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  • 1.
    Chu, Xia
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Monazzan, Azita
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Razmara, Masoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Quantitative Protein Profiling of Adrenal Glands in a Men1 Mouse ModelManuskript (preprint) (Annet vitenskapelig)
  • 2.
    Kolliopoulos, Constantinos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Raja, Erna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Razmara, Masoud
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Heldin, Paraskevi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Heldin, Carl-Henrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    van der Heide, Lars P
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output2019Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, nr 11, s. 4119-4136Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    TGFβ signaling via SMAD proteins and protein kinase pathways up- or down-regulates the expression of many genes and thus affects physiological processes, such as differentiation, migration, cell cycle arrest, and apoptosis during developmental or adult tissue homeostasis. We here report that NUAK family kinase 1 (NUAK1) and NUAK2 are two TGFβ target genes. NUAK1/2 belong to the AMP-activated protein kinase (AMPK) family, whose members control central and protein metabolism, polarity and overall cellular homeostasis. We found that TGFβ-mediated transcriptional induction of NUAK1 and NUAK2 requires SMAD family members 2, 3 and 4 (SMAD2/3/4) and mitogen activated protein kinase (MAPK) activities, which provided immediate and early signals for the transient expression of these two kinases. Genomic mapping identified an enhancer element within the first intron of the NUAK2 gene that can recruit SMAD proteins, which, when cloned, could confer induction by TGFβ.  Furthermore, NUAK2 formed protein complexes with SMAD3 and the TGFβ type I receptor. Functionally, NUAK1 suppressed and NUAK2 induced TGFβ signaling. This was evident during TGFβ-induced epithelial cytostasis, mesenchymal differentiation and myofibroblast contractility, in which NUAK1 or NUAK2 silencing enhanced or inhibited these responses, respectively. In conclusion, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity.

    Fulltekst (pdf)
    fulltext
  • 3.
    Monazzam, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Li, Su-Chen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Razmara, Masoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

    Fulltekst (pdf)
    fulltext
  • 4.
    Razmara, M
    et al.
    Karolinska institutet.
    Hjemdahl, P
    Ostenson, C-G
    Li, N
    Platelet hyperprocoagulant activity in Type 2 diabetes mellitus: attenuation by glycoprotein IIb/IIIa inhibition.2008Inngår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, nr 12, s. 2186-92Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Platelets are hyperactive in Type 2 diabetes mellitus (T2DM), and antiplatelet treatment with glycoprotein (GP) IIb/IIIa inhibitors provides better thrombotic protection in DM than in non-diabetic subjects.

    OBJECTIVE: We hypothesized that diabetic platelets are hyperprocoagulant, and that this hyperactivity can be inhibited by GPIIb/IIIa blockade.

    METHODS: Patients with T2DM and gender/age/body mass index-matched non-diabetic controls were recruited (n = 12 for both) to study the effect of GPIIb/IIIa blockade on platelet procoagulant activity. Platelet phosphotidylserine (PS), factor (F) Va expression, and platelet-derived microparticle (PDMP) generation were measured by whole blood flow cytometry. Platelet-dependent thrombin generation and plasma clotting time were monitored in recalcified platelet-rich plasma.

    RESULTS: Compared to controls, basal platelet activation was similar, while thrombin receptor activating peptide stimulated activation was enhanced in patients with T2DM. Diabetic platelets also displayed more profound elevations of platelet PS exposure, FVa binding, and PDMP generation upon stimulation. These alterations resulted in a hyperprocoagulant state, as evidenced by a marked increase in the platelet procoagulant index, enhanced thrombin generation, and a shortened plasma clotting time. GPIIb/IIIa blockade by c7E3 or SR121566 decreased platelet PS exposure and FVa binding, and diminished platelet procoagulant activity in patients with T2DM.

    CONCLUSIONS: Platelets have increased procoagulant activity in patients with T2DM. The hyperprocoagulant activity is counteracted by GPIIb/IIIa blockade.

  • 5.
    Razmara, M
    et al.
    Karolinska institutet.
    Hu, H
    Masquelier, M
    Li, N
    Glycoprotein IIb/IIIa blockade inhibits platelet aminophospholipid exposure by potentiating translocase and attenuating scramblase activity.2007Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 64, nr 7-8, s. 999-1008Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study investigated the mechanisms underlying the inhibition of platelet phosphatidylserine (PS) exposure by GPIIb/IIIa blockade. Platelet PS exposure induced by thrombin stimulation was cell-cell contact dependent. GPIIb/IIIa blockade by c7E3 or SR121566 inhibited thrombin-induced platelet PS exposure. Thrombin stimulation induced mild, while A23187 induced extensive platelet-derived microparticle (PDMP) generation. Thrombin-induced PDMP generation was not inhibited by GPIIb/IIIa blockade. Aminophospholipid translocase activity was reduced upon platelet activation by thrombin. The reduction of non-PS-exposing platelets was attenuated by GPIIb/IIIa blockade, while little translocase activity was seen in PS-exposing platelets. Thrombin increased scramblase activity slightly in non-PS-exposing platelets, which was inhibited by GPIIb/IIIa blockade, and markedly enhanced scramblase activity in PS-exposing platelets. Activation of platelet calpain and caspase-3 or cytosolic calcium mobilization were not altered by GPIIb/IIIa inhibition. Thus, GPIIb/IIIa blockade inhibits platelet PS exposure by enhancing translocase activity and attenuating scramblase activity, but does not inhibit PDMP generation.

  • 6.
    Razmara, Masoud
    Karolinska institutet.
    Effects of high glucose on platelet activation2006Licentiatavhandling, med artikler (Annet vitenskapelig)
  • 7.
    Razmara, Masoud
    Karolinska institutet.
    Platelet dysfunction in diabetes: Impact of hyperglycemia and GPIIb/IIIa inhibition2009Doktoravhandling, med artikler (Annet vitenskapelig)
  • 8.
    Razmara, Masoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Eger, Glenda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Rorsman, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    MKP3 negatively modulates PDGF-induced Akt and Erk5 phosphorylation as well as chemotaxis2012Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, nr 3, s. 635-640Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MAP kinase phosphatase-3 (MKP3), also known as DUSP6 or Pyst1, is a dual specificity phosphatase considered to selectively dephosphorylate extracellular-signal-regulated kinase 1/2 (Erk1/2). Here, we report that in NIH3T3 cells, MKP3 is induced in response to platelet-derived growth factor (PDGF)-BB treatment in an Erk1/2- and phosphatidylinositol 3-kinase (PI3K)-dependent manner, but independently of Erk5 expression. Silencing of MKP3 expression did not affect PDGF-BB-induced Erk1/2 or p38 phosphorylation; however, their basal level of phosphorylation was elevated. Furthermore, we found that PDGF-BB-mediated activation of Erk5 and Akt was enhanced when the MKP3 expression was reduced. Interfering with Mek1/2 or PI3K using the inhibitors CI-1040 and LY-294002, respectively, inhibited PDGF-BB-induced MKP3 expression. Functionally, we found that MKP3 silencing did not affect cell proliferation, but enhanced the chemotactic response toward PDGF-BB. Although both Akt and Erk5 have been linked to increased cell survival, downregulation of MKP3 did not alter the ability of PDGF-BB to protect NIH3T3 cells from starvation-induced apoptosis. However, we observed an increased apoptosis in untreated cells with reduced MKP3 expression. In summary, our data indicate that there is negative cross-talk between Erk1/2 and Erk5 that involves regulation of MKP3 expression, and that PI3K in addition to promoting Akt phosphorylation also negatively modulates Akt, through MKP3 expression.

  • 9.
    Razmara, Masoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Platelet-derived growth factor-induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-gamma1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D2013Inngår i: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 11, nr 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

     

    Mammalian target of rapamycin (mTOR) can be found in two multi-protein complexes, i.e. mTORC1 (containing Raptor) and mTORC2 (containing Rictor). Here, we investigated the mechanisms by which mTORC1 and mTORC2 are activated and their downstream targets in response to platelet-derived growth factor (PDGF)-BB treatment. Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2. We found that in Rictor-null mouse embryonic fibroblasts, or after prolonged rapamycin treatment of NIH3T3 cells, PDGF-BB was not able to promote phosphorylation of Ser473 in the serine/threonine kinase Akt, whereas Thr308 phosphorylation was less affected, suggesting that Ser473 in Akt is phosphorylated in an mTORC2-dependent manner. This reduction in Akt phosphorylation did not influence the phosphorylation of the S6 protein, a well established protein downstream of mTORC1. Consistently, triciribine, an inhibitor of the Akt pathway, suppressed PDGF-BB-induced Akt phosphorylation without having any effect on S6 phosphorylation. Thus, mTORC2 does not appear to be upstream of mTORC1. We could also demonstrate that in Rictor-null cells the phosphorylation of phospholipase Cgamma1 (PLCgamma1) and protein kinase C (PKC) was impaired, and the PKCalpha protein levels strongly reduced. Furthermore, interfering with the PLCgamma/Ca2+/PKC pathway inhibited PDGF-BB-induced Akt phosphorylation. In addition, PDGF-BB-induced activation of mTORC1, as measured by phosphorylation of the downstream S6 protein, was dependent on phospholipase D (PLD). It has been shown that Erk1/2 MAP-kinase directly phosphorylates and activates mTORC1; in partial agreement with this finding, we found that a Mek1/2 inhibitor delayed S6 phosphorylation in response to PDGF-BB, but it did not block it. Thus, whereas both mTORC1 and mTORC2 are activated in a PI3K-dependent manner, different additional signaling pathways are needed. mTORC1 is activated in a PLD-dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2, in concert with PLCgamma signaling, promotes Akt phosphorylation.

  • 10.
    Razmara, Masoud
    et al.
    Karolinska institutet.
    Hjemdahl, Paul
    Yngen, Marianne
    Ostenson, Claes-Göran
    Wallén, N Håkan
    Li, Nailin
    Food intake enhances thromboxane receptor-mediated platelet activation in type 2 diabetic patients but not in healthy subjects.2007Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 30, nr 1, s. 138-40Artikkel i tidsskrift (Fagfellevurdert)
  • 11.
    Razmara, Masoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Monazzam, Azita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration2018Inngår i: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, artikkel-id 64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin.

    METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells.

    RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells.

    CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.

    Fulltekst (pdf)
    fulltext
  • 12.
    Stålberg, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Razmara, Masoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Taslica, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Ståhlberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    An Integrative Genomic Analysis of Formalin Fixed Paraffin-Embedded Archived Serous Ovarian Carcinoma Comparing Long-term and Short-term Survivors2016Inngår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, nr 6, s. 1027-1032Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    This study aimed to perform an integrative genetic analysis of patients with matched serous ovarian cancer having long-term or short-term survival using formalin fixed paraffin-embedded (FFPE) tissue samples.

    METHODS:

    All patients with serous ovarian carcinoma who underwent surgery between 1998 and 2007 at the Department of Gynaecology, Uppsala University Hospital, Sweden were considered. From this cohort, we selected biomaterial from 2 groups of patients with long-term and short-term survival matched for age, stage, histologic grade, and outcome of surgery. Genomic DNA from FFPE sample was analyzed with SNP array and targeted next-generation sequencing of 26 genes.

    RESULTS:

    Forty-three samples (primary tumors and metastases) from 23 patients were selected for genomic profiling, the survival in the subgroups were 134 and 36 months, respectively. We observed a tendency toward increased genomic instability in those with long-term survival with higher proportion of somatic copy number alterations (P = 0.083) and higher average ploidy (P = 0.037). TP53 mutations were found in 50% of the patients. Frequency of TP53 mutations did not differ between the survival groups (P = 0.629).

    CONCLUSIONS:

    We validated both previous genomic findings in ovarian cancer and the proposed association between increased genomic instability and better survival. These results exemplify that analysis of genomic biomarkers is feasible on archived FFPE tissue.

  • 13. Sudic, Dzana
    et al.
    Razmara, Masoud
    Karolinska institutet.
    Forslund, Mikael
    Ji, Qiushang
    Hjemdahl, Paul
    Li, Nailin
    High glucose levels enhance platelet activation: involvement of multiple mechanisms.2006Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 133, nr 3, s. 315-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diabetes mellitus (DM) and hyperglycaemia are associated with platelet activation. The present study was designed to investigate how high glucose levels influence platelet function. Fasting human blood was incubated with different concentrations of D-glucose (5, 15 and 30 mmol/l) and other sugars without or with in vitro stimuli. Platelet activation was monitored by whole blood flow cytometry. High glucose levels enhanced adenosine diphosphate (ADP)- and thrombin receptor-activating peptide (TRAP)-induced platelet P-selectin expression, and TRAP-induced platelet fibrinogen binding. Similar effects were seen with 30 mmol/l L-glucose, sucrose and galactose. Hyperglycaemia also increased TRAP-induced platelet-leucocyte aggregation. Protein kinase C (PKC) blockade did not counteract the enhancement of platelet P-selectin expression, but abolished the enhancement of TRAP-induced platelet fibrinogen binding by hyperglycaemia. Superoxide anion scavenging by superoxide dismutase (SOD) attenuated the hyperglycaemic enhancement of platelet P-selectin expression, but did not counteract the enhancement of TRAP-induced platelet fibrinogen binding. Hyperglycaemia did not alter platelet intracellular calcium responses to agonist stimulation. Blockade of cyclo-oxygenase (COX), phosphotidylinositol-3 (PI3) kinase, or nitric oxide synthase, or the addition of insulin did not influence the effect of hyperglycaemia. In conclusion, high glucose levels enhanced platelet reactivity to agonist stimulation through elevated osmolality. This occurred via superoxide anion production, which enhanced platelet P-selectin expression (secretion), and PKC signalling, which enhanced TRAP-induced fibrinogen binding (aggregablity).

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