Biomedical subjects

Andrea Tannapfel

Publications and source records attributed to Andrea Tannapfel.

At least 19 recordsLinked to original sources

PubMed2026

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation.

BACKGROUND: Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. METHODS: We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. RESULTS: Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association. CONCLUSIONS: Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.

Humans↗

PubMed2006

Pathophysiological role of platelets in acute experimental pancreatitis: influence of endothelin A receptor blockade.

The potential pathophysiological role of platelet-endothelium interactions was investigated during ischemia/reperfusion (I/R), and the effect of a selective endothelin(A) receptor antagonist (ET(A)-RA) was evaluated in an acute pancreatitis model. Acute pancreatitis was induced by warm ischemia (60 min) in Wistar rats, and its effects with and without antagonist treatment were investigated. Equivalent sham-operated animals were also studied. Microcirculatory changes were assessed by in vivo microscopy, and serum levels for lipase/amylase and histological specimens were investigated. Capillary constriction to 83.7 +/- 6.7% of sham-operated diameters was observed after 60 min of ischemia. A capillary density of 56.8 +/- 9.3% of the sham-operated group (396.3 +/- 15.8 mm(-1)) was measured after reperfusion. Stagnant leukocytes (329.5 +/- 30.4%) and platelets (337.5 +/- 32.3%) increased in postcapillary venules (P < 0.05). Administration of the ET(A)-RA significantly reduced I/R injury. Capillary diameters were maintained (101.4 +/- 4.5%), and capillary density was improved to 73.3 +/- 7.6% of sham-operated animals (P < 0.05). Stagnant leukocytes (152.3 +/- 10.6%) and platelets (207.1 +/- 19.8%) in sinusoids and postcapillary venules were reduced (P < 0.05). The extent of acute pancreatitis was reduced in the therapy group as indicated by serum lipase/amylase values and histological tissue damage (P < 0.05). Thus, ET(A)-RA therapy was effective in reducing I/R-induced pancreatitis in this experimental model.

Acute Disease↗

PubMed2006

Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis.

CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell transfer model of colitis. Using Foxp3 as a marker of regulatory T cell activity, we now provide a comprehensive analysis of the in vivo distribution of Foxp3+CD4+CD25+ cells in wild-type mice, and during cure of experimental colitis. In both cases, Foxp3+CD4+CD25+ cells were found to accumulate in the colon and secondary lymphoid organs. Importantly, Foxp3+ cells were present at increased density in colon samples from patients with ulcerative colitis or Crohn's disease, suggesting similarities in the behavior of murine and human regulatory cells under inflammatory conditions. Cure of murine colitis was dependent on the presence of IL-10, and IL-10-producing CD4+CD25+ T cells were enriched within the colon during cure of colitis and also under steady state conditions. Our data indicate that although CD4+CD25+ T cells expressing Foxp3 are present within both lymphoid organs and the colon, subsets of IL-10-producing CD4+CD25+ T cells are present mainly within the intestinal lamina propria suggesting compartmentalization of the regulatory T cell response at effector sites.

Animals↗

PubMed2006

Protein microarrays for the detection of biomarkers in head and neck squamous cell carcinomas.

Protein microarrays are of increasing importance for high-throughput screening of fresh tissues. In our study, protein microarrays were generated by printing antibodies onto membranes to characterize protein profiles expressed by head and neck squamous cell carcinomas (HNSCCs). Cellular proteomes of 30 matched normal squamous epithelial cells and carcinoma specimens were analyzed after tissue microdissection using microarrays composed of 83 different antibodies. As controls, Western blot analysis and tissue microarrays (TMAs) containing 98 HNSCC specimens were used. Of the 83 proteins examined, 14 showed differential expression between HNSCCs and normal epithelium. The protein microarray approach revealed an upregulation of 8 proteins and a downregulation of 6 proteins. Bag-1, Cox-2, Hsp-70, Stat3, pescadillo, MMP-7 (matrilysin), IGF-2, and cyclin D1 were identified to be significantly upregulated, whereas suppressor of cytokine signaling 1, thrombospondin, TGF-beta1, Jun, Fos, and Fra-2 were downregulated. The differential expression of these proteins was confirmed using Western blot and TMA. Upon correlation of differentially regulated proteins with the clinicopathologic data of our patients, MMP-7 (matrilysin) was found to be associated with survival in univariate, but not multivariate, analysis. These data indicate that our protein arrays provide protein information in a systematic, reproducible, and also high-throughput fashion.

Biomarkers, Tumor↗

PubMed2006

Elevated microsatellite alterations at selected tetranucleotides (EMAST) and mismatch repair gene expression in prostate cancer.

Elevated microsatellite alterations at selected tetranucleotides (EMAST), a new form of microsatellite instability (MSI) affecting tetranucleotide repeats, was recently described to be frequent in several tumor types (e.g., bladder, lung, ovarian, and skin cancers). EMAST was found as a form of microsatellite alteration distinct from the MSI phenotype in hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors which mostly affects mono- and dinucleotide repeats. To date, no study has investigated the role of EMAST in prostate cancer. We therefore analyzed 81 prostate tumors using 10 markers frequently detecting EMAST in other cancer types and the National Cancer Institute-consensus panel for HNPCC detection plus BAT40. In addition, we investigated p53 gene alterations [loss of heterozygosity (LOH)] and the expression of p53 and the mismatch repair (MMR) genes hMLH1 and hMSH2 on tissue microarrays. EMAST was detected in 4/81 (5%) cases and MSI in 6/79 (7.6%) cases. LOH of p53 was found in 9/45 (20%) informative cases. There was no correlation between MSI status and the histopathological or molecular characteristics of the tumors. Immunohistochemistry revealed p53 positivity in 5/61 (8%) tumors. There was a significant correlation between tumors showing a recurrence within 3 years after treatment and p53 positivity (p=0.029). Reduced hMLH1 expression, but no complete loss, was detected in 9/41 (22%) tumors without any correlations to histopathological or clinical features. Analysis of hMSH2 expression was available from 58/81 (72%) tumors. Staining intensity was as follows: negative in 7/58 (12%), weak staining in 16/58 (27.5%) samples, moderate staining in 19/58 (33%) samples, and strong staining in 16/58 (27.5%) samples. When negative/weak staining and moderate/strong staining were considered as two groups, there was a significant association between hMSH2 expression and tumor recurrence (p=0.039). In conclusion, our data show that MSI and EMAST are infrequent but distinct patterns of MSI in prostate tumors not related to MMR defects, p53 alterations, and histopathological characteristics. p53 positivity and moderate to strong hMSH2 expression of prostate tumors are correlated with early disease recurrence and indicate an unfavorable clinical course of the disease. These two genes could be useful biomarkers for the prediction of patients' outcome and should be analyzed in prospective studies.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Epigenetic silencing of the PTEN gene in melanoma.

Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) seems to be an important tumor suppressor gene in melanoma. Because the PTEN gene is only infrequently deleted or mutated, and because the PTEN protein is low to absent in a significant number of melanomas, we investigated alternative methods of epigenetic silencing. We did quantitative positional methylation analysis (pyrosequencing) on 37 sera from melanoma patients and on 21 pairs of corresponding sera and melanoma specimens in addition to Taqman reverse transcription-PCR. We report significant positional PTEN promoter methylation in 62% of circulating DNA isolated from sera of patients with metastatic melanoma. The percentage of methylation of a selected CpG island in blood showed a correlation with methylation levels in the corresponding melanoma tissue. Moreover, high percentages of PTEN methylation were associated with low PTEN transcription levels. Using the demethylation agent 5-aza-2'-deoxycytidine, reduced methylation and a corresponding increase in PTEN protein were observed in BLM melanoma cells, leading to reduced AKT activity in an in vitro kinase assay. In summary, epigenetic PTEN silencing seems to be a relevant mechanism of inactivating this tumor suppressor gene in melanoma that may promote melanoma development by derepression of the AKT pathway.

Aged↗

PubMed2006

STAT5 phosphorylation in malignant melanoma is important for survival and is mediated through SRC and JAK1 kinases.

Altered signaling pathways are key regulators of cellular functions in tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)3 and -5 may be involved in tumor formation and progression. We have investigated the role of STAT5 in cutaneous melanoma metastases using various RNA and protein techniques. In melanoma specimens, Stat5b transcripts were upregulated approximately 3.8-fold. In 13 of 21 (62%) human melanoma metastases, STAT5 was phosphorylated in comparison to normal human melanocytes and benign nevi. The STAT5 target gene Bcl-2 was frequently upregulated. The investigation of the underlying mechanism revealed specific STAT5 activation by recombinant human epidermal growth factor (rEGF). rEGF-induced activation of STAT5 occurred in vitro through the non-receptor tyrosine kinases transforming gene (src) of Rous Sarcoma virus and Janus kinase 1. Inhibition of Stat5b expression by small interfering RNA strongly reduced the expression of Bcl-2 and led to decreased cell viability and increased apoptosis in the melanoma cell lines A375 and BLM. Transfection with dominant-negative Stat5b caused enhanced cell death and G1 arrest in A375 cells. Our study identifies phosphorylated STAT5 in melanoma and shows regulation through rEGF; STAT5 may thus act as a survival factor for growth of human melanoma and may represent a potential target for molecular therapy.

Aged↗

PubMed2006

Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma.

BACKGROUND: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. METHODS: We analyzed 6 MTCs and 1 C-cell hyperplasia (CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. RESULTS: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wild-type RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. CONCLUSION: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.

Carcinoma, Medullary↗

PubMed2006

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery.

BACKGROUND: ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. CASE PRESENTATION: A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled (111)In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. CONCLUSION: This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative radioguided surgery using (111)In-pentetreotide and a gamma probe.

Adrenocorticotropic Hormone↗

PubMed2006

Effects of salt loading and various therapies on cardiac hypertrophy and fibrosis in young spontaneously hypertensive rats.

We investigated the effects of salt loading on blood pressure, cardiac hypertrophy and fibrosis as well as on the effectiveness of various antihypertensive therapies in young spontaneously hypertensive rats (SHR). Twenty-five male SHR were salt-stimulated by drinking 1% NaCl from 3 to 6 months of age. Eighteen of them were treated for the last 2 weeks of salt loading with either the angiotensin-converting enzyme inhibitor captopril, the beta-adrenergic receptor blocker propranolol or the calcium-channel antagonist verapamil. Age-matched male Wistar-Kyoto (WKY) rats and SHR drinking only water served as controls. At the age of 6 months, SHR had significantly elevated blood pressure that was unchanged by salt loading. Relative heart weight was increased in SHR without (3.3) and even more so with salt intake (3.6 vs. 2.4 in WKY). Left ventricular (LV) hypertrophy was accompanied by a 17-fold increase in the expression of mRNA for atrial natriuretic factor (ANF) both in untreated and salt-loaded SHR compared to WKY (p<0.001). Collagen I and III mRNA increased 1.7-1.8-fold in SHR without and with additional salt intake (p<0.01). None of the therapies significantly reduced blood pressure or hypertrophy. Although captopril had no antihypertensive effect, it reduced ANF, collagen I and III mRNA in LV to control level. Less pronounced effects were achieved with verapamil. These findings emphasize the cardioprotective role of captopril which may not be fully expressed in the presence of elevated salt intake.

Adrenergic beta-Antagonists↗

PubMed2006

Expression of c-kit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice.

AIM: To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma (CC) and to evaluate the efficacy of in vitro and in vitro treatment with imatinib mesilate. METHODS: The protein expression of c-kit in the human biliary tract cancer cell lines Mz-ChA-2 and EGI-1 and histological sections from 19 patients with extrahepatic CC was assessed by immunoblotting, immunocytochemistry, and immunohistochemistry. The anti-proliferative effect of imatinib mesilate on biliary tract cancer cell lines Mz-ChA-2 and EGI-1 was studied in vitro by automated cell counting. In addition, immunodeficient NMRI mice (Taconic) were subcutaneously injected with 5x10(6) cells of cell lines MzChA-2 and EGI-1. After having reached a tumour volume of 200 mm3, daily treatment was started intraperitoneally with imatinib mesilate at a dose of 50 mg/kg or normal saline (NS). Tumor volume was calculated with a Vernier caliper. After 14 d, mice were sacrificed with tumors excised and tumor mass determined. RESULTS: Immunoblotting revealed presence of c-kit in Mz-ChA-2 and absence in EGI-1 cells. Immunocytochemistry with c-kit antibodies displayed a cytoplasmatic and membraneous localization of receptor protein in Mz-ChA-2 cells and absence of c-kit in EGI-1 cells. c-kit was expressed in 7 of 19 (37%) extrahepatic human CC tissue samples, 2 showed a moderate and 5 a rather weak immunostaining. Imatinib mesilate at a low concentration of 5 micromol/L caused a significant growth inhibition in the c-kit positive cell line Mz-ChA-2 (31%), but not in the c-kit negative cell line EGI-1 (0%) (P<0.05). Imatinib mesilate at an intermediate concentration of 10 micromol/L inhibited cellular growth of both cell lines (51% vs 57%). Imatinib mesilate at a higher concentration of 20 micromol/L seemed to have a general toxic effect on both cell lines. The IC50 values were 9.7 micromol/L and 11 micromol/L, respectively. After 14 d of in vitro treatment with imatinib mesilate, using the chimeric mouse model, c-kit positive Mz-ChA-2 tumors had a significantly reduced volume and mass as compared to NS treatment (P<0.05). In contrast to that, treatment of mice bearing c-kit negative EGI-1 tumors did not result in any change of tumor volume and mass as compared to NS treatment. CONCLUSION: c-kit expression is detectable at a moderate to low protein level in biliary tract cancer. Imatinib mesilate exerts marked effects on tumor growth in vitro and in vitro dependent on the level of c-kit expression.

Animals↗

PubMed2006

Collagen foil (TissuFoil E) reduces the formation of adhesions when using polypropylene mesh for the repair of experimental abdominal wall defects.

BACKGROUND AND AIMS: Polypropylene meshes (PPMs) are routinely used in the treatment of incisional hernias to achieve a tension-free closure of the abdominal wall. Severe adhesions are a common cause of intestinal obstruction, or even intestinal fistulas. Using a porcine model, we investigated whether applying a collagen foil (CF) to the undersurface of a PPM will reduce adhesion formation. METHODS: In ten domestic pigs (20-25 kg), a median laparotomy was performed. In each animal the abdominal wall was reconstructed using three types of closure: simple closure by a running suture (control), PPM only, and PPM covered with CF (PPM-CF). After 6 weeks, the abdominal wall with adherent tissue was resected en bloc for macroscopic (quality and quantity of adhesion formation) and histological work-up. RESULTS: The PPM-CF showed significantly less severe (1.9 vs 3.0 according to a scoring system), and also less extended (23.8 vs 55.9% total coverage of the mesh), adhesions to the resected abdominal wall. Histological examination revealed fewer and less severe inflammatory reactions, necrosis, and foreign body reactions for the mesh and CF (PPM-CF). CONCLUSION: To combine meshes with the anti-adhesion properties of a CF may be another option to achieve more physiological and more tolerable prosthetic materials.

Animals↗

PubMed2006

Mitogen-activated protein kinase signaling is activated in prostate tumors but not mediated by B-RAF mutations.

OBJECTIVES: A dysregulated mitogen-activated protein kinase (MAPK) pathway plays an important role in various malignancies and is often mediated by mutations in several oncogenes (eg, RAF, RAS). B-RAF mutations, predominantly the specific V600E mutation and additional alterations in exons 11 and 15, were frequently detected in malignant melanomas, papillary thyroid tumors, and colorectal cancers with microsatellite instability (MSI). The present study investigated B-RAF mutations, MSI status, and activation of MAPK signaling in prostate tumors. METHODS: The V600E mutation of the B-RAF gene was analyzed using allele-specific polymerase chain reaction in 79 archival prostatic adenocarcinomas (pT1aG1 to pT3cG3, median Gleason score 6); exons 11 and 15 were sequenced. MSI status was determined using the National Cancer Institute consensus panel for hereditary nonpolyposis colorectal carcinoma (HNPCC) detection. Active MAPK signaling was investigated using immunohistochemistry for p44/ERK1 and p42/ERK2. RESULTS: No B-RAF mutations could be detected. Six of 79 tumors showed MSI positivity. Active MAPK signaling was detected in 51% of the analyzed tumors. No correlation was found between MAPK activity and histopathologic/clinical characteristics. CONCLUSION: The most frequent B-RAF gene alterations are not involved in prostate carcinogenesis. MSI is infrequent in prostate cancer and is not linked to B-RAF mutations. MAPK signaling is frequently activated in prostate tumors and might be suitable for a therapeutic approach.

Aged↗

PubMed2006

Prediction of upper aerodigestive tract cancer by slide-based cytometry.

AIM: To evaluate slide-based cytometry in screening for and following up of carcinoma of the upper aerodigestive tract using swabs for a minimal-invasive approach. METHODS: Laser scanning cytometry (LSC) was used for multiparametric analysis of cells stained for cytokeratin and DNA to determine the DNA-index (DI) of the tumor cells. Histograms with 0.95 < DI < 1.05 and 1.9 < DI < 2.1 were defined as DNA euploid and any other DI as DNA aneuploid. After subsequent HE-staining, single cells were relocalized in order to document morphology. Conventional cytology was also performed on a subset of the slides. Routine histopathology of parallel biopsies served as gold standard in all cases. RESULTS: 115 swabs from 109 patients were obtained from the entire upper aerodigestive tract. 16 swabs were classified as insufficient for LSC. In the remaining 99 specimens, 1 benign lesion was misclassified as malignant, while 61 of the 75 malignant lesions were correctly identified. This corresponds to predictive values of 98.4% and 62.2% for the detection of malignant and benign samples by LSC. CONCLUSION: This pilot study demonstrates the validity of LSC screening for the identification of tumor malignancy in the upper aerodigestive tract from swab collected cytological material.

Humans↗

PubMed2006

Role of epigenetic alterations in cholangiocarcinoma.

Intrahepatic cholangiocarcinomas are rare malignant epithelial liver tumors arising from intrahepatic bile ducts. The prognosis of affected patients is poor. Several risk factors, including hepatolithiasis, liver fluke infection, and anatomical abnormalities associated with inflammation of the biliary tract have been described. At present, little is known about the cellular and molecular mechanisms leading to the development of cholangiocarcinoma. In recent years, in addition to genetic alterations, epigenetic inactivation of (tumor suppressor) genes by promoter CpG island hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. This review discusses the epi-genetic inactivation of different tumor suppressor genes in cholangiocarcinoma.

Adenocarcinoma↗

PubMed2006

p16, p14, p53, cyclin D1, and steroid hormone receptor expression and human papillomaviruses analysis in primary squamous cell carcinoma of the endometrium.

Pathogenetically, endometrioid adenocarcinomas of the endometrium are associated with hyperestrogenism and serous papillary carcinomas with alterations of p53. The etiology of primary endometrial squamous cell carcinoma (ESCC), however, is speculative. The purpose of this study was to evaluate the role of p14, p16, p53, cyclin D1, steroid hormone receptors, and human papillomaviruses (HPV) infection in the pathogenesis of primary endometrial squamous cell carcinoma. The expression of p16, p14, p53, cyclin D1, and steroid hormone receptors (estrogen, progesterone, and androgen) was examined immunohistochemically in 8 primary ESCCs. HPV analysis was performed using general primers and HPV typing. The median age of the patients was 62.1 years. Four cases showed positive nuclear and cytoplasmic p16 staining in an insular pattern, and 1 case nuclear positivity for p53 and estrogen receptors, respectively. Four of 8 cases were positive for progesterone receptor analysis and cyclin D1. All cases were negative for p14 and androgen receptor staining. All but one case were negative for HPV analysis. Five patients were alive with and without evidence of disease after a mean follow-up of 6.1 years. The results of this study suggest that alterations of the p16 pathway may play an etiologic role in at least a proportion of the ESCC, but without any association to HPV infection. Factors known to play a pathogenetic role in types 1 and 2 of endometrial carcinomas are not associated with primary ESCC. However, prognostically, ESCCs are more related to type 1 cancers.

Adult↗

PubMed2006

[Efficient diagnosis of pathological fractures].

Pathological fractures are defined as fractures, which appear at diseased and mechanically weakened bones due to systemic or local processes. Their frequency is below 5%. This study demonstrates typical results and diagnostic criteria of pathological fractures. It will be shown, how diagnostic analysis is supposed to be performed to recognize pathological fractures. Based just on the X-ray image, diagnostic algorithms should provide all tools required for the radiologist to create a final diagnosis or to refer to other appropriate imaging modalities followed by a correct diagnosis and, if necessary, to allow interdisciplinary causal therapies.

Diagnosis, Differential↗

PubMed2006

Attenuation of proinflammatory gene expression and microcirculatory disturbances by endothelin A receptor blockade after orthotopic liver transplantation in pigs.

BACKGROUND: Endothelin-1 (ET-1), a very potent mediator of vasoconstriction, leads to microcirculatory disturbances and release of proinflammatory cytokines under pathophysiologic conditions. Our aim was to evaluate the effect of a selective ET(A)-receptor antagonist (ET(A)-RA) on cold ischemia/reperfusion (I/R) injury in a pig model. METHODS: Twenty pigs revealed orthotopic liver transplantation. The animals were randomized into 2 groups: control pigs received isotonic saline; the treated group received the selective ET(A)-RA BSF 208075 at the beginning of reperfusion. On postoperative days 4 and 7, animals were re-laparotomized to obtain tissue specimens. Liver tissue samples were collected and quantitative mRNA expression for prepro-ET-1, ET(A) receptor, pro-IL-1beta, pro-IL-6, pro-TNF-alpha, and endothelial nitric oxide synthase was analyzed using the TaqMan system. Additionally, immunohistochemical analysis for ET-1 was performed. Hepatic microcirculation was evaluated by laser Doppler flow measurement and partial pressure of oxygen and carbon dioxide measurements with the Paratrend sensor. Postischemic liver damage was monitored by measurement of liver enzymes and by histologic analysis using a semiquantitative scoring classification. RESULTS: Treatment with the ET(A)-RA significantly reduced the severity of I/R injury evidenced by lower serum AST, ALT and GLDH. Analysis of partial pressure of oxygen and blood flow revealed a significant improvement of capillary perfusion and blood flow in the treated group and was associated with a relevant reduction of tissue injury. One hour after reperfusion, quantitative RT-PCR revealed significantly lower expression of prepro-ET-1, ET(A) receptor, endothelial nitric oxide synthase, pro-TNF-alpha, pro-IL-1beta and pro-IL-6 in the therapy group. Immunohistochemical analysis demonstrated significantly reduced ET-1 immunostaining after therapy. Histologic investigation suggested less tissue damage in treated animals. CONCLUSIONS: Treatment with the selective ET(A)-RA BSF 208075 has protective effects on microcirculation after liver transplantation. ET(A)-RA not only affects the expression of vasoactive genes, but also decreases gene expression of proinflammatory cytokines such as TNF-alpha, IL-1beta and IL-6.

Animals↗