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  • Tobin, N. P., et al. (författare)
  • An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors
  • 2016
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 22:10, s. 2417-2426
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. (C) 2016 AACR.
  • Yang, Lie, et al. (författare)
  • Biological Function and Prognostic Significance of Peroxisome Proliferator-Activated Receptor delta in Rectal Cancer
  • 2011
  • Ingår i: CLINICAL CANCER RESEARCH. - American Association for Cancer Research, Inc.. - 1078-0432. ; 17:11, s. 3760-3770
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Purpose: To investigate the expression significance of PPAR beta/delta in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients. Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR delta antibody. Survival probability was computed by the Kaplan-Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR delta knockdown. Results: PPAR delta was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR delta was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR delta was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR delta knockdown. Conclusions: RT decreases the PPAR delta expression in primary rectal cancers and lymph node metastases. PPAR delta is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR delta predicts favorable survival in the rectal cancer patients either with or without preoperative</p>
  • Green, Henrik, et al. (författare)
  • mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy
  • 2006
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:3 pt 1, s. 854-859
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><em>Purpose:</em> P-glycoprotein, encoded by the <em>mdr-1</em> gene, confers<sup> </sup>multidrug resistance to a variety of antineoplastic agents,<sup> </sup>e.g., paclitaxel. Recently, different polymorphisms in the <em>mdr-1</em><sup> </sup>gene have been identified and their consequences for the function<sup> </sup>of P-glycoprotein, as well as for the treatment response to<sup> </sup>P-glycoprotein substrates, are being clarified. We analyzed<sup> </sup>the allelic frequencies at polymorphic sites G2677T/A and C3435T<sup> </sup>in ovarian cancer patients with good or poor response to treatment<sup> </sup>with paclitaxel in combination with carboplatin in order to<sup> </sup>evaluate their predictive values.<sup> </sup></p> <p><em>Experimental Design:</em> Fifty-three patients were included in the<sup> </sup>study; 28 of them had been relapse-free for at least 1 year<sup> </sup>and 25 had progressive disease or relapsed within 12 months.<sup> </sup>A reference material consisting of 200 individuals was also<sup> </sup>analyzed. The genotypes of each single nucleotide polymorphism<sup> </sup>(SNP) were determined using Pyrosequencing.<sup> </sup></p> <p><em>Results:</em> The G2677T/A SNP was found to significantly correlate<sup> </sup>with treatment outcome. The probability of responding to paclitaxel<sup> </sup>treatment was higher in homozygously mutated patients (T/T or<sup> </sup>T/A; Fisher's exact test; <em>P</em> &lt; 0.05). The frequency of the<sup> </sup>T or A alleles was also higher in the group of patients who<sup> </sup>had a good response (<em>P</em> &lt; 0.05). There was also a dose-dependent<sup> </sup>influence of the number of mutated alleles on the response to<sup> </sup>paclitaxel treatment (Χ<sup>2</sup> test for linear-by-linear association;<sup> </sup><em>P</em> = 0.03). However, the C3435T SNP was not found to correlate<sup> </sup>to treatment outcome.<sup> </sup></p> <p><em>Conclusions:</em> The mdr-1 polymorphism G2677T/A in exon 21 correlates<sup> </sup>with the paclitaxel response in ovarian cancer and may be important<sup> </sup>for the function of P-glycoprotein and resistance to paclitaxel<sup> </sup>and provide useful information for individualized therapy.<sup> </sup></p>
  • Bostner, Josefine, et al. (författare)
  • Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
  • 2010
  • Ingår i: Clinical Cancer Research. - American Association for Cancer Research, Inc.. - 1078-0432 .- 1557-3265. ; 16:5, s. 1624-1633
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Purpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy. Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment. Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P less than 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment. Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.</p>
  • Thielen, Noortje, et al. (författare)
  • Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy
  • 2016
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 22:16, s. 4030-4038
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)-positive CD34(+)CD38(-) bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177). Experimental design: Two flow cytometry-based cell sorting methods were used with multiparameter-directed CD45-(MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively. Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34(+)CD38(-) cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions. Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. (C) 2016 AACR.</p>
  • Aaltonen, Kirsimari, et al. (författare)
  • Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers
  • 2008
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:7, s. 1976-83
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.</p>
  • Ambros, Inge M, et al. (författare)
  • A multilocus technique for risk evaluation of patients with neuroblastoma.
  • 2011
  • Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 17:4, s. 792-804
  • Tidskriftsartikel (refereegranskat)abstract
    • Precise and comprehensive analysis of neuroblastoma genetics is essential for accurate risk evaluation and only pangenomic/multilocus approaches fulfill the present-day requirements. We present the establishment and validation of the PCR-based multiplex ligation-dependent probe amplification (MLPA) technique for neuroblastoma.
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