| 1. |
- Jeddi-Tehrani, Mahmood, et al.
(författare)
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Construction and characterization of a new chimeric antibody against HER2
- 2013
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Ingår i: Immunotherapy. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1750-743X .- 1750-7448.
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Immunotherapy with anti-HER2 antibodies has shown promising results in patients with HER2-positive breast cancer. We have recently reported characterization of a mouse monoclonal antibody (mAb) against HER2, which binds to an epitope different from that recognized by trastuzumab and specifically inhibits proliferation of tumor cells overexpressing HER2. In the present study we report chimerization of this antibody. Materials & methods: The immunoglobulin variable region heavy and light chain genes of 1T0 hybridoma cells were amplified and ligated to human -1 and constant region genes using splice overlap extension PCR. The chimeric antibody was subsequently expressed and characterized by ELISA, western blot and flow cytometry. Results: The purified chimeric antibody specifically binds to recombinant HER2 and HER2-overexpressing tumor cells and inhibits proliferation of these cells. The binding affinity of the chimeric mAb was comparable with the parental mouse mAb. Conclusion: This chimeric anti-HER2 mAb is a potentially valuable tool for targeted immunotherapy.
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| 2. |
- Bahrami, Behdokht, et al.
(författare)
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Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy
- 2015
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Ingår i: Tumor Biology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1423-0380 .- 1010-4283.
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Tidskriftsartikel (refereegranskat)abstract
- The selective and efficient drug delivery to tumor cells can remarkably improve different cancer therapeutic approaches. There are several nanoparticles (NPs) which can act as a potent drug carrier for cancer therapy. However, the specific drug delivery to cancer cells is an important issue which should be considered before designing new NPs for in vivo application. It has been shown that cancer cells over-express folate receptor (FR) in order to improve their growth. As normal cells express a significantly lower levels of FR compared to tumor cells, it seems that folate molecules can be used as potent targeting moieties in different nanocarrier-based therapeutic approaches. Moreover, there is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo. In this review, we will discuss about the efficiency of different folate-conjugated NPs in cancer therapy.
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| 3. |
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| 4. |
- Du, Likun, et al.
(författare)
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Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis
- 2012
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 209:2, s. 291-305
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Tidskriftsartikel (refereegranskat)abstract
- Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
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| 5. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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Frequency analysis of HLA class I alleles in Iranian patients with progressive and non-progressive chronic lymphocytic leukemia
- 2013
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Ingår i: Human Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1879-1166 .- 0198-8859.
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is a malignant disorder of B cell origin, with low incidence in Asian populations. In this study we investigated the HLA-class I A and B allele frequencies in 87 Iranian CLL patients and 64 healthy controls using sequence specific primer-polymerase chain reaction (SSP-PCR) technique. Our results showed increased frequencies of HLA-A11:01 (p=0.02) and HLA-B35:01 (p=0.002) alleles and HLA-A11:01/B35:01 haplotype (p=0.036) and decreased frequencies of HLA-A01:01 (p=0.02), HLA-A26:01 (p=0.03), HLA-B65:01 (p=0.03) and HLA-B53:01 (p<0.00001) alleles in CLL patients compared to the control group. Classification of the patients into non-progressive and progressive groups did not reveal significant differences for the frequency of any of the HLA-A and -B alleles or haplotypes between these two subtypes. Comparison between patients with immunoglobulin heavy chain variable region genes (IGHV) mutated (n=56) and unmutated (n=31) subtypes showed a significant increase in HLA-A32:01 (p=0.05) and HLA-A33:01 (p=0.05) alleles in IGHV unmutated patients compared to IGHV mutated patients. Similarly, a higher frequency of HLA-B52:01 (p=0.037) alleles was observed in CD38+ compared with CD38- patients. Our results obtained from an Iranian population indicate that CLL is associated with distinct HLA class I alleles and haplotypes some of which are linked to disease prognostic factors.
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| 6. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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Immunophenotypic characterization of the leukemic B-cells from Iranian patients with chronic lymphocytic leukemia : association between CD38 expression and disease progression
- 2008
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Ingår i: Iranian Journal of Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1735-1383.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with B-cell chronic lymphocytic leukemia (B-CLL) have heterogeneous clinical courses, thus several biological parameters need to be added to the current clinical staging systems to predict disease outcome. Recent immunophenotypic studies performed mainly in Western populations have demonstrated the prognostic value of CD38 and ZAP-70 expression in B-CLL. Objectives: To investigate the expression pattern of a variety of membrane antigens on leukemic cells from Iranian patients with CLL and to find out if there are any differences in the expression of these markers between indolent and progressive groups. Methods: In the present study, peripheral blood samples from 87 Iranian patients with B-CLL were analysed by flow cytometry. Results: In all cases, the neoplastic cells displayed B-CLL phenotype (CD5+/CD19+/sIg+). The vast majority of the cases expressed CD23, but failed to stain for CD3 or CD14. The leukemic cells of most patients expressed CD27 (84/87, 95.4%) and CD45RO (74/87, 83.9%) molecules, suggesting a memory B-cell phenotype. Comparison between the indolent (n=42) and progressive (n=37) patients revealed significantly higher frequency and intensity of CD38 expression in progressive group (40.5%) compared to indolent (11.9%) patients (p<0.05). None of the other membrane antigens were differentially expressed in these two groups of patients. Conclusion: Our results obtained in an Asian ethnic population confirm and extend previous findings obtained from Western populations regarding the association of CD38 expression and disease progression in B-CLL.
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| 7. |
- Hojjat-Farsangi, Mohammad
(författare)
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Novel and emerging targeted-based cancer therapy agents and methods
- 2015
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Ingår i: Tumor Biology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1423-0380 .- 1010-4283.
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Tidskriftsartikel (refereegranskat)abstract
- After several decades of uncovering the cancer features and following the improvement of therapeutic agents; however cancer remains as one of the major reasons of mortality. Chemotherapy is one of the main treatment options and has significantly improved the overall survival of cancer patients, but these agents are highly toxic for normal cells. Therefore, there is a great unmet medical need to develop new therapeutic principles and agents. Targeted-based cancer therapy (TBCT) agents and methods have revolutionized the cancer treatment efficacy. Monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) are among the most effective agents of TBCT. These drugs have improved the prognosis and survival of cancer patients; however, the therapeutic resistance has subdued the effects. Several mechanisms lead to drug resistance such as mutations in the drug targets, activation of compensatory pathways and intrinsic or acquired resistance of cancer stem cells. Therefore, new modalities, improving current generation of inhibitors and mAbs as well as optimizing the combinational therapy regimens are necessary to decrease the current obstacles in front of TBCT. Moreover, the success of new TBCT agents such as mAbs, SMIs and immunomodulatory agents has sparked further therapeutic modalities with novel targets to inhibit. Due to the lack of cumulative information describing different agents and methods of TBCT, this review focuses on the most important agents and methods of TBCT that are currently under investigation.
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| 8. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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RETRACTED: Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma 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
- RETRACTED ARTICLE. Retraction: PLoS One. 2022 May 5;17(5):e0268357. The receptor tyrosine kinase (RTK) ROR1 is overexpressed and of importance for the survival of various malignancies, including lung adenocarcinoma, breast cancer and chronic lymphocytic leukemia (CLL). There is limited information however on ROR1 in melanoma. In the present study we analysed in seven melanoma cell lines ROR1 expression and phosphorylation as well as the effects of anti-ROR1 monoclonal antibodies (mAbs) and ROR1 suppressing siRNA on cell survival. ROR1 was overexpressed at the protein level to a varying degree and phosphorylated at tyrosine and serine residues. Three of our four self-produced anti-ROR1 mAbs (clones 3H9, 5F1 and 1A8) induced a significant direct apoptosis of the ESTDAB049, ESTDAB112, DFW and A375 cell lines as well as cell death in complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC). The ESTDAB081 and 094 cell lines respectively were resistant to direct apoptosis of the four anti-ROR1 mAbs alone but not in CDC or ADCC. ROR1 siRNA transfection induced downregulation of ROR1 expression both at mRNA and protein levels proceeded by apoptosis of the melanoma cells (ESTDAB049, ESTDAB112, DFW and A375) including ESTDAB081, which was resistant to the direct apoptotic effect of the mAbs. The results indicate that ROR1 may play a role in the survival of melanoma cells. The surface expression of ROR1 on melanoma cells may support the notion that ROR1 might be a suitable target for mAb therapy.
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| 9. |
- Hojjat-Farsangi, Mohammad
(författare)
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Small-molecule inhibitors of the receptor tyrosine kinases : promising tools for targeted cancer therapies
- 2014
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Ingår i: International Journal of Molecular Sciences. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1422-0067.
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.
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| 10. |
- 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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| 11. |
- Hojjat-Farsangi, Mohammad
(författare)
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Targeting non-receptor tyrosine kinases using small molecule inhibitors : an overview of recent advances
- 2015
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Ingår i: Journal of Drug Targeting. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1061-186X. ; 24:3, s. 192-211
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Tidskriftsartikel (refereegranskat)abstract
- Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.
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| 12. |
- 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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| 13. |
- Kokhaei, Parviz, et al.
(författare)
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Ibrutinib-A double-edge sword in cancer and autoimmune disorders
- 2015
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Ingår i: Journal of Drug Targeting. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1061-186X. ; 24:5, s. 373-385
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Tidskriftsartikel (refereegranskat)abstract
- Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton’s tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.
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| 14. |
- Shabani, Mahdi, et al.
(författare)
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Comparative expression profile of orphan receptor tyrosine kinase ROR1 in Iranian patients with lymphoid and myeloid leukemias
- 2011
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Ingår i: Avicenna Journal of Medical Biotechnology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 2008-2835.
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Tidskriftsartikel (refereegranskat)abstract
- It has recently been shown that ROR1, a member of the receptor tyrosine kinase family, is overexpressed in leukemic B cells of Chronic Lymphocytic Leukemia (CLL) and a subset of Acute Lymphoblastic Leukemia (ALL). In this comparative study the expression profile of ROR1 mRNA was investigated in Iranian patients with CLL and Acute Myelogenous Leukemia (AML) and the results were compared with those previously reported in our Iranian ALL patients. RT-PCR was performed on bone marrow and/or peripheral blood samples of 84 CLL and 12 AML patients. CLL samples were classified into immunoglobulin heavy chain variable region (IGHV) gene mutated (n = 55) and unmutated (n = 29) and also indolent (n = 42) and progressive (n = 39) subtypes. ROR1 expression was identified in 94% of our CLL patients, but none of the AML patients expressed ROR1. No significant differences were observed between different CLL subtypes for ROR1 expression. Taken together the present data and our previous results on ROR1 expression in ALL, our findings propose ROR1 as a tumor-associated antigen overexpressed in a large proportion of lymphoid (CLL and ALL), but not myeloid (AML) leukemias. Expression of ROR1 seems to be associated to lineage and differentiation stages of leukemic cells with a potential implication for immunotherapy.
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| 15. |
- Shabani, Mahdi, et al.
(författare)
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Ligation of human Fc receptor like-2 (FCRL2) by monoclonal antibodies downregulates B cell receptor mediated signaling
- 2014
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Ingår i: Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 0019-2805 .- 1365-2567.
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Tidskriftsartikel (refereegranskat)abstract
- B cell antigen receptor (BCR) signaling and its regulation through negative and positive regulators are critical for balancing B cell response and function. Human Fc receptor like-2 (FCRL2), a member of the newly identified FCRL family, could influence B cell signaling due to possession of both immunoreceptor tyrosine-based activation and inhibitory motifs (ITAM and ITIM). Since the natural ligand of FCRL2 has not been identified yet, we generated FCRL2-specific monoclonal antibodies (mAbs) and employed them to investigate the influence of FCRL2 stimulation on BCR signaling in a FCRL2-expressing B cell line. Two anti-FCRL2 mAb-producing hybridoma clones (5A7-E7 and 3D8-G8) were selected. None of the mAbs displayed any cross-reactivity with the other members of the FCRL family including recombinant FCRL1, 3, 4 and 5, as tested by FACS and ELISA techniques. Engagement of the FCRL2 by these mAbs resulted in significant inhibition of BCR signaling mediators such as calcium mobilization and phosphorylation of the MAP kinases Erk, p38 and Jnk MAP. These findings indicate that the FCRL2 ITIM motifs are functional and the anti-FCRL2 mAbs may mimic the natural ligand of FCRL2 by induction of inhibitory signals in B cells.
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| 16. |
- Shabani, Mahdi, et al.
(författare)
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Targeting receptor tyrosine kinases using monoclonal antibodies : the most specific tools for targeted-based cancer therapy
- 2015
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Ingår i: Current Drug Targets. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1389-4501 .- 1873-5592.
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Tidskriftsartikel (refereegranskat)abstract
- Receptor tyrosine kinases (RTKs) family is comprised of different cell surface glycoproteins. These enzymes participate and regulate vital processes such as cell proliferation, polarity, differentiation, cell to cell interactions, signaling, and cell survival. Dysregulation of RTKs contributes to the development of different types of tumors. RTKs deregulation in cancer has been reported for more than 30 RTKs. Due to critical roles of these molecules in cancer, the specific targeting of RTKs in malignancies is a promising approach. Targeted cellular and molecular therapies have been known as a new type of therapeutics, preventing tumor cell proliferation and invasion by interrupting with molecules necessary for tumor growth and survival. Specific targeting of RTKs using monoclonal antibodies (mAbs) in malignancies as well as in autoimmune disorders is of great interest. The growing number of mAbs approved by the authorities implies on the increasing attentions and applications of these therapeutic tools. Due to the high specificity, mAbs are the most promising substances that target RTKs expressed on the tumor cell surface. In this communication, we review the recent progresses in development of mAbs targeting oncogenic RTKs for cancer treatment.
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| 17. |
- Staff, Caroline, et al.
(författare)
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Induction of IgM, IgA and IgE Antibodies in Colorectal Cancer Patients Vaccinated with a Recombinant CEA Protein
- 2012
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 32:4, s. 855-865
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Tidskriftsartikel (refereegranskat)abstract
- Previous clinical studies have indicated that natural IgM antibodies have the ability to induce apoptosis of tumor cells but IgE and IgA may also mediate tumor cell killing (in addition to IgG). The aim of the study was to analyse induction of IgM, IgA and IgE antibodies in patients vaccinated with the tumor associated antigen CEA. Twenty-four resected CRC patients without macroscopic disease were immunized seven times with CEA +/- GM-CSF. Four different dose schedules were used over a 12-month period. IgM, IgA and IgE antibody responses against recombinant CEA were determined by ELISA. Patients were monitored immunologically for 36 months and clinically for 147 months. GM-CSF significantly augmented the anti-CEA response for all three antibody classes. Low dose of CEA tended to induce a higher IgM, IgA or IgE anti-CEA antibody response than higher. Anti-CEA IgA antibodies could lyse CEA positive tumor cells in antibody dependent cellular cytotoxicity (ADCC) as well as in complement dependent cytotoxicity (CDC). A significant correlation between survival and high IgA anti-CEA titers was noted (p = 0.02) irrespective of GM-CSF treatment. The observation that IgA anti-CEA antibodies were cytotoxic and associated with improved survival might indicate that also these antibodies may exert a clinical anti-tumor effect.
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| 18. |
- Stenman, Adam, et al.
(författare)
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Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior
- 2019
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Ingår i: American Journal of Surgical Pathology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0147-5185 .- 1532-0979. ; 43:3, s. 409-421
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGL, are believed to exhibit malignant potential-but only subsets of cases will display full-blown malignant properties. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) algorithm is a proposed histologic system to detect potential for aggressive behavior, but little is known regarding the coupling to underlying molecular genetics. In this study, a total of 92 PPGLs, previously characterized for susceptibility gene status and mRNA expressional profiles, were histologically assessed using the PASS criteria. A total of 32/92 PPGLs (35%) exhibited a PASS score amp;gt;= 4, including all 8 cases with malignant behavior (7 with known metastases and 1 with extensively infiltrative local recurrence). Statistical analyzes between expressional data and clinical parameters as well as individual PASS criteria yielded significant associations to Chromogranin B (CHGB), BRCA2, HIST1H3B, BUB1B, and RET to name a few, and CHGB had the strongest correlation to both PASS and metastasis/local recurrence of all analyzed genes. Evident CHGB downregulation was observed in PPGLs with high PASS and overtly malignant behavior, and was also associated with shorter disease-related survival. This finding was validated using quantitative real-time polymerase chain reaction, in which CHGB expression correlated with both PASS and metastasis/local recurrence with consistent findings obtained in the TCGA cohort. Moreover, immunohistochemical analyses of subsets of tumors showed a correlation between high PASS scores and negative or weak CHGB protein expression. Patients with PPGLs obtaining high PASS scores postoperatively, also exhibited low preoperative plasma levels of CHGB. These data collectively point out CHGB as a possible preoperative and postoperative marker for PPGLs with potential for aggressive behavior.
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| 19. |
- Yousefi, Mehdi, et al.
(författare)
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The skewed balance between regulatory T cells and Th17 in chronic lymphocytic leukemia
- 2015
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Ingår i: Future Oncology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1479-6694 .- 1744-8301.
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Tidskriftsartikel (refereegranskat)abstract
- While Tregs maintain self-tolerance and inhibit antitumor responses, T helper (Th)17 cells may enhance inflammatory and antitumor responses. The balance between these two important T-cell subsets has been skewed in many immunopathologic conditions such as autoimmune and cancer diseases. B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western world and is characterized with monoclonal expansion of B lymphocytes. There is evidence which implies that the progression of CLL is associated with expansion of Treg and downregulation of Th17 cells. In this review, we will discuss about immunobiology of Treg and Th17 cells and their role in immunopathogenesis of CLL as well as their reciprocal changes during disease progression.
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