Peter Fritz

Publications (86)335.49 Total impact

• Source

  Available from: Juergen Dippon

  Article: Postoperative Survival of Lung Cancer Patients: Are There Predictors beyond TNM?

  Godehard Friedel, Peter Fritz, Sven Goletz, Ralf Kristen, Friedhelm Brinkmann, Rainer Dierkesmann, Matthias Schwab, German Ott, Jürgen Dippon, Mark Dominik Alscher
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  ABSTRACT: Background/Aim: We report on survival data of 595 patients with stage I-III lung cancer with respect to TNM classification. We constructed a basic model consisting of stage and grade, and assessed the improvement of survival prediction after adding comorbidity data, spirometric data, clinical and laboratory parameters. Body mass index (BMI) and presence of a cardiac disease reached statistical significance for prediction of overall survival in a Cox regression model. In addition to BMI (<25 kg/m(2)) and the presence of cardiovascular disease, the spirometric variable (FEV1) predicted early death (less than five months postoperatively). When the survival random forest method was employed to predict disease outcome, creatinine levels and VO2 max became additional variables of interest for predicting survival. We propose that our lung cancer database may help to identify variables (aside from histomorphological variables) that are suitable for identifying patients at risk of death after surgical treatment of lung cancer.
  Anticancer research 04/2013; 33(4):1609-19. · 1.73 Impact Factor
• Article: PERIOSTIN: A MATRICELLULAR PROTEIN INVOLVED IN PERITONEAL INJURY DURING PERITONEAL DIALYSIS.

  Niko Braun, Kontheari Sen, M Dominik Alscher, Peter Fritz, Martin Kimmel, Johann Morelle, Eric Goffin, Achim Jorres, Rudolf P Wuethrich, Clemens D Cohen, Stephan Segerer
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  ABSTRACT: BACKGROUND: Periostin is a matricellular protein involved in tissue remodeling through the promotion of adhesion, cell survival, cellular dedifferentiation, and fibrogenesis. It can be induced by transforming growth factor beta and high glucose concentrations. We hypothesized that this protein might be expressed in the peritoneal cavity of patients on peritoneal dialysis (PD) and even more in patients with signs of encapsulating peritoneal sclerosis (EPS). Method: In this retrospective study, we included peritoneal biopsies from patients on PD with EPS (n = 7) and without signs of EPS (n = 10), and we compared them with biopsies taken during hernia repair from patients not on PD (n = 11) and during various procedures from uremic patients not on PD (n = 6). Periostin was localized by immunohistochemistry, scored semiquantitatively, and quantified by morphometry. Periostin protein concentrations were measured by ELISA in dialysates from 15 patients. Periostin messenger RNA was quantified in vitro in peritoneal fibroblasts. RESULTS: In control biopsies, periostin was present in the walls of larger arteries and focally in extracellular matrix in the submesothelial zone. Patients on PD demonstrated interstitial periostin in variable amounts depending on the severity of submesothelial fibrosis. In EPS, periostin expression was very prominent in the sclerosis layer. The area of periostin was significantly larger in EPS biopsies than in control biopsies, and the percentage of periostin-positive area correlated with the thickness of the submesothelial fibrosis zone. Periostin concentrations in dialysate increased significantly with time on PD in patients without signs of EPS; in patients with EPS, periostin concentrations in dialysate were low and demonstrated the smallest increase with time. In vitro, periostin was found to be strongly expressed by peritoneal fibroblasts. CONCLUSION: Periostin is strongly expressed by fibroblasts and deposited in the peritoneal cavity of patients with EPS and with simple peritoneal fibrosis on PD. This protein might play a role in the progression of peritoneal injury, and low levels of periostin after prolonged time on PD might be a marker of EPS.
  Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 02/2013;
• Article: PHENOTYPES OF ENCAPSULATING PERITONEAL SCLEROSIS--MACROSCOPIC APPEARANCE, HISTOLOGIC FINDINGS, AND OUTCOME.

  Joerg Latus, Christoph Ulmer, Peter Fritz, Bianka Rettenmaier, Dagmar Biegger, Thomas Lang, German Ott, Martin Kimmel, Wolfgang Steurer, M Dominik Alscher, Stephan Segerer, Niko Braun
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  ABSTRACT: BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis (PD), with clinical signs of abdominal pain, bowel obstruction, and weight loss in late stages. METHODS: We retrospectively analyzed all patients who were diagnosed with EPS between March 1998 and October 2011 in our department of nephrology. We focused on the 24 EPS patients who underwent surgery because of symptomatic late-stage EPS. We identified 3 different macroscopic phenotypes of EPS that we categorized as types I - III. We correlated histologic findings with those macroscopic phenotypes of EPS. The postoperative and long-term outcomes were evaluated by macroscopic phenotype. RESULTS: Duration of PD was longer in type III than in types I and II EPS (p = 0.05). We observed no other statistically significant differences between the groups in baseline characteristics, except for operation time, which was longer in the type I than in the type III group (p = 0.02). Furthermore, we observed no statistically significant difference between the groups with respect to the onset of complaints before surgery (7.8 ± 5.9 months vs 7.0 ± 7.0 months vs 6.5 ± 5.3 months). Concerning patient outcomes, there was no evidence that any of the macroscopic EPS types was associated with more major or minor complications after surgery. For all study patients, follow-up was at least 3 years, with 19 patients still being alive, and 16 having no or very mild complaints. The typical histologic findings of EPS were present in all macroscopic types; only fibrin deposits were more prominent in type II than in type III. CONCLUSIONS: We describe 3 subtypes of EPS based on macroscopic findings. Postoperative treatment should probably not be influenced by the macroscopic EPS phenotype. Whether the different phenotypes represent different pathophysiologic processes remains unclear and has to be further evaluated.
  Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 02/2013;
• Article: Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism.

  Joerg Latus, Renate Lehmann, Meike Roesel, Peter Fritz, Niko Braun, Christoph Ulmer, Wolfgang Steurer, Dagmar Biegger, German Ott, Juergen Dippon, M Dominik Alscher, Martin Kimmel
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  ABSTRACT: The presentation of patients with primary hyperparathyroidism is often atypical and ranges from normocalcemic, primary hyperparathyroidism to severe, symptomatic hypercalcemia. G-protein-coupled, calcium-sensing receptor (CaSR), vitamin D receptor (VDR), and fibroblast growth factor receptor (FGFR)/klotho complexes seem to be involved in the development of pHPT. Parathyroid glands from 53 patients with pHPT and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional detailed morphological and immunohistochemical analyses of parathyroid glands were performed after dividing each slide in a 3 × 3 array. From morphology, the number of lipocytes was significantly lower in parathyroid tissue glands in the pHPT group (p < 0.001). Protein expressions of klotho, CaSR, and VDR were significantly reduced in the pHPT compared with the control group (p = 0.004, p = 0.007, p < 0.001). No differences were seen between the two groups (p = 0.35) regarding expression of FGFR. Correlations between expression showed significant positively correlations between klotho and CaSR and FGFR and VDR. No correlations between klotho expression and serum calcium levels could be detected (R = -0.13, p = 0.66), but there were positive correlations between expressions of CaSR/serum phosphate and klotho/serum phosphate. Impaired protein expression of CaSR and VDR seem to be involved in the development of pHPT. The role of the FGFR/klotho-axis remains still unclear. Correlations between protein expression of CaSR and serum phosphate and klotho and serum phosphate levels could be detected. Whether these findings give new insights into the pathogenesis of the disease is yet unknown and has to be elucidated.
  Endocrine 01/2013; · 1.42 Impact Factor
• Article: Transcriptional patterns in peritoneal tissue of encapsulating peritoneal sclerosis, a complication of chronic peritoneal dialysis.

  Fabian R Reimold, Niko Braun, Zsuzsanna K Zsengellér, Isaac E Stillman, S Ananth Karumanchi, Hakan R Toka, Joerg Latus, Peter Fritz, Dagmar Biegger, Stephan Segerer, M Dominik Alscher, Manoj K Bhasin, Seth L Alper
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  ABSTRACT: Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value<0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment.
  PLoS ONE 01/2013; 8(2):e56389. · 4.09 Impact Factor
• Article: Analysis of α-Klotho, Fibroblast Growth Factor-, Vitamin-D and Calcium-Sensing Receptor in 70 Patients with Secondary Hyperparathyroidism.

  Joerg Latus, Renate Lehmann, Meike Roesel, Peter Fritz, Niko Braun, Christoph Ulmer, Wolfgang Steurer, Dagmar Biegger, German Ott, Juergen Dippon, M Dominik Alscher, Martin Kimmel
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  ABSTRACT: Background/Aims: Secondary hyperparathyroidism (sHPT) is known as a very common complication in patients with chronic kidney disease, and G-protein-coupled calcium-sensing receptor (CaSR), Vitamin D receptor (VDR) and Fibroblast growth factor receptor (FGFR)/Klotho complexes seem to be involved in its development. Methods: Hyperplastic parathyroid glands from 70 sHPT patients and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional morphological and immunohistochemical analysis of parathyroid glands was performed after dividing each slide in a 3x3 array. Results: The presence of lipocytes in the normal parathyroid gland and tissue architecture (nodal in patients with sHPT) allows for discrimination between normal parathyroid glands and parathyroid glands of patients with sHPT. Protein expression of Klotho, FGFR, CaSR and VDR was higher in the normal parathyroid glands compared to the sHPT group (p<0.001, p=0.07, p =0.01 and p=0.001). The variability of each protein expression within each tissue slide was high. Therefore correlations between the different immunohistochemical variables were analyzed for each of the nine fields and than analyzed for all patients. Using this analysis, a highly significant positive correlation could be found between the expression of FGFR and VDR (p=0.0004). Interestingly, in terms of VDR we found a shift to a more mixed nuclear/cytoplasmic staining in the HPT group compared to normal parathyroid gland cells, which showed solitary nuclear staining for VDR (p>0.05). Conclusions: CaSR, VDR and an impaired Klotho-FGFR-axis seem to be the major players in the development of sHPT. Whether the detected correlation between FGFR and VDR and the shift to a more mixed nuclear/cytoplasmic staining of VDR will yield new insights into the pathogenesis of the disease has to be evaluated in further studies.
  Kidney and Blood Pressure Research 01/2013; 37(1):84-94. · 1.46 Impact Factor
• Article: Encapsulating peritoneal sclerosis: a rare, serious but potentially curable complication of peritoneal dialysis-experience of a referral centre in Germany.

  Joerg Latus, Christoph Ulmer, Peter Fritz, Bianka Rettenmaier, Dagmar Biegger, Thomas Lang, German Ott, Christoph Scharpf, Martin Kimmel, Wolfgang Steurer, M Dominik Alscher, Niko Braun
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  ABSTRACT: Background Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), the most severe complication associated with long-term PD.Methods In this study, we retrospectively analysed 49 EPS patients regarding clinical presentation, histopathological findings, treatment and long-term clinical outcome at our referral centre. Patients were divided into two clinical categories: severe and mild/moderate.ResultsAll patients in the severe group and most patients in the mild/moderate group had symptoms consistent with EPS. The most common computed tomographic findings were peritoneal thickening in both groups. Small bowel dilatation was frequently present in the severe group. The time of onset of symptoms consistent with EPS to the surgical procedure was median 5 months with an inter-quartile range of 2-12 months in the severe group. To date, 25 of 31 patients in the severe group (follow-up 45.6 ± 39.0 months after surgery) are alive. In the mild/moderate group, 8 of 11 patients are alive (follow-up 41.6 ± 21.6 months). The histological features were consistent with EPS in all biopsies.Conclusions The outcome of patients even with severe EPS is not worse. It is a precondition that these patients are treated in specialized referral centres. The time of first clinical symptoms consistent with EPS to requirement of surgery is very short. Earlier diagnosis of the disease is mandatory, even in asymptomatic patients.
  Nephrology Dialysis Transplantation 06/2012; · 3.40 Impact Factor
• Article: TKTL-1 expression in lung cancer.

  Peter Fritz, Johannes F Coy, Thomas E Mürdter, German Ott, Mark Dominik Alscher, Godehard Friedel
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  ABSTRACT: Study of the physiological changes associated with the development of malignancy demonstrates a metabolic signature for the different stages of tumorigenesis. Increased glucose uptake and lactate production have been detected during malignant transformation. Based on energy production, malignancies can be divided into two subclasses: (a) tumor cells which use the mitochondrial machinery for ATP synthesis, and (b) tumor cells which generate ATP by glucose fermentation and lactate production even in the presence of oxygen (aerobic glycolysis). Recently, transketolase-like protein 1 (TKTL1) gene expression has been shown to contribute to carcinogenesis through increased aerobic glycolysis and hypoxia-inducible factor alpha stabilization. In the present study, 197 patients suffering from lung cancer were investigated by immunohistochemistry for the presence of TKTL1 protein expression. We detected: (1) moderate to strong TKTL1 expression (immune reactive score>100) in 39.1% of the investigated lung cancer patients; (2) a complete lack of TKTL1 by immunohistochemistry in 12.7% of lung cancer cases, with small cell lung cancer (SCLC) being most frequent in this subgroup; (3) no correlation of TKTL1 with overall survival, disease-free survival, any of the established variables of the TNM system, grading, stage, smoking status, or gender. Based on this data, we conclude that TKTL1 could be a target protein for improved therapeutic strategies in some cases of lung cancer.
  Pathology - Research and Practice 03/2012; 208(4):203-9. · 1.21 Impact Factor
• Article: Histological Criteria for Encapsulating Peritoneal Sclerosis - A Standardized Approach.

  Niko Braun, Peter Fritz, Christoph Ulmer, Joerg Latus, Martin Kimmel, Dagmar Biegger, German Ott, Fabian Reimold, Klaus-Peter Thon, Juergen Dippon, Stephan Segerer, M Dominik Alscher
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  ABSTRACT: BACKGROUND: The two most relevant pathologies of long-term peritoneal dialysis (PD) are simple sclerosis and encapsulating peritoneal sclerosis (EPS). The histological differentiation of those two entities is difficult. The Aim of the study was to establish a method to standardize and facilitate the differentiation between simple sclerosis and EPS METHODS: We investigated 58 peritoneal biopsies - 31 EPS patients and 27 PD patients. Two blinded investigators analyzed 20 histological characteristics in EPS and PD patients. RESULTS: THE FOLLOWING FINDINGS WERE SIGNIFICANTLY MORE COMMON IN EPS THAN IN PATIENTS ON PD WITHOUT EPS: fibroblast like cells (FLC) (p<0.0001), mesothelial denudation (p<0.0001), decreased cellularity (p = 0.008), fibrin deposits (p<0.03), Fe deposits (p = 0.05), podoplanin vascular (p<0.0001), podoplanin avascular (p<0.0001). Using all predictor variables we trained the classification method Random Forest to categorize future cases. Podoplanin vascular and avascular were taken together (p<0.0001), FLC (p<0.0001), mesothelial denudation (p = 0.0005), calcification (p = 0.0026), acellular areas (p = 0.0094), and fibrin deposits (p = 0.0336) showed up as significantly important predictor variables. Estimated misclassification error rate when classifying new cases turned out to be 14%. CONCLUSION: The introduced statistical method allows discriminating between simple sclerosis and EPS. The misclassification error will likely improve with every new case added to the database.
  PLoS ONE 01/2012; 7(11):e48647. · 4.09 Impact Factor
• Article: The spectrum of podoplanin expression in encapsulating peritoneal sclerosis.

  Niko Braun, M Dominik Alscher, Peter Fritz, Joerg Latus, Ilka Edenhofer, Fabian Reimold, Seth L Alper, Martin Kimmel, Dagmar Biegger, Maja Lindenmeyer, Clemens D Cohen, Rudolf P Wüthrich, Stephan Segerer
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  ABSTRACT: Encapsulating peritoneal sclerosis (EPS) is a life threatening complication of peritoneal dialysis (PD). Podoplanin is a glycoprotein expressed by mesothelial cells, lymphatic endothelial cells, and myofibroblasts in peritoneal biopsies from patients with EPS. To evaluate podoplanin as a marker of EPS we measured podoplanin mRNA and described the morphological patterns of podoplanin-positive cells in EPS. Included were 20 peritoneal biopsies from patients with the diagnosis of EPS (n = 5), patients on PD without signs of EPS (n = 5), and control patients (uremic patients not on PD, n = 5, non-uremic patients n = 5). EPS patient biopsies revealed significantly elevated levels of podoplanin mRNA (p<0.05). In 24 peritoneal biopsies from patients with EPS, podoplanin and smooth muscle actin (SMA) were localized by immunohistochemistry. Four patterns of podoplanin distribution were distinguishable. The most common pattern (8 of 24) consisted of organized, longitudinal layers of podoplanin-positive cells and vessels in the fibrotic zone ("organized" pattern). 7 of 24 biopsies demonstrated a diffuse distribution of podoplanin-positive cells, accompanied by occasional, dense clusters of podoplanin-positive cells. Five biopsies exhibited a mixed pattern, with some diffuse areas and some organized areas ("mixed"). These contained cuboidal podoplanin-positive cells within SMA-negative epithelial structures embedded in extracellular matrix. Less frequently observed was the complete absence of, or only focal accumulations of podoplanin-positive fibroblasts outside of lymphatic vessels (podoplanin "low", 4 of 24 biopsies). Patients in this group exhibited a lower index of systemic inflammation and a longer symptomatic period than in EPS patients with biopsies of the "mixed" type (p<0.05). In summary we confirm the increased expression of podoplanin in EPS, and distinguish EPS biopsies according to different podoplanin expression patterns which are associated with clinical parameters. Podoplanin might serve as a useful adjunct to the morphological workup of peritoneal biopsies.
  PLoS ONE 01/2012; 7(12):e53382. · 4.09 Impact Factor
• Article: Olfactomedin-4 is a glycoprotein secreted into mucus in active IBD.

  Michael Gersemann, Svetlana Becker, Sabine Nuding, Lena Antoni, German Ott, Peter Fritz, Naohide Oue, Wataru Yasui, Jan Wehkamp, Eduard F Stange
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  ABSTRACT: Olfactomedin-4 (OLFM4) is a glycoprotein characteristic of intestinal stem cells and apparently involved in mucosal defense of the stomach and colon. Here we studied its expression, regulation and function in IBD. The expression of OLFM4, mucins Muc1 and Muc2, the goblet cell differentiation factor Hath1 and the proinflammatory cytokine IL-8 was measured in inflamed or noninflamed colon in IBD patients and controls. OLFM4 protein was located by immunohistochemistry, quantified by Dot Blot and its binding capacity to defensins HBD1-3 was investigated. The influence of bacteria with or without the Notch blocker dibenzazepine (DBZ) and of several cytokines on OLFM4 expression was determined in LS174T cells. OLFM4 mRNA and protein were significantly upregulated in inflamed CD (4.3 and 1.7-fold) and even more pronounced in UC (24.8 and 3.7-fold). OLFM4 expression was correlated to IL-8 but not to Hath1. In controls immunostaining was restricted to the lower crypts but in inflamed IBD it expanded up to the epithelial surface including the mucus. OLFM4 bound to HBD1-3 without profoundly inactivating these defensins. In LS174T-cells OLFM4 mRNA was significantly augmented after incubation with Escherichia coli K12, Escherichia coli Nissle and Bacteroides vulgatus. DBZ downregulated OLFM4 expression and blocked bacterial induction whereas IL-22 but not TNF-α was stimulatory. OLFM4 is overexpressed in active IBD and secreted into mucus. The induction is triggered by bacteria through the Notch pathway and also by the cytokine IL-22. OLFM4 seems to be of functional relevance in IBD as a mucus component, possibly by binding defensins.
  Journal of Crohn s and Colitis 11/2011; 6(4):425-34. · 2.57 Impact Factor
• Article: A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.

  Martin Filipits, Margaretha Rudas, Raimund Jakesz, Peter Dubsky, Florian Fitzal, Christian F Singer, Otto Dietze, Richard Greil, Andrea Jelen, Paul Sevelda, [......], Werner Schroth, Hiltrud Brauch, Matthias Schwab, Peter Fritz, Karsten E Weber, Inke S Feder, Guido Hennig, Ralf Kronenwett, Mathias Gehrmann, Michael Gnant
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  ABSTRACT: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324]. In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively. The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.
  Clinical Cancer Research 08/2011; 17(18):6012-20. · 7.74 Impact Factor
• Source

  Available from: Heiko Mahrholdt

  Article: Coronary artery spasm as a cause for myocardial infarction in patients with systemic inflammatory disease.

  Peter Ong, Anastasios Athanasiadis, Mark Dominik Alscher, Peter Fritz, Heiko Mahrholdt, Udo Sechtem, Juan-Carlos Kaski
  International journal of cardiology 04/2011; 151(1):e32-4. · 7.08 Impact Factor
• Article: Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis.

  Niko Braun, Dominik M Alscher, Peter Fritz, Ilka Edenhofer, Martin Kimmel, Ariana Gaspert, Fabian Reimold, Beata Bode-Lesniewska, Urs Ziegler, Dagmar Biegger, Rudolf P Wüthrich, Stephan Segerer
  [show abstract] [hide abstract]
  ABSTRACT: Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS.
  Nephrology Dialysis Transplantation 03/2011; 26(3):1033-41. · 3.40 Impact Factor
• Article: Difference in the expression of hormone receptors and fibrotic markers in the human peritoneum--implications for therapeutic targets to prevent encapsulating peritoneal sclerosis.

  Niko Braun, Peter Fritz, Dagmar Biegger, Martin Kimmel, Fabian Reimold, Christoph Ulmer, M Dominik Alscher
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  ABSTRACT: Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal dialysis (PD). The optimal management of patients with EPS is uncertain. In the present study, we investigated differences in the expression of nuclear receptors [progesterone (PR), androgen (AR), vitamin D (VDR), and glucocorticoid (GCR)] in the human peritoneum. We also investigated estrogen receptor (ER), matrix metalloproteinase 9 (MMP9), and transforming growth factor β1 (TGFβ1) in the context of their potential role in tamoxifen therapy. We analyzed clinical and histologic characteristics of 72 peritoneal biopsy specimens (22 from EPS patients, 11 from PD patients, 15 from uremic patients, and 24 from control subjects undergoing hernia repair). For immunophenotyping, we used antibodies against VDR, GCR, ER, PR, AR, MMP9, and TGFβ1. In human peritoneum, VDR and GCR are highly expressed (98.6% and 87.3% respectively). Except in the case of VDR (p = 0.0012), we observed no significant difference in receptor expression between the groups. Expression of ER and PR was sparse (11.4% and 31% respectively), with higher expression in women, and AR was absent. Minimal MMP9 expression and moderate TGFβ1 expression were observed in all groups. The differences between the groups were nonsignificant. Nuclear receptors are present in human peritoneum. Except in the case of VDR, the pattern for any one group is nonspecific. Glucocorticoids, vitamin D, and angiotensin converting-enzyme inhibitors or angiotensin II receptor blockers (via the vitamin D/angiotensin II pathway) might be suitable interventions for preservation of the integrity of the peritoneal membrane. The mechanism of action of tamoxifen is still not elucidated, ER expression in the peritoneum is sparse, and data about the studied pathways (MMP9, TGFβ) are inconsistent.
  Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 03/2011; 31(3):291-300.
• Article: Automated extraction of DNA and RNA from a single formalin-fixed paraffin-embedded tissue section for analysis of both single-nucleotide polymorphisms and mRNA expression.

  Guido Hennig, Mathias Gehrmann, Udo Stropp, Hiltrud Brauch, Peter Fritz, Michel Eichelbaum, Matthias Schwab, Werner Schroth
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  ABSTRACT: There is an increasing need for the identification of both DNA and RNA biomarkers from pathodiagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples for the exploration of individualized therapy strategies in cancer. We investigated a fully automated, xylene-free nucleic acid extraction method for the simultaneous analysis of RNA and DNA biomarkers related to breast cancer. We copurified both RNA and DNA from a single 10-μm section of 210 paired samples of FFPE tumor and adjacent normal tissues (1-25 years of archival time) using a fully automated extraction method. Half of the eluate was DNase I digested for mRNA expression analysis performed by using reverse-transcription quantitative PCR for the genes estrogen receptor 1 (ESR1), progesterone receptor (PGR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2), epoxide hydrolase 1 (EPHX1), baculoviral IAP repeat-containing 5 (BIRC5), matrix metallopeptidase 7 (MMP7), vascular endothelial growth factor A (VEGFA), and topoisomerase (DNA) II alpha 170kDa (TOP2A). The remaining undigested aliquot was used for the analysis of 7 single-nucleotide polymorphisms (SNPs) by MALDI-TOF mass spectrometry. In 208 of 210 samples (99.0%) the protocol yielded robust quantification-cycle values for both RNA and DNA normalization. Expression of the 8 breast cancer genes was detected in 81%-100% of tumor tissues and 21%-100% of normal tissues. The 7 SNPs were successfully genotyped in 91%-97% of tumor and 94%-97% of normal tissues. Allele concordance between tumor and normal tissue was 98.9%-99.5%. This fully automated process allowed an efficient simultaneous extraction of both RNA and DNA from a single FFPE section and subsequent dual analysis of selected genes. High gene expression and genotyping detection rates demonstrate the feasibility of molecular profiling from limited archival patient samples.
  Clinical Chemistry 12/2010; 56(12):1845-53. · 7.91 Impact Factor
• Source

  Available from: Pratima Srivastava

  Article: Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation.

  Santhi D Konduri, Rajesh Medisetty, Wensheng Liu, Benny Abraham Kaipparettu, Pratima Srivastava, Hiltrud Brauch, Peter Fritz, Wendy M Swetzig, Amanda E Gardner, Sohaib A Khan, Gokul M Das
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  ABSTRACT: Estrogen receptor alpha (ERalpha) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERalpha binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERalpha suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERalpha represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21(Waf1/Cip1) (CDKN1A) gene, a prototypic transcriptional target of p53. While 17beta-estradiol (E2) enhanced ERalpha binding to p53 and inhibited p21 transcription, antiestrogens decreased ERalpha recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERalpha target gene, pS2/TFF1. These results suggest that ERalpha uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERalpha binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.
  Proceedings of the National Academy of Sciences 08/2010; 107(34):15081-6. · 9.68 Impact Factor
• Article: Microsomal epoxide hydrolase expression in the endometrial uterine corpus is regulated by progesterone during the menstrual cycle.

  Simone L Popp, Ina S Abele, Miriam B Buck, Matthias B Stope, Leen J Blok, Payman Hanifi-Moghaddam, Curt W Burger, Peter Fritz, Cornelius Knabbe
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  ABSTRACT: We have shown previously that high expression levels of microsomal epoxide hydrolase (mEH) correlate with a poor prognosis of breast cancer patients receiving tamoxifen, suggesting that enhanced mEH expression could lead to antiestrogen resistance (Fritz et al. in J Clin Oncol 19:3-9, 2001). Thus, the purpose of this study was to gain insights into the role of mEH in hormone-responsive tissues. We analyzed biopsy samples of the endometrium by immunohistochemical staining, pointing to a regulation of mEH during the menstrual cycle: during the first half mEH expression was low, increased during the second half and reached highest levels during pregnancy. Additionally, the progesterone receptor (PR) positive human endometrial cell lines IKPRAB-36 (estrogene receptor alpha [ERalpha] negative) and ECC1-PRAB72 (ERalpha positive) were chosen to further investigate the hormonal regulation of mEH expression. Western Blot and quantitative RT-PCR analysis revealed an increase of mEH expression after treatment with medroxy-progesterone 17-acetate (MPA) in the ERalpha containing ECC1-PRAB72 cells. In contrast our results suggest that MPA had no influence on the mEH protein level in the ERalpha- IKPRAB-36 cells. In conclusion, mEH expression is regulated by progesterone in the presence of both PRs and ERalpha.
  Journal of molecular histology 04/2010; 41(2-3):111-9. · 1.75 Impact Factor
• Article: A new approach to the investigation of sexual offenses-cytoskeleton analysis reveals the origin of cells found on forensic swabs.

  Martin M Schulz, Maximilian G D Buschner, Richard Leidig, Heinz-D Wehner, Peter Fritz, Karina Häbig, Michael Bonin, Monika Schütz, Thomas Shiozawa, Frank Wehner
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  ABSTRACT: There are forensic inquiries in which an identification of epithelial cell types would provide important probative evidence. In cancer diagnosis, this information is yielded by histological examination of cytokeratin (Ck). Therefore, we tested 19 antibodies against different Cks (Ck1, Ck2e, Ck4, Ck5-6, Ck7, Ck8, Ck9, CK10, Ck13, Ck14, Ck15, Ck16, Ck17, Ck18, Ck19, Ck20, Ck903, PanCkAE1_3, and CAM5-2) on histological sections of epidermis, buccal mucosa, vaginal mucosa, penis, urogenital tract, and rectum and could identify two antigens unique to buccal-cell and vaginal-cell (Ck4) and skin epithelial-cell (Ck10) cytokeratin. Subsequently, we developed an immunocytological technique for distinguishing swabbed skin and mucosal cells up to at least 1 year after sampling. By the detection of the Ck4 and Ck10 mRNAs in biopsy and laser capture microdissection collected samples via quantitative real-time polymerase chain reaction, we were able to confirm our immunological findings. Hence, this study offers techniques to discriminate between skin and mucosal cells (buccal and vaginal) in forensic casework.
  Journal of Forensic Sciences 03/2010; 55(2):492-8. · 1.23 Impact Factor
• Article: A New Approach to the Investigation of Sexual Offenses—Cytoskeleton Analysis Reveals the Origin of Cells Found on Forensic Swabs*

  Martin M. Schulz Ph.D, Maximilian G.D. Buschner, Richard Leidig, Heinz-D. Wehner M.D, Peter Fritz M.D, Karina Häbig, Michael Bonin Ph.D, Monika Schütz Ph.D, Thomas Shiozawa M.D, Frank Wehner M.D, Martin M. Schulz, Heinz‐D. Wehner, Peter Fritz, Michael Bonin, Monika Schütz, Thomas Shiozawa, Frank Wehner
  [show abstract] [hide abstract]
  ABSTRACT:   There are forensic inquiries in which an identification of epithelial cell types would provide important probative evidence. In cancer diagnosis, this information is yielded by histological examination of cytokeratin (Ck). Therefore, we tested 19 antibodies against different Cks (Ck1, Ck2e, Ck4, Ck5-6, Ck7, Ck8, Ck9, CK10, Ck13, Ck14, Ck15, Ck16, Ck17, Ck18, Ck19, Ck20, Ck903, PanCkAE1_3, and CAM5-2) on histological sections of epidermis, buccal mucosa, vaginal mucosa, penis, urogenital tract, and rectum and could identify two antigens unique to buccal-cell and vaginal-cell (Ck4) and skin epithelial-cell (Ck10) cytokeratin. Subsequently, we developed an immunocytological technique for distinguishing swabbed skin and mucosal cells up to at least 1 year after sampling. By the detection of the Ck4 and Ck10 mRNAs in biopsy and laser capture microdissection collected samples via quantitative real-time polymerase chain reaction, we were able to confirm our immunological findings. Hence, this study offers techniques to discriminate between skin and mucosal cells (buccal and vaginal) in forensic casework.
  Journal of Forensic Sciences 02/2010; 55(2):492 - 498. · 1.23 Impact Factor