| 1. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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Spontaneous immunity against the receptor tyrosine kinase ROR1 in patients with chronic lymphocytic leukemia
- 2015
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Ingår i: PLOS One. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Background: ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients. Materials and Methods: Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay. Results: The majority of CLL patients had antibodies against ROR1. Significantly higher titers of antiROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p < 0.05). Conclusion: ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.
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| 2. |
- Lehmann, Sören, et al.
(författare)
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Targeting p53 in Vivo : a First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer
- 2012
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSEAPR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.PATIENTS AND METHODSAPR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.RESULTSMTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.CONCLUSION We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
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| 3. |
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| 4. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells
- 2013
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Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
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| 5. |
- Joudi, Ali, et al.
(författare)
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Influence of reflective interior surfaces on indoor thermal environment and energy use using a coupling model for energy simulation and CFD
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The importance of reducing the building energy use and maintaining the desired indoor climate has long inspired creative solution such as optimized optical properties for building surfaces. This paper aims to address the influence of interior thermal reflective surfaces on both indoor thermal environments with high spatial resolution and energy use. To do so, this work employs a coupling method using building energy simulation (BES) and computational fluid dynamics (CFD). The results indicate increase in the mean radiation temperature (MRT) and reduction in the floor heating energy use by the use of interior reflective surfaces. The study yields analysis of operative temperatures and interior surface heat fluxes. Overall, the interior reflective surfaces can contribute to improved building thermal performance and energy saving.
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| 6. |
- Joudi, Ali, et al.
(författare)
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Numerical and experimental investigation of the influence of infrared reflective interior surfaces on building temperature distributions
- 2017
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Ingår i: Indoor + Built Environment. - : Sage Publications. - 1420-326X .- 1423-0070. ; 26:3, s. 355-367
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Tidskriftsartikel (refereegranskat)abstract
- Radiative properties of interior surfaces can affect not only the building heat flux but also the indoor environment, the latter of which has not been thoroughly investigated. The aim of this study is to analyse the effect of surface emissivity on indoor air and surface temperature distributions in a test cabin with reflective interior surfaces. This was done by comparing experimental and simulation data of the test cabin with that of a normal cabin. This study employs transient computational fluid dynamics (CFD) using re-normalisation group (RNG) k-epsilon model, surface-to-surface radiation model and an enhanced wall function. Boundary conditions were assigned to exterior surfaces under variable outdoor conditions. The numerical and the measurement results indicate that using interior reflective surfaces will affect the indoor air temperature distribution by increasing the vertical temperature gradient depending on the time of the day. CFD simulations with high spatial resolution results show increased interior surface temperature gradients consistent with the increased vertical air temperature gradient. The influence of reflective surfaces is potentially greater with higher indoor surface temperature asymmetry. The vertical indoor air temperature gradient and surface temperatures are important parameters for indoor thermal comfort.
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| 7. |
- Joudi, Ali, 1980-
(författare)
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Radiation properties of coil-coated steel in building envelope surfaces and the influence on building thermal performance
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies have shown that the optical properties of building exterior surfaces are important in terms of energy use and thermal comfort. While the majority of the studies are related to exterior surfaces, the radiation properties of interior surfaces are less thoroughly investigated. Development in the coil-coating industries has now made it possible to allocate different optical properties for both exterior and interior surfaces of steel-clad buildings. The aim of this thesis is to investigate the influence of surface radiation properties with the focus on the thermal emittance of the interior surfaces, the modeling approaches and their consequences in the context of the building energy performance and indoor thermal environment.The study consists of both numerical and experimental investigations. The experimental investigations include parallel field measurements on three similar test cabins with different interior and exterior surface radiation properties in Borlänge, Sweden, and two ice rink arenas with normal and low emissive ceiling in Luleå, Sweden. The numerical methods include comparative simulations by the use of dynamic heat flux models, Building Energy Simulation (BES), Computational Fluid Dynamics (CFD) and a coupled model for BES and CFD. Several parametric studies and thermal performance analyses were carried out in combination with the different numerical methods.The parallel field measurements on the test cabins include the air, surface and radiation temperatures and energy use during passive and active (heating and cooling) measurements. Both measurement and comparative simulation results indicate an improvement in the indoor thermal environment when the interior surfaces have low emittance. In the ice rink arenas, surface and radiation temperature measurements indicate a considerable reduction in the ceiling-to-ice radiation by the use of low emittance surfaces, in agreement with a ceiling-toice radiation model using schematic dynamic heat flux calculations.The measurements in the test cabins indicate that the use of low emittance surfaces can increase the vertical indoor air temperature gradients depending on the time of day and outdoor conditions. This is in agreement with the transient CFD simulations having the boundary condition assigned on the exterior surfaces. The sensitivity analyses have been performed under different outdoor conditions and surface thermal radiation properties. The spatially resolved simulations indicate an increase in the air and surface temperature gradients by the use of low emittance coatings. This can allow for lower air temperature at the occupied zone during the summer.The combined effect of interior and exterior reflective coatings in terms of energy use has been investigated by the use of building energy simulation for different climates and internal heat loads. The results indicate possible energy savings by the smart choice of optical properties on interior and exterior surfaces of the building.Overall, it is concluded that the interior reflective coatings can contribute to building energy savings and improvement of the indoor thermal environment. This can be numerically investigated by the choice of appropriate models with respect to the level of detail and computational load. This thesis includes comparative simulations at different levels of detail.
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| 8. |
- Lehmann, S, et al.
(författare)
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Targeting p53 in vivo : a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer
- 2012
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.PATIENTS AND METHODS: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.RESULTS: MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.CONCLUSION: We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
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| 9. |
- Lindberg, Jenny, et al.
(författare)
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Monocyte and Neutrophil Chemotactic Activity at the Site of Interstitial Inflammation in Patients on High-Flux Hemodialysis or Hemodiafiltration
- 2009
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Ingår i: Blood Purification. - : S. Karger AG. - 0253-5068 .- 1421-9735. ; 28:1, s. 47-52
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: We have observed a difference between patients on low-flux hemodialysis (HD) or peritoneal dialysis and patients on hemodiafiltration (HDF) or high-flux HD in the capacity of transmigrated leukocytes to mobilize CD11b in response to inflammatory stimuli compared with healthy subjects. This could be due to different interstitial chemokine concentrations. Methods: We measured concentrations of circulating and interstitial macrophage inflammatory protein-1 alpha (MIP-1 alpha), matrix metalloproteinase-9 (MMP-9)/neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in 10 patients on HDF or high-flux HD and 11 healthy subjects by using immunoassay. Results: The interstitial concentrations of MIP-1 alpha, MMP-9/NGAL and IL-8 were similar in patients and healthy subjects, while the corresponding concentration of MCP-1 was significantly higher in patients on HDF or high-flux HD as compared with healthy subjects (p < 0.01). Conclusion: We suggest that an equal or higher concentration of chemokines in the interstitium in patients with HDF or high-flux HD might be one mechanism responsible for the preserved function of transmigrated leukocytes. Copyright (C) 2009 S. Karger AG, Basel
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| 10. |
- Moshfegh, Ali
(författare)
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The biological mechanisms in neutrophil and eosinophil adhesion and transmigration in vitro and theur relation to the inflammatory process in vivo
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In inflammatory reactions, eosinophils and neutrophils constitute the major classes of granulocytes that emigrate from the bloodstream into the tissues. The recruitment of inflammatory cells constitutes a multi-step process that includes sequential adhesion and transmigration through, the endothelial lining, the underlying basement membrane and a variety of extracellular matrix components. This thesis examines the adhesion and transmigration properties of neutrophil and eosinophil during different inflammatory processes. We have investigated the in vitro effect of eotaxin on human peripheral blood eosinophils (PBE) with respect to CD11b/CD18 expression and adhesion properties to the matrix protein fibronectin. We demonstrate that eotaxin is involved in the quantitative up-regulation of CD11b/CD1 8 expression and increases the adhesion properties in primed, but not resting, human eosinophils. We hypothesise that eotaxin and IL-5, but not MP, act synergistically in these respects. The adhesion and transmigration assays were set up to simultaneous analysis of eosinophil and neutrophil adhesion and transmigration in mixed granulocyte cell populations, based on analysis of eosinophil cationic protein (ECP) and myeloperoxidase (WO) as markers for eosinophils and neutrophils, respectively. These models can be useful tools in exploring the mechanisms whereby neutrophils and eosinophils integrate chemotactic signals, communicate and to evaluate the impact of this communication on the overall leukocyte accumulation at disparate inflammatory sites. We examined the capacity of circulating neutrophils, collected before, during and after hemodialysis with cuprophan, low- and high-flux polysulfone dialyzers, to transmigrate through a fibronectin covered membrane in vitro. The high-flux polysulfone treatment, as opposed to low-flux and cuprophan dialyzers, ameliorates the transmigration properties of circulating neutrophils, despite similar effects on adhesion molecule phenotypes. Eosinophils in the neonatal period possess an enhanced responsiveness against the bacterialrelated peptide MP, as judged by enhanced transmigration capacity and CD11b upregulation, presumably due to the ability to express the fMLP receptor. We therefore suggest that eosinophils in the neonatal period represent a first line of cellular defence that might be triggered by bacterial antigen stimulation initiated by the early colonisation of the surfaces of the mucosa. We demonstrate that PBE in allergic, but not in healthy children possess an increased spontaneous, as well as eotaxin-induced capacity to transmigrate in vitro. This increased capacity is further enhanced within 2 hours after an allergen challenge in vivo without accompanying signs of eosinophil activation in terms of increased PBE counts or ECP levels. These observations are probably related to the phenomenon designated "priming".
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