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  • 1
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; carcinoma ; KINASE ; DISEASE ; PROTEIN ; DIFFERENTIATION ; TUMORS ; CONTRAST ; ACTIVATED PROTEIN-KINASE ; PHOSPHORYLATION ; BREAST ; IN-SITU ; LESIONS ; immunohistochemistry ; MALIGNANCIES ; PATTERNS ; EPITHELIAL-CELLS ; CARCINOMAS ; INTERCELLULAR COMMUNICATION ; MALIGNANCY ; MOLECULAR-BASIS ; BASAL LAMINA ; breast carcinoma ; connexin43 ; GAP JUNCTIONAL COMMUNICATION ; gap junctions
    Abstract: We applied an antiserum (SA226P) specifically recognizing the phosphorylated form of connexin43 (P-Cx43) to human breast samples including normal breast samples, with fibrocystic disease (FCD), fibroadenomas (FA), in situ and infiltrating carcinomas of all major types, and miscellaneous extramarnmary tumors. The findings were compared with those obtained with commercial antisera recognizing all Cx43 forms (pan-Cx43). A subset of samples was stained for Her2-neu and p44/42 to mitogen-activated protein kinase. Paraffin step sections were used. Immunoblots were performed on frozen samples of a representative subset of cases. In the normal breast, FCD, and FA, SA226P stained strongly and extensively most myoepithelial cells (MECs); luminal cells remained unstained. In proliferative FCD and some cellular FA, SA226P stained MEC and the capillary endothelium (CE). In ductal and lobular in situ carcinomas, SA226P reacted strongly and diffusely with the remaining MEC, the CE, and the transformed luminal cells. SA226P stained all infiltrating carcinomas except the tubular variant. In all breast carcinomas, the CE within and adjacent to tumors and some myofibroblasts stained with SA226P. By contrast, pan-Cx43 stained weakly and sporadically the MEC and rare samples of invasive carcinomas. Notably, Mab p44/42 reacted in parallel with the samples stained with SA226P, whereas reactions with Her2 were negative. Immunoblot findings paralleled those obtained immunohistochemically. We conclude that P-Cx43, restricted to MEC in the normal breast, is up-regulated in the same cells in hyperplasias and dysplasias and FA and is strongly up-regulated in invasive carcinomas. Notably, in some proliferative FCD and in most in situ and infiltrating carcinomas, P-Cx43 is strongly expressed in CE within and adjacent to the lesions but not away from them. These findings were paralleled by the strong nuclear reactions noted with Mab p44/42. These phenomena, although not exclusive to malignancy, are particularly conspicuous in breast carcinomas and seemingly reflect active proliferation associated with abnormal gap junctional intercellular communication. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15948121
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  • 2
    Keywords: CANCER ; THERAPY ; GENE ; ACTIVATION ; immunohistochemistry ; B-RAF ; POINT MUTATIONS ; KRAS ; LOW-GRADE ; MOLECULAR-GENETIC-ANALYSIS ; allele-specific PCR ; BRAF mutation ; MEK INHIBITION ; PAPILLARY THYROID-CARCINOMA ; Serous ovarian tumors
    Abstract: Mutations of components of the mitogen-activated protein kinase pathway, mainly BRAF, are common in serous ovarian borderline tumors, whereas high-grade serous ovarian carcinomas rarely show this feature. With the advent of specific kinase inhibitors active against BRAF-mutated cancers, rapid and sensitive detection of the BRAF V600E, by far the most common mutation of this gene, is of great practical relevance. Currently, BRAF mutations are detected by DNA-based techniques. Recently, a monoclonal antibody (VE1) specific for the BRAF V600E protein suitable for archival tissues has been described. In this study, we compared detection of the V600E mutation in serous ovarian tumors by VE1 immunostaining and by allele-specific polymerase chain reaction. All 141 cases of high-grade serous ovarian cancer showed negative or rarely weak, diffuse background VE1 immunostaining, and BRAF wild type was confirmed by molecular analysis in all tested cases. In contrast, 1 (14%) of 7 low-grade serous carcinomas and 22 (71%) of 31 serous borderline tumors revealed moderate to strong VE1 positivity. Immunostaining was clearly evaluable in all cases with sufficient tumor cells, and only rare cases with narrow cytoplasm were difficult to interpret. The V600E mutation was confirmed by allele-specific polymerase chain reaction and sequencing in all VE1-positive cases. Two VE1-positive cases with low epithelial cell content required repeat microdissection to confirm the presence of the mutation. Immunohistochemistry with the VE1 antibody is a specific and sensitive tool for detection of the BRAF V600E mutation in serous ovarian tumors and may provide a practical screening test, especially in tumor samples with low epithelial content.
    Type of Publication: Journal article published
    PubMed ID: 23089489
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  • 3
    Keywords: DISEASE ; GENE ; FACTOR-I RECEPTOR ; POLYMORPHISMS ; antibody ; chemotherapy ; adenocarcinoma ; paclitaxel ; CARBOPLATIN ; EGFR
    Abstract: The purpose of this study was to characterize the prevalence of insulin-like growth factor 1 receptor (IGF1R) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non-small cell lung cancers in relation to patient characteristics and prognosis. This retrospective study was conducted on 304 patients with non-small cell lung cancers who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF1R gene alterations (n = 304) and protein expression (n = 181) were evaluated by polymerase chain reaction based assays and immunohistochemistty, respectively. Membranous and cytoplasmic staining were analyzed separately. In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF1R gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF1R SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (P=.025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF1R staining was higher in squamous cell carcinomas versus other histologies (P〈.0001) and showed a trend to longer survival (P=.08). No association between SNP variations and protein expression was found. Membranous IGF1R protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbor prognostic value. These alterations may be of interest when evaluating the IGF1R as potential therapeutic target and should receive further research.
    Type of Publication: Journal article published
    PubMed ID: 24745618
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  • 4
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; GENE-EXPRESSION ; PROTEIN ; transcription ; METABOLISM ; EPITHELIA ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; TISSUES ; SEQUENCE ; ACID ; ACIDS ; antibodies ; antibody ; ADENOMAS ; SURFACE ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; fatty acids ; FATTY-ACIDS ; adenocarcinoma ; ADENOCARCINOMAS ; carcinoma,epithelial tumors,fatty acid metabolism,small intestine ; CHAIN ACYL-COA ; DEPENDENT REGULATION ; fatty acid metabolism ; SMALL-INTESTINE
    Abstract: Fatty acids are implicated in tumorigenesis, but data are limited concerning endogenous fatty acid metabolism of tumor cells in adenomas and adenocarcinomas of the small intestine. The recently cloned human acyl-CoA-synthetase 5 (ACS5) is predominantly found in the small intestine and represents a key enzyme in providing cytosolic acyl-CoA thioesters. Protein synthesis and mRNA expression of ACS5 were studied in human intestinal tissues using different methods, including a newly established monoclonal antibody. In the healthy small intestine, expression of ACS5 was restricted to the villus surface epithelium but was not detectable in enterocytes lining crypts. ACS5 protein and mRNA were progressively diminished in epithelial cells of adenomas and adenocarcinomas of the small intestine. In conclusion, altered expression of ACS5 is probably related to the adenoma-carcinoma sequence of small intestinal epithelial tumors due to an impaired acyl-CoA thioester synthesis. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14608540
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  • 5
    Keywords: EXPRESSION ; tumor ; carcinoma ; Germany ; human ; IN-VIVO ; LUNG ; THERAPY ; VIVO ; DIAGNOSIS ; SYSTEM ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; LINES ; kidney ; MARKER ; colon ; TISSUES ; BINDING ; CELL-LINES ; BREAST ; antibodies ; antibody ; NERVOUS-SYSTEM ; PROGRESSION ; immunohistochemistry ; METASTASIS ; CERVIX ; CELL-LINE ; LINE ; MELANOMA ; ADHESION ; CELL-ADHESION ; MIGRATION ; MONOCLONAL-ANTIBODIES ; BENIGN ; INTEGRIN ; CARCINOMAS ; adenocarcinoma ; ADENOCARCINOMAS ; L1 ; MALIGNANT-MELANOMA ; ADHESION MOLECULE ; CELL-ADHESION MOLECULE ; cell lines ; LUNG-CARCINOMA ; DOMAINS ; ADULTS ; ENDOMETRIAL ; RE ; cell adhesion ; SUBTYPES ; CD171 ; lung carcinoma ; in vivo ; PREDICTOR ; RENAL-CARCINOMA ; OVARIAN ; molecular marker ; pediatric ; nongynecological tumors ; OVARIAN-CARCINOMA CELLS ; tumors of female genital tract
    Abstract: L1 cell adhesion molecule (CD171) represents a strongly unfavorable prognostic biomarker for ovarian and endometrial carcinomas. Here we carried out an immunohistochemical survey of L1 expression in normal adults and in a broad range of benign and malignant tumors using monoclonal antibody L1-11A and the novel monoclonal antibody L1-14.10. In normal tissues, L1 was expressed in the collecting tubules of adult tissues and pediatric kidney and in peripheral nerve bundles. In tumors of the female genital tract, L 1 was detected in adenocarcinomas of the cervix and fallopian tubes, in addition to ovarian and endometrial carcinomas. Nongynecological tumors expressing L1 comprised malignant melanoma, colon adenocarcinoma positive to chromogranin, clear-cell adenocarcinoma of the urinary bladder, pheochromocytoma, small cell lung carcinoma, and tumors of the nervous system. L1 was absent in breast carcinoma, gastrointestinal tract carcinomas, gastrointestinal carcinoids, renal clear-cell carcinomas, prostate adenocarcinomas, and mesotheliomas. Surprisingly, L1 expression in established breast and renal carcinoma cell lines was not a predictor for its presence in these human tumors in vivo. Our results suggest that L1 expression in tumors is not ubiquitous but restricted to certain subtypes and may be a helpful molecular marker for differential diagnosis and target for antibody-based therapy. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16867862
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  • 6
    Keywords: CANCER ; EXPRESSION ; GENE ; TUMORS ; MOLECULAR-BIOLOGY ; p53 ; HIGH-FREQUENCY ; Ras ; p16(INK4A) ; senescence
    Abstract: Carcinogenesis of squamous cell carcinomas (SCCs) in the anogenital tract and head and neck region is heterogeneous. A substantial proportion of SCC in the vulva, anus, and head and neck follows a human papillomavirus (HPV)-induced carcinogenic pathway. However, the molecular pathways of carcinogenesis in the HPV-independent lesions are not completely understood. We hypothesized that oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations might represent a carcinogenic mechanism in a proportion of those HPV-negative cancers. Considering the repeated observation of KRAS-associated p16INK4a overexpression in human tumors, it was assumed that KRAS mutations might be particularly present in the group of HPV-negative, p16INK4a-positive cancers. To test this hypothesis, we analyzed 66 anal, vulvar, and head and neck SCC with known immunohistochemical p16INK4a and HPV DNA status for KRAS mutations in exon 2 (codons 12, 13, and 15). We enriched the tumor collection with HPV DNA-negative, p16INK4a-positive cancers. A subset of 37 cancers was also analyzed for mutations in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene. None of the 66 tumors harbored mutations in KRAS exon 2, thus excluding KRAS mutations as a common event in SCC of the anogenital and head and neck region and as a cause of p16INK4a expression in these tumors. In addition, no BRAF mutations were detected in the 37 analyzed tumors. Further studies are required to determine the molecular events underlying HPV-negative anal, vulvar, and head and neck carcinogenesis. Considering HPV-independent p16INK4a overexpression in some of these tumors, particular focus should be placed on alternative upstream activators and potential downstream disruption of the p16INK4a pathway.
    Type of Publication: Journal article published
    PubMed ID: 25257576
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  • 7
    Abstract: Pituicytoma is a rare benign neoplasm arising in the sellar region, usually found in the posterior lobe and/or pituitary stalk. Here, we report the case of a 67-year-old woman who presented with bitemporal hemianopsia and visual impairment accompanied by mildly elevated prolactin. Pathologic and molecular examination of the tissue removed transsphenoidally revealed 2 distinct tumors: pituitary adenoma and pituicytoma. To the best of our knowledge, histologically proven pituicytoma and pituitary adenoma have never been reported together.
    Type of Publication: Journal article published
    PubMed ID: 26476569
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; FACTOR RECEPTOR ; Germany ; human ; PATHWAY ; PROSTATE ; SYSTEM ; RISK ; PROTEIN ; PROTEINS ; COMPONENTS ; TISSUE ; TUMORS ; PATIENT ; LIGAND ; MARKER ; ANTIGEN ; BINDING ; hormone ; PROGRESSION ; immunohistochemistry ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; PARAMETERS ; LIGANDS ; BENIGN ; PHENOTYPE ; adenocarcinoma ; ADENOCARCINOMAS ; intraepithelial neoplasia ; PREDICTORS ; BEHAVIOR ; FACTOR-I ; protein expression ; P27(KIP1) ; insulin ; SERUM ; IGF-I ; RE ; FRACTION ; intensity ; development ; BINDING PROTEIN-3 ; RECEPTOR SUBSTRATE-1 ; LEVEL ; insulin-like growth factor ; SERUM-LEVELS ; TUMOR BEHAVIOR ; HIGH-GRADE ; IGF-BINDING PROTEIN-3 ; insulinlike growth factor system
    Abstract: There is an evidence that components of the insulin-like growth factor (IGF)-signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein-3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein-3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16260272
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  • 9
    Keywords: EXPRESSION ; PROGRESSION ; POOR-PROGNOSIS ; CELL CARCINOMA ; CLINICAL-SIGNIFICANCE ; ANDROGEN RECEPTOR ; HISTONE CHAPERONE ; PSA RECURRENCE ; PANCREATIC NEUROENDOCRINE TUMORS ; DAXX
    Abstract: Molecular markers reliably predicting the aggressiveness of prostate cancer are currently lacking. Death-domain-associated protein (DAXX) has been implicated in the regulation of chromatin remodeling, transcription, and apoptosis that are integral to oncogenesis and cancer progression. DAXX expression was analyzed by immunohistochemistry on a tissue microarray containing 7478 prostate cancer specimens. Results were compared with tumor phenotype, biochemical recurrence, and v-ets erythroblastosis virus E26 oncogene homolog (ERG) status. DAXX expression was predominantly seen in the nucleus. DAXX expression was detectable in 4609 (80.6%) of 5718 interpretable cancers and considered strong in 5.9%, moderate in 45.8%, and weak in 28.9%. Strong DAXX expression was associated with both transmembrane protease, serine 2 (TMPRSS2)/ERG rearrangement and ERG expression (P 〈 .0001 each). Strong DAXX expression was tightly linked to high Gleason grade, advanced pT stage, increased cell proliferation index, and early prostate-specific antigen recurrence (P 〈 .0001 each). The prognostic role of DAXX expression was independent of Gleason grade, pT stage, and pN stage. Our study establishes DAXX as a novel independent prognosticator in prostate cancer and suggests an important role of DAXX expression for both prostate cancer development and progression. Furthermore, DAXX appears to exert biologically different effects in ERG-positive and ERG-negative prostate cancers.
    Type of Publication: Journal article published
    PubMed ID: 23642739
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  • 10
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