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Sökning: WFRF:(Nilsson Mikael 1958)

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1.
  • Forsberg, Kalle, et al. (författare)
  • A Systematic Review Of Erythropoietin In Experimental Stroke
  • 2009
  • Ingår i: Stroke. - 0039-2499. ; 40:4
  • Konferensbidrag (refereegranskat)abstract
    • Introduction: Erythropoietin (EPO), a hematopoietic growth factor, has promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also is hypothesized to promote regeneration post stroke. Here we report a systematic review and meta-analysis of the published animal data characterizing the efficacy of EPO. Methods We conducted a systematic review and random effects weighted mean difference meta-analysis only including studies describing the efficacy of EPO in models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral score. A stratified analysis to identify the impact of elements of study quality and design was also conducted. Results Only 11 of 943 studies met our inclusion criteria. Infarct size was reported in 15 experiments using 191 animals. Neurobehavioral score was reported in 16 experiments using 287 animals. EPO improved infarct size by 30.5% (95%Cl 19.3%-41.7%) and neurobehavioral score by 37.4% (31.2– 43.7%). For infarct size, EPO was least effective in thrombotic models of ischemia, (16% versus to 44.8% and 24% in permanent and transient models of ischemia respectively, X2 =1.47 x 10–04). Using a scoring system derived from the STAIR criteria,study quality was modest with a median score of 4 out of 11 for both outcomes. Studies that randomized to treatment group reported smaller infarct sizes compared to those that did not (18.0% versus 44.8%, n=113 versus 78 animals, X2 = 3.4 x 10–05). Studies that blinded assessment of outcome also showed a smaller improvement in neurobehavioral score (31.1% versus 41.6%, n=107 versus 167, X2 = 8.9 x 10–4). Only 11.7% of the animals in the total dataset had a co-morbidity common to human stroke (hypertension) and this co-morbidity was only reported for neurobehavioral comparisons, not for infarct size. Blinded induction of ischemia was reported in 2 experiments (21.5% of animals) measuring infarct volume. Conclusions: Aggregation of the animal data for EPO in ischemic stroke indicates mean effect sizes of 30.5% and 37.4% for infarct volume and neurobehavioral score respectively. However, when the impact of common sources of bias are considered these effect sizes fall suggesting we are overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works would be beneficial before clinical trialing.
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2.
  • Nilsson, Peter, et al. (författare)
  • Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
  • 2007
  • Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
  • Tidskriftsartikel (refereegranskat)abstract
    • Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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3.
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4.
  • Schoultz, Elin, et al. (författare)
  • Tissue architecture delineates field cancerization in brafv600e-induced tumor development
  • 2022
  • Ingår i: DMM Disease Models and Mechanisms. - 1754-8403 .- 1754-8411. ; 15:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAFmutant lineage becomes a cancerized lineage. The TgCreERT2; BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.
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5.
  • Zhu, Yihong, 1974, et al. (författare)
  • Formation and barrier function of tight junctions in human ovarian surface epithelium
  • 2004
  • Ingår i: Biol Reprod. ; 71:1, s. 53-9
  • Tidskriftsartikel (refereegranskat)abstract
    • The normal ovarian surface epithelium (OSE) is a primitive epithelium made up by a single layer of mesothelial-type epithelial cells. When these cells get trapped in the ovarian stroma, expression of epithelial specific markers, such as E-cadherin, are induced. Most epithelial cells are also characterized by the ability to form tight junctions (TJ). Incomplete TJ have earlier been demonstrated in the OSE by electron microscopy studies. We have investigated expression and localization of the TJ proteins ZO-1, occludin, and claudin-1 in tissue biopsies from normal human ovaries and OSE in culture. The dynamics of TJ formation were studied in human OSE cultured on porous filters in culture inserts by measuring trans epithelial resistance (TER) including Ca(2+) switch experiments. Confluent OSE cells were also analyzed by electron microscopy. The results show that normal human OSE has expression of all three TJ proteins investigated. These proteins, ZO-1, occludin, and claudin-1, were localized to OSE cell borders both in ovarian biopsies and in cultured OSE. There was no difference in this regard between fertile and postmenopausal women. Cells in culture were polarized and presented junctional complexes seen by electron microscopy. In the Ca(2+) switch experiments, removing free Ca(2+) transiently, TER decreased significantly (P < 0.05) in the Ca(2+)-free group compared with nontreated OSE. TER was fully restored after 24 h. N-cadherin but not E-cadherin was expressed in the OSE and localized to the cell borders. We conclude that normal human OSE express and form functional TJ both in vivo and vitro. This report also describes a method to study the influence of ovarian-derived mediators on TJ in cultured OSE.
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6.
  • Andersson, Louise, 1979, et al. (författare)
  • Role of EphA4 receptor signaling in thyroid development: regulation of folliculogenesis and propagation of the C-cell lineage.
  • 2011
  • Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:3, s. 1154-64
  • Tidskriftsartikel (refereegranskat)abstract
    • Transcriptome analysis revealed that the tyrosine kinase receptor EphA4 is enriched in the thyroid bud in mouse embryos. We used heterozygous EphA4-EGFP knock-in mice in which enhanced green fluorescent protein (EGFP) replaced the intracellular receptor domain (EphA4(+/EGFP)) to localize EphA4 protein in thyroid primordial tissues. This showed that thyroid progenitors originating in the pharyngeal floor express EphA4 at all embryonic stages and when follicles are formed in late development. Also, the ultimobranchial bodies developed from the pharyngeal pouch endoderm express EphA4, but the ultimobranchial epithelium loses the EGFP signal before it merges with the median thyroid primordium. Embryonic C cells invading the thyroid are exclusively EphA4-negative. EphA4 expression continues in the adult thyroid. EphA4 knock-out mice and EphA4-EGFP homozygous mutants are euthyroid and have a normal thyroid anatomy but display subtle histological alterations regarding number, size, and shape of follicles. Of particular interest, the pattern of follicular abnormality differs between EphA4(-/-) and EphA4(EGFP/EGFP) thyroids. In addition, the number of C cells is reduced by >50% exclusively in animals lacking EphA4 forward signaling (EphA4(EGFP/EGFP)). Heterozygous EphA4 mutants have no apparent thyroid phenotype. We conclude that EphA4 is a novel regulator of thyroid morphogenesis that impacts on postnatal development of the two endocrine cell lineages of the differentiating gland. In this process both EphA4 forward signaling (in the follicular epithelium) and reverse signaling mediated by its cognate ligand(s) (A- and/or B-ephrins expressed in follicular cells and C cells, respectively) are probably functionally important.
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7.
  • Betz, Mattias J., et al. (författare)
  • Presence of Brown Adipocytes in Retroperitoneal Fat From Patients With Benign Adrenal Tumors: Relationship With Outdoor Temperature
  • 2013
  • Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:10, s. 4097-4104
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. Objective: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. Patients: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. Main Outcome Measures: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. Results: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. Conclusions: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.
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8.
  • Brinkmalm, Gunnar, et al. (författare)
  • An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid β and amyloid precursor protein in human and cat cerebrospinal fluid.
  • 2012
  • Ingår i: Journal of mass spectrometry : JMS. - : Wiley. - 1096-9888 .- 1076-5174. ; 47:5, s. 591-603
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid precursor protein (APP) is the precursor protein to amyloid β (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD). Endogenous Aβ peptides reflect the APP processing, and greater knowledge of different APP degradation pathways is important to understand the mechanism underlying AD pathology. When one analyzes longer Aβ peptides by low-energy collision-induced dissociation tandem mass spectrometry (MS/MS), mainly long b-fragments are observed, limiting the possibility to determine variations such as amino acid variants or post-translational modifications (PTMs) within the N-terminal half of the peptide. However, by using electron capture dissociation (ECD), we obtained a more comprehensive sequence coverage for several APP/Aβ peptide species, thus enabling a deeper characterization of possible variants and PTMs. Abnormal APP/Aβ processing has also been described in the lysosomal storage disease Niemann-Pick type C and the major large animal used for studying this disease is cat. By ECD MS/MS, a substitution of Asp7 → Glu in cat Aβ was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human Aβ (a previously unknown glycosylation type), were identified also in cat cerebrospinal fluid (CSF). It is therefore likely that this unusual type of glycosylation is common for (at least) species belonging to the magnorder Boreoeutheria. We here describe a detailed characterization of endogenous APP/Aβ peptide species in CSF by using an online top-down MS-based method.
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9.
  • Demelash, Abeba, 1962, et al. (författare)
  • Selenium has a protective role in caspase-3-dependent apoptosis induced by H2O2 in primary cultured pig thyrocytes.
  • 2004
  • Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 0804-4643. ; 150:6, s. 841-9
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Hydrogen peroxide (H2O2), necessary for thyroid hormonogenesis, is produced at the apical surface of the thyroid follicular epithelium. Excess H2O2 is potentially cytotoxic and may contribute to the development of hypothyroidism, e.g. in severe selenium deficiency. Yet it is unclear how H2O2 contributes to thyroid cell death. DESIGN AND METHODS: H2O2-induced apoptosis and necrosis were studied in primary cultured pig thyroid cells. Glutathione peroxidase (GPx) activity was altered by culture in low serum with or without selenite substitution. Apoptosis was evaluated by spectrofluorometric measurement of caspase-3-specific substrate cleavage, and by analysis of DNA fragmentation by agarose gel electrophoresis. Necrosis was detected by 51Cr release from prelabeled cells. RESULTS: Exogenous H2O2 dose-dependently (100-400 micromol/l) activated caspase-3 within 3-12 h, and DNA degradation was observed after 24 h. The potency of H2O2 to induce apoptosis was low compared with that of staurosporine, a strong proapoptotic agent. H2O2-treated cells with reduced GPx activity showed increased caspase-3 activation. Incubation of serum-starved cells with selenite (10-100 nmol/l) normalized the GPx activity and reduced the activation of caspase-3 by H2O2. High H2O2 concentrations (400-800 micromol/l) were required to obtain necrosis. The H2O2-induced necrosis was exaggerated by both low GPx activity and catalase inhibition. CONCLUSIONS: Cytotoxic effects of H2O2 on thyroid cells include caspase-3-dependent apoptosis that occurs at H2O2 concentrations insufficient to induce necrosis. Selenium deficiency aggravates the apoptotic response, probably due to impaired capacity of GPx to degrade H2O2.
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10.
  • Enerbäck, Sven, 1958, et al. (författare)
  • Acidosis and Deafness in Patients with Recessive Mutations in FOXI1
  • 2018
  • Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 29:3, s. 1041-1048
  • Tidskriftsartikel (refereegranskat)abstract
    • Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.
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11.
  • Fagman, Henrik, 1975, et al. (författare)
  • Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse.
  • 2004
  • Ingår i: American Journal of Pathology. - 0002-9440. ; 164:5, s. 1865-72
  • Tidskriftsartikel (refereegranskat)abstract
    • Thyroid dysgenesis encountered in 85% of patients with congenital hypothyroidism is a morphologically heterogeneous condition with primarily unknown pathogenesis. Here we identify sonic hedgehog (Shh) as a novel regulator of thyroid development. In Shh knockout mice the thyroid primordium is correctly specified in the pharyngeal endoderm, but budding and dislocation are slightly delayed. In late development the thyroid fails to form a bilobed gland. Instead a single thyroid mass is found unilaterally and mostly to the left of the midline. Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation. Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-/- embryos. The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin. Shh mRNA is not expressed in the thyroid precursor cells at any developmental stage. The results indicate that Shh signaling indirectly governs the symmetric bilobation of the thyroid during late organogenesis. Shh also seems to repress inappropriate thyroid differentiation in nonthyroid embryonic tissues. This study provides clues to the molecular mechanisms that might be dysregulated in thyroid hemiagenesis and development of ectopic thyroid tissue outside the thyroglossal duct.
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12.
  • Fagman, Henrik, 1975, et al. (författare)
  • Morphogenesis of the thyroid gland.
  • 2010
  • Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 323:1, s. 35-54
  • Forskningsöversikt (refereegranskat)abstract
    • Congenital hypothyroidism is mainly due to structural defects of the thyroid gland, collectively known as thyroid dysgenesis. The two most prevalent forms of this condition are abnormal localization of differentiated thyroid tissue (thyroid ectopia) and total absence of the gland (athyreosis). The clinical picture of thyroid dysgenesis suggests that impaired specification, proliferation and survival of thyroid precursor cells and loss of concerted movement of these cells in a distinct spatiotemporal pattern are major causes of malformation. In normal development the thyroid primordium is first distinguished as a thickening of the anterior foregut endoderm at the base of the prospective tongue. Subsequently, this group of progenitors detaches from the endoderm, moves caudally and ultimately differentiates into hormone-producing units, the thyroid follicles, at a distant location from the site of specification. In higher vertebrates later stages of thyroid morphogenesis are characterized by shape remodeling into a bilobed organ and the integration of a second type of progenitors derived from the caudal-most pharyngeal pouches that will differentiate into C-cells. The present knowledge of thyroid developmental dynamics has emerged from embryonic studies mainly in chicken, mouse and more recently also in zebrafish. This review will highlight the key morphogenetic steps of thyroid organogenesis and pinpoint which crucial regulatory mechanisms are yet to be uncovered. Considering the co-incidence of thyroid dysgenesis and congenital heart malformations the possible interactions between thyroid and cardiovascular development will also be discussed.
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13.
  • Fagman, Henrik, 1975, et al. (författare)
  • Morphogenetics of early thyroid development.
  • 2011
  • Ingår i: Journal of molecular endocrinology. - 1479-6813. ; 46:1
  • Forskningsöversikt (refereegranskat)abstract
    • The thyroid develops from the foregut endoderm. Yet uncharacterized inductive signals specify endoderm progenitors to a thyroid cell fate that assembles in the pharyngeal floor from which the primordium buds and migrates to the final position of the gland. The morphogenetic process is regulated by both cell-autonomous (e.g. activated by NKX2-1, FOXE1, PAX8, and HHEX) and mesoderm-derived (e.g. mediated by TBX1 and fibroblast growth factors) mechanisms acting in concert to promote growth and survival of progenitor cells. The developmental role of TSH is limited to thyroid differentiation set to work after the gross anatomy of the gland is already sculptured. This review summarizes recent advances on the molecular genetics of thyroid morphogenesis put into context of endoderm developmental traits and highlights established and novel mechanisms of thyroid dysgenesis of potential relevance to congenital hypothyroidism in man.
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14.
  • Fagman, Henrik, 1975, et al. (författare)
  • The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning.
  • 2007
  • Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:3, s. 276-85
  • Tidskriftsartikel (refereegranskat)abstract
    • Thyroid dysgenesis is the major cause of congenital hypothyroidism in humans. The underlying molecular mechanism is in most cases unknown, but the frequent co-incidence of cardiac anomalies suggests that the thyroid morphogenetic process may depend on proper cardiovascular development. The T-box transcription factor TBX1, which is the most probable gene for the 22q11 deletion syndrome (22q11DS/DiGeorge syndrome/velo-cardio-facial syndrome), has emerged as a central player in the coordinated formation of organs and tissues derived from the pharyngeal apparatus and the adjacent secondary heart field from which the cardiac outflow tract derives. Here, we show that Tbx1 impacts greatly on the developing thyroid gland, although it cannot be detected in the thyroid primordium at any embryonic stage. Specifically, in Tbx1-/- mice, the downward translocation of Titf1/Nkx2.1-expressing thyroid progenitor cells is much delayed. In late mutant embryos, the thyroid fails to form symmetric lobes but persists as a single mass approximately one-fourth of the normal size. The hypoplastic gland mostly attains a unilateral position resembling thyroid hemiagenesis. The data further suggest that failure of the thyroid primordium to re-establish contact with the aortic sac is a key abnormality preventing normal growth of the midline anlage along the third pharyngeal arch arteries. In normal development, this interaction may be facilitated by Tbx1-expressing mesenchyme filling the gap between the pharyngeal endoderm and the detached thyroid primordium. The findings indicate that Tbx1 regulates intermediate steps of thyroid development by a non-cell-autonomous mechanism. Thyroid dysgenesis related to Tbx1 inactivation may explain an overrepresentation of hypothyroidism occurring in patients with the 22q11DS.
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15.
  • Fagman, Henrik, 1975, et al. (författare)
  • The developing mouse thyroid: embryonic vessel contacts and parenchymal growth pattern during specification, budding, migration, and lobulation.
  • 2006
  • Ingår i: Developmental dynamics : an official publication of the American Association of Anatomists. - : Wiley. - 1058-8388. ; 235:2, s. 444-55
  • Tidskriftsartikel (refereegranskat)abstract
    • Normal mouse thyroid development has been revised to identify critical morphogenetic events. The early thyroid primordium associates with the aortic sac endothelium at the time of specification and budding. The vascular contact is lost after the thyroid buds from the pharyngeal endoderm, but is resumed before the gland divides to form two lobes. Lateral expansion of parenchyma takes place along the course of the third pharyngeal arch arteries. Thyroid precursor cells expressing Titf1/Nkx2.1 do not proliferate until the migration stage, implicating that progenitors likely are recruited from outside the thyroid placode. Early lobulation involves engulfment of the entire ultimobranchial bodies by the growing midline thyroid. At the same time, proliferation of the ultimobranchial body epithelium is silenced preceding the differentiation of C cells. Before folliculogenesis, thyroid lobe enlargement is reminiscent of a budding-branching-like growth pattern. It is suggested that thyroid inductive signals arise from embryonic vessels, and that this provides ideas to conceptually new pathogenetic mechanisms of thyroid dysgenesis.
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16.
  • Gao, Jingfang, et al. (författare)
  • TGF-β isoforms induce EMT independent migration of ovarian cancer cells.
  • 2014
  • Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Transforming growth factor beta (TGF-β) plays major roles in tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis. The epithelial markers E-cadherin, claudin-3 and claudin-4, commonly decreased in human adenocarcinomas are actually up regulated during ovarian carcinogenesis. In human ovarian cancer TGF-β1 may either suppress or promote tumor progression, but whether other TGF-β isoforms (TGF-β2 and TGF-β3) exert similar effects is not known.
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17.
  • Gracias, J., et al. (författare)
  • Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
  • 2022
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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18.
  • Hagnell, J, et al. (författare)
  • How to trap a slug: Commercial versus homemade slug traps
  • 2006
  • Ingår i: Crop Protection. - : Elsevier BV. - 1873-6904 .- 0261-2194. ; 25:3, s. 212-215
  • Tidskriftsartikel (refereegranskat)abstract
    • The Iberian Slug, Arion lusitanicus Mabille (Stylomatophora: Arionidae), has developed into a destructive pest in Swedish gardens and orchards over the past 10-20 years. Many attempts to eradicate this pest have been made using a variety of different methods. The aim of this study was to investigate the effectiveness of two different types of homemade traps made from simple, inexpensive materials (plastic PET bottle or an ice-cream box) compared to one type of commercially sold trap (Slugtrap((R)) IT-PAC A B, Sweden) used with bait and beer as attractants. Experiments were carried out on a private property outside Lund, Sweden, over a period of 7 days. The results showed that a homemade trap, i.e. a box trap, can be as efficient as a commercial trap, particularly due to their similar design. In contrast, the homemade bottle trap was not very successful. Additionally, it was discovered that the bait used in the commercial traps did not increase the number of slugs trapped. It was concluded that the beer was the main slug attractant. Ultimately this study suggests a low-cost alternative for small scale to the rather expensive commercially sold traps.
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19.
  • Ingeson-Carlsson, Camilla, et al. (författare)
  • Differential effects of MAPK pathway inhibitors on migration and invasiveness of BRAF(V600E) mutant thyroid cancer cells in 2D and 3D culture
  • 2015
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 338:2, s. 127-135
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor microenvironment influences targeted drug therapy. In this study we compared drug responses to RAF and MEK inhibitors on tumor cell migration in 2D and 3D culture of BRAF(V600E) mutant cell lines derived from human papillary (BCPAP) and anaplastic (SW1736) thyroid carcinomas. Scratch wounding was compared to a double-layered collagen gel model developed for analysis of directed tumor cell invasion during prolonged culture. In BCPAP both PLX4720 and U0126 inhibited growth and migration in 2D and decreased tumor cell survival in 3D. In SW1736 drugs had no effect on migration in 2D but decreased invasion in 3D, however this related to reduced growth. Dual inhibition of BRAF(V600E) and mEK reduced but did not prevent SW1736 invasion although rebound phosphorylation of ERK in response to PLX4720 was blocked by U0126. These findings indicate that anti-tumor drug effects in vitro differ depending on culture conditions (2D vs. 3D) and that the invasive features of anaplastic thyroid cancer depend on non-MEK mechanism(s). (C) 2015 Elsevier Inc. All rights reserved.
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20.
  • Ingeson-Carlsson, Camilla, et al. (författare)
  • Dual contribution of MAPK and PI3K in epidermal growth factor-induced destabilization of thyroid follicular integrity and invasion of cells into extracellular matrix
  • 2014
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 326:2, s. 210-218
  • Tidskriftsartikel (refereegranskat)abstract
    • Normal thyrocytes grown as reconstituted follicles in collagen gel were evaluated for drug effects of small molecule kinase inhibitors on growth factor-induced cell migration in a 3D context. MEK inhibition by U0126 only partially antagonized EGF/serum-induced cell migration from the basal follicular surface into the matrix. Combined treatment with U0126 and LY294002, a PI3K blocker, was necessary to abolish migration. However, exposure to only LY294002 facilitated the response to EGF by breakdown of the original follicular structure. In the same time EGF promoted thyroid cell survival that was compromised by LY294002 in absence of EGF. Cells treated with EGF and LY294002 retained the ability to form follicles. The findings indicate that dual inhibition of MAPK and PI3K/AKT pathways is required to fully block matrix invasion of EGF-stimulated thyroid cells. Conversely, single drug treatment with PI3K inhibitor adversely promotes invasiveness probably by destabilizing the follicular epithelium. (C) 2014 Elsevier Inc. All rights reserved.
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21.
  • Ingeson-Carlsson, Camilla, et al. (författare)
  • Switching from MAPK-dependent to MAPK-independent repression of the sodium-iodide symporter in 2D and 3D cultured normal thyroid cells.
  • 2013
  • Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 381:1-2, s. 241-54
  • Tidskriftsartikel (refereegranskat)abstract
    • Loss of sodium-iodide symporter (NIS) expression in thyroid tumour cells primarily caused by constitutive MAPK pathway activation is often refractory to small molecule MAPK inhibitors. Suggested mechanisms are rebound MAPK signalling and activation of alternative signalling pathways. Here we provide evidence that failure to recover down-regulated NIS by MEK inhibition is not specific to tumour cells. NIS mRNA levels remained repressed in TSH-stimulated primary thyroid cells co-treated with epidermal growth factor (EGF) and pan-MEK inhibitor U0126 in the presence of 5% fetal bovine serum or, independently of serum, in 3D cultured thyroid follicles. This led to inhibited iodide transport and iodination. In contrast, U0126 restituted thyroglobulin synthesis in EGF-treated follicular cells. Serum potentiated TSH-stimulated NIS expression in 2D culture. U0126 blocked down-regulation of NIS only in serum-starved cells with a diminished TSH response. Together, this suggests that morphogenetic signals modify the expression of NIS and recovery response to MEK inhibition.
  •  
22.
  • Johansson, Ellen, et al. (författare)
  • Asynchrony of Apical Polarization, Luminogenesis, and Functional Differentiation in the Developing Thyroid Gland
  • 2021
  • Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Follicular thyroid tissue originates from progenitors derived from a midline endodermal primordium. Current understanding infers that folliculogenesis in the embryonic thyroid designates the latest morphogenetic event taking place after the final anatomical shape and position of the gland is established. However, this concept does not consider the fact that the thyroid isthmus develops chronologically before the lobes and also contains all progenitors required for lobulation. To elucidate whether cells committed to a thyroid fate might be triggered to differentiate asynchronously related to maturation and developmental stage, mouse embryonic thyroid tissues from E12.5-17.5 were subjected to immunofluorescent labeling of biomarkers (progenitors: NKX2-1; differentiation: thyroglobulin/TG); folliculogenesis: E-cadherin/CDH1; luminogenesis: mucin 1/MUC1; apical polarity: pericentrin/PCNT; basement membrane: laminin; growth: Ki67), quantitative RT-PCR analysis (Nkx2.1, Tg, Muc1) and transmission electron microscopy. Tg expression was detectable as early as E12.5 and gradually increased >1000-fold until E17.5. Muc1 and Nkx2.1 transcript levels increased in the same time interval. Prior to lobulation (E12.5-13.5), MUC1 and TG distinguished pre-follicular from progenitor cells in the developing isthmus characterized by intense cell proliferation. Luminogenesis comprised redistribution of MUC1+ vesicles or vacuoles, transiently associated with PCNT, to the apical cytoplasm and the subsequent formation of MUC1+ nascent lumens. Apical polarization of pre-follicular cells and lumen initiation involved submembraneous vesicular traffic, reorganization of adherens junctions and ciliogenesis. MUC1 did not co-localize with TG until a lumen with a MUC1+ apical membrane was established. MUC1 delineated the lumen of all newly formed follicles encountered in the developing lobes at E15.5-17.5. Folliculogenesis started before establishment of a complete follicular basal lamina. These observations indicate that embryonic thyroid differentiation is an asynchronous process consistent with the idea that progenitors attaining a stationary position in the connecting isthmus portion undergo apical polarization and generate follicles already at a primordial stage of thyroid development, i.e. foregoing growth of the lobes. Although the thyroid isthmus eventually comprises minute amounts of the total thyroid volume and contributes little to the overall hormone production, it is of principal interest that local cues related to the residence status of cells – independently of a prevailing high multiplication rate – govern the thyroid differentiation program. Copyright © 2021 Johansson, Liang, Moccia, Carlsson, Andersson, Fagman and Nilsson.
  •  
23.
  • Larsson, Fredrik, 1976, et al. (författare)
  • TSH receptor signaling via cyclic AMP inhibits cell surface degradation and internalization of E-cadherin in pig thyroid epithelium.
  • 2004
  • Ingår i: Cellular and molecular life sciences : CMLS. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 61:14, s. 1834-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Incorporation of E-cadherin into the adherens junction is a highly regulated process required to establish firm cell-cell adhesion in most epithelia. Less is known about the mechanisms that govern the clearance of E-cadherin from the cell surface in both normal and pathological states. In this study, we found that the steady-state removal of E-cadherin in primary cultured pig thyroid cell monolayers is slow and involves intracellular degradation. Experimental abrogation of adhesion by a Ca2+ switch induces rapid cell surface proteolysis of E-cadherin. At the same time, endocytosed intact E-cadherin and newly synthesized E-cadherin accumulate in intracellular compartments that largely escape further degradation. Acute stimulation with thyroid-stimulating hormone (TSH) or forskolin prevents all signs of accelerated E-cadherin turnover. The findings indicate that TSH receptor signaling via cyclic AMP stabilizes the assembly and retention of E-cadherin at the cell surface. This suggests a new mechanism by which TSH supports maintenance of thyroid follicular integrity.
  •  
24.
  • Liang, Shawn, 1981, et al. (författare)
  • A branching morphogenesis program governs embryonic growth of the thyroid gland
  • 2018
  • Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 145:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The developmental program that regulates thyroid progenitor cell proliferation is largely unknown. Here, we show that branching-like morphogenesis is a driving force to attain final size of the embryonic thyroid gland in mice. Sox9, a key factor in branching organ development, distinguishes Nkx2-1(+) cells in the thyroid bud from the progenitors that originally form the thyroid placode in anterior endoderm. As lobes develop the thyroid primordial tissue branches several generations. Sox9 and Fgfr2b are co-expressed distally in the branching epithelium prior to folliculogenesis. The thyroid in Fgf10 null mutants has a normal shape but is severely hypoplastic. Absence of Fgf10 leads to defective branching and disorganized angiofollicular units although Sox9/Fgfr2b expression and the ability of cells to differentiate and form nascent follicles are not impaired. These findings demonstrate a novel mechanism of thyroid development reminiscent of the Fgf10-Sox9 program that characterizes organogenesis in classical branching organs, and provide clues to aid understanding of how the endocrine thyroid gland once evolved from an exocrine ancestor present in the invertebrate endostyle.
  •  
25.
  • Lidell, Martin, 1970, et al. (författare)
  • Evidence for two types of brown adipose tissue in humans
  • 2013
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 19:5, s. 631-634
  • Tidskriftsartikel (refereegranskat)abstract
    • The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was
  •  
26.
  • Lidell, Martin, 1970, et al. (författare)
  • The Adipocyte-Expressed Forkhead Transcription Factor Foxc2 Regulates Metabolism Through Altered Mitochondrial Function
  • 2011
  • Ingår i: Diabetes. - 0012-1797. ; 60:2, s. 427-435
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin-sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function. RESEARCH DESIGN AND METHODS: The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR. The potential of a direct transcriptional regulation of regulated genes was tested in promoter assays, and mitochondrial morphology was investigated by electron microscopy. Mitochondrial function was tested by measuring oxygen consumption and extracellular acidification rates as well as palmitate oxidation. RESULTS: Enhanced expression of FOXC2 in adipocytes or in cells with no endogenous Foxc2 expression induces mitochondriogenesis and an elongated mitochondrial morphology. Together with increased aerobic metabolic capacity, increased palmitate oxidation, and upregulation of genes encoding respiratory complexes and of brown fat-related genes, Foxc2 also specifically induces mitochondrial fusion genes in adipocytes. Among tested forkhead genes, Foxc2 is unique in its ability to trans-activate the nuclear-encoded mitochondrial transcription factor A (mtTFA/Tfam) gene--a master regulator of mitochondrial biogenesis. In human adipose tissue the expression levels of mtTFA/Tfam and of fusion genes also correlate with that of Foxc2. CONCLUSIONS: We previously showed that a high-calorie diet and insulin induce Foxc2 in adipocytes; the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism.
  •  
27.
  • Lindencrona, Ulrika, 1971, et al. (författare)
  • Adsorption and volatility of free 211At and 125I-.
  • 2005
  • Ingår i: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine. - : Elsevier BV. - 0969-8043. ; 62:3, s. 395-403
  • Tidskriftsartikel (refereegranskat)abstract
    • The present study was undertaken to extend our knowledge of the behaviour of 211At in the laboratory environment. An unexpectedly high volatility of free 211At was found, up to 85% during an hour. Free 211At also adsorbed more onto the plastic material studied than 125I-. The results of this study show that it is of great importance to pay careful attention to radiation protection procedures during the practical handling of free 211At.
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28.
  • Lindencrona, Ulrika, 1971, et al. (författare)
  • Transport of free 211At and 125I- in thyroid epithelial cells: effects of anion channel blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid on apical efflux and cellular retention.
  • 2007
  • Ingår i: Nuclear medicine and biology. - : Elsevier BV. - 0969-8051. ; 34:5, s. 523-30
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Astatine ((211)At; alpha-emitter; t(1/2)=7.21 h) shares several features with its halogen neighbour iodine. In the present study, we investigated whether 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) can be used to increase the cellular retention time of (211)At and radioiodide in thyroid epithelial cells. METHODS: The transepithelial transport and cellular uptake of (211)At and (125)I(-) were studied simultaneously in porcine thyrocytes cultured in bicameral chambers. The cells were prestimulated with thyroid-stimulating hormone (TSH) or epidermal growth factor (EGF) for 48 h. In addition, the acute effects of DIDS and forskolin were investigated. RESULTS: The transepithelial transport of both radionuclides was stimulated by TSH and down-regulated by EGF. DIDS rapidly reduced the efflux and increased the cellular content of (125)I(-) in control and TSH-stimulated cells, whereas DIDS had no effect on (125)I(-) transport in EGF-treated cells. DIDS blocked the (211)At efflux only in TSH-stimulated cells. Unexpectedly, DIDS caused an accelerated efflux of (211)At in both control and EGF-stimulated cells and, furthermore, reduced the cellular content of (211)At in the EGF-stimulated cultures. DIDS had no effect on the forskolin-induced efflux of the two radionuclides. CONCLUSIONS: The magnitude of thyroidal (211)At uptake and efflux is similar to that of (125)I(-), strongly dependent on the functional activity of the cells. However, (211)At efflux likely involves several permeating mechanisms with different sensitivity to DIDS, which are at least partly not shared by (125)I(-). The results suggest that anion channel blockage is potentially useful to increase the absorbed dose from both (211)At and radioiodine in NIS-expressing tumours.
  •  
29.
  • Lundgren, Ted, 1959, et al. (författare)
  • Junctional proteins and Ca2+ transport in the rat odontoblast-like cell line MRPC-1.
  • 2001
  • Ingår i: Calcified tissue international. - 0171-967X. ; 68:3, s. 192-201
  • Tidskriftsartikel (refereegranskat)abstract
    • A transcellular bulk flow of Ca2+ ions through the odontoblast layer is of central importance during dentinogenesis. For this, specialized mechanisms may exist, which by a concerted action, gate Ca2+ into the proximal end of the cells and extrude the ions towards the mineralization front. To elucidate these mechanisms, an in vitro model would be useful. Mature odontoblasts are, however, post-mitotic cells and cannot be propagated in cell culture. The aim of the present study was, therefore, to characterize the odontoblast-like rat cell line MRPC-1(1) with regard to transcellular Ca2+ transport, barrier function, and intercellular junctions when cultured on membranes in Transwell chambers. The MRPC-1 cells grew as epithelial-like cells in a continuous bilayer separated by a thin collagenous matrix and with intercellular junctional complexes. They exhibited properties of a low-resistance epithelium, maintained a Ca(2+)-dependent diffusion barrier, and exhibited a functional diversity between the two cell layers. MRPC-1 cells expressed ZO-1, occludin, E-, and N-cadherins in addition to alpha-, beta-, gamma- and p120cat catenins, thereby demonstrating some traits in common with, but also differences from, epithelial cells and major differences from fibroblasts. The transcellular Ca2+ flux was inhibitable by nifedipine unidirectionally, giving evidence for an active intracellular Ca2+ transport through voltage-gated channels of the L-type. Similarities with native odontoblasts indicate that MRPC-1 cells may be useful for in vitro studies of transcellular Ca2+ transport mechanisms of importance for the calcification process.
  •  
30.
  • Lundh, Charlotta, 1977, et al. (författare)
  • Biodistribution of free 211At and 125I- in nude mice bearing tumors derived from anaplastic thyroid carcinoma cell lines.
  • 2006
  • Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 21:6, s. 591-600
  • Tidskriftsartikel (refereegranskat)abstract
    • Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC. METHODS: Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined. RESULTS: Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types. CONCLUSIONS: The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.
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31.
  • Lundh, Charlotta, 1977, et al. (författare)
  • Radiation-induced thyroid stunning: differential effects of (123)I, (131)I, (99m)Tc, and (211)At on iodide transport and NIS mRNA expression in cultured thyroid cells.
  • 2009
  • Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 50:7, s. 1161-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent clinical and experimental data demonstrate that thyroid stunning is caused by previous irradiation and may influence the efficacy of (131)I radiation therapy of thyroid cancer and possibly hyperthyroidism. To avoid stunning, many clinics have exchanged (131)I for (123)I for pretherapeutic diagnostic imaging and dose planning. Furthermore, recent in vitro studies indicate that (131)I irradiation reduces iodide uptake by downregulating the expression of the sodium iodide symporter (NIS). The rationale for this study was therefore to study effects on iodide transport and NIS messenger RNA (mRNA) expression in thyrocytes exposed to both (123)I and (131)I in addition to some other potentially interesting radionuclides. METHODS: Thyrotropin-stimulated thyroid cell monolayers were exposed to 0.5 Gy of (123)I, (131)I, (99m)Tc, or (211)At, all being radionuclides transported via NIS, in the culture medium for 6 h, or to various absorbed doses of (123)I or (131)I for 48 h. NIS mRNA expression was analyzed using quantitative reverse-transcriptase polymerase chain reaction. RESULTS: Iodide transport and NIS mRNA expression were reduced by all radionuclides. At the same absorbed dose, iodide transport was reduced the most by (211)At, followed by (123)I and (99m)Tc (equally potent), whereas (131)I was least effective. The onset of NIS downregulation was rapid (<1 d after irradiation) in cells exposed to (123)I or (211)At and was delayed in cells irradiated with (131)I or (99m)Tc. Iodide transport and NIS expression were recovered only for (211)At. (123)I reduced the iodine transport and the NIS mRNA expression more efficiently than did (131)I at an equivalent absorbed dose, with a relative biological effectiveness of about 5. CONCLUSION: The stunning effect per unit absorbed dose is more severe for (123)I than for (131)I. Despite the lower absorbed dose per unit activity for (123)I than for (131)I, stunning by (123)I cannot be excluded in patients. The degree to which iodide transport capacity and NIS mRNA expression are reduced seems to be related to the biological effectiveness of the type of radiation delivering the absorbed dose to the target, with (211)At (which has the highest relative biological effectiveness) causing the highest degree of stunning per unit absorbed dose in the present study.
  •  
32.
  • Lundh, Charlotta, 1977, et al. (författare)
  • Reduced iodide transport (stunning) and DNA synthesis in thyrocytes exposed to low absorbed doses from 131I in vitro.
  • 2007
  • Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 48:3, s. 481-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Thyroid stunning refers to reduced uptake of (131)I in the thyroid tissue (or tumor) during radioiodine ((131)I) therapy compared with the uptake measured after the previous administration of (131)I for diagnostic purposes. The phenomenon is clinically important, as it can potentially lead to the undertreatment of thyroid cancer or to unnecessarily high absorbed doses in critical organs. Previous clinical and experimental studies indicated that thyroid stunning is absorbed dose dependent. The aim of this study was to investigate the effects of (131)I irradiation on (125)I(-) transport and cell proliferation at low absorbed doses in vitro. METHODS: Primary cultured porcine thyroid cells were grown to form a confluent monolayer of epithelial cells on a filter in a bicameral culture system. The cells were continuously irradiated with (131)I in the culture medium for 48 h to obtain 0.0015-1.5 Gy. At 3 d after irradiation was stopped, the transepithelial iodide transport capacity was evaluated by measuring (125)I(-) transport from the basal chamber compartment to the apical chamber compartment. The effect of (131)I irradiation on DNA synthesis was estimated by pulse labeling with (3)H-thymidine of both subconfluent and confluent cells irradiated with up to 9 Gy. Total DNA content was measured to quantify cell numbers. RESULTS: A statistically significant reduction in (125)I(-) transport was seen at absorbed doses of >or=0.15 Gy, with a 50% reduction at 1.5 Gy, compared with the results observed for nonirradiated control cells. (3)H-Thymidine incorporation was already statistically significantly reduced at absorbed doses of 0.01-0.1 Gy, but 0.15-0.3 Gy did not affect DNA synthesis. However, absorbed doses of >or=1 Gy again resulted in reduced DNA synthesis. A 50% reduction was obtained at 4 Gy. Total DNA measurements revealed a statistically significant reduction in cell numbers at 8 Gy. CONCLUSION: The lowest absorbed dose from (131)I that reduced iodide transport was 0.15 Gy. Because stunning was found at low absorbed doses, it might occur for (131)I treatment not only of thyroid cancer but also of thyrotoxicosis. On the basis of differences in dose responses, radiation-induced thyroid stunning and cell cycle arrest may be independent phenomena.
  •  
33.
  • Lyckesvärd, Madeleine Nordén, et al. (författare)
  • Linking loss of sodium-iodide symporter expression to DNA damage
  • 2016
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 344:1, s. 120-131
  • Tidskriftsartikel (refereegranskat)abstract
    • Radiotherapy of thyroid cancer with I-131 is abrogated by inherent loss of radioiodine uptake due to loss of sodium iodide symporter (NIS) expression in poorly differentiated tumor cells. It is also known that ionizing radiation per se down-regulates NIS (the stunning effect), but the mechanism is unknown. Here we investigated whether loss of NIS-mediated iodide transport may be elicited by DNA damage. Calicheamicin, a fungal toxin that specifically cleaves double-stranded DNA, induced a full scale DNA damage response mediated by the ataxia-telangiectasia mutated (ATM) kinase in quiescent normal thyrocytes. At sublethal concentrations (< 1 nM) calicheamicin blocked NIS mRNA expression and transepithelial iodide transport as stimulated by thyrotropin; loss of function occurred at a much faster rate than after I-131 irradiation. KU-55933, a selective ATM kinase inhibitor, partly rescued NIS expression and iodide transport in DNA-damaged cells. Prolonged ATM inhibition in healthy cells also repressed NIS-mediated iodide transport. ATM-dependent loss of iodide transport was counteracted by IGF-1. Together, these findings indicate that NIS, the major iodide transporter of the thyroid gland, is susceptible to DNA damage involving ATM-mediated mechanisms. This uncovers novel means of poor radioiodine uptake in thyroid cells subjected to extrinsic or intrinsic genotoxic stress. (C) 2016 Elsevier Inc. All rights reserved.
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34.
  • Macedo, António Filipe, Senior Lecturer, 1976-, et al. (författare)
  • Predictors of problems reported on the EQ-5D-3L dimensions among people with impaired vision in northern Portugal
  • 2022
  • Ingår i: Health and Quality of Life Outcomes. - : BioMed Central (BMC). - 1477-7525. ; 20:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:The EQ-5D index often fails to detect the effect of ophthalmic diseases and sight loss. Investigating predictors of individual EQ-5D health dimensions might reveal the underlying reasons. The aim of this study was to investigate predictors of health dimension ratings obtained with the EQ-5D-3L from participants with impaired vision representing a spectrum of eye diseases.Methods: Observational cross-sectional study with participants recruited at four public hospitals in Portugal. Outpatients with visual acuity of 0.30 logMAR(6/12) or worse in the better-seeing eye were invited to participate. Participants completed two instruments: the EQ-5D-3L (measures participants’ perceived health-related quality-of-life) and the Massof Activity Inventory (measures visual ability–ability to perform vision-related activities). This study used logistic regression models to identify factors associated with responses to the EQ-5D-3L.Results: The study included 492 participants, mean age 63.4 years (range = 18–93), 50% females. The most common diagnosis was diabetic retinopathy (37%). The mean visual acuity in the better seeing eye was 0.65 logMAR (SD = 0.48) and the mean visual ability was 0.62 logits (SD = 2.04), the correlation between the two was r = − 0.511 (p < 0.001). Mobility and self-care were the health dimensions with the fewest problems (1% reported extreme problems), anxiety and depression the dimension with the most problems (24% reported extreme problems). ROC curve analysis showed that the EQ-5D index was a poor predictor of cases of vision impairment whilst visual ability given was a good predictor of cases of vision impairment. Visual ability was an independent predictor of the response for all dimensions, higher ability was always associated with a reduced odds of reporting problems. The odds of reporting problems were increased for females in 3 out of 5 dimensions. Comorbidities, visual acuity and age-category were predictors of the odds of reporting problems for one dimension each.Conclusions: The odds of reporting problems for the five health dimensions of the EQ-5D-3L were strongly influenced by the ability to perform vision-related activities (visual ability). The EQ-5D index showed poor performance at detecting vision impairment. These findings are informative and relevant for the clinic and for research evaluating the impact of eye diseases and disease treatments in ophthalmology.
  •  
35.
  • Malmberg, Per, 1974, et al. (författare)
  • Depth profiling of cells and tissues by using C-60(+) and SF5+ as sputter ions
  • 2007
  • Ingår i: APPLIED SURFACE SCIENCE. - : Elsevier BV. - 0169-4332. ; 255:4, s. 926-928
  • Tidskriftsartikel (refereegranskat)abstract
    • In the present study, SF5+ and C-60(+) were used as primary ions for sputtering and Bi-3(+) was used as primary ions for analysis. The depth profiling procedure was utilized to make 3D images of the chemistry of single cultured cells and tissue samples of intact intestinal epithelium. The results show sputtering of organic material from cells and tissue with both SF5+ and C-60(+) sources. Cholesterol fragments were found in the superficial layers when sputtering with C-60(+). Spectra were collected revealing the change in yield along the z-axis of the sample. 3D images of the localization of Na, K, phosphocholine and cholesterol were constructed with both ion sources for single cell cultures and the mouse intestine. Cryostate sections of mouse intestine were analysed in 2D and the results were compared with the 3D image of the intestine. The localization of cholesterol and phosphocholine was found to be similar in cryostate sections analysed in two dimensions and the sputtered, freeze-dried intestine analysed in 3D. The comparison of 2D and 3D images suggest that the phosphocholine signal faded with C-60(+) sputtering. In conclusion, both C-60(+) and SF5+ can be used as primary ion sources for sputtering of organic material from cells and tissues. Consecutive analysis with a Bi-3(+) source can be used to obtain image stacks that could be used for reconstruction of 3D images. (C) 2008 Elsevier B. V. All rights reserved.
  •  
36.
  • Nilsson, Daniel, 1975, et al. (författare)
  • Foxc2 is essential for podocyte function.
  • 2019
  • Ingår i: Physiological reports. - : Wiley. - 2051-817X. ; 7:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Foxc2 is one of the earliest podocyte markers during glomerular development. To circumvent embryonic lethal effects of global deletion of Foxc2, and to specifically investigate the role of Foxc2 in podocytes, we generated mice with a podocyte-specific Foxc2 deletion. Mice carrying the homozygous deletion developed early proteinuria which progressed rapidly into end stage kidney failure and death around postnatal day 10. Conditional loss of Foxc2 in podocytes caused typical characteristics of podocyte injury, such as podocyte foot process effacement and podocyte microvillus transformation, probably caused by disruption of the slit diaphragm. These effects were accompanied by a redistribution of several proteins known to be necessary for correct podocyte structure. One target gene that showed reduced glomerular expression was Nrp1, the gene encoding neuropilin 1, a protein that has been linked to diabetic nephropathy and proteinuria. We could show that NRP1 was regulated by Foxc2 invitro, but podocyte-specific ablation of Nrp1 in mice did not generate any phenotype in terms of proteinuria, suggesting that the gene might have more important roles in endothelial cells than in podocytes. Taken together, this study highlights a critical role for Foxc2 as an important gene for podocyte function.
  •  
37.
  • Nilsson, I. A. K., et al. (författare)
  • Plasma neurofilament light chain concentration is increased in anorexia nervosa
  • 2019
  • Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (median(AN) = 15.6 pg/ml, IQR(AN) = 12.1-21.3, median(CTRL) = 9.3 pg/ml, IQR(CTRL) = 6.4-12.9, and p < 0.0001), AN vs AN-REC (median(AN-REC) = 11.1 pg/ml, IQR(AN-REC) = 8.6-15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (beta (+/- se) = -0.62 +/- 0.087 and p = 6.9. 10(-12)). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.
  •  
38.
  • Nilsson, Mikael, 1958, et al. (författare)
  • Development of the thyroid gland
  • 2017
  • Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 144:12, s. 2123-2140
  • Forskningsöversikt (refereegranskat)abstract
    • Thyroid hormones are crucial for organismal development and homeostasis. In humans, untreated congenital hypothyroidism due to thyroid agenesis inevitably leads to cretinism, which comprises irreversible brain dysfunction and dwarfism. Elucidating how the thyroid gland - the only source of thyroid hormones in the body - develops is thus key for understanding and treating thyroid dysgenesis, and for generating thyroid cells in vitro that might be used for cell-based therapies. Here, we review the principal mechanisms involved in thyroid organogenesis and functional differentiation, highlighting how the thyroid forerunner evolved from the endostyle in protochordates to the endocrine gland found in vertebrates. New findings on the specification and fate decisions of thyroid progenitors, and the morphogenesis of precursor cells into hormone-producing follicular units, are also discussed.
  •  
39.
  • Nilsson, Mikael, 1958, et al. (författare)
  • Mechanisms of thyroid development and dysgenesis: an analysis based on developmental stages and concurrent embryonic anatomy
  • 2013
  • Ingår i: Current Topics in Developmental Biology. Volum 106. Endocrine Gland Development and Disease. - Burlington : Elsevier. - 9780124160217 ; , s. 123-170
  • Bokkapitel (refereegranskat)abstract
    • Thyroid dysgenesis is the most common cause of congenital hypothyroidism that affects 1 in 3000 newborns. Although a number of pathogenetic mutations in thyroid developmental genes have been identified, the molecular mechanism of disease is unknown in most cases. This chapter summarizes the current knowledge of normal thy- roid development and puts the different developmental stages in perspective, from the time of foregut endoderm patterning to the final shaping of pharyngeal anatomy, for understanding how specific malformations may arise. At the cellular level, we will also discuss fate determination of follicular and C-cell progenitors and their subsequent embryonic growth, migration, and differentiation as the different thyroid primordia evo- lve and merge to establish the final size and shape of the gland.
  •  
40.
  •  
41.
  • Nordén, Madeleine, 1979, et al. (författare)
  • Down-regulation of the sodium/iodide symporter explains 131I-induced thyroid stunning.
  • 2007
  • Ingår i: Cancer research. - 0008-5472. ; 67:15, s. 7512-7
  • Tidskriftsartikel (refereegranskat)abstract
    • (131)I radiation therapy of differentiated thyroid cancer may be compromised by thyroid stunning (i.e., a paradoxical inhibition of radioiodine uptake caused by radiation from a pretherapeutic diagnostic examination). The stunning mechanism is yet uncharacterized at the molecular level. We therefore investigated whether the expression of the sodium/iodide symporter (NIS) gene is changed by irradiation using (131)I. Confluent porcine thyroid cells on filter were stimulated with thyroid-stimulating hormone (TSH; 1 milliunit/mL) or insulin-like growth factor-I (IGF-I; 10 ng/mL) and simultaneously exposed to (131)I in the culture medium for 48 h, porcine NIS mRNA was quantified by real-time reverse transcription-PCR using 18S as reference, and transepithelial iodide transport was monitored using (125)I(-) as tracer. TSH increased the NIS expression >100-fold after 48 h and 5- to 20-fold after prolonged stimulation. IGF-I enhanced the NIS transcription at most 15-fold but not until 5 to 7 days. (131)I irradiation (7.5 Gy) decreased both TSH-stimulated and IGF-I-stimulated NIS transcription by 60% to 90% at all investigated time points. TSH and IGF-I stimulated NIS synergistically 15- to 60-fold after 5 days. NIS expression was reduced by (131)I also in costimulated cells, but the transcription level remained higher than in nonirradiated cells stimulated with TSH alone. Changes in NIS mRNA always correlated with altered (125)I(-) transport in cultures with corresponding treatments. It is concluded that down-regulation of NIS is the likely explanation of (131)I-induced thyroid stunning. Enhanced NIS expression by synergistically acting agents (TSH and IGF-I) partly prevents the loss of iodide transport expected from a given absorbed dose, suggesting that thyroid stunning might be pharmacologically treatable.
  •  
42.
  • Nygren, Håkan, 1952, et al. (författare)
  • Bioimaging TOF-SIMS: High resolution 3D imaging of single cells.
  • 2007
  • Ingår i: Microscopy research and technique. - : Wiley. - 1059-910X .- 1097-0029. ; 70:11, s. 969-74
  • Tidskriftsartikel (refereegranskat)abstract
    • The distribution of phosphocholine ions (m/z 184, m/z 86), sodium ions, and potassium ions in thyroid tumor cells was analyzed by imaging TOF-SIMS. Repeated sputtering with a C(60) (+) source and subsequent analysis with a Bi(3) (+) gun produced a series of 138 images that were stacked to make a 3D display of the chemistry of cells. Phosphocholine was seen in the plasma membrane (m/z 184) and intracellular membranes (m/z 86). The different fragmentation of the phospholipid probably reflects the chemical composition of membranes at these sites. High intensity of secondary ion signals of potassium was seen in membrane-encompassed cellular compartments. The data indicate that potassium ions are compartmentalized in thyroid tumor cells.
  •  
43.
  • Postgård, Per, et al. (författare)
  • Stunning of iodide transport by (131)I irradiation in cultured thyroid epithelial cells.
  • 2002
  • Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 0161-5505. ; 43:6, s. 828-34
  • Tidskriftsartikel (refereegranskat)abstract
    • The existence of thyroid stunning (i.e., inhibited thyroidal iodide uptake after administration of diagnostic amounts of (131)I) is controversial and is currently a subject of debate. To our knowledge, the stunning phenomenon has not been investigated previously in vitro. METHODS: Growth-arrested porcine thyroid cells that formed a tight and polarized monolayer in a bicameral chamber were irradiated with 3-80 Gy (131)I present in the surrounding culture medium for 48 h. The iodide transport capacity after irradiation was evaluated 3 d later by measuring the transepithelial (basal to apical) flux of trace amounts of (125)I. RESULTS: The basal-to-apical (125)I transport decreased with increasing absorbed dose acquired from (131)I; a nearly 50% reduction was observed already at 3 Gy. Stable iodide at the same molarity as (131)I (10(-8) mol/L) had no effect on the (125)I transport. Cell number and epithelial integrity were not affected by irradiation. CONCLUSION: Stunning of iodide transport is detected after (131)I irradiation of cultured thyroid cells. The degree of inhibition of transport is dependent on the absorbed dose.
  •  
44.
  • Rask, Mikael, 1958-, et al. (författare)
  • Validity and reliability of a Swedish version of the Relationship Assessment Scale (RAS) : a pilot study
  • 2010
  • Ingår i: Canadian journal of cardiovascular nursing. - Ottawa : Canadian Council of Cardiovascular Nurses. - 0843-6096. ; 20:1, s. 16-21
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There is a need for a short and easily administered scale, in the Swedish language, for assessing partner relationships in the health care of persons with cardiac disease. PURPOSE: To establish the reliability and validity of the Swedish version of the Relationship Assessment Scale (RAS). DESIGN: The present pilot study has a methodological design. FINDINGS: Content validity has been tested for relevance, clarity and readability. The scale was tested for construct validity with explorative factor analysis. The reliability was tested by internal consistency and test-retest analysis. The result showed a two-factor solution, which does not correspond to the original proposed one-factor solution. The factor analyses revealed two quite distinct factors of RAS, labelled "Relationship built on expectations and satisfaction of needs" and "Relationship built on love and devotion". CONCLUSIONS: The scale has satisfactory psychometric properties in terms of content validity, construct validity, homogeneity and stability in a population of persons with cardiac disease. Wider evaluations of the RAS for other populations and settings are recommended.
  •  
45.
  • Sandblom, Viktor, 1987, et al. (författare)
  • Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.
  • 2019
  • Ingår i: PloS One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
  •  
46.
  • Sandblom, Viktor, 1987, et al. (författare)
  • Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors : Increased effect on medullary thyroid cancer by combining radiation with tyrosine kinase inhibitors
  • 2020
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.
  •  
47.
  •  
48.
  • Sandblom, Viktor, 1987, et al. (författare)
  • Tyrosinkinashämmare kan öka effekten från strålbehandling av medullär tyreoideacancer
  • 2019
  • Ingår i: Nationellt möte om sjukhusfysik.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • SYFTE Medullär tyreoideacancer (MTC) är en neuroendokrin cancertyp som har sitt ursprung i sköldkörtelns hormonproducerande C-celler. Många MTC överuttrycker receptorer för somatostatin vilket möjliggör radionuklidterapi med exempelvis 177Lu-oktreotat. Få patienter botas dock helt och optimering av behandlingen behövs. Ett sätt att optimera behandlingen är att kombinera 177Lu-oktreotat med ett annat läkemedel i syfte att öka effekten från strålningen. Nyligen godkändes två tyrosinkinashämmare (vandetanib och cabozantinib) för behandling av MTC. Syftet med denna studie var att undersöka ifall en ökad effekt kan fås då strålbehandling kombineras med tyrosinkinashämmare för behandling av MTC. METOD Nakna möss (BALB/c) transplanterades med humana MTC-celler (GOT2) och behandlades med extern strålbehandling och/eller tyrosinkinashämmare. Behandlings-effekten, som tumörvolym efter behandling, jämfördes med den hos obehandlade möss. För att möjliggöra detektion av en eventuellt ökad behandlingseffekt hos de möss som fick kombinationsbehandling (både strålbehandling och tyrosinkinas¬hämmare) valdes den absorberade dosen och mängden läkemedel så att en suboptimal effekt erhölls då respektive behandling gavs som singelbehandling. RESULTAT Kombinationsbehandling resulterade i störst minskning av tumörvolym och längst tid till progression. Exempelvis hade tumörvolymen hos de möss som fick kombinationsbehandling minskat med ca 70-75% efter två veckor jämfört med obehandlade möss. Även som singelbehandling resulterade båda behandlingar i en tydlig effekt på tumörvolymen, med en minskning på ca 50-65% efter två veckor. KONKLUSIONER Effekten från strålbehandling av möss med MTC-tumörer kan ökas genom kombinationsbehandling med tyrosinkinashämmare. Framtida studier bör utvärdera möjligheten att använda en kombination av 177Lu-oktreotat och tyrosinkinashämmare för behandling av patienter med MTC.
  •  
49.
  • Schoultz, Elin, et al. (författare)
  • Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor
  • 2023
  • Ingår i: ISCIENCE. - 2589-0042. ; 26:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Cells of origin in cancer determine tumor phenotypes, but whether lineage-defining transcription factors might influence tissue specificity of tumorigenesis among organs with similar developmental traits are unknown. We demonstrate here that tumor development and progression markedly differ in lung and thyroid targeted by Braf mutation in Nkx2.1CreER(T2) mice heterozygous for Nkx2-1. In absence of tamoxifen, non-induced Nkx2.1CreER(T2);Braf(CA/+) mutants developed multiple full-blown lung adenocarcinomas with a latency of 1-3 months whereas thyroid tumors were rare and constrained, although minute Braf(CA) activation documented by variant allele sequencing was similar in both tissues. Induced oncogene activation accelerated neoplastic growth only in the lungs. By contrast, NKX2-1(+) progenitor cells were equally responsive to constitutive expression of mutant Braf during lung and thyroid development. Both lung and thyroid cells transiently downregulated NKX2-1 in early tumor stages. These results indicate that BRAF(V600E)-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.
  •  
50.
  • Sukonina, Valentina, et al. (författare)
  • FOXK1 and FOXK2 regulate aerobic glycolysis.
  • 2019
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
  • Tidskriftsartikel (refereegranskat)abstract
    • Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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