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  • D'Arcy, Pádraig, et al. (författare)
  • Inhibition of proteasome deubiquitinating activity as a novel cancer therapy
  • 2011
  • Ingår i: Nature Medicine. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1546-170X. ; 40
  • Tidskriftsartikel (refereegranskat)abstract
    • Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.
  • Olsson-Stromberg, Ulla, et al. (författare)
  • Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy plus G-CSF in patients with chronic myelogenous leukemia in first chronic phase
  • 2006
  • Ingår i: Leukemia & Lymphoma. - Taylor & Francis. - 1042-8194. ; 47:9, s. 1768-1773
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients 556 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m(2) and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m(2) 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 mu g s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34(+) cells was > 5/ml blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m(2)/day and 1 hour i.v infusion, etoposide 100 mg/m(2)/day and 1 hour i.v. infusion and ara-C 1g/m(2)/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 mg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC > 3.5 x 10(8)/kg, CFU-GM > 1.0 x 10(4)/kg, CD34(+) cells > 2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n=16] or partially successfully ( as defined above but 1-34% Ph+ cells in the apheresis product) [n=7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN < 0.5 x 10(9)/l was 10 (range 7-49) and with platelets 520610 9/1 was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47-90%), with a median follow-up time of 5.2 years. We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph-BSC sufficient for use in auto-SCT.
  • Sarhan, Dhifaf, et al. (författare)
  • A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells
  • 2013
  • Ingår i: Cancer immunology, immunotherapy : CII. - 1432-0851. ; 62:8, s. 1359-1368
  • Tidskriftsartikel (refereegranskat)abstract
    • The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p<0.0002) and T cell (p=0.02) –mediated cytotoxicity. Treatment with b-AP15 resulted in increased TRAIL [tumor necrosis factor-related apoptosis-inducing ligand] receptor-2 expression (p=0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p=0.006), T cells (p<0.0001), or b-AP15 alone (p=0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p≤0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anti-cancer effects of adoptively infused NK and T cells in patients with cancer.
  • Zhang, Xiaonan, et al. (författare)
  • Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments.
  • 2014
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 5:Feb 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.
  • Aftab, Obaid, 1984-, et al. (författare)
  • Label-free detection and dynamic monitoring of drug-induced intracellular vesicle formation enabled using a 2-dimensional matched filter
  • 2014
  • Ingår i: Autophagy. - 1554-8627 .- 1554-8635. ; 10:1, s. 57-69
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Analysis of vesicle formation and degradation is a central issue in autophagy research and microscopy imaging is revolutionizing the study of such dynamic events inside living cells. A limiting factor is the need for labeling techniques that are labor intensive, expensive, and not always completely reliable. To enable label-free analyses we introduced a generic computational algorithm, the label-free vesicle detector (LFVD), which relies on a matched filter designed to identify circular vesicles within cells using only phase-contrast microscopy images. First, the usefulness of the LFVD is illustrated by presenting successful detections of autophagy modulating drugs found by analyzing the human colorectal carcinoma cell line HCT116 exposed to each substance among 1266 pharmacologically active compounds. Some top hits were characterized with respect to their activity as autophagy modulators using independent in vitro labeling of acidic organelles, detection of LC3-II protein, and analysis of the autophagic flux. Selected detection results for 2 additional cell lines (DLD1 and RKO) demonstrate the generality of the method. In a second experiment, label-free monitoring of dose-dependent vesicle formation kinetics is demonstrated by recorded detection of vesicles over time at different drug concentrations. In conclusion, label-free detection and dynamic monitoring of vesicle formation during autophagy is enabled using the LFVD approach introduced.</p>
  • Bengtsson, Sofia, et al. (författare)
  • Large-scale proteomics analysis of human ovarian cancer for biomarkers
  • 2007
  • Ingår i: Journal of Proteome Research. - 1535-3893 .- 1535-3907. ; 6:4, s. 1440-1450
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Ovarian cancer is usually found at a late stage when the prognosis is often bad. Relative survival rates decrease with tumor stage or grade, and the 5-year survival rate for women with carcinoma is only 38%. Thus, there is a great need to find biomarkers that can be used to carry out routine screening, especially in high-risk patient groups. Here, we present a large-scale study of 64 tissue samples taken from patients at all stages and show that we can identify statistically valid markers using nonsupervised methods that distinguish between normal, benign, borderline, and malignant tissue. We have identified 217 of the significantly changing protein spots. We are expressing and raising antibodies to 35 of these. Currently, we have validated 5 of these antibodies for use in immunohistochemical analysis using tissue microarrays of healthy and diseased ovarian, as well as other, human tissues.</p>
  • Berndtsson, Maria, et al. (författare)
  • Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
  • 2009
  • Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 124:6, s. 1463-1469
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis.</p>
  • Brnjic, Slavica, et al. (författare)
  • Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress
  • 2014
  • Ingår i: Antioxidants and Redox Signaling. - 1523-0864 .- 1557-7716. ; 21:17, s. 2271-2285
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of alpha-subunit of eukaryotic initiation factor 2 phosphorylation. Innovation: The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Conclusion: Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15. Antioxid. Redox Signal. 21, 2271-2285.</p>
  • Brodin, Ola, et al. (författare)
  • Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study
  • 2015
  • Ingår i: Nutrients. - MDPI. - 2072-6643 .- 2072-6643. ; 7:6, s. 4978-4994
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.</p>
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