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| 2. |
- Domanski, A M., et al.
(författare)
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Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients
- 2013
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Ingår i: Cytopathology. - : Blackwell Publishing. - 0956-5507 .- 1365-2303. ; 24:1, s. 21-25
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Tidskriftsartikel (refereegranskat)abstract
- A.M. Domanski, N. Monsef, H.A. Domanski, D. Grabau and M. Ferno Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients Objective: The use of cytological specimens to evaluate tumour biomarkers in metastatic breast cancer lesions has attracted increased interest because of the considerable number of reports that have shown discordance between the primary tumour and metastatic lesion. Oestrogen receptor (ER) and progesterone receptor (PgR) assays are crucial for the management of patients with breast cancer, in both adjuvant and palliative settings. The aim of this study was to compare the ER and PgR immunocytochemical analysis of fine needle aspiration (FNA) samples with the immunohistochemistry (IHC) of surgical specimens and core biopsies from primary breast cancers. Methods: The FNA specimens were prepared as cell blocks (n = 25) or ThinPreps (n = 258) for the immunocytochemistry (IC) ER and PgR analyses. Sixteen patients were excluded because of lack of follow-up (n = 1), neoadjuvant therapy (n = 3) or cell counts in their fine needle aspirates that were too low (n = 12). The results of IC on 25 cell blocks and 242 ThinPreps were compared with IHC on the corresponding core needle biopsies (n = 16) or excised tumours (n = 251). The ER and PgR status was defined as negative (when less than 10% of the nuclei were stained) or positive (when equal or more than 10% of the nuclei were stained). Kappa statistics were used to evaluate the concordance. Results: The ER concordance was 98% with ThinPrep (kappa = 0.93) and 92% with cell block (kappa = 0.82). The corresponding values for PgR were 96% (kappa = 0.91) and 96% (kappa = 0.92). Conclusions: Our results confirm that, in cases in which biopsies or surgical specimens are not available, IC (with either cell block or ThinPrep techniques) is a reliable method for the determination of the ER and PgR status performed under strict conditions using primary breast carcinomas, and is therefore potentially useful in metastatic settings.
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| 3. |
- Forsberg, Daniel, et al.
(författare)
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Evaluating Cell Nuclei Segmentation for Use on Whole-Slide Images in Lung Cytology
- 2014
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Ingår i: 2014 22nd International Conference on Pattern Recognition (ICPR). - : IEEE Computer Society. - 9781479952083 ; , s. 3380-3385
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Konferensbidrag (refereegranskat)abstract
- This paper presents results from an evaluation of three previously presented methods for segmentation of cell nuclei in lung cytology samples scanned by whole-slide scanners. Whole-slide images from seven cases of endobronchial ultrasound-guided transbronchial needle aspiration samples were used for extracting a number of regions of interest, in which approximately 2700 cell nuclei were manually segmented to form the ground truth. The segmented cells included benign bronchial epithelium, lymphocytes, granulocytes, histiocytes and malignant epithelial cells. The best results were obtained with a method based upon adaptive thresholding and an added step of clustering for distinguishing between cytoplasm and cell nuclei. This method achieved a mean DICE-score of 0.81 and a sensitivity and specificity of 0.88 and 0.81 respectively. In addition, this method was by far the fastest method, with a mean processing time of 7.8 s per image (2048 x 2048 pixels per image). By further improvements, such as lowering the false positive rate and using parallel computing hardware, this method has the potential to form the first building block in a system for computerized screening of whole-slide images in lung cytology.
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| 4. |
- Monsef, Nastaran, et al.
(författare)
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HIF1 alpha isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation
- 2010
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1 alpha (HIF1 alpha), in both benign and malignant NE prostate cells. HIF1 alpha and HIF1 beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1 alpha in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1 alpha isoforms. Methods: We studied the HIF1 alpha isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization. Results: We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1 alpha 1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1 alpha immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1 alpha present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1 beta. Conclusion: Our results indicate that the cytoplasmic stabilization of HIF1 alpha in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1 alpha isoform, HIF1 alpha 1.2. Co-localization of this isoform with HIF1 beta indicates that the HIF1 alpha 1.2 isoform might sequester HIF1 beta in the cytoplasm.
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| 5. |
- Monsef, Nastaran
(författare)
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Prostate cancer and neuroendocrine differentiation. Molecular aspects in prostate cancer development
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hormone refractory prostate cancer occurs when androgen-deprivation therapy (ADT) fails to stop the growth of prostate cancer for any longer. Recent studies point towards a role for neuroendocrine (NE) differentiation in the development of hormone refractory disease. It has been hypothesized that NE-differentiated malignant tumor cells survive during ADT and promote development of androgen-independent disease through autocrine and paracrine signaling pathways. In vitro studies have shown that androgen depletion, stimulation with growth factors such as IL-6 and cAMP inducing agents cause NE-differentiation in prostate cancer cell lines. In this thesis, we have analyzed the tumorogenic characteristics of NE tumor cells with regard to expression of key transcription factors, stem cell markers and clinical prognostic markers. Hypoxia has been shown to induce increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors overexpressing hypoxia inducible factors (HIF1a and HIF2a), important transcriptional activators of oxygen-regulated genes, are resistant to chemo- and radiotherapy. We found overexpression and cytoplasmic stabilization of HIF1a and HIF2a in androgen receptor negative NE cells in benign and malignant prostate tissue. Furthermore, we showed that stabilization of HIF1a in NE cells in prostate cancer is due to the presence of a HIF1a isoform, HIF1a1.2. This isoform is co-localized with ARNT, a subunit important for the function of HIF1 transcription factor. This finding indicates that the HIF1a1.2 isoform might sequester ARNT in the cytoplasm. We also studied presence of stem cell marker Oct 3/4 in prostate cancer and benign prostate hyperplasia. Transcription of type 1 of Oct 3/4 as well as protein expression with nuclear localization of Oct 3/4 were not detected in any of prostate tumors or benign prostate hyperplasia but we found only the cytoplasmic isoform 2 of Oct3/4 in prostate tumors with NE-differentiation and also in benign prostate hyperplasia. We studied NE-differentiation in hormone-naive high-grade prostate adenocarcinoma with four immunohistochemial NE markers, Chromogranin A (CgA), synaptophysin, serotonin and neuron-specific enolase (NSE). We showed that synaptophysin immunoreactivity detects the highest number of NE-differentiated tumors. In addition, NE-differentiation measured with synaptophysin, serotonin and NSE immunoreactivity, was correlated to Gleason grade 4 rather than Gleason grade 5 cancer. Univariate statistical analysis revealed that the immunoexpression of CgA, serotonin and NSE is correlated to longer patient survival time. In conclusion, NE-differentiation in hormone-naive high-grade prostate adenocarcinoma, measured with three of four NE markers, is correlated to Gleason grade 4 cancer, a better prognosis and longer patient survival time.
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| 6. |
- Munksgaard Persson, Matilda, et al.
(författare)
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HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 180:2, s. 494-504
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Tidskriftsartikel (refereegranskat)abstract
- Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1 alpha repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-kappa B signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.
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| 7. |
- Olsson, Hans, et al.
(författare)
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Immunohistochemical Evaluation of Cell Cycle Regulators : Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer
- 2012
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Ingår i: ISRN Urology. - : Hindawi Publishing Corporation. - 2090-5807 .- 2090-5815. ; 2012
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration. The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs, and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder (UCB).Patients and Methods. This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder. Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs.Results. Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence. Also, normal p16 expression was related to a lower risk of tumour progression. MMP2, p21, cyclin D1, and pRb showed no significant results that could estimate progression or recurrence.Conclusions. Normal p16 expression is associated with a lower risk of tumour progression, but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB.
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| 8. |
- Panagopoulos, Ioannis, et al.
(författare)
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Characterization of an alternative transcript of the human CREB3L2 gene.
- 2010
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 24:5, s. 1133-1139
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Tidskriftsartikel (refereegranskat)abstract
- CREB3L2, a member of the CREB3 family of transcription factors, spans >120 kbp and is composed of 12 exons. We characterized a widely expressed transcript of CREB3L2 generated by an intronic polyadenylation site in intron 4 of the gene. It could be translated to a CREB3L2 variant which is localized both in the nucleus and the endoplasmatic reticulum. The protein retains the N-terminal transactivation domain but lacks the DNA-binding domain, the transmembrane domain and the C-terminal part. Experiments using a GAL4 DNA-binding domain fusion model showed that the transcript is a transactivator but it cannot exert its function through the CRE and ATF6 binding sites and has little effect on the GRP78 promoter. Whether this transcript has a cellular function or is targeted for degradation by nonsense-mediated RNA decay system of RNA surveillance is currently unknown.
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