| 11. |
- Berglund, Pontus, et al.
(author)
-
Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
- 2008
-
In: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
-
Journal article (peer-reviewed)abstract
- Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
|
|
| 12. |
- Brennan, Donal J., et al.
(author)
-
CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance
- 2006
-
In: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6421-6431
-
Journal article (peer-reviewed)abstract
- Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients. Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage 11 breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years. Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1 alpha Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027). Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
|
|
| 13. |
- Brennan, D. J., et al.
(author)
-
The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER alpha, and is an independent prognostic factor in node-negative breast cancer
- 2012
-
In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 31:30, s. 3483-3494
-
Journal article (peer-reviewed)abstract
- Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ER alpha in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. Oncogene (2012) 31, 3483-3494; doi:10.1038/onc.2011.519; published online 5 December 2011
|
|
| 14. |
- Busch, S., et al.
(author)
-
Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer
- 2012
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
-
Journal article (peer-reviewed)abstract
- Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. Conclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.
|
|
| 15. |
- Busch, Susann, et al.
(author)
-
TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer
- 2015
-
In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 34:1, s. 27-38
-
Journal article (peer-reviewed)abstract
- Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-beta family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n = 252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n = 319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (CI): 0.360-0.793, P = 0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-beta pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-beta pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.
|
|
| 16. |
- Degerman, Sofie, et al.
(author)
-
Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias
- 2014
-
In: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 16:7, s. 606-615
-
Journal article (peer-reviewed)abstract
- We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.
|
|
| 17. |
|
|
| 18. |
- Ekselius, Lisa, et al.
(author)
-
Personlighetssyndrom, kiniska riktlinjer för utredning och behandling
- 2017
-
Book (other academic/artistic)abstract
- Personer med personlighetssyndrom hör till de mest sårbara inom psykiatrin. De uppvisar mellanmänskliga problem liksom lidande och svårigheter att klara vardagens utmaningar. De blir ofta en utmaning för vården, eftersom deras interaktion med omgivningen många gånger är problematisk och konfliktfylld.Det finns ett stort behov av kunskap om personlighetssyndrom och ett av huvudsyftena med de nu presenterade riktlinjerna är att beskriva vad som kännetecknar personlighetssyndromen. Genom att tidigt kunna identifiera dem och det lidande de förorsakar kan realistiska behandlingsmål formuleras, vilket minskar risken för att patienten hamnar i ofruktsamma behandlingskontakter. Riktlinjerna har en stark klinisk förankring med fokus på tillämpbarhet i det dagliga arbetet med patienter och deras närstående och ger handfast vägledning i omhändertagande och behandling. Dessa kliniska riktlinjer för utredning och behandling av personlighetssyndrom är en uppdatering och omarbetning av de riktlinjer som publicerades 2006. Boken Personlighetssyndrom är i första hand skriven för alla som företräder den psykiatriska vården, men är även användbar för företrädare från andra specialiteter och för professioner utanför vården. Studenter och personer under fortbildning har utbyte av att läsa boken.
|
|
| 19. |
- Erratico, Claudio, et al.
(author)
-
Human hydroxylated metabolites of BDE-47 and BDE-99 are glucuronidated and sulfated in vitro
- 2015
-
In: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 236:2, s. 98-109
-
Journal article (peer-reviewed)abstract
- Polybrominated diphenyl ethers (PBDEs) were used worldwide as additive flame retardants and are classified as persistent, bioaccumulable and toxic environmental pollutants. In humans, the hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) formed in vitro have also been detected in vivo. To further characterize the metabolism of BDE-47 and BDE-99 and to identify candidate markers for monitoring the human exposure to PBDEs using non-invasive approaches, glucuronidation and sulfation of hydroxylated metabolites of BDE-47 and BDE-99 were investigated using human liver microsomes and cytoplasm, respectively. The formed Phase II metabolites were analyzed by liquid chromatography-tandem mass spectrometry using a novel approach to develop analytical methods in absence of authentic standards. All available standards for hydroxylated metabolites of BDE-47 and BDE-99 were glucuronidated and sulfated, showing that glucuronidation and sulfation are part of the metabolism pathway of BDE-47 and BDE-99 in vitro. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-47 were (a) 2,4-DBP-Gluc and 5-Gluc-BDE-47, and (b) 2'-Sulf-BDE-28, 4-Sulf-BDE-42 and 3-Sulf-BDE-47, respectively. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-99 were (a) 2,4,5-TBP-Gluc and 6'-Gluc-BDE-99, and (b) 3'-Sulf-BDE-99 and 5'-Sulf-BDE-99, respectively. Apparent K-m values associated with the formation of sulfated metabolites of BDE-47 and BDE-99 were ten times lower than those of the corresponding glucuronidated metabolites, suggesting that sulfated rather than glucuronidated metabolites of OH-PBDEs might be used as markers of human exposure to PBDEs using a non-invasive approach based on urine sample collection.
|
|
| 20. |
|
|
