66 results on '"Katrin Friedrich"'
Search Results
2. PR interval duration is associated with the presence of white matter hyperintensities: Insights from the epidemiologic LIFE-Adult Study.
- Author
-
Jelena Kornej, Katrin Friedrich, Matthias L Schroeter, A Veronica Witte, Maryna Polyakova, Arno Villringer, Markus Löffler, and Samira Zeynalova
- Subjects
Medicine ,Science - Abstract
BackgroundPR interval prolongation is a preliminary stage of atrial cardiomyopathy which is considered as an intermediate phenotype for atrial fibrillation (AF). AF is a known risk factor for cerebrovascular adverse outcomes including stroke. Cerebral ischemia is one cause of white matter hyperintensities (WMHs), and cognitive dysfunction.AimTo analyze the relationship between PR interval and WMHs.Materials and methodsWe performed a cross-sectional analysis with individuals from the LIFE-Adult-Study (a population-based cohort study of randomly selected individuals from Leipzig, Germany) with available brain MRI and ECG. The Fazekas stages were used to quantify WMHs (0 = none; 1 = punctate foci; 2 = beginning confluence; 3 = large confluent areas). Stages 2-3 were defined as advanced WMHs. The PR interval was measured from resting 12-lead ECG. PR duration >200ms was defined as PR interval prolongation. We used a binary logistic regression for statistical analysis. We examined the relationship between MRI and ECG measures and adjusted them for clinical risk factors.ResultsWe included 2464 individuals (age 59±15 years, 47% women) into analyses. The median PR interval was 160ms (interquartile range 143-179), and 319 (13%) individuals with advanced WMHs, were significantly older, had more cardiovascular comorbidities and risk factors compared to individuals without WMHs (all pConclusionPR interval duration is associated with advanced WMHs beside advanced age, hypertension, and history of stroke. Further research is needed to determine whether changes in PR interval indices are clinically relevant for changes in WMHs.
- Published
- 2022
- Full Text
- View/download PDF
3. Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors
- Author
-
Jan RH Hanauer, Lisa Gottschlich, Dennis Riehl, Tillmann Rusch, Vivian Koch, Katrin Friedrich, Stefan Hutzler, Steffen Prüfer, Thorsten Friedel, Kay-Martin Hanschmann, Robert C Münch, Christian Jost, Andreas Plückthun, Klaus Cichutek, Christian J Buchholz, and Michael D Mühlebach
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
- Published
- 2016
- Full Text
- View/download PDF
4. Chromosomal Genotype in Breast Cancer Progression: Comparison of Primary and Secondary Manifestations
- Author
-
Katrin Friedrich, Theresa Weber, Jens Scheithauer, Wolfdietrich Meyer, Gunter Haroske, Klaus Dietmar Kunze, and Gustavo Baretton
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
The purpose of this study was to compare the chromosomal genotype between breast cancers with and without secondary manifestations and between primary tumors and their secondary manifestations. Eighty six breast cancers, twenty lymph node metastases, ten distant metastases and ten local recurrences were analyzed by comparative genomic hybridization. Tumors with local recurrences showed significant more frequent losses at 2q32 than the tumors without recurrences. Lymph node positive cases showed significant more frequent losses at 9p21 than node negative cases. Lymph node metastases exhibited significant more frequent losses at 7q11, 14q24.3–q31 and 17q22–q24 than their primary tumors. In cases with distant metastases, losses at 5q23 were more frequent than in those without, but not reaching the significance level. The distant metastases showed significant more frequent losses at 5p15, 12q24 and 17q22–q24 than the primary tumors. These results reveal strong evidence that the potential for progression is determined in the primary tumor and that different ways of the development of local recurrences, lymph node and distant metastases exist. After confirmation of the results by interphase FISH on tissue micro arrays, the detection of these specific chromosomal imbalances may contribute to a more individual prediction of prognosis in breast cancer.
- Published
- 2008
- Full Text
- View/download PDF
5. DNA Ploidy and Chromosomal Imbalances in Invasive Ductal Breast Cancer. A Comparative Study of DNA Image Cytometry and Comparative Genomic Hybridization (CGH)
- Author
-
Katrin Friedrich, Jens Scheithauer, Volker Dimmer, Wolfdietrich Meyer, Franz Theissig, Gunter Haroske, and Klaus Dietmar Kunze
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Chromosomal imbalances were analyzed in 62 breast cancers with different DNA ploidy by CGH. The results of DNA image cytometry and CGH are consistent with peridiploid and aneuploid cases. The peritetraploid tumors harbored a high number of chromosomal imbalances, as a hint for an unfavorable prognosis. The quantitative analysis of imbalances highlighted the role of different physical constituents of the chromosome, and of chromosomal losses in different DNA ploidy groups. The peritetraploid and aneuploid tumors differed from the peridiploid tumors in losses at 8p and 18q. The peritetraploid cancers exhibited more gains at 8q, the aneuploid tumors more losses at 17p than their peridiploid counterparts. The aneuploid cases differed from the peritetraploid tumors in a higher number of losses at 11q and 14q. Combinations of imbalances provide further insights into the genetic background of DNA ploidy. Hypotheses for the progression from peridiploid to nondiploid breast cancers are given.
- Published
- 2000
- Full Text
- View/download PDF
6. Morphological Heterogeneity of p53 Positive and p53 Negative Nuclei in Breast Cancers Stratified by Clinicopathological Variables
- Author
-
Katrin Friedrich, Volker Dimmer, Gunter Haroske, Wolfdietrich Meyer, Franz Theissig, Berit Thieme, and Klaus Dietmar Kunze
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
The study was aimed to detect differences in nuclear morphology between nuclear populations as well as between tumours with different p53 expression in breast cancers with different clinicopathological features, which also reflect the stage of tumour progression. The p53 immunohistochemistry was performed on paraffin sections from 88 tumour samples. After the cells had been localised by means of an image cytometry workstation and their immunostaining had been categorised visually, the sections were destained and stained by the Feulgen protocol. The nuclei were relocated and measured cytometrically by the workstation.
- Published
- 1997
- Full Text
- View/download PDF
7. Correlation between p53 Status, DNA Ploidy, Proliferation Rate and Nuclear Morphology in Breast Cancer. An Image Cytometric Study
- Author
-
Katrin Friedrich, Volker Dimmer, Gunter Haroske, Wolfdietrich Meyer, Franz Theissig, and Klaus Dietmar Kunze
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
The study was designed to detect differences in the nuclear morphology of tumours and tumour cell populations with different p53 expression in correlation with DNA ploidy and proliferation rate. The paraffin sections from routinely processed samples of 88 breast cancers were immunostained with the monoclonal p53‐antibody DO‐1. After localization and evaluation with a scoring system the sections were destained and stained by the Feulgen method. The nuclei were relocated automatically and measured by means of the image cytometry workstation. Significant differences between the tumours and tumour cell populations with different p53 expression were found in the euploid tumours as well as in the aneuploid tumours and in the breast cancers with a high proliferation rate. The breast cancers with a low immunoreactive score (IRS 1–4) differ from the negative cancers as well as from the cancers with a higher immunoreactive score (IRS 5–12). Evaluating the nuclear populations of the p53 positive cancers, there were differences in the features of the chromatin amount and distribution in the groups of the euploid breast cancers and in cancer with a high proliferation rate. In contrast, the nuclear populations of the aneuploid cancers did not show any differences in their nuclear morphology.
- Published
- 1997
- Full Text
- View/download PDF
8. Data from Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
- Author
-
Georg Breier, Dietmar Vestweber, Gustavo Baretton, Katrin Friedrich, Daniela E. Aust, Hans J. Schnittler, and Myriam Labelle
- Abstract
Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-β (TGF-β), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-β signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-β signaling. Our findings may have important implications for the clinical application of anti–VE-cadherin strategies. [Cancer Res 2008;68(5):1388–97]
- Published
- 2023
9. Supplementary Tables 1-2, Figures 1-15 from Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
- Author
-
Georg Breier, Dietmar Vestweber, Gustavo Baretton, Katrin Friedrich, Daniela E. Aust, Hans J. Schnittler, and Myriam Labelle
- Abstract
Supplementary Tables 1-2, Figures 1-15 from Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
- Published
- 2023
10. Einflussfaktoren für die Teilnahme an Sporttherapie in der psychiatrischen Versorgung
- Author
-
Katrin Friedrich, Julia Krieger, Marc Ziegenbein, Marcel Wendt, and Vanessa Rößner-Ruff
- Subjects
03 medical and health sciences ,0302 clinical medicine ,General Medicine ,030217 neurology & neurosurgery ,030227 psychiatry - Abstract
ZusammenfassungEine Vielzahl von Forschungsvorhaben weist auf die positive Wirkung von Sport und Bewegung bei der Behandlung von Menschen mit psychischen Erkrankungen hin. In der teil- und vollstationären psychiatrischen Versorgung werden in sporttherapeutischen Maßnahmen funktionelle, psychosoziale und pädagogische Ziele verfolgt. Die Studienlage deutet auf eine positive Wirkung von körperlicher Aktivität auf die psychische und physische Gesundheit hin. Neben Wirksamkeitsuntersuchungen fehlt es dennoch an praxisorientierten Fragestellungen, die sich mit der Umsetzung sporttherapeutischer Maßnahmen und deren Inanspruchnahme im klinischen Alltag befassen. Die vorliegende Studie untersucht mit qualitativen Methoden Einflussfaktoren für die Teilnahme an der Sporttherapie in einem psychiatrisch-psychosomatischen Fachkrankenhaus in Niedersachsen. Dabei wurden sowohl Mitarbeiter als auch Patienten in teil- und vollstationären Settings befragt. Es wurden intrapersonelle, organisatorische, interpersonelle und umweltbedingte Einflussfaktoren unterschieden, die für die Beteiligung an der Sporttherapie von Bedeutung sind. Die erarbeiteten Aspekte können Anhaltspunkte für die Praxis und für weitere Forschungsvorhaben bieten.
- Published
- 2020
11. Abstract P134: PR Interval Length is Associated With Presence of the White Matter Lesions: Insights From the Epidemiological LIFE-Adult Study
- Author
-
Markus Löffler, Samira Zeynalova, Veronika Witte, Jelena Kornej, Katrin Friedrich, Matthias L. Schroeter, and Arno Villringer
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Atrial fibrillation ,Magnetic resonance imaging ,medicine.disease ,Hyperintensity ,Physiology (medical) ,Internal medicine ,Epidemiology ,medicine ,Cardiology ,Risk factor ,PR interval ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,Electrocardiography - Abstract
Background: PR interval prolongation is associated with increased risk for atrial fibrillation (AF). AF is a known risk factor for cerebrovascular complications including microbleeds and stroke. This might explain the occurrence of white matter lesions (WML) and consequent cognitive dysfunction. The aim of the current study was to analyze the relationship between PR interval and WML in an epidemiological study. Methods: The LIFE-Adult-Study is a population-based cohort study of randomly selected participants from Leipzig, Germany. In this cross-sectional analysis, individuals without AF, with available brain MRI and ECG were included. The Fazekas scale was used to quantify the amount of WML and was graded into four Fazekas stages: 0=none; 1=punctate foci; 2= beginning confluence; 3=large confluent areas. Stages 2-3 were considered as advanced WML. Results: The study population comprised 2421 individuals (age 59±15 years, 1287 (53.2%) males). The median PR interval was 160 ms (IQR 143; 179). There were 319 (13.2%) individuals with advanced WML (stages 2 and 3). These probands were significantly older, had more often cardiovascular comorbidities, diabetes and stroke than patients without WML (all p Conclusions: The PR interval is associated with advanced WML.
- Published
- 2020
12. Ovarian borderline tumors in the 2014 WHO classification
- Author
-
Steffen Hauptmann, Katrin Friedrich, Raymond W. Redline, and Stephanie Avril
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Diagnostic criteria ,Serous carcinoma ,CLINICOPATHOLOGICAL ANALYSIS ,Population ,Ovary ,MOLECULAR-GENETIC-ANALYSIS ,World Health Organization ,WHO classification 2014 ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,PROLIFERATIVE SEROUS TUMORS ,Terminology as Topic ,Borderline tumor ,Carcinoma ,Humans ,Medicine ,Pseudomyxoma peritonei ,COMPARATIVE GENOMIC HYBRIDIZATION ,education ,Molecular Biology ,Lymph node ,Neoplasm Staging ,Ovarian Neoplasms ,education.field_of_study ,business.industry ,PSEUDOMYXOMA-PERITONEI ,METASTATIC MUCINOUS CARCINOMAS ,CLEAR-CELL-CARCINOMA ,Cell Biology ,General Medicine ,MALIGNANT POTENTIAL BORDERLINE ,medicine.disease ,LOW-GRADE ,3. Good health ,Serous fluid ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Clear cell carcinoma ,MATURE CYSTIC TERATOMAS ,Female ,business - Abstract
Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Since BOT were first identified > 40 years ago, they have inspired controversies disproportionate to their incidence. This review discusses diagnostic criteria for the histologic subtypes of BOT, highlighting areas of diagnostic challenges, ongoing controversies, and changes in terminology implemented by the recent 2014 WHO Classification of Tumours of the Female Genital Organs. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. Serous borderline tumors (SBT) share molecular and genetic alterations with low-grade serous carcinomas and can present at higher stages with peritoneal implants and/or lymph node involvement, which validates their borderline malignant potential. All other (non-serous) subtypes of BOT commonly present at stage I confined to the ovary(ies) and are associated with overall survival approaching that of the general population. An important change in the WHO 2014 classification is the new terminology of non-invasive implants associated with SBT, as any invasive foci (previously called "invasive implants") are now in line with their biological behavior considered peritoneal low-grade serous carcinoma (LGSC). The controversy regarding the terminology of non-serous borderline tumors, called by some pathologists "atypical proliferative tumor" in view of their largely benign behavior, has not been resolved. The concepts of intraepithelial carcinoma and microinvasion may evolve in further studies, as their presence appears to have no prognostic impact and is subject to considerable inter-observer variability.
- Published
- 2017
13. 03 - SHOULD I STAY OR SHOULD I GO… PERSONAL CONSIDERATIONS AND OPPORTUNITIES OF PEOPLE USING INPATIENT REINTEGRATION SUPPORT TO MOVE OUT INTO INDEPENDENT LIVING
- Author
-
Iris Tatjana Graef-Calliess, Felix Wedegärtner, Marie-Luise Dierks, Fabian Wolf Schottky, Vanessa Rößner-Ruff, Katrin Friedrich, and Julia Krieger
- Published
- 2019
14. 07 - FACTORS OF PARTICIPATION IN EXERCISE THERAPY DURING IN-PATIENT TREATMENT
- Author
-
Dr. Rainer Brase, Iris Tatjana Graef-Calliess, Dr. Marcel Wendt, Vanessa Rößner-Ruff, Julia Krieger, and Katrin Friedrich
- Published
- 2019
15. Automated detection of the HER2 gene amplification status in Fluorescencein situhybridization images for the diagnostics of cancer tissues
- Author
-
Daniela E. Aust, Robert Mantey, Ingo Roeder, Christian Sperling, Gustavo Baretton, Torsten Wenke, Pia Hönscheid, Katrin Friedrich, Walter de Back, Falk Zakrzewski, Martin Weigert, and Silke Zeugner
- Subjects
Receptor, ErbB-2 ,Pipeline (computing) ,lcsh:Medicine ,Computational biology ,Biology ,Article ,Automation ,Deep Learning ,Imaging, Three-Dimensional ,Neoplasms ,Gene duplication ,Pathology ,medicine ,Humans ,HER2 Amplification ,lcsh:Science ,Human Epidermal Growth Factor Receptor 2 ,In Situ Hybridization, Fluorescence ,Cell Nucleus ,medicine.diagnostic_test ,lcsh:R ,Laboratory techniques and procedures ,Gene Amplification ,Cancer ,Signal Processing, Computer-Assisted ,medicine.disease ,Chromosome 17 (human) ,HER2 Gene Amplification ,lcsh:Q ,Neoplasm Grading ,Fluorescence in situ hybridization - Abstract
The human epidermal growth factor receptor 2 (HER2) gene amplification status is a crucial marker for evaluating clinical therapies of breast or gastric cancer. We propose a deep learning-based pipeline for the detection, localization and classification of interphase nuclei depending on their HER2 gene amplification state in Fluorescence in situ hybridization (FISH) images. Our pipeline combines two RetinaNet-based object localization networks which are trained (1) to detect and classify interphase nuclei into distinct classes normal, low-grade and high-grade and (2) to detect and classify FISH signals into distinct classes HER2 or centromere of chromosome 17 (CEN17). By independently classifying each nucleus twice, the two-step pipeline provides both robustness and interpretability for the automated detection of the HER2 amplification status. The accuracy of our deep learning-based pipeline is on par with that of three pathologists and FISH images on a set of 57 validation images containing several hundreds of nuclei are accurately classified. The automatic pipeline is a first step towards assisting pathologists in evaluating the HER2 status of tumors using FISH images, for analyzing FISH images in retrospective studies, and for optimizing the documentation of each tumor sample by automatically annotating and reporting of the HER2 gene amplification specificities.
- Published
- 2018
16. Impact of breast cancer subtypes and patterns of metastasis on outcome
- Author
-
Katrin Friedrich, Pauline Wimberger, Carmen Werner, A Petzold, Theresa Link, Barbara Richter, Gustavo B. Baretton, Karin Kast, Olaf Schoffer, Antje Niedostatek, Andreas Werner, Axel Gatzweiler, and Stefanie J. Klug
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Breast Neoplasms ,Disease ,Metastasis ,Breast cancer ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Metastasis ,skin and connective tissue diseases ,Survival analysis ,business.industry ,Cancer ,Luminal a ,Prognosis ,medicine.disease ,Survival Analysis ,Female ,business ,Primary breast cancer ,Adjuvant - Abstract
Clinical outcome of patients with stage IV breast cancer is dependent on tumor biology, extent, and localization of metastases. Routine imaging diagnostics for distant metastasis is not recommended by the national guidelines for breast cancer follow-up. In this study, we evaluated different patterns of metastases of cancer subtypes in order to generate hypotheses on individualization of follow-up after breast cancer in the adjuvant setting. Patients of the Regional Breast Cancer Center Dresden diagnosed within the years 2006-2011 were classified into the five intrinsic subtypes luminal A (ER+, Her2-, G1/2), luminal B/Her2 negative (ER+, Her2-, G3), triple positive (ER+, PR+, Her2+), Her2-enriched (ER-, Her2+), and triple negative (ER-, PR-, Her2-) and with a median follow-up of 45 months. Tumor stage at time of first diagnosis of breast cancer as well as time and site of metastasis at first diagnosis of distant metastatic disease was analyzed. Tumor specimen of 2284 female patients with primary breast cancer was classified into five subtypes. Distant recurrence-free survival at 3 years was most unfavorable in Her2-enriched (66.8 %), triple negative (75.9 %), and triple-positive breast cancer (81.7 %). The same subtypes most frequently presented with visceral metastases only at first presentation: Her2-enriched 46.9 %, triple negative 45.5 %, and triple-positive breast cancer 37.5 %. Longest median survival of 2.3 years was seen in luminal A and in Her2-enriched metastatic disease, respectively. Median survival was significantly better in the luminal A, Her2-enriched, and triple-positive subtype compared to triple-negative breast cancer (p < 0.005). Differences in time to metastatic disease, first localization of metastases, and overall survival after diagnosis of metastatic disease were shown. Considering new targeted therapies and the option of surgery of oligometastases, screening for visceral metastases might be reasonable after diagnosis of Her2-positive subtypes.
- Published
- 2015
17. A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother
- Author
-
Christian Kubisch, Anna Aulitzky, Dieter Gläser, Katrin Friedrich, Alexander E Volk, Regina Gastl, and Albert C. Ludolph
- Subjects
Adult ,Male ,Heterozygote ,Spastin ,Adolescent ,Hereditary spastic paraplegia ,Mothers ,Biology ,medicine.disease_cause ,Young Adult ,medicine ,Humans ,Genetic Testing ,Spasticity ,Family history ,Genetic testing ,Adenosine Triphosphatases ,Genetics ,Mutation ,medicine.diagnostic_test ,Mosaicism ,Spastic Paraplegia, Hereditary ,Genetic heterogeneity ,Siblings ,Heterozygote advantage ,medicine.disease ,Neurology ,Female ,Neurology (clinical) ,medicine.symptom - Abstract
Hereditary spastic paraplegias (HSPs) represent a clinically and genetically heterogeneous group of diseases. Major symptoms comprise progressive bilateral leg stiffness, spasticity at rest and diffuse muscle weakness. Complex forms are characterized by additional symptoms like dementia, cerebellar dysfunction or seizures. Autosomal dominant, autosomal recessive, X-linked recessive and possibly mitochondrial inheritance have been described in familial HSP. The most frequently mutated gene in familial cases of uncomplicated autosomal dominant HSP is SPAST, however de novo mutations in SPAST are rarely found. Here, we report on the clinical and genetic findings in a family with three children afflicted by complex HSP and their unaffected parents. Although autosomal dominant inheritance seemed unlikely in this family, genetic testing revealed a novel SPAST mutation, c.1837G>C (p.Asp613His), in a heterozygous state in all affected individuals and somatic mosaicism of this mutation in the unaffected mother. Our study thus expands the knowledge on SPAST-associated HSP and emphasizes that de novo mutations and somatic mosaicism should be taken into consideration in HSP families presenting with a family history not suggestive for an autosomal dominant inheritance pattern.
- Published
- 2014
18. Para-Fluoro Postpolymerization Chemistry of Poly(pentafluorobenzyl methacrylate): Modification with Amines, Thiols, and Carbonylthiolates
- Author
-
Janina-Miriam Noy, Kyle Batten, Yiwen Pei, Rhiannon Batchelor, Ann-Katrin Friedrich, Peter J. Roth, Ariella Kristanti, Mathamsanqa N. Bhebhe, and Nicolas Busatto
- Subjects
Substitution reaction ,chemistry.chemical_classification ,Polymers and Plastics ,Organic Chemistry ,Thio ,02 engineering and technology ,Fluorine-19 NMR ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Methacrylate ,01 natural sciences ,0104 chemical sciences ,Inorganic Chemistry ,chemistry ,Polymerization ,Tacticity ,Polymer chemistry ,Materials Chemistry ,Thiol ,Amine gas treating ,0210 nano-technology - Abstract
A methacrylic polymer undergoing highly efficient para-fluoro substitution reactions is presented. A series of well-defined poly(2,3,4,5,6-pentafluorobenzyl methacrylate) (pPFBMA) homopolymers with degrees of polymerization from 28 to 132 and Ð ≤ 1.29 was prepared by the RAFT process. pPFBMA samples were atactic (with triad tacticity apparent in 1H and 19F NMR spectra) and soluble in most organic solvents. pPFBMA reacted quantitatively through parafluoro substitution with a range of thiols (typically 1.1 equiv thiol, base, RT, < 1h) in the absence of any observed side reactions. Para-fluoro substitution with different (thio)carbonylthio reagents was possible and allowed for subsequent one-pot cleavage of dithioester pendent groups with concurrent thia-Michael side group modification. Reactions with aliphatic amines (typically 2.5 equiv amine, 50–60 °C, overnight) resulted in complete substitution of the para-fluorides without any observed ester cleavage reactions. However, for primary amines, H2NR, double substitution reactions yielding tertiary (–C6F4)2NR amine bridges were observed, which were absent with secondary amine reagents. No reactions were found for attempted modifications of pPFBMA with bromide, iodide, methanethiosulfonate, or thiourea, indicating a highly selective reactivity toward nucleophiles. The versatility of this reactive platform is demonstrated through the synthesis of a pH-responsive polymer and novel thermoresponsive polymers: an oligo(ethylene glycol)-functional species with an LCST in water and two zwitterionic polymers with UCSTs in water and aqueous salt solution (NaCl concentration up to 178 mM).
- Published
- 2017
19. Inverse association of rab31 and mucin-1 (CA15-3) antigen levels in estrogen receptor-positive (ER+) breast cancer tissues with clinicopathological parameters and patients' prognosis
- Author
-
Matthias, Kotzsch, Thomas, Kirchner, Susanne, Soelch, Sonja, Schäfer, Katrin, Friedrich, Gustavo, Baretton, Viktor, Magdolen, and Thomas, Luther
- Subjects
Original Article - Abstract
Dysregulated expression of rab31, a member of the large Rab protein family of the Ras superfamily of small GTPases, has been observed in several types of cancer, including breast cancer. Rab31, depending on its expression level, may regulate the switch between an invasive versus proliferative phenotype of breast cancer cells in vitro. Moreover, gene expression of rab31 is induced by the C-terminal subunit of mucin-1 (MUC1-C) and estrogen receptors (ER). To gain further insights into the clinical relevance of rab31 and mucin-1 expression in breast cancer, we analyzed the relation between rab31 and mucin-1 (CA15-3) antigen levels in detergent tissue extracts of ER-positive (ER+) tumors and clinicopathological parameters as well as patients’ prognosis. No significant correlation was observed between rab31 and CA15-3 antigen levels. Elevated rab31 antigen levels in tumor tissue extracts were significantly associated with higher tumor grade (P = 0.021). Strikingly, an inverse significant association was observed for CA15-3 with tumor grade (P = 0.032). Furthermore, high rab31 antigen levels were significantly associated with a high S-phase fraction (SPF, P = 0.047), whereas a trend for lower CA15-3 antigen levels in tumor tissue displaying higher SPF was observed. High rab31 antigen levels were significantly associated with poor 5-year disease-free survival (DFS) of ER+ breast cancer patients in univariate Cox regression analysis (HR = 1.91, 95% CI = 1.14-3.17, P = 0.013). In contrast, high levels of CA15-3 antigen levels were associated with better patients’ prognosis (HR = 0.56, 95% CI = 0.33-0.95, P = 0.031). In multivariable analysis, rab31 antigen levels contributed independent prognostic information for DFS when adjusted for prognostically relevant clinicopathological parameters with a HR for high versus low values of 1.97 (95% CI = 1.09-3.54, P = 0.024), whereas CA15-3 antigen levels were not significant. Our results strongly suggest that rab31 antigen levels in tumor tissue are associated with the proliferative status, and rab31 represents an independent biomarker for prognosis in ER+ breast cancer patients. Total mucin-1 (CA 15-3) levels are rather inversely associated with tumor grade and SPF, and elevated levels even indicate prolonged DFS in ER+ breast cancer patients.
- Published
- 2017
20. Identification and Functional Validation of RAD23B as a Potential Protein in Human Breast Cancer Progression
- Author
-
Katrin Friedrich, Martin Clynes, Annett Linge, Gustavo B. Baretton, Annemarie Larkin, Michael Henry, Priyanka Maurya, Shane Kelly, and Paula Meleady
- Subjects
CA15-3 ,Cytoplasm ,RAD23B ,Breast Neoplasms ,Kaplan-Meier Estimate ,Biology ,Bioinformatics ,Biochemistry ,Breast cancer ,Downregulation and upregulation ,Tandem Mass Spectrometry ,Cell Line, Tumor ,Carcinoma ,medicine ,Humans ,Receptor ,Cell Nucleus ,Carcinoma, Ductal, Breast ,General Chemistry ,medicine.disease ,DNA-Binding Proteins ,DNA Repair Enzymes ,Receptors, Estrogen ,Disease Progression ,Cancer research ,Biomarker (medicine) ,Immunohistochemistry ,Female - Abstract
Identification of protein targets that play a role in breast cancer invasion may help to understand the rapid progression of cancer and may lead to the development of new biomarkers for the disease. In this study, we compared two highly invasive and two poorly invasive breast cancer cell lines using comparative label-free LC-MS profiling in order to identify differentially expressed proteins that may be linked to the invasive phenotype in vitro. Forty-five proteins were found to be upregulated, and 34 proteins, downregulated. UV excision repair protein RAD23 homologue B (RAD23B) was found among the downregulated proteins in highly invasive breast cancer cell lines. In poorly invasive breast cancer cell lines, siRNA-mediated downregulation of RAD23B subsequently led to an increase in invasion and adhesion in vitro. Immunohistochemistry analysis of 164 specimens of invasive breast cancer showed that having a high percentage (>80%) of RAD23B positive nuclei was significantly associated with histopathological grades 1 and 2 breast cancer and with low mitotic activity. In addition, a high staining intensity for RAD23B in the cytoplasm was significantly associated with histopathological grade 3 breast cancer. This study suggests a potential role of RAD23B in breast cancer progression and may further imply a tumor suppressor role of nuclear RAD23B in breast cancer.
- Published
- 2014
21. Imaging mass spectrometry to discriminate breast from pancreatic cancer metastasis in formalin-fixed paraffin-embedded tissues
- Author
-
Rita, Casadonte, Mark, Kriegsmann, Friederike, Zweynert, Katrin, Friedrich, Gustavo, Baretton, Gustavo, Bretton, Mike, Otto, Sören-Oliver, Deininger, Rainer, Paape, Eckhard, Belau, Detlev, Suckau, Daniela, Aust, Christian, Pilarsky, and Jörg, Kriegsmann
- Subjects
Proteomics ,MALDI imaging ,Pathology ,medicine.medical_specialty ,Formalin fixed paraffin embedded ,Breast Neoplasms ,Bioinformatics ,Biochemistry ,Mass spectrometry imaging ,Metastasis ,Diagnosis, Differential ,Formaldehyde ,Pancreatic cancer ,Biomarkers, Tumor ,Carcinoma ,medicine ,Humans ,Molecular Biology ,Paraffin Embedding ,business.industry ,Liver Neoplasms ,Histology ,medicine.disease ,Immunohistochemistry ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Female ,business - Abstract
Diagnosis of the origin of metastasis is mandatory for adequate therapy. In the past, classification of tumors was based on histology (morphological expression of a complex protein pattern), while supportive immunohistochemical investigation relied only on few "tumor specific" proteins. At present, histopathological diagnosis is based on clinical information, morphology, immunohistochemistry, and may include molecular methods. This process is complex, expensive, requires an experienced pathologist and may be time consuming. Currently, proteomic methods have been introduced in various clinical disciplines. MALDI imaging MS combines detection of numerous proteins with morphological features, and seems to be the ideal tool for objective and fast histopathological tumor classification. To study a special tumor type and to identify predictive patterns that could discriminate metastatic breast from pancreatic carcinoma MALDI imaging MS was applied to multitissue paraffin blocks. A statistical classification model was created using a training set of primary carcinoma biopsies. This model was validated on two testing sets of different breast and pancreatic carcinoma specimens. We could discern breast from pancreatic primary tumors with an overall accuracy of 83.38%, a sensitivity of 85.95% and a specificity of 76.96%. Furthermore, breast and pancreatic liver metastases were tested and classified correctly.
- Published
- 2014
22. A single amino acid substitution in the measles virus F2 protein reciprocally modulates membrane fusion activity in pathogenic and oncolytic strains
- Author
-
Irene C. Schneider, Katrin Friedrich, Jan R.H. Hanauer, Steffen Prüfer, Sabine Heidmeier, Michael D. Mühlebach, Klaus Cichutek, and Christian J. Buchholz
- Subjects
chemistry.chemical_classification ,Cancer Research ,Methionine ,biology ,biology.organism_classification ,Molecular biology ,Virus ,Oncolytic virus ,Amino acid ,Measles virus ,chemistry.chemical_compound ,Infectious Diseases ,Biochemistry ,chemistry ,Valine ,Virology ,Glycoprotein ,Membrane Fusion Activity - Abstract
Differences in fusion activity between measles virus (MV) attenuated, oncolytic strain MVNSe and pathogenic MVwt323 are reflected in amino acid 94 of the fusion (F) proteins. A valine 94 in FNSe (naturally) or Fwt323 (introduced) correlated with enhanced cell–cell fusion activity during transient glycoprotein expression or recombinant MV infections irrespective of the strains’ targeted receptors, whereas the reverse effect was found for methionine 94. Enhanced fusogenicity was determined by weaker glycoprotein interaction and correlated positively with cytotoxicity in both virus strains. Amino acid 94 of F can be used to tailor fusogenicity and cytotoxicity of recombinant MV, while the cellular receptor triggering fusion is not decisive.
- Published
- 2014
23. Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors
- Author
-
Robert C. Münch, Tillmann Rusch, Klaus Cichutek, Thorsten Friedel, Stefan Hutzler, Lisa Gottschlich, Katrin Friedrich, Jan R.H. Hanauer, Steffen Prüfer, Christian J. Buchholz, Christian Jost, Vivian Koch, Dennis Riehl, Michael D. Mühlebach, Kay-Martin Hanschmann, Andreas Plückthun, University of Zurich, and Mühlebach, Michael D
- Subjects
0301 basic medicine ,Cancer Research ,610 Medicine & health ,lcsh:RC254-282 ,Article ,HER2/neu ,03 medical and health sciences ,Antigen ,Cancer stem cell ,In vivo ,10019 Department of Biochemistry ,2736 Pharmacology (medical) ,1306 Cancer Research ,Pharmacology (medical) ,Tumor marker ,biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Molecular biology ,In vitro ,Oncolytic virus ,030104 developmental biology ,Oncology ,DARPin ,1313 Molecular Medicine ,biology.protein ,Cancer research ,570 Life sciences ,Molecular Medicine ,2730 Oncology - Abstract
To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
- Published
- 2016
24. Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population
- Author
-
Renata Žunec, Melita Balija, Peter Nürnberg, Davor Lessel, Zeljko Kastelan, Mislav Grgić, Mohammad R. Toliat, Christian Kubisch, Tomislav Kuliš, Katrin Friedrich, Marija Gamulin, and Josef Högel
- Subjects
Adult ,Male ,Cancer Research ,Candidate gene ,Adolescent ,Croatia ,Population ,Single-nucleotide polymorphism ,Biology ,testicular germ cell cancer, genetic susceptibility, Croatian population ,Testicular Neoplasms ,testicular germ cell cancer ,Croatian population ,Genetic variation ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,education ,Aged ,Genetic association ,Genetics ,education.field_of_study ,Case-control study ,General Medicine ,Odds ratio ,Middle Aged ,Neoplasms, Germ Cell and Embryonal ,Case-Control Studies - Abstract
Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P- values between 2.1e-10 (rs995030 ; odds ratio [OR] 3.08) and 0.01739 (rs4635969 ; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression.
- Published
- 2012
25. High frequency of autosomal-recessive DFNB59 hearing loss in an isolated Arab population in Israel
- Author
-
Mordechai Shohat, Lina Basel-Vanagaite, Moien Kanaan, Alexander E Volk, Katrin Friedrich, Guntram Borck, Nurit Magal, Christian Kubisch, Limor Rainshtein, Ellen Taub, and S Hellman-Aharony
- Subjects
medicine.medical_specialty ,Hearing loss ,media_common.quotation_subject ,Nonsense ,Nonsense mutation ,Auditory neuropathy ,Genes, Recessive ,Nerve Tissue Proteins ,Consanguinity ,Audiology ,Gene Frequency ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Israel ,Hearing Loss ,Allele frequency ,Genetics (clinical) ,media_common ,business.industry ,Haplotype ,medicine.disease ,Arabs ,Pedigree ,Haplotypes ,Codon, Nonsense ,medicine.symptom ,business ,Founder effect - Abstract
Autosomal-recessive non-syndromic hearing impairment (DFNB) is usually of prelingual onset with a moderate to profound degree of hearing loss. More than 70 DFNB loci have been mapped and ~40 causative genes have been identified. Non-syndromic hearing impairment caused by mutations of DFNB59 (encoding pejvakin) has been described in a couple of families in which affected individuals presented with either auditory neuropathy or hearing loss of cochlear origin. We have identified and clinically evaluated three consanguineous families of Israeli Arab origin with prelingual non-syndromic hearing impairment and absent otoacoustic emissions in a total of eight affected individuals. All the families originate from the same village and bear the same family name. We have identified a c.406C>T (p.R136X) nonsense mutation in the DFNB59 gene in affected individuals from these families. Among the inhabitants of the village, we found an exceptionally high carrier frequency of ~1 in 12 individuals (7/85; 8.2%). The high prevalence of hearing impairment can be explained by a founder effect and the high consanguinity rate among the inhabitants of this village.
- Published
- 2011
26. An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group
- Author
-
Gudrun Nürnberg, Jan Freudenberg, Dost Muhammad Baloch, Johannes Oldenburg, Katrin Friedrich, Shakeela Daud, Jamil Ahmad, Guntram Borck, Rüstem Yilmaz, Christian Kubisch, Naseebullah Kakar, Jochen Hoch, and Peter Nürnberg
- Subjects
Male ,Candidate gene ,Genetic Linkage ,Population ,Alu element ,Locus (genetics) ,Biology ,N-Acetylglucosaminyltransferases ,Polymorphism, Single Nucleotide ,Cataract ,Consanguinity ,Exon ,Alu Elements ,Genetics ,medicine ,Humans ,education ,Genetics (clinical) ,Sequence Deletion ,education.field_of_study ,Base Sequence ,Sequence Analysis, DNA ,Disease gene identification ,medicine.disease ,Molecular biology ,eye diseases ,Pedigree ,Blood Group Antigens ,Congenital cataracts ,Female ,Founder effect - Abstract
We performed homozygosity mapping in a consanguineous Pakistani family segregating autosomal-recessive congenital cataracts and identified linkage to a 3.03 Mb locus on chromosome 6p24 containing the GCNT2 gene. GCNT2 encodes glucosaminyl (N-acetyl) transferase 2, an enzyme responsible for the formation of the blood group I antigen. Rare biallelic GCNT2 mutations have been shown to cause the association of congenital cataracts and the adult i blood group, making GCNT2 the prime candidate gene for the observed phenotype. Indeed, we identified a homozygous deletion segregating with cataracts that encompasses exons 1B, 1C, 2 and 3 of GCNT2. Long-range polymerase chain reaction and breakpoint sequencing revealed that affected individuals in this and in a second, apparently unrelated Pakistani family segregating congenital cataracts are homozygous for the same 93 kb deletion. The deletion is flanked by Alu repeats of the AluS family on both sides and microsatellite genotyping suggested that its occurrence in the two families was the product of recurrent Alu-Alu repeat-mediated nonhomologous recombinations or an old founder effect. Subsequently, we showed that cataract-affected individuals in both families have the adult i blood group, whereas unaffected individuals have blood group I as the vast majority of the population. Because the GCNT2 locus is rich in Short INterspersed Elements (SINE repeats) and thus likely prone to genomic rearrangements, microdeletions or microduplications at this locus might cause a larger than currently anticipated fraction of apparently isolated autosomal-recessive cataracts.
- Published
- 2011
27. Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma
- Author
-
Sybille Albrecht, Katrin Friedrich, Thomas Luther, Katharina Bernt, Gustavo Baretton, Elvira Luther, Matthias Kotzsch, Christian Zietz, Axel Gatzweiler, and Viktor Magdolen
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,Stromal cell ,Tissue microarray ,business.industry ,Cancer ,General Medicine ,medicine.disease ,biological factors ,Pathology and Forensic Medicine ,Metastasis ,Urokinase receptor ,enzymes and coenzymes (carbohydrates) ,Breast cancer ,Cancer research ,Carcinoma ,Medicine ,Breast disease ,biological phenomena, cell phenomena, and immunity ,skin and connective tissue diseases ,business ,neoplasms - Abstract
Kotzsch M, Bernt K, Friedrich K, Luther E, Albrecht S, Gatzweiler A, Magdolen V, Baretton G, Zietz C & Luther T (2010) Histopathology 57, 461–471 Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma Aims: The urokinase-type plasminogen activator receptor (uPAR) is a key molecule for pericellular proteolysis in tumour cell invasion and metastasis. The aim was to evaluate the prognostic impact of uPAR in invasive breast cancer dependent on which cell types within the tumour express uPAR. Methods and results: uPAR expression was analysed by immunohistochemistry in 270 tumour tissue specimens of invasive ductal breast carcinomas using tissue microarrays. For evaluation of uPAR immunoexpression we used the epitope-mapped, uPAR domain II-specific monoclonal antibody IID7. High uPAR score values in both tumour cells (uPAR-Tc) and stromal cells were significantly related to high tumour grade (G3), and inversely correlated with oestrogen receptor status. On multivariate analysis, high uPAR-Tc values contributed independent prognostic information for disease-free survival (hazard ratio 1.93, P = 0.007) when adjusted for prognostically relevant clinicopathological parameters, whereas uPAR expression in stromal cells was not related to prognosis. In addition, elevated uPAR-Tc values were found to be prognostic indicators in clinically relevant subgroups of patients with invasive breast cancer. Conclusions: In invasive breast cancer uPAR expression in invasive carcinoma cells, but not in stromal cells, has a significant impact on patients’ prognosis, and contributes to a more aggressive tumour phenotype.
- Published
- 2010
28. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations
- Author
-
George M. Martin, Norberto López, Kivanc Cefle, Davor Lessel, Sukru Ozturk, Junko Oshima, Joerg Schmidtke, P. F. Ippel, Bhaskar Saha, Gudrun Nürnberg, Joseph Boak, Fuki M. Hisama, Dru F. Leistritz, Daniel Eyman, Martin Poot, Katrin Friedrich, Holger Hoehn, Dincy Peter, María J. Garcia-F-Villalta, Lin Lee, Theda Wessel, Carolien M. Kets, Peter Nürnberg, Peter C. van den Akker, Christian Kubisch, Vítor Tedim Cruz, Birgit Groff-Kellermann, Chumei Li, Goli Compoginis, and Translational Immunology Groningen (TRIGR)
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Werner Syndrome Helicase ,Mutation, Missense ,Locus (genetics) ,VARIANTS ,SYNDROME GENE ,Article ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Chromosome Breakpoints ,Exon ,NEUREGULIN-1 ,SCHIZOPHRENIA ,Genetics ,medicine ,Humans ,EPIDEMIOLOGY ,Missense mutation ,SYNDROME LOCUS ,education ,Genetics (clinical) ,Werner syndrome ,education.field_of_study ,RecQ Helicases ,IDENTIFICATION ,biology ,NUCLEAR-LOCALIZATION ,DNA HELICASE ,nutritional and metabolic diseases ,Helicase ,medicine.disease ,Founder Effect ,Introns ,SYNDROME PROTEIN ,Human genetics ,Exodeoxyribonucleases ,Mutation ,biology.protein ,Female ,Werner Syndrome ,Founder effect - Abstract
Item does not contain fulltext Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere. 01 juli 2010
- Published
- 2010
29. Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
- Author
-
Dietmar Vestweber, Hans J. Schnittler, Myriam Labelle, Katrin Friedrich, Gustavo Baretton, Georg Breier, and Daniela E. Aust
- Subjects
Cancer Research ,Breast Neoplasms ,Mammary Neoplasms, Animal ,Biology ,Mice ,Antigens, CD ,Transforming Growth Factor beta ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Mice, Inbred BALB C ,Mammary tumor ,Neovascularization, Pathologic ,Cell adhesion molecule ,Cell growth ,Gene Expression Profiling ,Cancer ,Cadherins ,medicine.disease ,Oncology ,Tumor progression ,Disease Progression ,Cancer research ,Breast disease ,Signal transduction ,Neoplasm Transplantation ,Signal Transduction ,Transforming growth factor - Abstract
Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-β (TGF-β), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-β signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-β signaling. Our findings may have important implications for the clinical application of anti–VE-cadherin strategies. [Cancer Res 2008;68(5):1388–97]
- Published
- 2008
30. Chromosomal Genotype in Breast Cancer Progression: Comparison of Primary and Secondary Manifestations
- Author
-
Jens Scheithauer, W. Meyer, Gustavo Baretton, Theresa Weber, Gunter Haroske, Klaus Kunze, and Katrin Friedrich
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Lymph node positive ,Genotype ,comparative genomic hybridization ,Breast Neoplasms ,lcsh:RC254-282 ,Pathology and Forensic Medicine ,Breast cancer ,Internal medicine ,medicine ,Chromosomes, Human ,Humans ,Neoplasm Metastasis ,lcsh:QH573-671 ,metastases ,Lymph node ,local recurrences ,Chromosome Aberrations ,business.industry ,lcsh:Cytology ,Cell Biology ,General Medicine ,medicine.disease ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Primary tumor ,Node negative ,medicine.anatomical_structure ,Tissue Array Analysis ,Lymphatic Metastasis ,Disease Progression ,Molecular Medicine ,%22">Fish ,Other ,Neoplasm Recurrence, Local ,business ,Comparative genomic hybridization - Abstract
The purpose of this study was to compare the chromosomal genotype between breast cancers with and without secondary manifestations and between primary tumors and their secondary manifestations. Eighty six breast cancers, twenty lymph node metastases, ten distant metastases and ten local recurrences were analyzed by comparative genomic hybridization. Tumors with local recurrences showed significant more frequent losses at 2q32 than the tumors without recurrences. Lymph node positive cases showed significant more frequent losses at 9p21 than node negative cases. Lymph node metastases exhibited significant more frequent losses at 7q11, 14q24.3–q31 and 17q22–q24 than their primary tumors. In cases with distant metastases, losses at 5q23 were more frequent than in those without, but not reaching the significance level. The distant metastases showed significant more frequent losses at 5p15, 12q24 and 17q22–q24 than the primary tumors. These results reveal strong evidence that the potential for progression is determined in the primary tumor and that different ways of the development of local recurrences, lymph node and distant metastases exist. After confirmation of the results by interphase FISH on tissue micro arrays, the detection of these specific chromosomal imbalances may contribute to a more individual prediction of prognosis in breast cancer.
- Published
- 2008
31. Fulminant Liver Failure Following Infection by Clostridium perfringens
- Author
-
Hendrik Bergert, Till Illert, Katrin Friedrich, and Detlef Ockert
- Subjects
Microbiology (medical) ,Infectious Diseases ,Surgery - Published
- 2004
32. Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA-and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study
- Author
-
Bernd Wallner, Andrea Griesmacher, Anelia Dietmann, Florian Deisenhammer, Erich Schmutzhard, Katrin Friedrich, Louise Jilek-Aall, William Matuja, Christoph Seger, Andrea Sylvia Winkler, Bettina Pfausler, and Rebekka König
- Subjects
Adult ,Male ,medicine.medical_specialty ,N-Methylaspartate ,Adolescent ,Pilot Projects ,nodding syndrome, epilepsy, anti-neuronal antibodies, pyridoxal-phosphate ,Tanzania ,Nodding Syndrome ,Epilepsy ,Seizures ,Internal medicine ,medicine ,Humans ,Generalized epilepsy ,Receptor ,Aged ,Autoantibodies ,Neurons ,biology ,Seizure types ,business.industry ,Autoantibody ,General Medicine ,Articles ,Middle Aged ,medicine.disease ,Endocrinology ,Potassium Channels, Voltage-Gated ,Case-Control Studies ,Pyridoxal Phosphate ,biology.protein ,NMDA receptor ,Female ,Antibody ,business - Abstract
Background: Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients.Methods: Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured.Results: Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans.Conclusions: In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.Key words: nodding syndrome, epilepsy, anti-neuronal antibodies, pyridoxal-phosphate
- Published
- 2014
33. STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly
- Author
-
Guntram Borck, Peter Nürnberg, William B. Dobyns, Janine Altmüller, Christian Kubisch, Deborah J. Morris-Rosendahl, Naseebullah Kakar, Jamil Ahmad, Gotthold Barbi, and Katrin Friedrich
- Subjects
Adult ,Male ,Microcephaly ,Adolescent ,Locus (genetics) ,Consanguinity ,Biology ,Young Adult ,Holoprosencephaly ,Genetics ,medicine ,Humans ,Pakistan ,Genetics (clinical) ,Exome sequencing ,Genetic heterogeneity ,Intracellular Signaling Peptides and Proteins ,Infant ,Lobar holoprosencephaly ,medicine.disease ,Human genetics ,Child, Preschool ,Mutation ,Female - Abstract
Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.
- Published
- 2014
34. Purification and immunodetection of the complete recombinant HER-2[neu] receptor produced in yeast
- Author
-
Katrin Friedrich, Dietmar Kunze, Frank Sonntag, Kirsten Simon, Martin Giersberg, Keith Baronian, Gotthard Kunze, Alexandre Chamas, Steffen Uhlig, and Publica
- Subjects
protein solubilization ,Receptor, ErbB-2 ,Enzyme-Linked Immunosorbent Assay ,Epitope ,law.invention ,breast cancer ,Chaps ,Cell surface receptor ,law ,medicine ,Humans ,Receptor ,biology ,medicine.diagnostic_test ,Surface Plasmon Resonance ,biology.organism_classification ,Molecular biology ,Yeast ,Recombinant Proteins ,Arxula adeninivorans ,Immunoassay ,Saccharomycetales ,Recombinant DNA ,A. adeninivorans ,surface plasmon resonance (SPR) ,Biotechnology - Abstract
For the first time, the full length recombinant HER-2[neu] receptor has been produced in a yeast (Arxula adeninivorans). It is one of the most studied membrane receptors in oncology and is involved in aggressive tumor formation. A yeast integration rDNA cassette containing the human gene coding for the HER-2[neu] protein was constructed and a screening procedure was performed to select the most productive transformant. Different detergents were tested for efficient solubilization of the membrane bound protein, with CHAPS giving the best results. To increase the yield of the recombinant protein from HER-2[neu] producing A. adeninivorans, optimal culture parameters were established for cultivation in bioreactor. The recombinant protein was subsequently assayed using ELISA and SPR immunoassays systems with antibodies raised against two different epitopes of the human receptor. In both cases, elution fractions containing the recombinant HER-2[neu] receptor successfully reacted with the immunoassays with limits of quantification below 100 ng ml−1. These results demonstrate that the full length recombinant HER-2[neu] reported here has the potential to be a new standard for the detection of HER-2 type cancer.
- Published
- 2014
35. Clinical characteristics of people with head nodding in southern Tanzania
- Author
-
Katrin Friedrich, Aslam Kidunda, Michael Meindl, Erich Schmutzhard, William Matuja, Amir Nassri, Louise Jilek-Aall, and Andrea Sylvia Winkler
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Time Factors ,Adolescent ,Head nodding ,Severity of Illness Index ,Tanzania ,Young Adult ,Epilepsy ,Sex Factors ,Severity of illness ,Humans ,Medicine ,Prospective Studies ,Age of Onset ,Young adult ,Child ,Prospective cohort study ,biology ,business.industry ,Nodding Syndrome ,Age Factors ,Public Health, Environmental and Occupational Health ,medicine.disease ,biology.organism_classification ,Surgery ,Treatment Outcome ,Infectious Diseases ,Educational Status ,Anticonvulsants ,Female ,Age of onset ,Cognition Disorders ,business ,Head - Abstract
Summary We have previously described a seizure disorder characterized by head nodding (HN). In a prospective study in southern Tanzania, we evaluated 62 patients with HN. Here, we report the patients’ clinical characteristics and those of their seizures, which indicate high seizure frequency, unsatisfactory seizure control, a high burden of cognitive impairment and disease-associated barriers to education.
- Published
- 2010
36. Detection of Genomic DNA Fragmentation during Apoptosis (DNA Ladder) and the Simultaneous Isolation of RNA from Low Cell Numbers
- Author
-
Isrid Sturm, Peter Bendzko, Peter T. Daniel, Bernd Dörken, Silke Ritschel, Katrin Friedrich, and Timo Hillebrand
- Subjects
T-Lymphocytes ,Biophysics ,Apoptosis ,DNA Fragmentation ,Thymus Gland ,Biology ,Sensitivity and Specificity ,Biochemistry ,Jurkat Cells ,Mice ,chemistry.chemical_compound ,Gene expression ,Animals ,Humans ,fas Receptor ,Fragmentation (cell biology) ,Molecular Biology ,Cells, Cultured ,Gel electrophoresis ,Mice, Inbred BALB C ,Reverse Transcriptase Polymerase Chain Reaction ,Apoptotic DNA fragmentation ,Antibodies, Monoclonal ,RNA ,DNA ,Cell Biology ,Molecular biology ,Molecular Weight ,genomic DNA ,chemistry ,DNA fragmentation ,Female ,Adsorption - Abstract
In the present paper we describe a rapid and sensitive method for the simultaneous isolation of total RNA and genomic plus low-molecular-weight DNA from apoptotic cells. Using this method, we were able to detect a DNA ladder from as low as 30,000 apoptotic cells in only 45 min including gel electrophoresis. In addition, RNA can be readily obtained from the same specimen to assess gene expression during apoptosis. This method therefore appears to be advantageous when sensitivity and low amounts of sample material are a limiting factor.
- Published
- 1999
37. Morphological Heterogeneity of p53 Positive and p53 Negative Nuclei in Breast Cancers Stratified by Clinicopathological Variables
- Author
-
W. Meyer, Klaus Kunze, Katrin Friedrich, Theissig F, Gunter Haroske, V. Dimmer, and Berit Thieme
- Subjects
Pathology ,medicine.medical_specialty ,p53 immunohistochemistry ,Breast Neoplasms ,Biology ,lcsh:RC254-282 ,Image cytometry ,breast cancer ,medicine ,Image Processing, Computer-Assisted ,Humans ,Population Characteristics ,Feulgen stain ,lcsh:QH573-671 ,Stage (cooking) ,Lymph node ,Neoplasm Staging ,chromatin structure ,Cell Nucleus ,lcsh:Cytology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,Chromatin ,Staining ,Cell nucleus ,medicine.anatomical_structure ,Image Cytometry ,Female ,Other ,Tumor Suppressor Protein p53 ,Immunostaining - Abstract
The study was aimed to detect differences in nuclear morphology between nuclear populations as well as between tumours with different p53 expression in breast cancers with different clinicopathological features, which also reflect the stage of tumour progression. The p53 immunohistochemistry was performed on paraffin sections from 88 tumour samples. After the cells had been localised by means of an image cytometry workstation and their immunostaining had been categorised visually, the sections were destained and stained by the Feulgen protocol. The nuclei were relocated and measured cytometrically by the workstation.There were significant differences in the nuclear features between tumours as well as between nuclear populations with different p53 expression in the most subgroups. The variability of nuclear shape in tumour groups, classified by the tumour size or the lymph node status, increase with the p53 immunoreactive score, whereas in tumours grouped by the Bloom–Richardson grade features of the chromatin distribution were different between the p53 staining categories.The nuclear subpopulations showed differences in the amount and distribution of chromatin in most subgroups.The results demonstrate the relationship between the nuclear morphology and the p53 expression in different stages of breast cancers. The p53 status is an important factor of the biological behaviour but not the only one.
- Published
- 1997
38. A longitudinal study on nodding syndrome--a new African epilepsy disorder
- Author
-
Luise Jilek-Aall, Bernd Wallner, Bettina Pfausler, Katrin Friedrich, Erich Schmutzhard, William Matuja, Iris Unterberger, and Andrea Sylvia Winkler
- Subjects
Adult ,Male ,Longitudinal study ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Head nodding ,Electroencephalography ,Audiology ,Nodding Syndrome ,Epilepsy ,Young Adult ,Seizures ,Surveys and Questionnaires ,medicine ,Humans ,In patient ,Ictal ,Longitudinal Studies ,Age of Onset ,Child ,Africa South of the Sahara ,medicine.diagnostic_test ,business.industry ,Brain ,medicine.disease ,Neurology ,Generalized slowing ,Disease Progression ,Female ,Neurology (clinical) ,business ,Follow-Up Studies - Abstract
Summary Objectives Nodding syndrome (NS), a new epilepsy disorder of sub-Saharan Africa, has only recently been classified. In a study conducted in southern Tanzania in 2005, 62 patients with NS were analyzed in great detail. The present study, a follow-up investigation, was conducted to evaluate the progression of NS over time and to obtain serial electroencephalography (EEG) data. Methods Of the 62 NS patients, 53 (85.5%), the majority of whom were currently on some form of antiepileptic treatment, could be reevaluated in 2009 with a standardized questionnaire. A subset of these patients (25/53) underwent EEG investigation. Results In patients with “head nodding (HN) only” in 2005, 10 (43.5%) of 23 remained with the same diagnosis, whereas 5 (21.7%) of 23 had developed “HN plus” (i.e., HN and generalized tonic–clonic seizures). Six patients (26.1%) had seizures other than HN only, and two patients (8.7%) had fully recovered. In the “HN plus” group of 2005, 9 (30.0%) of 30 patients remained “HN plus,” and 15 patients (50.0%) had seizures other than HN only. Four patients (13.3%) reverted to “HN only,” and two patients (6.7%) stopped all seizures. In 11 (44.0%) of 25 patients, electroencephalography (EEG) showed generalized slowing. Six (54.6%) of these 11 abnormal EEG studies further showed generalized epileptiform discharges: (1) ictal electroencephalographic pattern with generalized 2.5 Hz spike and waves in two patients and (2) interictal bursts of 1.5–2 Hz spike and waves in four patients. Significance This follow-up study confirms that HN represents an epilepsy disorder, possibly of the atypical absence type with dynamic development over time.
- Published
- 2013
39. A single amino acid substitution in the measles virus F₂ protein reciprocally modulates membrane fusion activity in pathogenic and oncolytic strains
- Author
-
Sabine, Heidmeier, Jan R H, Hanauer, Katrin, Friedrich, Steffen, Prüfer, Irene C, Schneider, Christian J, Buchholz, Klaus, Cichutek, and Michael D, Mühlebach
- Subjects
Cell Fusion ,Amino Acid Substitution ,Cell Survival ,Measles virus ,Chlorocebus aethiops ,Animals ,Mutant Proteins ,Virus Internalization ,Vero Cells ,Viral Fusion Proteins - Abstract
Differences in fusion activity between measles virus (MV) attenuated, oncolytic strain MV(NSe) and pathogenic MV(wt323) are reflected in amino acid 94 of the fusion (F) proteins. A valine 94 in F(NSe) (naturally) or F(wt323) (introduced) correlated with enhanced cell-cell fusion activity during transient glycoprotein expression or recombinant MV infections irrespective of the strains' targeted receptors, whereas the reverse effect was found for methionine 94. Enhanced fusogenicity was determined by weaker glycoprotein interaction and correlated positively with cytotoxicity in both virus strains. Amino acid 94 of F can be used to tailor fusogenicity and cytotoxicity of recombinant MV, while the cellular receptor triggering fusion is not decisive.
- Published
- 2013
40. DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety
- Author
-
Christian Jost, Kay Martin Hanschmann, Katrin Friedrich, Robert C. Münch, Steffen Prüfer, Jan R.H. Hanauer, Roberto Cattaneo, Iris Völker, Klaus Cichutek, Christian J. Buchholz, Christodoulos Filippis, Michael D. Mühlebach, Andreas Plückthun, Kah Whye Peng, University of Zurich, and Mühlebach, Michael D
- Subjects
CHO Cells ,Mice, SCID ,Virus ,Measles virus ,Mice ,Cricetulus ,1311 Genetics ,Viral entry ,Cell Line, Tumor ,Cricetinae ,Drug Discovery ,10019 Department of Biochemistry ,1312 Molecular Biology ,Genetics ,Animals ,Humans ,Virotherapy ,Molecular Biology ,Tropism ,Pharmacology ,Oncolytic Virotherapy ,biology ,3002 Drug Discovery ,biology.organism_classification ,Virology ,Oncolytic virus ,3004 Pharmacology ,DARPin ,1313 Molecular Medicine ,Cancer cell ,570 Life sciences ,Molecular Medicine ,Original Article - Abstract
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics.
- Published
- 2013
41. Interplay between neural-cadherin and vascular endothelial-cadherin in breast cancer progression
- Author
-
Myriam Labelle, Gustavo Baretton, Maryam Rezaei, Georg Breier, Antje Kettelhake, Katrin Friedrich, Aleksandar Kuzmanov, Ben Wielockx, Hans Schnittler, Koch Institute for Integrative Cancer Research at MIT, and Labelle, Myriam
- Subjects
Epithelial-Mesenchymal Transition ,Vimentin ,Breast Neoplasms ,Nerve Tissue Proteins ,Biology ,Mice ,Breast cancer ,Antigens, CD ,Cell Line, Tumor ,medicine ,Carcinoma ,Gene silencing ,Animals ,Humans ,Breast ,RNA, Small Interfering ,beta Catenin ,Cell Proliferation ,Medicine(all) ,Mice, Inbred BALB C ,Tissue microarray ,Cadherin ,Cell Membrane ,Cancer ,RNA-Binding Proteins ,medicine.disease ,Cadherins ,HEK293 Cells ,Cancer research ,biology.protein ,Disease Progression ,Female ,RNA Interference ,Endothelium, Vascular ,Neoplasm Transplantation ,Transforming growth factor ,Research Article - Abstract
Introduction: Deregulation of cadherin expression, in particular the loss of epithelial (E)-cadherin and gain of neural (N)-cadherin, has been implicated in carcinoma progression. We previously showed that endothelial cell-specific vascular endothelial (VE)-cadherin can be expressed aberrantly on tumor cells both in human breast cancer and in experimental mouse mammary carcinoma. Functional analyses revealed that VE-cadherin promotes tumor cell proliferation and invasion by stimulating transforming growth factor (TGF)-β signaling. Here, we investigate the functional interplay between N-cadherin and VE-cadherin in breast cancer. Methods: The expression of N-cadherin and VE-cadherin was evaluated by immunohistochemistry in a tissue microarray with 84 invasive human breast carcinomas. VE-cadherin and N-cadherin expression in mouse mammary carcinoma cells was manipulated by RNA interference or overexpression, and cells were then analyzed by immunofluorescence, reverse transcriptase-polymerase chain reaction, and western blot. Experimental tumors were generated by transplantation of the modified mouse mammary carcinoma cells into immunocompetent mice. Tumor growth was monitored, and tumor tissue was subjected to histological analysis. Results: VE-cadherin and N-cadherin were largely co-expressed in invasive human breast cancers. Silencing of N-cadherin in mouse mammary carcinoma cells led to decreased VE-cadherin expression and induced changes indicative of mesenchymal-epithelial transition, as indicated by re-induction of E-cadherin, localization of β-catenin at the cell membrane, decreased expression of vimentin and SIP1, and gain of epithelial morphology. Suppression of N-cadherin expression also inhibited tumor growth in vivo, even when VE-cadherin expression was forced. Conclusions: Our results highlight the critical role of N-cadherin in breast cancer progression and show that N-cadherin is involved in maintaining the malignant tumor cell phenotype. The presence of N-cadherin prevents the re-expression of E-cadherin and localization of β-catenin at the plasma membrane of mesenchymal mammary carcinoma cells. N-cadherin is also required to maintain the expression of VE-cadherin in malignant tumor cells but not vice versa. Thus, N-cadherin acts in concert with VE-cadherin to promote tumor growth., Deutsche Forschungsgemeinschaft (DFG-Br 1336/3-1), Deutsche Forschungsgemeinschaft (DFG-Br 1336/3-2), Germany. Bundesministerium für Bildung und Forschung
- Published
- 2012
42. Exploratory investigation of PSCA-protein expression in primary breast cancer and its clinical relevance
- Author
-
Michael S. Kramer, Pauline Wimberger, Andreas Werner, Armin Ehninger, Friederike Kuithan, Barbara Richter, Katrin Friedrich, Jan Dominik Kuhlmann, Theresa Link, and Axel Gatzweiler
- Subjects
Cancer Research ,business.industry ,Glycosylphosphatidylinositol ,fungi ,food and beverages ,PSCA Protein ,Prostate Stem Cell Antigen ,carbohydrates (lipids) ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,chemistry ,Prostate ,Cancer research ,Medicine ,lipids (amino acids, peptides, and proteins) ,Clinical significance ,Primary breast cancer ,business ,Surface protein - Abstract
e23267Background: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein, which can be up-regulated in various human malignancies such as prostate, ...
- Published
- 2016
43. Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature
- Author
-
Karin Kast, Mechthild Krause, Andrea Bier, Markus K. Schuler, Barbara Thamm, Katrin Friedrich, Stefan Krüger, and Wolfgang Distler
- Subjects
Adult ,Oncology ,Heterozygote ,Cancer Research ,medicine.medical_specialty ,Genetic counseling ,Population ,Case Report ,Breast Neoplasms ,Genetic Counseling ,lcsh:RC254-282 ,Li-Fraumeni Syndrome ,Germline mutation ,Breast cancer ,LFS ,Internal medicine ,Genetics ,Humans ,Medicine ,TP53 ,education ,Screening procedures ,education.field_of_study ,business.industry ,Li-Fraumeni-Syndrome ,Liposarcoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Penetrance ,Treatment ,Li–Fraumeni syndrome ,Female ,Tumor Suppressor Protein p53 ,Secondary cancer ,Radiation-induced cancer ,business - Abstract
Background Li-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed. Case report We report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients. Conclusion Management of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.
- Published
- 2012
44. ID: 96
- Author
-
Staeheli Peter, Vanessa Zimmermann, Cindy Nürnberger, Katrin Friedrich, and Melanie Gerhardt
- Subjects
Genetics ,Immunology ,Orthomyxoviridae ,RNA ,Hematology ,GTPase ,Biology ,biology.organism_classification ,Biochemistry ,Virology ,Virus ,Inbred strain ,Interferon ,medicine ,Immunology and Allergy ,Allele ,Molecular Biology ,Gene ,medicine.drug - Abstract
Type I and III interferon-regulated Mx genes encode evolutionary conserved antiviral restriction factors which inhibit a broad range of RNA viruses in most vertebrate species. In mice, the Mx1 locus confers resistance to members of the Orthomyxoviridae, such as influenza A and Thogoto viruses. Mice of strain A2G carry a functional Mx1 gene, while most other laboratory inbred mouse strains carry truncated and therefore defective Mx1 alleles. A recent study (Ferris MT et al. PLOS pathogens 9(2) 2013) investigating how genetic factors might contribute to influenza susceptibility showed that CAST/EiJ mice, an inbred strain derived from wild Mus musculus castaneus, are susceptible to influenza virus challenge although they carry a full-length Mx1 gene. Here we characterized CAST-derived Mx1 in order to better understand the molecular basis of its altered antiviral properties. We were able to show that CAST-derived Mx1 retains a low degree of anti-influenza activity but, surprisingly, is still able to confer full protection against Thogoto virus challenge. Sequencing revealed that CAST-derived Mx1 differs by two amino acids from A2G-derived Mx1 which are both localized in the GTPase (G) domain of the protein. These mutations lead to a reduction in GTPase activity. They further diminish Mx1 protein levels in organs of animals after interferon stimulation in vivo. Interestingly, these mutations have no effect on mRNA levels, suggesting that the reduced Mx1 protein levels might be attributed to differences in protein stability. In summary, our findings are able to explain the unexpected virus susceptibility of CAST/EiJ mice.
- Published
- 2015
45. Coronary Artery Disease in a Werner Syndrome-Like Form of Progeria Characterized by Low Levels of Progerin, a Splice Variant of Lamin A
- Author
-
Matthew Pastore, Davor Lessel, Gary S. Gottesman, Bhaskar Saha, Junko Oshima, Dru F. Leistritz, Fuki M. Hisama, George M. Martin, Katrin Friedrich, Christian Kubisch, and Kim L. McBride
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Laminopathy ,Coronary Artery Disease ,Biology ,Article ,LMNA ,Young Adult ,Progeria ,Genetics ,medicine ,Humans ,Protein Precursors ,Child ,Genetics (clinical) ,Werner syndrome ,integumentary system ,Base Sequence ,Genetic disorder ,nutritional and metabolic diseases ,Facies ,Nuclear Proteins ,Exons ,Middle Aged ,medicine.disease ,Progerin ,Lamin Type A ,Alternative Splicing ,Mutation ,Female ,Werner Syndrome ,Restrictive dermopathy ,Lamin - Abstract
Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.
- Published
- 2011
46. Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma
- Author
-
Matthias, Kotzsch, Katharina, Bernt, Katrin, Friedrich, Elvira, Luther, Sybille, Albrecht, Axel, Gatzweiler, Viktor, Magdolen, Gustavo, Baretton, Christian, Zietz, and Thomas, Luther
- Subjects
Carcinoma, Ductal, Breast ,Biomarkers, Tumor ,Humans ,Breast Neoplasms ,Female ,Microarray Analysis ,Prognosis ,Immunohistochemistry ,Disease-Free Survival ,Receptors, Urokinase Plasminogen Activator - Abstract
The urokinase-type plasminogen activator receptor (uPAR) is a key molecule for pericellular proteolysis in tumour cell invasion and metastasis. The aim was to evaluate the prognostic impact of uPAR in invasive breast cancer dependent on which cell types within the tumour express uPAR.uPAR expression was analysed by immunohistochemistry in 270 tumour tissue specimens of invasive ductal breast carcinomas using tissue microarrays. For evaluation of uPAR immunoexpression we used the epitope-mapped, uPAR domain II-specific monoclonal antibody IID7. High uPAR score values in both tumour cells (uPAR-Tc) and stromal cells were significantly related to high tumour grade (G3), and inversely correlated with oestrogen receptor status. On multivariate analysis, high uPAR-Tc values contributed independent prognostic information for disease-free survival (hazard ratio 1.93, P = 0.007) when adjusted for prognostically relevant clinicopathological parameters, whereas uPAR expression in stromal cells was not related to prognosis. In addition, elevated uPAR-Tc values were found to be prognostic indicators in clinically relevant subgroups of patients with invasive breast cancer.In invasive breast cancer uPAR expression in invasive carcinoma cells, but not in stromal cells, has a significant impact on patients' prognosis, and contributes to a more aggressive tumour phenotype.
- Published
- 2010
47. Correlation of centrosomal aberrations with cell differentiation and DNA ploidy in prostate cancer
- Author
-
Marieta I, Toma, Katrin, Friedrich, Wolfdietrich, Meyer, Michael, Fröhner, Susanne, Schneider, Manfred, Wirth, and Gustavo B, Baretton
- Subjects
Adult ,Centrosome ,Chromosome Aberrations ,Male ,Ploidies ,Prostatic Neoplasms ,Cell Differentiation ,DNA, Neoplasm ,Adenocarcinoma ,Middle Aged ,Cell Transformation, Neoplastic ,Tubulin ,Image Processing, Computer-Assisted ,Humans ,Antigens ,Aged - Abstract
To analyze the centrosomal abnormalities in correlation with DNA ploidy and clinicopathologic data in prostate cancer.Formalin-fixed, paraffin-embedded material from 63 prostate cancers (PCa) and 10 normal control cases were studied. Centrosomal features (number, area and shape) were assessed by immunohistochemistry with a gamma-tubulin monoclonal antibody. For each case centrosomal features were assessed in 100 cells, and the mean and median value was calculated. Statistical analysis was done by Student's t test, Mann-Whitney U test and multivariate analysis. The colocalization of gamma-tubulin and pericentrin at the centrosome was proven by double immunofluorescence staining. The DNA ploidy status was analyzed on Feulgen-stained, disintegrated paraffin sections using the OPTIMAS-based work station (Media Cybernetics, Silver Spring, Maryland, U.S.A.).PCa cells showed centrosomal aberrations when compared to normal tissue. Poorly differentiated PCa showed more centrosomal abnormalities than well differentiated PCa (p0.05). Twenty-seven percent PCa were DNA nondiploid and 73% PCa were DNA diploid, respectively, just as all control specimens. DNA nondiploid status correlates with centrosomal abnormalities (p0.05). pT4 tumors showed significantly more centrosomes than pT2 and pT3 tumors (p0.05).Changes in centrosome features indicate disturbed centrosome function and are significantly correlated with loss of differentiation in PCa. This is the first image analysis study of centrosome features in PCa, confirming that centrosome defects are involved in the acquisition of chromosomal aberrations in PCa.
- Published
- 2010
48. A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features
- Author
-
Christian Kubisch, George M. Martin, Davor Lessel, Fuki M. Hisama, Bhaskar Saha, Dru F. Leistritz, Katrin Friedrich, and Junko Oshima
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Partial Lipodystrophy ,Wild type ,nutritional and metabolic diseases ,Locus (genetics) ,Biology ,medicine.disease ,Familial partial lipodystrophy ,LMNA ,Exon ,medicine ,Original Article ,Genetics (clinical) ,Lamin ,Werner syndrome - Abstract
Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.
- Published
- 2010
49. Microsatellite instability and loss of heterozygosity in squamous cell carcinoma of the head and neck
- Author
-
Hella Luksch, Ramon Martinez, Eberhard Kuhlisch, Susanne Koy, Jens Plaschke, Uwe Eckelt, and Katrin Friedrich
- Subjects
Adult ,Genetic Markers ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Loss of Heterozygosity ,DNA Mismatch Repair ,Loss of heterozygosity ,Sequence Analysis, Protein ,Carcinoma ,medicine ,Humans ,Basal cell carcinoma ,neoplasms ,Adaptor Proteins, Signal Transducing ,Aged ,Aged, 80 and over ,business.industry ,Microsatellite instability ,Cancer ,Nuclear Proteins ,Exons ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,digestive system diseases ,stomatognathic diseases ,Otorhinolaryngology ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Cancer research ,Carcinoma, Squamous Cell ,DNA mismatch repair ,Female ,Microsatellite Instability ,business ,MutL Protein Homolog 1 - Abstract
Microsatellite instability (MSI) in head and neck squamous cell carcinoma (HNSCC) has been reported with a wide range of frequencies. The aim of our study was to disclose the frequency and basis of MSI in HNSCC and to correlate MSI and findings on loss of heterozygosity (LOH) with the clinical data.We analyzed MSI and LOH in 91 tumors. All tumors presenting instability were analyzed for the expression of mismatch repair genes (MMR) proteins.Low-level microsatellite instability (MSI-L) was seen in 7.7% of the HNSCC. None of the MSI-L tumors had aberrant MMR protein expression. LOH rates up to 57% were identified for different regions on chromosome 3p. For the marker D10S197, we found a significant correlation between LOH and tumor stage IV.Our results indicate that MMR gene inactivation is rare among primary HNSCC. In contrast, the MSI-L phenotype plays a role in a small subset of tumors. LOH on chromosome arm 3p and 10p12 seems to be involved in tumorigenesis and progression HNSCC, respectively.
- Published
- 2008
50. The head nodding syndrome--clinical classification and possible causes
- Author
-
Iris Unterberger, Rebekka König, Raimund Helbok, Thaddaeus Gotwald, Erich Schmutzhard, Louise Jilek-Aall, Katrin Friedrich, Aslam Kidunda, Andrea Sylvia Winkler, Jaffer Dharsee, William Matuja, Michael Meindl, and Sandeep Velicheti
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,Electroencephalography ,Onchocerciasis ,Gastroenterology ,Tanzania ,Central nervous system disease ,Epilepsy ,Young Adult ,Cerebrospinal fluid ,Nodding disease ,Seizures ,Internal medicine ,parasitic diseases ,Medicine ,Animals ,Humans ,Ictal ,Prospective Studies ,Child ,Skin ,medicine.diagnostic_test ,biology ,business.industry ,Nodding Syndrome ,Syndrome ,biology.organism_classification ,medicine.disease ,Onchocerca volvulus ,Magnetic Resonance Imaging ,Neurology ,Female ,Neurology (clinical) ,business ,Head - Abstract
Summary Purpose: In the 1960s in Tanzania, L. Jilek-Aall observed a seizure disorder characterized by head nodding (HN). Decades later, “nodding disease,” reminiscent of what was seen in Tanzania, was reported from Sudan. To date this seizure disorder has not been classified and possible causes still remain obscure. Methods: In a prospective study in southern Tanzania, we evaluated 62 patients with HN. Selected patients underwent blood (n = 51) and cerebrospinal fluid (CSF) (n = 48) analyses. Others were chosen for MRI (n = 12) and EEG (n = 10). Results: Seizure type was classified as “head nodding only” and “head nodding plus,” the latter being combined with other types of seizure (n =34). During HN, consciousness was impaired in 11 patients (17.7%) and supportive signs of epileptic seizures were described by 15 (24.2%) patients. Precipitating factors were confirmed by 11 (17.7%) patients. Fifty-six (90.3%) patients had at least one relative with epilepsy. EEG confirmed interictal epileptic activity in two patients and unspecific changes in four patients. MRI showed hippocampus pathologies (n = 5) and gliotic changes (n = 5). Skin polymerase chain reaction (PCR) positivity for Onchocerca volvulus was significantly associated with lesions on MRI. However, PCR of the CSF was negative in all cases. Conclusions: We present a comprehensive clinical description of the “HN syndrome,” possibly a new epilepsy disorder in sub-Saharan Africa. MRI lesions and their association with positive skin PCR for O. volvulus despite negative PCR of the CSF is intriguing and deserves attention. Furthermore, the high prevalence of hippocampus sclerosis and familial clustering of epilepsy may point toward other potential pathogenetic mechanisms.
- Published
- 2008
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.