| 1. |
- Bødker, Anders, et al.
(författare)
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Estrogen receptors in the human male bladder, prostatic urethra, and prostate. An immunohistochemical and biochemical study
- 1995
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 29:2, s. 161-165
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Tidskriftsartikel (refereegranskat)abstract
- The distribution and quantity of estrogen receptors (ERs) in the human male bladder, prostatic urethra and the prostate were studied in eight males with recurrent papillomas of the bladder or monosymptomatic hematuria (median age 61 years), 14 men undergoing transurethral resection due to benign prostatic hyperplasia (median age 70 years), and nine men undergoing cystectomy due to malignant tumour of the bladder (median age 70 years). In the first group of patients, biopsies for immunohistochemical examination were obtained from the bladder vault, bottom, both side-walls, the trigone area, and the mid-portion of the prostatic urethra, and in the second group from three locations of the prostatic urethra (bladder neck, mid-portion and veramontanum). In the third group, tissue specimens were taken from the vault of the bladder, prostatic urethra, and the prostate, for immunohistochemical as well as biochemical analysis. In the first group, ERs were found in three out of eight specimens of the prostatic urethra, and in one of these, ERs were confined to periurethral glands. ERs could not be demonstrated in any of the bladder-biopsies. In the second group, ERs were not found in the bladder neck, but were seen in four preparations from the veramontanum and in two from the midportion of the urethra. ERs were located in the urothelium and periurethral glands. In the third group, ERs were seen immunohistochemically in the prostatic urethra (two cases) and the prostatic stromal tissue (two cases). ERs could be demonstrated in the bladder neither by immunohistochemistry nor biochemically.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2. |
- Aguila, Julio, et al.
(författare)
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Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's Disease
- 2021
-
Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson's Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.
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| 3. |
- Andersson, Eva, 1958-, et al.
(författare)
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Fysisk aktivitet vid depression
- 2021. - 4
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Ingår i: FYSS 2021. - : Läkartidningens förlag. - 9789198509823 ; , s. 319-324
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Andreassen, Eva, et al.
(författare)
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Kokbok för förändringsledare : Metdoder för att stötta engagerade människor att förverkliga idéer
- 2020
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Det här är en kokbok för förändringsledare. Du kan använda denna bok om du ska leda utvecklingsaktiviteter och letar efter bra och beprövade metoder för att leda grupper och processer. Vi beskriver metoderna som vi har använt inom vårt projekt SMICE, i vilket sammanhang metoderna använts och när de olika metoderna fungerat bra. Vår förhoppning med att nedteckna dessa metoder är att du ska inspireras och vågar prova något nytt för att skapa nytta. Vi tror att ett detaljerat sätt att dokumentera metoderna gör dem mer användbara för dig men också för oss själva. Metoderna är graderade efter vilket behov av förkunskap och förberedelser du behöver, från det enklaste, där du kan öppna kokboken och använda metoden på en gång, till metoder som kräver utbildning eller specialistkompetens innan du sätter igång. Boken är indelad i fyra huvuddelar; Starta, Forma, Utveckla och förankra och Bygga vidare. Till dessa delar har vi identifierat metodstöd som kan användas vid en rad olika tillfällen; vid idégenerering, vid idéutveckling, vid affärsutveckling, för att inspirera, för att skapa samsyn och samverkan och för att mobilisera större grupper av människor och organisationer. Något för alla, alltså. Avslutningsvis finner du tips och stöd för att driva dessa utvecklingsprocesser på distans med digitala verktyg i digitala möten. Ska vi sammanfatta någon lärdom av detta arbete så blir det våra nycklar som presenteras på nästa sida. Du kan se dessa nycklar som våra bästa råd för att du ska lyckas med ditt arbete med att leda processer och att ordna möten. Lycka till! Metoderna har testats och utvecklats inom SMICE - Samskapande Mittnordisk Innovationsarena för Cirkulär Ekonomi, ett projekt inom Interreg som pågått 2017-2020.
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| 5. |
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| 6. |
- Asplund, Sofia, et al.
(författare)
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Self-rated exhaustion disorder and associated health-related factors among municipal employees in rural areas of northern Sweden
- 2021
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer. - 0340-0131 .- 1432-1246. ; , s. 659-668
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aims of this study among municipal employees in rural areas of northern Sweden were to assess the prevalence of self-rated exhaustion disorder (s-ED), describe plausible between-group differences in self-reported health-related factors among employees with or without s-ED, and identify health-related factors associated with s-ED.METHODS: In a cross-sectional study, data were collected from 1093 municipal employees (76.1% women) in two rural areas using an instrument measuring s-ED and health variables drawn from the Modern Worklife Questionnaire (MWQ), the Perceived Stress Scale (PSS), and the National Board of Health and Welfare's questions about physical activity. Comparisons were made between an s-ED and a non-s-ED group. Health-related factors associated with s-ED were identified through a logistic regression.RESULTS: Self-rated exhaustion disorder was reported by 21.5% of the participants. Health-related factors associated with s-ED were cognitive problems, sleep problems, depressive symptoms, high stress, poor self-rated health, and stomach problems. There was no statistically significant difference in the prevalence of participants who met the criteria of physical activity among s-ED and non-s-ED group.CONCLUSION: Findings from this study suggest that s-ED is more common among municipal employees in rural areas than in other working populations in Sweden. Several health-related factors were associated with s-ED. Regular use of a self-rated instrument in evaluating the organizational and social work environment can identify people at risk of developing exhaustion disorder and requiring long-term sick leave.
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| 7. |
- Barde, Swapnali, et al.
(författare)
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Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons
- 2024
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 78, s. 54-63
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.
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| 8. |
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| 9. |
- Cao, Renhai, et al.
(författare)
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Mouse corneal lymphangiogenesis model.
- 2011
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Ingår i: Nature protocols. - : Springer Science and Business Media LLC. - 1750-2799 .- 1754-2189. ; 6:6, s. 817-26
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Tidskriftsartikel (refereegranskat)abstract
- This protocol describes a powerful in vivo method to quantitatively study the formation of new lymphatic vessels in the avascular cornea without interference of pre-existing lymphatics. Implantation of 100 ng of lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, VEGF-C or fibroblast growth factor-2, together with slow-release polymers, into a surgically created micropocket in the mouse cornea elicits a robust lymphangiogenic response. Newly formed lymphatic vessels are detected by immunohistochemical staining of the flattened corneal tissue with lymphatic endothelial-specific markers such as lymphatic vessel endothelial hyaluronan receptor-1; less-specific markers such as vascular endothelial growth factor receptor 3 may also be used. Lymphatic vessel growth in relation to hemangiogenesis can be readily detected starting at day 5 or 6 after pellet implantation and persists for ∼14 d. This protocol offers a unique opportunity to study the mechanisms underlying lymphatic vessel formation, remodeling and function.
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| 10. |
- Cheng, Arthur J., et al.
(författare)
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Intact single muscle fibres from SOD1(G93A) amyotrophic lateral sclerosis mice display preserved specific force, fatigue resistance and training-like adaptations
- 2019
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Ingår i: Journal of Physiology. - : Cambridge University Press. - 0022-3751 .- 1469-7793. ; 597:12, s. 3133-3146
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Tidskriftsartikel (refereegranskat)abstract
- Key points:How defects in muscle contractile function contribute to weakness in amyotrophic lateral sclerosis (ALS) were systematically investigated.Weakness in whole muscles from late stage SOD1G93A mice was explained by muscle atrophy as seen by reduced mass and maximal force.On the other hand, surviving single muscle fibres in late stage SOD1G93A have preserved intracellular Ca2+ handling, normal force-generating capacity and increased fatigue resistance.These intriguing findings provide a substrate for therapeutic interventions to potentiate muscular capacity and delay the progression of the ALS phenotype.Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of motor neurons, leading to severe muscle weakness and paralysis. The SOD1G93A mouse model of ALS displays motor neuron degeneration and a phenotype consistent with human ALS. The purpose of this study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles. In the current study, motor neuron loss and decreased force were evident in whole flexor digitorum brevis (FDB) muscles of mice in the late stage of disease (125–150 days of age). However, in intact single muscle fibres, specific force, tetanic myoplasmic free [Ca2+] ([Ca2+]i), and resting [Ca2+]i remained unchanged with disease. Fibre-type distribution was maintained in late-stage SOD1G93A FDB muscles, but remaining muscle fibres displayed greater fatigue resistance compared to control and showed increased expression of myoglobin and mitochondrial respiratory chain proteins that are important determinants of fatigue resistance. Expression of genes central to both mitochondrial biogenesis and muscle atrophy where increased, suggesting that atrophic and compensatory adaptive signalling occurs simultaneously within the muscle tissue. These results support the hypothesis that muscle weakness in SOD1G93A is primarily attributed to neuromuscular degeneration and not intrinsic muscle fibre defects. In fact, surviving muscle fibres displayed maintained adaptive capacity with an exercise training-like phenotype, which suggests that compensatory mechanisms are activated that can function to delay disease progression.
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| 11. |
- Correia, Jorge C., et al.
(författare)
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Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
- 2021
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:11, s. 2215-2230
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Tidskriftsartikel (refereegranskat)abstract
- Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1a1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.
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| 12. |
- Dimova, Tanya, et al.
(författare)
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Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua : a phenotypic study of paired decidual and peripheral blood samples.
- 2011
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Ingår i: American Journal of Reproductive Immunology and Microbiology. - : John Wiley & Sons. - 8755-8920 .- 1046-7408. ; 66:Suppl 1, s. 44-56
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Tidskriftsartikel (refereegranskat)abstract
- PROBLEM: Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women.METHOD OF STUDY: Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR.RESULTS: The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFβ1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells.CONCLUSION: (i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.
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| 13. |
- Eleonora Hedlund, Eva-Maria, et al.
(författare)
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Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:2, s. 654-659
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Tidskriftsartikel (refereegranskat)abstract
- The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.
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| 14. |
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| 15. |
- Fredriksson Adman, Anna, 1967-
(författare)
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Heymericus de Campo: Dyalogus super Reuelacionibus beate Birgitte : A Critical Edition with an Introduction
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation contains an edition of Dyalogus super Reuelacionibus beate Birgitte, which is a discussion and defence of the Revelations (Reuelaciones) of St. Birgitta of Sweden (ca. 1303-1373). In legal proceedings at the Council of Basle (1431-1449), the Reuelaciones were accused of heresy, examined and defended. Among the defenders was Heymericus de Campo (1395-1460), who at that time was professor of theology at the University of Cologne. In addition to the formal examination reports, Heymericus wrote a dialogue on the subject. The Dyalogus, which was probably composed as a contribution to a debate, is tentatively dated to have been written between October 1434 and February 17, 1435. The main part of Dyalogus consists of 123 text passages extracted from the Reuelaciones and accused of heresy, and Heymericus’ defence of these text passages. The aim of the defence is to prove that the Reuelaciones are truly orthodox and thus inspired by God. In addition, Heymericus intends to display the reasons and arguments the impugners had for questioning the Reuelaciones. Dyalogus and the other defences were read and copied foremost within the Birgittine order. The judgement passed at the proceedings called for a commentary before the Reuelaciones could be disseminated to the whole of their extent. To the Birgittines the defences of Basle filled this purpose, at least for some time.The extensive introduction of the thesis deals with the historical context of the text, its use and importance, its place within the author’s literary production, the contents and language of the text, and finally the textual transmission. Vadstena Abbey’s copy of the text is chosen as base manuscript for the edition.
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| 16. |
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| 17. |
- Hansson, Lena, 1967-, et al.
(författare)
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Vitamin D, liver-related biomarkers, and distribution of fat and lean mass in young patients with Fontan circulation
- 2022
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Ingår i: Cardiology in the Young. - : Cambridge University Press. - 1047-9511 .- 1467-1107. ; 32:6, s. 861-868
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Tidskriftsartikel (refereegranskat)abstract
- Introduction/aim: Young patients with Fontan circulation may have low serum 25-hydroxyvitamin D levels, an affected liver, and unhealthy body compositions. This study aimed to explore the association between vitamin D intake/levels, liver biomarkers, and body composition in young Fontan patients.Method: We collected prospective data in 2017 to 2018, obtained with food-frequency questionnaires, biochemical analyses of liver biomarkers, and dual-energy X-ray absorptiometry scans in 44 children with Fontan circulation. Body compositions were compared to matched controls (n = 38). Linear regression analyses were used to investigate associations of biomarkers, leg pain, and lean mass on serum levels of 25-hydroxyvitamin D. Biomarkers were converted to z scores and differences were evaluated within the Fontan patients.Results: Our Fontan patients had a daily mean vitamin D intake of 9.9 µg and a mean serum 25-hydroxyvitamin D of 56 nmol/L. These factors were not associated with fat or lean mass, leg pain, or biomarkers of liver status. The Fontan patients had significantly less lean mass, but higher fat mass than controls. Male adolescents with Fontan circulation had a greater mean abdominal fat mass than male controls and higher cholesterol levels than females with Fontan circulation.Conclusion: Vitamin D intake and serum levels were not associated with body composition or liver biomarkers in the Fontan group, but the Fontan group had lower lean mass and higher fat mass than controls. The more pronounced abdominal fat mass in male adolescents with Fontan circulation might increase metabolic risks later in life.
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| 18. |
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| 19. |
- Hedlund, Eva
(författare)
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Cytochrome P450 in the rat brain : characterization and regulation
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytochrome P450s (CYPs) are key enzymes in the metabolism of cholesterol and fatty acids and their derivatives in the body. In the adrenals and gonads these enzymes are involved in steroid hormone biosynthesis, in the liver in bile acid synthesis, in the kidney in synthesis of the calcitropic hormone, calcitriol, and in the cardiovascular system in synthesis of thromboxane A2, a potent inducer of vasoconstriction and platelet aggregation. In addition, in the liver, lungs, intestines and kidneys, members of this superfamily of enzymes are involved in metabolism of dietary components, therapeutic drugs, environmental pollutants and solvents, a group of chemicals collectively referred to as xenobiotics. The level of CYPs in the brain is low, but the pattern of isozymes expressed is unique. This suggests specific functions for brain CYPs, but very few such functions have been defined. The aims of this thesis were to characterize the isozymes in the brain, to identify cells which harbor these enzymes and to determine how these enzymes are regulated in the brain, in particular why many inducers of liver CYPs do not induce brain CYPs. We found that the hepatic CYP isozymes, CYP2B1/2 and CYP3A1/2 proteins, could not be detected in the brain, and concluded that published evidence from immunohistochemical studies indicating the abundant expression of these enzymes in the brain were methodological artifacts. With protein microsequencing we identified several CYP isozymes in the brain, including. CYP2C22, CYP2C24, CYP3A13, CYP4F1, CYP4F4 and CYP4F6. CYP2C22 was particularly interesting since it was highly expressed in the newborn and was sexually differentiated in the adult brain. Since one of its substrates was dihydroprogesterone the inference was made that this enzyme may be involved in regulating the level of anesthetic steroids (5[alpha]-reduced metabolites of progesterone) in the brain. CNS-active drugs, such as clozapine, mianserin and sulpiride, as well as the solvent toluene increased the overall level of CYPs in the brain. Specific isozymes were induced but there were no measurable changes in the level of mRNA in any of the induced CYPs. From this we concluded that posttranscriptional mechanisms are important in regulating brain CYP levels. In order to understand why the transcriptional mechanisms which are so prominent in regulating liver CYPs do not apply to the brain, we investigated the pregnane X receptor (PXR) in brain. This receptor, which is involved in the induction of xenobiotic-metabolizing forms of CYP in liver, was expressed in the brain, but the predominant splice variant in brain was PXR.2. This receptor variant has a shortened ligand binding domain and is activated by fewer ligands than the liver predominant form, PXR.1. The presence of PXR.2 in brain may be one likely explanation for the observation that many drugs which induce CYPs in the liver are not inducers in the brain. Finally, with immunohistochemical methods we found that although the overall level of CYP in the brain is low, certain specific isozymes are highly expressed in selected neurons. These enzymes may therefore play important roles in neuronal function.
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| 20. |
- Hedlund, Eva-Maria, et al.
(författare)
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Harnessing Induced Essentiality : Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts
- 2019
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Triple Negative Breast Cancer (TNBC) is aggressive, metastatic and drug-resistant, limiting the spectrum of effective therapeutic options for breast cancer patients. To date, anti-angiogenic agents have had limited success in the treatment of systemic breast cancer, possibly due to the exacerbation of tumor hypoxia and increased metastasis. Hypoxia drives increased expression of downstream effectors, including Carbonic Anhydrase IX (CAIX), a critical functional component of the pro-survival machinery required by hypoxic tumor cells. Here, we used the highly metastatic, CAIX-positive MDA-MB-231 LM2-4 orthotopic model of TNBC to investigate whether combinatorial targeting of CAIX and angiogenesis impacts tumor growth and metastasis in vivo to improve efficacy. The administration of a small molecule inhibitor of CAIX, SLC-0111, significantly reduced overall metastatic burden, whereas exposure to sunitinib increased hypoxia and CAIX expression in primary tumors, and failed to inhibit metastasis. The administration of SLC-0111 significantly decreased primary tumor vascular density and permeability, and reduced metastasis to the lung and liver. Furthermore, combining sunitinib and SLC-0111 significantly reduced both primary tumor growth and sunitinib-induced metastasis to the lung. Our findings suggest that targeting angiogenesis and hypoxia effectors in combination holds promise as a novel rational strategy for the effective treatment of patients with TNBC.
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| 21. |
- Hedlund, Eva-Maria
(författare)
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The impact of vascular structure and function on tumor growth, retinopathy, and antiangiogenic therapy
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumors produce multiple angiogenic factors to stimulate neovascularization that is essential for tumor growth, invasion and metastasis. Despite the known angiogenic functions of each individual factor, the interplay between these angiogenic factors in the tumor local environment and in modulation of the host functions remain poorly understood. This thesis addresses these important and complex issues using various in vitro and in vivo experimental models. The findings from these studies provide mechanistic insights on the of complex interplay between various angiogenic factors and on the systemic impact of these tumor-derived factors on the host. In paper I, we showed one of the first examples of two unrelated angiogenic factors, i.e., FGF-2 and PDGF-BB that reciprocally modulate tumor angiogenesis and metastasis. We found that FGF-2 markedly upregulates the expression levels of PDGFRα and β in endothelial cells, leading to the hypersensitive response of these cells toward PDGF-BB stimulation. Reciprocally, PDGF-BB is also able to upregulate the expression level of FGFR-1 in perivascular cells. The angiogenic synergism and vascular remodeling by these two factors markedly accelerates tumor growth rates, leading to an invasive phenotype in a mouse xenograft tumor model. In paper II, we describe a negative interplay between two angiogenic factors that significantly modulate the number and structure of tumor blood vessels. PlGF could negatively modulate VEGF functions by the formation of heterodimers during their synthesis in the same cell. We show that the PlGF-VEGF heterodimers are less potent than VEGF homodimers and thus significantly reduce the angiogenic activity of VEGF. Surprisingly, we found that modulation of the VEGF-induced angiogenic activity by PlGF markedly normalize tumor vessels. PlGF-induced vascular normalization may imply increased therapeutic efficacy of antiangiogenic drugs. In paper III, we showed that tumor-derived VEGF and PlGF can enter into the circulation and systemically impair vascular functions of other tissue and organs. In this paper, we proposed a new mechanism of cancer-associated retinopathy caused by tumor-derived angiogenic factors. Unlike vasculatures distributed in other tissues, the retinal vasculature predominantly expresses VEGFR1, but lacks a detectable level of VEGFR2. Tumor-derived VEGF and PlGF significantly ablate vascular pericytes, leading to increased leakiness of the retinal vasculature. These findings suggest that targeting tumor-derived VEGF, PlGF or other related angiogenic factors might provide a new therapeutic strategy for the treatment of cancer-associated retinopathy, which otherwise remains untreatable. In paper IV, we discovered a new mechanism underlying the combination therapy between antiangiogenic drugs and chemotherapeutics. Based on preclinical findings, we propose that decreased chemotoxicity by antiangiogenic drugs might significantly contribute to survival advantages of patient receiving a combination of these two classes of drugs. We have also rationalized the optimal delivery of these two drugs by using a sequential procedure rather than a simultaneous schedule as currently recommended in clinical settings. Taken together, this thesis work reveals several novel mechanisms of tumor angiogenesis and provides novel information of antiangiogenic therapy, which can be further optimized based on the work reported in this thesis. This thesis work represents translational and that mechanistic studies which can lead to clinically meaningful implications and our eventual goal is to improve survival and the quality of life for millions of cancer patients.
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| 22. |
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| 23. |
- Hedlund, Johanna, et al.
(författare)
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New records of the Paleotropical migrant Hemianax ephippiger in the Caribbean and a review of its status in the Neotropics
- 2020
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Ingår i: International Journal of Odonatology. - : Worldwide Dragonfly Association. - 1388-7890 .- 2159-6719. ; 23:4, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- Tropical America is currently experiencing the establishment of a new apex insect predator, the Paleotropical dragonfly Hemianax ephippiger (Odonata: Aeshnidae). H. ephippiger is migratory and is suggested to have colonised the eastern Neotropics by chance Trans-Atlantic displacement. We report the discovery of H. ephippiger at three new locations in the Caribbean, the islands of Bonaire, Isla de Coche (Venezuela), and Martinique, and we review its reported distribution across the Neotropics. We discuss the establishment of H. ephippiger as a new apex insect predator in the Americas, both in terms of ecological implications and the possible provision of ecosystem services. We also provide an additional new species record for Bonaire, Pantala hymenaea (Odonata: Libellulidae).
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| 24. |
- Hedlund, Ulf, et al.
(författare)
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Occupational exposure to dust, gases and fumes, a family history of asthma and impaired respiratory health
- 2008
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Ingår i: Scandinavian Journal of Work Environment & Health. - Helsinki : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 34:5, s. 381-386
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives This study assessed the impact of occupational exposure to dust, gases, and fumes on respiratory symptoms, obstructive lung diseases, or the use of asthma medication among persons with and without a family history of asthma. Methods A population-based cohort was followed for 10 years. This study included all 1739 men and 1594 women occupationally active at the first survey. Exposure and respiratory health were assessed from questionnaires. Multiple logistic regression was used to estimate the effects in relation to occupational groups, with age, gender, and smoking habits as possible confounders, using both cross-sectional and longitudinal analyses. The susceptibility to impaired respiratory health was determined from a family history of asthma. Results A family history of asthma was reported by 27% of the men and 34% of the women. Both occupational exposure and a family history of asthma were associated with impaired respiratory health. The etiologic fractions showed that up to about 70% of the symptoms could be explained by a family history of asthma among those exposed to low levels of air pollutants, as well as among those with high exposure. However, high exposure contributed up to 35% of the symptoms both among those with and among those without a family history of asthma. The study indicates that the relative risk of occupational exposure to pollutants is similar for both persons with and those without a family history of asthma. Conclusions The relative risk for impaired respiratory health after exposure to occupational air pollutants seems to be similar for persons with and those without a susceptibility to impaired respiratory health.
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| 25. |
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| 26. |
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| 27. |
- Hedlund, Åsa, et al.
(författare)
-
Are return to work beliefs, psychological well-being and perceived health related to return-to-work intentions among women on long-term sick leave for common mental disorders? A cross-sectional study based on the Theory of Planned Behaviour
- 2021
-
Ingår i: BMC Public Health. - : Springer. - 1471-2458. ; 21:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term sick leave due to common mental disorders (CMDs) is a great burden in several countries. Women are more likely to be affected by CMDs. A strong intention to return to work (RTW) as well as symptom relief may facilitate RTW in this group. However, there is a lack of knowledge regarding what constitutes a strong intention. The Theory of Planned Behaviour is well-suited to identifying underlying beliefs about intentions to perform a behaviour. By including psychological well-being and perceived health, a more comprehensive picture of determinants of RTW intention might be achieved. Thus, the aim of the present study was to identify associations between RTW beliefs, psychological well-being, perceived health and RTW intentions among women on long-term sick leave due to CMDs, and to do so based on the Theory of Planned Behaviour.Methods: The study was cross-sectional. Between October 2019 and January 2020, 282 women on long-term sick leave (>2 months) due to CMDs were included in the study. The questionnaires for data collection were: “RTW Beliefs Among Women-Questionnaire”, the “General Health Questionnaire -12” and the “EuroQol Visual Analogue Scale”. Standard multiple regression analysis was performed both with and without adjustment for potential confounders.Results: The results showed that more positive attitude towards RTW, stronger social pressure to RTW, higher perceived control over RTW and higher psychological well-being were associated with stronger RTW intention. The adjusted analysis eliminated the importance of psychological well-being for RTW intention, but showed that women who reported that their employer had taken actions to facilitate their RTW had stronger RTW intention. Conclusion: The RTW beliefs, derived from the Theory of Planned Behaviour, were all important for a strong RTW intention, while psychological well-being and perceived health showed weaker associations. Furthermore, having an employer that take actions for facilitating RTW was associated with stronger RTW intentions. Though some caution is warranted regarding the representativeness of the sample, the results do improve our understanding of some important determinants of RTW intention among women on long-term sick leave for CMDs.
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| 28. |
- Hedlund, Åsa, et al.
(författare)
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Beliefs about return to work among women during/after long-term sick leave for common mental disorders: a qualitative study based on the theory of planned behaviour
- 2021
-
Ingår i: Journal of occupational rehabilitation. - : Springer. - 1053-0487 .- 1573-3688. ; 31, s. 604-612
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Long-term sick leave due to common mental disorders (CMDs) is an increasing problem, especially among women. To help these women return to work (RTW) sustainably, we need to know more about their own beliefs about RTW. One applicable theory is the theory of planned behaviour (TPB). Thus, the present study aimed to describe, based on the TPB, women's beliefs about RTW during or after long-term sick leave for a CMD.Methods: A qualitative approach was used. Twenty women were included during a long-term sick leave period due to a CMD. A deductive content analysis was conducted using predetermined factors from the TPB: behavioural beliefs (advantages – disadvantages of RTW), normative beliefs (supporters and non-supporters of RTW), and control beliefs (facilitators of – barriers to RTW).Results: The women believed that RTW would give them meaning and balance in life, but also that it would be challenging to maintain balance after RTW. They believed they had several supporters of RTW, but that the support was sometimes perceived as stressful rather than encouraging. Furthermore, individual adaptation and high demands were the most mentioned facilitator and barrier, respectively. Workplace conditions and personal strategies were thought to be important aspects.Conclusions: By using the TPB, the present study was able to offer new findings on women’s beliefs about RTW after long-term sick leave for a CMD. Based on the findings, we suggest that various RTW stakeholders should focus on striving to provide the tasks and work pace women need so they can maintain their professional competence and sense of meaning.
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| 29. |
- Hedlund, Åsa, et al.
(författare)
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Development and psychometric evaluation of a theory-based questionnaire measuring women’s return-to-work beliefs after long-term sick leave for common mental disorders
- 2023
-
Ingår i: Work. - : IOS Press. - 1051-9815 .- 1875-9270. ; 76:1, s. 109-124
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Tidskriftsartikel (refereegranskat)abstract
- Background: Common mental disorders (CMDs) are currently a major cause of long-term sick leave, with women being the most affected.Objective: Using the Theory of Planned Behaviour (TPB), we aimed to describe the development and psychometric evaluation of a new questionnaire to measure women's beliefs about return to work (RTW) after long-term sick leave for CMDs.Methods: Data were collected in central Sweden from women on long-term sick leave(2–24 months) for CMDs. The questionnaire was developed by conducting an elicitation study with 20 women and included direct and indirect measures. Subsequently, 282 women participated in a psychometric evaluation and 35 of them in a test-retest procedure. Psychometric properties were evaluated by determining reliability (internal consistency [Cronbach’s alpha] and test-retest stability [intraclasscorrelation coefficient]), construct validity (exploratory factor analysis) and content validity. Results: The development resulted in 60 questionnaire items. Content validity assessment showed that the women overall found it easy to complete the questionnaire. Reliability analyses showed satisfactory results for direct and indirect measures, with a few exceptions. Factor analyses of the indirect scales showed that items were generally in line with the TPB, but that items related to life as a whole/personal life and items related to work separated into two different factors. Conclusions: The questionnaire, called the RTW Beliefs Questionnaire, showed promising results and can among women with CMDs considered useful, especially scales for direct measures. This questionnaire gives the opportunity to identify new potential predictors for RTW.
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| 30. |
- Hedlund, Åsa, et al.
(författare)
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Predictors of return to work and psychological well-being among women during/after long-term sick leave due to common mental disorders - a prospective cohort study based on the theory of planned behaviour
- 2022
-
Ingår i: Health & Social Care in the Community. - : Wiley. - 0966-0410 .- 1365-2524. ; 30:6, s. 5245-5258
-
Tidskriftsartikel (refereegranskat)abstract
- Common mental disorders are associated with long-term sick leave, especially among women. There is a lack of theory-based research regarding the impact of personal factors on return to work and psychological well-being. Therefore, the aim of this study was to examine whether return-to-work beliefs and perceived health were predictors of return to work and psychological well-being among women during or after long-term sick leave for common mental disorders, based on the Theory of Planned Behaviour. This was a prospective cohort study with a 1-year follow-up. At baseline, women (n = 282) had been on full- or part-time sick leave for common mental disorders for 2–24 months. Data were collected in October 2019–January 2020 and October 2020–January 2021 in Sweden. The Social Insurance Agency identified the women at baseline. The Return-To-Work Beliefs Questionnaire, EuroQol Visual Analogue Scale and General Health Questionnaire-12 were used. Multiple logistic and linear regression analyses were conducted. The women were divided into two groups: full-time sick leave or part-time sick leave at baseline. The results showed that stronger return-to-work intention significantly predicted return to work among women on full-time sick leave at baseline. No significant predictors of return to work were found among women on part-time sick leave at baseline. Psychological well-being was predicted by stronger social pressure to return to work (full-time group) and a more positive attitude toward returning to work and better perceived health (part-time group). We concluded that the Theory of Planned Behaviour can be useful for understanding return to work among women on full-time sick leave, and what underlies psychological well-being in both groups. However, return to work and psychological well-being were predicted by different factors, indicating that a multifactorial approach should be used in supporting women to return to work after long-term sick leave for common mental disorders.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Jaitly, Rahul, et al.
(författare)
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The evolution of predator avoidance in cephalopods : A case of brain over brawn?
- 2022
-
Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 9
-
Forskningsöversikt (refereegranskat)abstract
- Predation is a major evolutionary driver of animal adaptation. However, understanding of anti-predator evolution is biased toward vertebrate taxa. Cephalopoda, a class in the invertebrate phylum Mollusca, are known for their diverse anti-predator strategies, characterised by their behavioural flexibility. While ancestral cephalopods were protected by a hard outer shell, extant cephalopods have greatly reduced their reliance on physical defences. Instead, cephalopods have evolved highly developed senses to identify potential threats, cryptic skin patterns to avoid detection, startle responses to deter attack, and elaborate means of escape. While cephalopod anti-predator repertoires are relatively well described, their evolution, and the selective pressures that shaped them, have received much less attention. This is despite their potential relevance, in turn, to elucidate evolution of the remarkable cognitive abilities of cephalopods. Here, we review cephalopod anti-predator evolution, considering four key aspects: (i) shell reduction and loss; (ii) the skin patterning system; (iii) the ecological context accompanying the evolution of advanced cognit.ive abilities; (iv) why the evolutionary trajectory taken by cephalopods is so unique among invertebrates. In doing so, we consider the unique physiology of cephalopods and discuss how this may have constrained or aided the development of their anti-predator repertoire. In particular, cephalopods are poorly equipped to defend themselves physically and escape predation by fish, due to a lack of comparable weaponry or musculature. We argue that this may have selected for alternative forms of defence, driving an evolutionary trajectory favouring crypsis and complex behaviours, and the promotion of sensory and cognitive adaptations. Unravelling the complexities of cephalopod anti-predator evolution remains challenging. However, recent technological developments available for cephalopod field and laboratory studies, coupled with new genomic data and analysis approaches, offer great scope to generate novel insights.
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| 35. |
- Jensen, Lasse Dahl, et al.
(författare)
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Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish
- 2009
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:43, s. 18408-18413
-
Tidskriftsartikel (refereegranskat)abstract
- The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system.
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| 36. |
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| 37. |
- Lingdell, Pär-Erik, et al.
(författare)
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Bottenfauna i sex småvatten i Västernorrlands län
- 2007
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Den här rapporten har upprättats på uppdrag av länsstyrelsen i Västernorrlands län. Rapporten beskriversammansättningen av vattenlevande smådjur, den sk bottenfaunan, i sex kustnära småvatten utifrån provinsamlade under såväl juni som juli år 2006. Syftet med projektet var bl.a. att ta reda på hur faunan i småvattenförhåller sig till dito i andra typer av stillastående vatten och hur bottenfaunan i var och en av de sex småvattnenförhåller sig till den i de övriga fem. Dessa förhållanden har analyserats utifrån ett antal index avsedda attbeskriva försurnings-, förorenings- och naturvärdesstatus samt diversitet och likhet med faunan i andra vatten.Vid analyserna har jämförelsematerial från skilda utsnitt ur Limnodatas databas använts. Det måste poängterasatt lämpliga jämförelsematerial provtagna med metod M42 från snarlika vattensamlingar saknas varför deindikationer som framkom vid analyserna inte behöver vara sanna i ett större sammanhang.De måste också poängteras att av de totalt ca 55 000 individer som påträffades i de sex vattensamlingarna har isnitt endast 13% bestämts till art. I sjöar och vattendrag bestäms i snitt 43% och i vattenkällor 28% till art. Attandelen artbestämda djur i de sex vattensamlingarna blev så låg beror på att de dominerades av djurformer somnormalt inte artbestäms. Sammanlagt noterades 123 skilda taxa varav endast 54 bestämdes till art. Antaletartbestämda individer skulle utökas om t.ex. hinnkräftor, hoppkräftor, fjädermyggslarver och ärtmusslorskickades till taxonomisk expertis.
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| 38. |
- Lång, Lars-Ove, et al.
(författare)
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Digital insamling av vattentäktsdata till databas DGV– exempel på metodik för miljömålsuppföljning
- 2007
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- SGU har under några år arbetat med att bygga upp ett system för överföring av vattentäktsdatafrån landets kommuner till en nationell databas för grundvattenförekomster och vattentäkter(DGV). Arbetet har främst varit inriktat mot landets allmänna vattentäkter, men även övrigavattentäkter som försörjer > 50 personer eller har ett uttag > 10m3/dygn ingår. Ett av huvudskälentill uppbyggnaden av databasen är behovet inom miljömålsarbetet av data avseende vattenförsörjningen.Användningen ligger framförallt inom miljömålet ”Grundvatten av god kvalitet”,men uppgifter i DGV har även tillämpning inom andra miljömål. Detta projekt är en del iarbetet med att utveckla DGV samt beskriva användbarheten utifrån miljömålssynpunkt.Arbetet med insamling av vattentäktsuppgifter direkt från kommunerna inleddes i slutet av2002. Under 2006 har för första gången en förfrågan om uppdatering av inlagrade uppgifterskett. I januari 2007 var 215 kommuner färdiga med inregistreringen av allmänna vattentäkter.Inlämningen av uppgifter från kommunerna är frivillig. Därför har inför efterfrågan av dataavstämning skett mot ett antal utvalda kontaktkommuner så att uppgiftslämnandet innebär enrimlig arbetsinsats. Det har också eftersträvats från SGUs sida att ha en effektiv teknisk supportoch kommunens egna data är alltid tillgängliga via webben. För att underlätta för kommunernainsamlas vattenanalysresultat direkt från anlitade laboratorier efter att avtal undertecknats avkommunerna eller vattentäktsinnehavare.I denna rapport ingår en sammanfattning av hur insamlingen av vattentäktsdata till DGV gårtill samt kortfattade beskrivningar av uppbyggnaden av databas och webbapplikation. För meruppgifter om den tekniska utformningen kan kontakt tas med SGU.En sammanfattning ingår också i rapporten avseende användningen av DGV-data imiljömålsarbetet på nationell, regional och lokal nivå. Uppgifter från DGV används vid framtagandeav indikatorer samt vid uppföljningen av dessa. DGV-data är ett av de viktigasteunderlagen i det nu pågående arbetet med den andra Fördjupade utvärderingen av miljömålet”Grundvatten av god kvalitet”.Arbetet med DGV är omfattande vad gäller kontakter och systemuppbyggnad. Ett stort antalpersoner har medverkat vid inmatningen av uppgifter hos kommunerna. Deras intresse ochengagemang har inneburit att de flesta av landets allmänna vattentäkter nu har registrerats iDGV. Arbetet med DGV innebär ett stort erfarenhetsutbyte mellan SGU, kommunerna ochandra berörda myndigheter. Förhoppningen är att verksamheten inom DGV ökar förståelsen församverkan mellan kommunerna och statliga myndigheter inom miljömålsarbetet. Denerfarenhet av webbaserad insamling av data som DGV-arbetet innebär bör kunna användas isamband med annat miljömålsarbete.
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| 39. |
- Månberg, Anna, 1985-, et al.
(författare)
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Altered perivascular fibroblast activity precedes ALS disease onset
- 2021
-
Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 27:4, s. 640-646
-
Tidskriftsartikel (refereegranskat)abstract
- Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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| 40. |
- Nissen, Lars Johan, et al.
(författare)
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Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis.
- 2007
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Ingår i: The Journal of clinical investigation. - 0021-9738. ; 117:10, s. 2766-77
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Tidskriftsartikel (refereegranskat)abstract
- Tumors produce multiple growth factors, but little is known about the interplay between various angiogenic factors in promoting tumor angiogenesis, growth, and metastasis. Here we show that 2 angiogenic factors frequently upregulated in tumors, PDGF-BB and FGF2, synergistically promote tumor angiogenesis and pulmonary metastasis. Simultaneous overexpression of PDGF-BB and FGF2 in murine fibrosarcomas led to the formation of high-density primitive vascular plexuses, which were poorly coated with pericytes and VSMCs. Surprisingly, overexpression of PDGF-BB alone in tumor cells resulted in dissociation of VSMCs from tumor vessels and decreased recruitment of pericytes. In the absence of FGF2, capillary ECs lacked response to PDGF-BB. However, FGF2 triggers PDGFR-alpha and -beta expression at the transcriptional level in ECs, which acquire hyperresponsiveness to PDGF-BB. Similarly, PDGF-BB-treated VSMCs become responsive to FGF2 stimulation via upregulation of FGF receptor 1 (FGFR1) promoter activity. These findings demonstrate that PDGF-BB and FGF2 reciprocally increase their EC and mural cell responses, leading to disorganized neovascularization and metastasis. Our data suggest that intervention of this non-VEGF reciprocal interaction loop for the tumor vasculature could be an important therapeutic target for the treatment of cancer and metastasis.
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| 41. |
- Nyström, Eva, 1966-
(författare)
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Containing Multitudes : Codex Upsaliensis Graecus 8 in Perspective
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study employs as its primary source a codex from Uppsala University Library, Codex Upsaliensis Graecus 8. Its aim is to contribute to a better understanding of the Late Byzantine and post-Byzantine miscellaneous book. It is argued that multitext books reflect the time and society in which they were created. A thorough investigation of such books sheds light on the interests and concerns of the scribes, owners, and readers of the books. Containing some ninety texts of different character and from different genres, Codex Upsaliensis Graecus 8 is a complex creation, but still an example of a type of book that was common during the Middle Ages and the Renaissance. This study takes a comprehensive view of the book in its entirety, making sense of its different parts in relation to the whole with the help of codicology and textual analysis. With that approach the original idea of the book is brought to the fore, and the texts are studied in the same context that the main scribe Theodoros chose and the early owners and readers of the book encountered.Through a systematic codicological analysis, the overall structure of the codex is explored and suggestions are made concerning the provenance. The examination of the scribal work procedure becomes a means to profile this otherwise fairly unknown scribe. The texts are grouped and characterized typologically to illustrate connections throughout the whole book as well as in relation to the separate structural units. The role of micro-texts and secondary layers of inscription is also considered. From the perspective of usability the texts are divided into four categories: narrative texts, rhetorical texts, philosophical-theological texts, and practical texts. Three texts are studied in greater depth, as examples of the width of the scribe's interests and the variety of the book's contents.
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| 42. |
- Osman, Ahmed M., et al.
(författare)
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Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain
- 2020
-
Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 31:9
-
Tidskriftsartikel (refereegranskat)abstract
- Cranial irradiation (IR), an effective tool to treat malignant brain tumors, triggers a chronic pro-inflammatory microglial response, at least in the adult brain. Using single-cell and bulk RNA sequencing, combined with histology, we show that the microglial response in the juvenile mouse hippocampus is rapid but returns toward normal within 1 week. The response is characterized by a series of temporally distinct homeostasis-, sensome-, and inflammation-related molecular signatures. We find that a single microglial cell simultaneously upregulates transcripts associated with pro- and anti-inflammatory microglial phenotypes. Finally, we show that juvenile and adult irradiated microglia are already transcriptionally distinct in the early phase after IR. Our results indicate that microglia are involved in the initial stages but may not be responsible for driving long-term inflammation in the juvenile brain.
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| 43. |
- Pereira, Maria, et al.
(författare)
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Direct Reprogramming of Resident NG2 Glia into Neurons with Properties of Fast-Spiking Parvalbumin-Containing Interneurons
- 2017
-
Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 9:3, s. 742-751
-
Tidskriftsartikel (refereegranskat)abstract
- Converting resident glia into functional and subtype-specific neurons in vivo by delivering reprogramming genes directly to the brain provides a step forward toward the possibility of treating brain injuries or diseases. To date, it has been possible to obtain GABAergic and glutamatergic neurons via in vivo conversion, but the precise phenotype of these cells has not yet been analyzed in detail. Here, we show that neurons reprogrammed using Ascl1, Lmx1a, and Nurr1 functionally mature and integrate into existing brain circuitry and that the majority of the reprogrammed neurons have properties of fast-spiking, parvalbumin-containing interneurons. When testing different combinations of genes for neural conversion with a focus on pro-neural genes and dopamine fate determinants, we found that functional neurons can be generated using different gene combinations and in different brain regions and that most of the reprogrammed neurons become interneurons, independently of the combination of reprogramming factors used. In this study, Parmar, Ottosson, and colleagues show how endogenous NG2 glia can be reprogrammed into GABAergic interneurons of different subtypes, the majority of them with properties of fast-spiking parvalbumin-containing interneurons. This neuronal subtype has been implicated in several neurological diseases, and the findings can open up new therapeutic options.
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| 44. |
- Rouhi, Pegah, et al.
(författare)
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Pathological angiogenesis facilitates tumor cell dissemination and metastasis
- 2010
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Ingår i: Cell Cycle. - : Landes Bioscience. - 1538-4101 .- 1551-4005. ; 9:5, s. 913-917
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Tidskriftsartikel (refereegranskat)abstract
- Clinically detectable metastases represent an ultimate consequence of the metastatic cascade that consists of distinct processes including tumor cell invasion, dissemination, metastatic niche formation, and re-growth into a detectable metastatic mass. Although angiogenesis is known to promote tumor growth, its role in facilitating early events of the metastatic cascade remains poorly understood. We have recently developed a zebrafish tumor model that enables us to study involvement of pathological angiogenesis in tumor invasion, dissemination and metastasis. This non-invasive in vivo model allows detection of single malignant cell dissemination under both normoxia and hypoxia. Further, hypoxia-induced VEGF significantly facilitates tumor cell invasion and dissemination. These findings demonstrate that VEGF-induced pathological angiogenesis is essential for tumor dissemination and further corroborates potentially beneficial effects of clinically ongoing anti-VEGF drugs for the treatment of various malignancies.
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| 45. |
- Rylander Hedlund, Eva
(författare)
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Cardiopulmonary function, quality of life and effects of exercise in children and adolescents with Fontan circulation
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Survival of children and adolescents with Fontan circulation has increased over the last decades, and today a large majority survive to adult age. There is increasing concern regarding these children’s impaired physical performance and quality of life. Little is known about the impact of exercise on cardiopulmonary function and quality of life in this patient group compared with the impact on healthy children. Aim: The aims of this thesis were to study activity, physical capacity, lung function, quality of life, and sleep before and after an exercise intervention in patients with Fontan circulation and healthy matched controls. A follow-up, one year after the training programme, was also performed. We wanted to evaluate if physical exercise could improve cardiopulmonary function and also, most importantly, quality of life in this patient group. Method: Patients with Fontan circulation (n = 30) and healthy controls (n = 25) performed measurements and/or assessments of physical activity including accelerometer recordings, submaximal and maximal exercise capacity, lung function, sleep, and quality of life. All examinations were done prior to and after an individualised endurance training programme for 12 weeks, and also after one year. Results: Patients with Fontan circulation reported less time in regular physical exercise than healthy controls, though the objectively measured activity was similar. Quality of life was reported significantly lower by the patients and by their parents compared with the controls. After the exercise intervention, submaximal exercise capacity had increased and quality of life was improved for the patients. However, the exercise intervention did not have an impact on maximal exercise capacity for the patients. After one year, patients showed further improvement of submaximal exercise capacity and quality of life was still improved, as after the exercise intervention. Moreover, children with Fontan circulation had impaired lung function and a reduced pulmonary diffusing capacity. Diffusing capacity increased with age in the patients, but less than in the control subjects. Moreover, endurance training improved vital capacity in the patient group. Fontan patients seemed to have a prolonged latency to sleep onset compared with healthy children. Increased time in physical activities seemed to be correlated with better sleep quality in patients with Fontan circulation. Conclusions: Structured individualized training programmes may improve submaximal exercise capacity, lung function, and quality of life in children with Fontan circulation. Also, the improvement of quality of life appears to remain, one year after the intervention. Increased amount of physical activity may also be beneficial for sleep quality for these patients. The clinical importance of our results is that increased physical activity is likely to be beneficial for cardiopulmonary function, quality of life, and sleep quality in this patient group. Thus, patients with Fontan palliation should be encouraged to regularly engage in individually designed sports and activities. Rehabilitation programmes should include structured individualised endurance training for improved outcome in this group of patients. Impaired health-related quality of life is most likely multifactorial and further research is needed to more fully understand the effects of exercise on cardiopulmonary function, sleep, and quality of life in this patient group. Also, more research is needed on how to individualise recommendations and find optimal regimens for exercise prescriptions from early age for these patients. The important message is, though, to encourage physical exercise for these patients for better health and well-being.
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| 46. |
- Sandberg, Camilla, et al.
(författare)
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Impaired knee extension muscle strength in adolescents but not in children with Fontan circulation
- 2020
-
Ingår i: Cardiology in the Young. - : Cambridge University Press. - 1047-9511 .- 1467-1107. ; 30:8, s. 1138-1143
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Impaired isometric muscle strength was previously reported in adults with Fontan circulation. However, it is unclear if this impairment is present in children and adolescents with Fontan circulation. We investigated isometric muscle strength of the lower limb in patients (6–18 years) with Fontan circulation in comparison with healthy controls.Method: In this cross-sectional study, 43 patients (6–18 years) with Fontan circulation and 43 age- and sex-matched controls were included. Isometric knee extension and plantar flexion muscle strength were assessed using dynamometry (Newton, N). Lean mass of the legs was assessed with dual-energy X-ray absorptiometry. Analyses were performed on group level (n = 43), and for subgroups that included children aged 6–12 years (n = 18) and adolescents aged 13–18 years (n = 25).Results: On group level, the patients with Fontan circulation had impaired isometric knee extension strength in comparison with the controls (p = 0.03). In subgroup analyses, impaired isometric knee extension strength was present in the adolescents (p = 0.009) but not in the children groups. For plantar flexion, there was no difference between patients and controls. There was no difference in lean mass between patients and controls (9.6 ± 4.3 kg vs. 10.8 ± 5.6 kg, p = 0.31). However, the lean mass was highly correlated to isometric knee extension strength (patients r = 0.89, controls r = 0.96, p < 0.001) and isometric plantar flexion strength (patients r = 0.7, controls r = 0.81, p < 0.001).Conclusion: The finding of impaired isometric knee extension muscle strength in adolescents (13–18 years) with Fontan circulation and no corresponding impairment in the children group (6–12 years) could imply that isometric muscle strength gets more impaired with age.
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| 47. |
- Schweingruber, Christoph, et al.
(författare)
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The Cell Autonomous and Non-Cell Autonomous Aspects of Neuronal Vulnerability and Resilience in Amyotrophic Lateral Sclerosis
- 2022
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Ingår i: Biology. - : MDPI AG. - 2079-7737. ; 11:8
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Forskningsöversikt (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading to spasticity, muscle atrophy, and paralysis. ALS involves several disease stages, and multiple cell types show dysfunction and play important roles during distinct phases of disease initiation and progression, subsequently leading to selective MN loss. Why MNs are particularly vulnerable in this lethal disease is still not entirely clear. Neither is it fully understood why certain MNs are more resilient to degeneration in ALS than others. Brain stem MNs of cranial nerves III, IV, and VI, which innervate our eye muscles, are highly resistant and persist until the end-stage of the disease, enabling paralyzed patients to communicate through ocular tracking devices. MNs of the Onuf’s nucleus in the sacral spinal cord, that innervate sphincter muscles and control urogenital functions, are also spared throughout the disease. There is also a differential vulnerability among MNs that are intermingled throughout the spinal cord, that directly relate to their physiological properties. Here, fast-twitch fatigable (FF) MNs, which innervate type IIb muscle fibers, are affected early, before onset of clinical symptoms, while slow-twitch (S) MNs, that innervate type I muscle fibers, remain longer throughout the disease progression. The resilience of particular MN subpopulations has been attributed to intrinsic determinants and multiple studies have demonstrated their unique gene regulation and protein content in health and in response to disease. Identified factors within resilient MNs have been utilized to protect more vulnerable cells. Selective vulnerability may also, in part, be driven by non-cell autonomous processes and the unique surroundings and constantly changing environment close to particular MN groups. In this article, we review in detail the cell intrinsic properties of resilient and vulnerable MN groups, as well as multiple additional cell types involved in disease initiation and progression and explain how these may contribute to the selective MN resilience and vulnerability in ALS.
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| 48. |
- Schyllert, Christian, et al.
(författare)
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Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study
- 2016
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Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 73:10, s. 663-669
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Occupational exposure to the composite measure vapours, gases, dusts and fumes (VGDF), contribute to the burden of asthma and rhinitis. The objective was to evaluate occupational exposure to VGDF, which is further divided into the components chemicals, organic and inorganic dust in relation to asthma and rhinitis. Methods Previously examined participants from three population-based cohorts in the Obstructive Lung disease In Northern Sweden (OLIN) studies were reexamined during 2002-2004. In total, 4036 participated in a structured interview and answered a questionnaire on occupational exposures. Results Occupational exposure to VGDF increased the risk of asthma, and concomitant asthma and rhinitis. Exposure to chemicals, but not dust, showed a similar pattern. Exposure to chemicals increased the risks (OR, 95% CI) of rhinitis without asthma (1.29, 1.10 to 1.52), asthma without rhinitis (1.42, 1.15 to 1.77) and concomitant asthma and rhinitis (1.60, 1.31 to 1.96) when adjusted for confounders such as age, smoking habits, body mass index and sex. The association between exposure to chemicals and asthma and rhinitis remained independent of exposure to dust and was also so when excluding exposure to isocyanates and welding fumes. The results were similar for women and men, as well as for never-smokers and participants without a history of allergy. Conclusions In this cross-sectional population-based study, occupational exposure to chemicals contributed substantially to the increased risk of asthma and rhinitis observed for occupational exposure to VGDF.
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| 49. |
- Stenborg, Georg, 1966-
(författare)
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Emmo: De qualitate caelestis patriae libri tres. : Edition with an Introduction.
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis contains the first critical edition of the eschatological florilegium De qualitate caelestis patriae by Emmo, compiled, during the Carolingian renaissance, in the first half of the ninth century.The subject matter covered by Emmo is theological and moral, comprising first and foremost the eschatological ends of heaven and hell, but also having a clear moral agenda, to inspire the reader to lead a righteous life through the virtues described and to avoid the vices leading to a sorry end of one’s life. It contains passages of various length from Church Fathers (patres) such as Augustine, Gregory, Isidore, and several lesser known authors of Late Antiquity and the early Middle Ages. Each chapter of its three books consists of one or several patristic quotations on a defined aspect of heaven, hell, purgatory or the last judgement, or on charity, patience, obedience and the other virtues, or the power of pious almsgiving and penitence.The primary reader, addressed in the preface, is a 'pater Willelmus', who has not been clearly identified despite several attempts, just as Emmo himself, who is not otherwise known. These questions are not solved definitely in this study either, but the evidence is collected and presented. The historical and intellectual setting of the Carolingian period is also briefly described.The sources of Emmo’s florilegium and his methods of compiling are exemplified and analysed in detail in the thesis. The florilegium genre represents a complex and unstable textual tradition where compilers borrow material either directly from the primary source (a Church Father) or from secondary sources, including other collections and florilegia. This enables several variants of contamination in manuscripts, rendering otherwise conclusive errors dubious as proofs of manuscript relations. This is also discussed in the thesis.
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| 50. |
- Stenqvist, Ann-Christin, 1981-, et al.
(författare)
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An efficient optimized method for isolation of villous trophoblast cells from human early pregnancy placenta suitable for functional and molecular studies
- 2008
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Ingår i: American Journal of Reproductive Immunology and Microbiology. - : Wiley. - 8755-8920 .- 1046-7408. ; 60:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- PROBLEM: The uniqueness of the human placenta cannot be replaced by animal models. In vitro studies are compulsory to elucidate the biology of human placenta and require isolation and purification of villous trophoblasts, which can be used in molecular and functional studies. Constant improvement in the isolation technique is required to obtain a high yield of pure trophoblast cells with high viability and well preserved morphology.METHOD OF STUDY: Optimized isolation procedure for human villous trophoblasts based on mild enzymatic treatment, Percoll gradient centrifugation and additional purification step involving positive or negative immunoselection on magnetic beads is described.RESULTS: A simple and effective isolation protocol gave a reasonably high yield of villous trophoblast cells with high purity and viability, and excellent morphology as assessed by flow cytometry and electron microscopy.CONCLUSION: This protocol provides an efficient, optimized method for isolation and enrichment of villous trophoblast cells, suitable for phenotypic, ultrastructural, molecular and functional analyses and for establishment of primary cultures.
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