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Sökning: WFRF:(Linderoth Johan)

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  • Ageberg, Malin, et al. (författare)
  • Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.
  • 2011
  • Ingår i: Experimental Cell Research. - Academic Press. - 1090-2422. ; 317, s. 1179-1191
  • Tidskriftsartikel (refereegranskat)abstract
    • Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.
  • Andréasson, Ulrika, et al. (författare)
  • Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells.
  • 2009
  • Ingår i: American Journal of Hematology. - John Wiley & Sons. - 0361-8609. ; 84, s. 803-808
  • Tidskriftsartikel (refereegranskat)abstract
    • Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process. Am. J. Hematol. 2010. (c) 2009 Wiley-Liss, Inc.
  • Berglund, Mattias, et al. (författare)
  • Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis.
  • 2005
  • Ingår i: Mod Pathol. - 0893-3952. ; 18:8, s. 1113-20
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • Diffuse large B-cell lymphoma (DLBCL) has been shown to be comprised of at least two prognostic entities, depending on its resemblance to normal germinal center or activated B cells, using global gene expression profiling. Also, the expression patterns of bcl-6, CD10 and IRF-4 ( also known as MUM1) have been suggested as alternative means of identifying the germinal- and nongerminal center ( activated B-cell like) groups. In the present study, we evaluated by immunohistochemistry the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 in a large material of 161 DLBCL patients. Using two different approaches, patients with germinal center phenotype displayed a significantly better survival than the nongerminal center group. Positive staining for bcl-6 or CD10 predicted for superior survival, while expression of IRF-4 alone showed no association with prognosis. Furthermore, expression of bcl-2 was associated with worse event-free survival and overall survival. In a multivariate analysis, a high international prognostic index score ( 3 - 5), non-GC phenotype and bcl-2 were independent adverse prognostic factors. Here we confirm the prognostic importance of determining the germinal- or nongerminal center phenotype in patients with DLBCL.
  • Fjordén, Karin, et al. (författare)
  • CD40 is a potential marker of favorable prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.
  • 2010
  • Ingår i: Leukemia & Lymphoma. - Taylor & Francis. - 1029-2403. ; 51, s. 1643-1648
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously shown that expression of CD40 has a favorable prognostic impact in diffuse large B-cell lymphoma (DLBCL) after anthracycline-based chemotherapy. Here we examined the prognostic value of immunohistochemically defined CD40 expression in 95 patients with DLBCL treated with both anthracycline-based chemotherapy and rituximab. Using a 10% cut-off level, 77% of the patients had CD40-positive tumors and showed a superior overall survival (p = 0.02 log-rank, hazard ratio 0.35, 95% CI 0.14-0.88, p = 0.03 Cox regression). When adjusted for International Prognostic Index in multivariate analysis, CD40 was not an independent prognostic factor (hazard ratio 0.39, 95% CI 0.15-1.04, p = 0.06 Cox regression). However, even after the introduction of immunochemotherapy, CD40 has a potential prognostic impact in DLBCL. Additional and larger studies are necessary, regarding the immunohistochemical robustness of CD40 and the biological mechanisms that contribute to the superior prognosis in CD40-expressing DLBCL.
  • Fjordén, Karin, et al. (författare)
  • Gene expression profiling indicates that immunohistochemical expression of CD40 is a marker of an inflammatory reaction in the tumor stroma of diffuse large B-cell lymphoma
  • 2012
  • Ingår i: Leukemia & Lymphoma. - Taylor & Francis. - 1042-8194. ; 53:9, s. 1764-1768
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunohistochemical expression of CD40 is seen in 60-70% of diffuse large B-cell lymphoma (DLBCL) and is associated with a superior prognosis. By using gene expression profiling we aimed to further explore the underlying mechanisms for this effect. Ninety-eight immunohistochemically defined CD40 positive or negative DLBCL tumors, 63 and 35 respectively, were examined using spotted 55K oligonucleotide arrays. CD40 expressing tumors were characterized by up-regulated expression of genes encoding proteins involved in cell-matrix interactions: collagens, integrin a V, proteoglycans and proteolytic enzymes, and antigen presentation. Immunohistochemistry confirmed that CD40 positive tumors co-express the proinflammatory proteoglycan biglycan (p = 0.005), which in turn correlates with the amount of infiltrating macrophages and CD4 and CD8 positive T-cells. We postulate that immunohistochemical expression of CD40 mainly reflects the inflammatory status in tumors. A high intratumoral inflammatory reaction may correlate with an increased autologous tumor response, and thereby a better prognosis.
  • Fridberg, Marie, et al. (författare)
  • Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: Higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN
  • 2007
  • Ingår i: Leukemia Lymphoma. - InformaWorld. - 1042-8194. ; 48:11, s. 2221-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-beta I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-beta II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-beta I and II differed in DLBCL cells, with the PKC-beta I isoform being expressed in both the cytoplasm and nucleus, while PKC-beta II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-beta I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.
  • Hasni, Muhammad Sharif, et al. (författare)
  • Estrogen receptor β1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker
  • 2017
  • Ingår i: Leukemia & Lymphoma. - Taylor & Francis. - 1042-8194. ; 58:2, s. 418-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor β (ERβ) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ERβ1 expression analysis in primary DLBCL’s by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERβ1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERβ1 is an interesting future therapeutic target for treatment of DLBCL, and that ERβ1 expression can be used as a prognostic marker.
  • Jakobsen, Lasse H, et al. (författare)
  • No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission: a Danish-Swedish population-based observational study.
  • 2016
  • Ingår i: British Journal of Haematology. - Federation of European Neuroscience Societies and Blackwell Publishing Ltd. - 0007-1048.
  • Tidskriftsartikel (refereegranskat)abstract
    • The use of routine imaging for patients with classical Hodgkin lymphoma (HL) in complete remission (CR) is controversial. In a population-based study, we examined the post-remission survival of Danish and Swedish HL patients for whom follow-up practices were different. Follow-up in Denmark included routine imaging, usually for a minimum of 2 years, whereas clinical follow-up without routine imaging was standard in Sweden. A total of 317 Danish and 454 Swedish comparable HL patients aged 18-65 years, diagnosed in the period 2007-2012 and having achieved CR following ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)/BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) therapy, were included in the study. The cumulative progression rates in the first 2 years were 4% (95% confidence interval [CI] 1-7) for patients with stage I-II disease vs. 12% (95% CI 6-18) for patients with stage III-IV disease. An imaging-based follow-up practice was not associated with a better post-remission survival in general (P = 0·2) or in stage-specific subgroups (P = 0·5 for I-II and P = 0·4 for III-IV). Age ≥45 years was the only independent adverse prognostic factor for survival. In conclusion, relapse of HL patients with CR is infrequent and systematic use of routine imaging in these patients does not improve post-remission survival. The present study supports clinical follow-up without routine imaging, as encouraged by the recent Lugano classification.
  • Linderoth, Johan, et al. (författare)
  • CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma.
  • 2007
  • Ingår i: Leukemia & Lymphoma. - Taylor & Francis. - 1042-8194. ; 48:9, s. 1774-1779
  • Tidskriftsartikel (refereegranskat)abstract
    • In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.
  • Linderoth, Johan (författare)
  • Diffuse large B-cell lymphoma - tumour characteristics on RNA and protein level associated with prognosis
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Popular Abstract in Swedish Diffust storcelligt B-celllymfom (DLBCL) är den vanligaste aggressiva lymfomsjukdomen, och drabbar ca 450 personer årligen i Sverige. Med modern antracyklin-innehållande cytostatikabehandling är DLBCL en potentiellt botbar sjukdom. Av patienter med lokaliserad sjukdom botas 70 %, med spridd sjukdom ca 50 %. Bakgrunden till arbete 1 i denna avhandling var en rapport där man med hjälp av genuttrycksprofilering av DLBCL funnit att patienter vars tumörer hade tydliga drag av gener aktiverade under den normala B-cellens germinalcenterfas (GC) hade betydligt bättre överlevnad än de patienter vars tumörer hade drag av ?aktiverade B-lymfocyter? (ABC)(Alizadeh et al, Nature 2000). Eftersom genuttrycksprofilering är kostnadskrävande och tekniskt komplicerat ville vi i studie 1 undersöka om man på ett enklare sätt kunde identifiera GC eller ABC profiler på proteinnivå med hjälp av immunhistokemi. Med hjälp av etablerade germinalcentermarkörer, CD10 och BCL6, och en förmodad postgerminalcentermarkör, CD138, kunde vi inte med hjälp av immunhistokemi identifiera prognostiskt skilda subgrupper i en grupp av 125 patienter, stad II-IV som cytostatikabehandlats pga DLBCL. Frekvensen av BCL6-positiva tumörer var ovanligt hög, 97 %, möjligen beroende på att den immunhistokemiska teknik som använts, EnVision metoden, var känsligare än äldre metoder. I studien användes också ytterligare två markörer för att identifiera germinalcenterfasen, CD23 och CD40, vars uttryck korrelerade med varandra men inte med de andra undersökta markörerna. Uttryck av CD23 och/eller CD40 var förenat med förlängd överlevnad för patienterna. I studie 2 kunde den prognostiskt gynnsamma effekten av CD40, men inte CD23, verifieras i ett nytt patientmaterial bestående av 125 patienter, stad II-IV, som cytostatikabehandlats pga DLBCL. CD40-effekten kunde inte förklaras av en association med GC-fenotypen och heller inte av ett ökat autologt tumörcellssvar, mätt som grad av tumörinfiltrerande hjälpar- och mördar-T-celler. Den prognostiskt gynnsamma effekten av en GC-fenotyp, definierad enl. Hans et al (Blood 2004), kunde påvisas. I studie 3 bekräftades misstanken att bruket av EnVision-tekniken, numera en standardmetod för påvisandet av immunohistokemiska reaktioner, i sig leder till en högre frekvens av BCL6-positivitet än vad användandet av äldre immunhistokemiska metoder gör. Vidare konstaterades att användandet av s.k. tissue microarrayteknik (TMA) inte lämpar sig för att bestämma om tumörer ska klassas som GC eller icke-GC. Detta beror framförallt på att BCL6 färgar in ojämnt, med hög risk för falskt negativa resultat. I studie 4 studerades genuttrycksprofilerna i DLBCL-tumörer från 24 patienter med botad sjukdom och 13 patienter med cytostatika-resistent sjukdom. De gener som bäst förmådde att skilja grupperna kodade i huvudsak för proteiner som uttrycks av celler i tumörernas omgivning, och inte för proteiner som uttrycks av tumörcellerna själva. Detta bekräftades genom imunhistokemiska analyser, där höga gennivåer motsvarades av ett högre proteinuttryck. I den botade gruppen var andelen tumörer som uttryckte proteiner som är inblandade i olika inflammatoriska processer mycket större än i den refraktära gruppen. Vidare analyser visade att dessa proteiner var lokaliserade i makrofager som, liksom tumörinfiltrerande mördarceller, mycket oftare fanns i tumörer från den botade gruppen.
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