020
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:572
-
Tidskriftsartikel (refereegranskat)abstract
- Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.
|
|
| 10. |
- Forsner, Maria, et al.
(författare)
-
Mitt i informationsflödet om Covid 19 pandemin, en internationell webbenkätstudie till föräldrar och barn 7-12 år
- 2020
-
Ingår i: State of Art- Covid 2019, Nationell digital konferens, Svenska läkarsällskpet.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund: Tidigt under våren 2020 drabbades Sverige av Covid 19 pandemin. Med pandemin följe en infodemi. Barn skolåldern och deras förälder hamnade mitt i detta informationsflöde. Syfte: Att undersöka hur barn får och tolkar information om Covid 19 pandemin. Metod: Anonymiserad webbenkät. 2 enkäter til barn, respektive föräldrar. Översatt till respektive språk. Deltagare 390 barn, 7-12 är (Sv 50) och 1234 föräldrar ( Sv 235). Insamling april – 1 juni ( Sv 22 maj-1 juni). Initierat av Lucy Bray med team, Edge Hills universitet Storbritannien. Omvårdnad forskare från Sverige, Kanada , Australien, Brasilien och Spanien. Resultat: Majoriteten av barn från andra länderna fick information från föräldrarna. Svaren från de svenska barnen speglade myndighetens rekommendationer. Utomhus skildrades som en positiv plats för de svenska barnen. Teckningar från Sverige visade i stor utsträckning munskydd på både människor och djur. Slutsats: De sveks barnen var medvetna om att coronaviruset kunde vara farligt, vikten av att hålla avstånd och tvätta händerna och skydda de äldre. Svaren från Sverige skiljde sig från de andra länderna med att skolan var främsta och önskade informationskällan. Utomhusaktiviteter uppskattades som önskvärt.
|
|
