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  • Berntsson, Jonna, et al. (författare)
  • The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite : A cohort study
  • 2017
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 141:8, s. 1654-1666
  • Tidskriftsartikel (refereegranskat)abstract
    • Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular referennfiltrating T cce to the anatomical subsite of the primary tumour. The density of CD3(+), CD8(+) and FoxP3(+) tumour-iells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5-year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8(+) cell density was a favourable prognostic factor for patients with right-sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29-0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8(+) cells and right-sidedness (p=0.031). High FoxP3(+) cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR=0.54, 95% CI 0.30-0.99), and CD3(+) cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3(+) or FoxP3(+) cells and sidedness. These results demonstrate that the prognostic impact of tumour-infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.
  • Boman, K., et al. (författare)
  • Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer
  • 2013
  • Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 108:11, s. 2321-2328
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.
  • Cepeda, Diana, et al. (författare)
  • CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
  • 2013
  • Ingår i: EMBO Molecular Medicine. - : Federation of European Neuroscience Societies and Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684. ; 5:7, s. 1067-1086
  • Tidskriftsartikel (refereegranskat)abstract
    • SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.
  • Hagerling, Catharina, et al. (författare)
  • The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients
  • 2012
  • Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Tumor associated macrophages (TAMs) are alternatively activated macrophages that enhance tumor progression by promoting tumor cell invasion, migration and angiogenesis. TAMs have an anti-inflammatory function resembling M2 macrophages. CD163 is regarded as a highly specific monocyte/macrophage marker for M2 macrophages. In this study we evaluated the specificity of using the M2 macrophage marker CD163 as a TAM marker and compared its prognostic value with the more frequently used pan-macrophage marker CD68. We also analyzed the prognostic value of the localization of CD163(+) and CD68(+) myeloid cells in human breast cancer. Methods: The extent of infiltrating CD163+ or CD68+ myeloid cells in tumor nest versus tumor stroma was evaluated by immunohistochemistry in tissue microarrays with tumors from 144 breast cancer cases. Spearman's Rho and chi(2) tests were used to examine the correlations between CD163(+) or CD68(+) myeloid cells and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the impact of CD163(+) and CD68(+) myeloid cells in tumor stroma and tumor nest, respectively, on recurrence free survival, breast cancer specific and overall survival. Results: We found that infiltration of CD163(+) and CD68(+) macrophages into tumor stroma, but not into tumor nest, were of clinical relevance. CD163(+) macrophages in tumor stroma positively correlated with higher grade, larger tumor size, Ki67 positivity, estrogen receptor negativity, progesterone receptor negativity, triple-negative/basal-like breast cancer and inversely correlated with luminal A breast cancer. Some CD163+ areas lacked CD68 expression, suggesting that CD163 could be used as a general anti-inflammatory myeloid marker with prognostic impact. CD68(+) macrophages in tumor stroma positively correlated to tumor size and inversely correlated to luminal A breast cancer. More importantly, CD68 in tumor stroma was an independent prognostic factor for reduced breast cancer specific survival. Conclusion: These findings highlight the importance of analyzing the localization rather than merely the presence of TAMs as a prognostic marker for breast cancer patients.
  • Hoeft, Birgit, et al. (författare)
  • Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk
  • 2010
  • Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 31:3, s. 466-472
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is the third most common malignant tumor and the fourth leading cause of cancer death worldwide. The crucial role of fatty acids for a number of important biological processes suggests a more in-depth analysis of inter-individual differences in fatty acid metabolizing genes as contributing factor to colon carcinogenesis. We examined the association between genetic variability in 43 fatty acid metabolism-related genes and colorectal risk in 1225 CRC cases and 2032 controls participating in the European Prospective Investigation into Cancer and Nutrition study. Three hundred and ninety two single-nucleotide polymorphisms were selected using pairwise tagging with an r(2) cutoff of 0.8 and a minor allele frequency of > 5%. Conditional logistic regression models were used to estimate odds ratios and corresponding 95% confidence intervals. Haplotype analysis was performed using a generalized linear model framework. On the genotype level, hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), phospholipase A2 group VI (PLA2G6) and transient receptor potential vanilloid 3 were associated with higher risk for CRC, whereas prostaglandin E receptor 2 (PTGER2) was associated with lower CRC risk. A significant inverse association (P < 0.006) was found for PTGER2 GGG haplotype, whereas HPGD AGGAG and PLA2G3 CT haplotypes were significantly (P < 0.001 and P = 0.003, respectively) associated with higher risk of CRC. Based on these data, we present for the first time the association of HPGD variants with CRC risk. Our results support the key role of prostanoid signaling in colon carcinogenesis and suggest a relevance of genetic variation in fatty acid metabolism-related genes and CRC risk.
  • Sherwood, Victoria, et al. (författare)
  • WNT5A-mediated β-catenin-independent signalling is a novel regulator of cancer cell metabolism.
  • 2014
  • Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 35:4, s. 784-794
  • Tidskriftsartikel (refereegranskat)abstract
    • WNT5A has been identified as an important ligand in the malignant progression of a number of tumours. Although WNT5A signalling is often altered in cancer, the ligand's role as either a tumour suppressor or oncogene varies between tumour types and is a contemporary issue for investigators of β-catenin-independent WNT signalling in oncology. Here, we report that one of the initial effects of active WNT5A signalling in malignant melanoma cells is an alteration in cellular energy metabolism and specifically an increase in aerobic glycolysis. This was found to be at least in part due to an increase in active Akt signalling and lactate dehydrogenase (LDH) activity. The clinical relevance of these findings was strengthened by a strong correlation (P < 0.001) between the expression of WNT5A and LDH isoform V in a cohort of melanocytic neoplasms. We also found effects of WNT5A on energy metabolism in breast cancer cells, but rather than promoting aerobic glycolysis as it does in melanoma, WNT5A signalling increased oxidative phosphorylation rates in breast cancer cells. These findings support a new role for WNT5A in the metabolic reprogramming of cancer cells that is a context- dependent event.
  • Svensson, Maria C., et al. (författare)
  • The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma
  • 2017
  • Ingår i: OncoTarget. - : IMPACT JOURNALS LLC. - 1949-2553 .- 1949-2553. ; 8:42, s. 72108-72126
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Several studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown. Results: High infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3(+), CD8(+) and FoxP3(+) with CD20(+) cells (p(interaction) = 0.012, 0.009 and 0.007, respectively) and for FoxP3(+) with IGKC(+) cells (p(interaction) = 0.034). In esophageal tumors, there was only a significant interaction for CD3(+) and CD20 (+) cells (p(interaction) = 0.028). Methods: Immunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3(+), CD8(+), FoxP3(+)) and NK cells (NKp46(+)) in chemoradiotherapy-naive tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20(+)) and plasma cells (IGKC(+)) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Conclusions: These data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.
  • Ahlin, Cecilia, et al. (författare)
  • High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers
  • 2017
  • Ingår i: Breast Cancer Research and Treatment. - : SPRINGER. - 0167-6806 .- 1573-7217. ; 164:3, s. 667-678
  • Tidskriftsartikel (refereegranskat)abstract
    • Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.
  • Allaoui, Roni, et al. (författare)
  • Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers
  • 2016
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Triple-negative (TN) breast cancers (ER â ' PR â ' HER2 â ') are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
  • Allaoui, Roni, et al. (författare)
  • Infiltration of γδ T cells, IL-17 + T cells and FoxP3 + T cells in human breast cancer
  • 2017
  • Ingår i: Cancer Biomarkers. - : IOS Press. - 1574-0153. ; 20:4, s. 395-409
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have a strong prognostic value in various forms of cancers. These data often refer to use of the pan-T cell marker CD3, or the cytotoxic T lymphocyte marker CD8α. However, T cells are a heterogeneous group of cells with a wide array of effector mechanisms ranging from immunosuppression to cytotoxicity. OBJECTIVE: In this study we have investigated the prognostic effects of some unconventional T cell subtypes in breast cancer; γδ T cells, IL-17+ T cells and FoxP3+ T cells (Tregs) in relation to the conventional CD3 and CD8α T cell markers. METHODS: This was done using immunohistochemistry on a human breast cancer tissue microarray consisting of 498 consecutive cases of primary breast cancer. RESULTS: Infiltration of γδ T cells and T cell infiltration in general (CD3), correlated with a good prognosis, while Treg infiltration with a worse. Infiltration of γδ T cells was associated with a significantly improved clinical outcome in all breast cancer subtypes except triple negative tumors. Only infiltration of either CD3+ or CD8α+ cells was independently associated with better prognosis for all breast cancer patients. CONCLUSIONS: This study sheds further light on the prognostic impact of various T cell subtypes in breast cancer.
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