Institute of Cytology

Hannover, Germany

Institute of Cytology

Hannover, Germany
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Antonov A.V.,University of Leicester | Antonov A.V.,Technological University | Krestyaninova M.,University of Helsinki | Knight R.A.,University of Leicester | And 5 more authors.
Oncogene | Year: 2014

Multiple clinical studies have correlated gene expression with survival outcome in cancer on a genome-wide scale. However, in many cases, no obvious correlation between expression of well-known tumour-related genes (that is, p53, p73 and p21) and survival rates of patients has been observed. This can be mainly explained by the complex molecular mechanisms involved in cancer, which mask the clinical relevance of a gene with multiple functions if only gene expression status is considered. As we demonstrate here, in many such cases, the expression of the gene interaction partners (gene 'interactome') correlates significantly with cancer survival and is indicative of the role of that gene in cancer. On the basis of this principle, we have implemented a free online datamining tool ( PPISURV automatically correlates expression of an input gene interactome with survival rates on >40 publicly available clinical expression data sets covering various tumours involving about 8000 patients in total. To derive the query gene interactome, PPISURV employs several public databases including protein-protein interactions, regulatory and signalling pathways and protein post-translational modifications. © 2014 Macmillan Publishers Limited.

Kreuter A.,Ruhr University Bochum | Potthoff A.,Ruhr University Bochum | Brockmeyer N.H.,Ruhr University Bochum | Gambichler T.,Ruhr University Bochum | And 5 more authors.
British Journal of Dermatology | Year: 2010

Background Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)-associated potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). There is a paucity of data published on the progression of high-grade AIN to invasive cancer as well as on clinical and virological characteristics comparing anal margin and anal canal carcinoma. Objectives To search for anal carcinoma and AIN in a large series of HIV-positive MSM, to assess treatment response of anal carcinoma, and to analyse lesional HPV spectrum of anal cancers. Methods Detection of anal carcinoma and AIN was performed using cytology, high-resolution anoscopy, and histology in case of abnormal findings. Additionally, HPV analyses for 36 high- and low-risk α-HPV types were performed in patients with anal carcinoma. Results In total, 446 German HIV-positive MSM were examined within an observation period of 5 years and 10 months. Of these, 116 (26·0%) patients had normal findings, 163 (36·5%) had low-grade AIN, 156 (35·0%) had high-grade AIN, and 11 (2·5%) had anal carcinoma as evidenced by the highest grade of cytology/histology. Five patients with anal cancer, who had refused treatment of their precancerous lesions, had progressed from high-grade AIN to invasive cancer within a median time of 8·6 months. All anal cancers carried high-risk α-HPV types. All five squamous cell carcinomas (SCCs) of the anal canal were HPV16 positive. In contrast, only one of the four anal margin SCCs were HPV16 positive (HPV31, HPV33 and HPV33 + HPV68 were found in the other three anal margin SCCs). HPV59 was found in two adenocarcinomas, one of which additionally carried HPV33. In contrast to the cancer biopsies, a broad spectrum of surface high- and low-risk HPV types was found in anal swabs of the patients. Surgical excision resulted in long-term disease control of all anal margin carcinomas, whereas combined chemoradiotherapy in carcinomas of the anal canal was associated with high recurrence rates, high toxicity, and high mortality. Conclusions Anal carcinoma and AIN are frequent in HIV-positive men, even in patients participating in anal cancer prevention programmes. High-grade dysplasia in these patients can progress to invasive cancer within a short period of time. Anal margin carcinoma and anal canal carcinoma differ substantially in their lesional HPV spectrum, prognosis and treatment response. © 2010 British Association of Dermatologists.

Silling S.,University of Cologne | Kreuter A.,Ruhr University Bochum | Hellmich M.,University of Cologne | Swoboda J.,Institute of Cytology | And 2 more authors.
Journal of Clinical Virology | Year: 2012

Background: Anal human papillomavirus (HPV) infection and anal dysplasia are frequent in HIV-positive men who have sex with men (HIV. +. MSM), and progression of low-grade (LSIL) to high-grade squamous intraepithelial lesions (HSIL) or anal cancer (AC) occurs faster than in HIV-negative individuals. High-risk (HR)-HPV-E6/E7 oncogene mRNA testing has a higher specificity and a higher positive predictive value (PPV) than HR-HPV-DNA testing for detecting high-grade cervical lesions. Objective: To evaluate the diagnostic accuracy of the NucliSENS-EasyQ HPV1.1 E6/E7-mRNA-assay for the detection of anal dysplasia in HIV + MSM. Study design: 289 intraanal swabs from HIV + MSM participating in a screening program that included anal cytology, high-resolution anoscopy and histology were analyzed. HR-HPV-DNA detection was performed by PCR and hybridization using a bead-based multiplex genotyping assay. E6/E7-mRNA detection of HR-HPV-types 16, 18, 31, 33 and 45 was performed using the NucliSENS-EasyQ assay. Results: 269 swabs had valid results in both test formats (111 normal, 10 ASCUS, 105 LSIL, 42 HSIL, 1 AC). For the detection of LSIL + (LSIL + HSIL. + cancer) sensitivity, specificity, negative predictive value (NPV) and PPV were 80.4%, 26.4%, 52.5%, and 57.2% for HR-HPV-DNA testing, respectively, compared to 75.7%, 57.9%, 66.0% and 68.7% for E6/E7-mRNA testing. The respective values for the detection of HSIL/cancer were 95.3%, 26.1%, 96.7%, 19.7% for HR-HPV-DNA and 95.3%, 46.0%, 98.1%, 25.2% for E6/E7-mRNA detection. Conclusion: Compared to HR-HPV-DNA detection, E6/E7-mRNA testing has an increased specificity (approximately two-fold), similar sensitivity and higher NPV and PPV for the detection of low- and high-grade anal dysplasia in HIV + MSM. © 2012 Elsevier B.V.

Fuchs W.,Ruhr University Bochum | Kreuter A.,Ruhr University Bochum | Kreuter A.,Helios St Elisabeth Hospital Oberhausen | Hellmich M.,University of Cologne | And 4 more authors.
British Journal of Dermatology | Year: 2016

Background HIV-positive men who have sex with men (HIV+MSM) have an increased risk for anal dysplasia and for sexually transmitted infections (STIs). Objectives We determined the positivity rates of Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG), Mycoplasma genitalium (MG) and syphilis in HIV+MSM participating in an anal cancer screening programme. Methods In total, 852 intra-anal swabs were collected from 503 HIV+MSM between 2012 and 2014. Anal cytology and polymerase chain reaction assays for human papillomavirus (HPV), CT, NG and MG detection were performed. The syphilis status was determined serologically. Risk factors for STIs were explored by multiple logistic regression analysis. Results In total 20·7% (104 of 503) of the patients had an STI other than HPV within the study period. The most common was CT, found in 10·9%, followed by NG (8·9%) and MG (4·2%). Early syphilis was detected in 4·6% and past syphilis in 44·5% of the HIV+MSM. Eighteen patients (3·6%) had more than one STI episode, and 90·6% of the 127 cases of STIs were asymptomatic. Age, anal HPV infection, abnormal anal cytology and previous syphilis were risk factors for STI. Conclusions Anal STIs are frequent and mostly asymptomatic in HIV+MSM participating in anal cancer screening. STI screening should be incorporated into anal cancer screening programmes for HIV+MSM. © 2015 British Association of Dermatologists.

Ellrichmann M.,University of Kiel | Sergeev P.,Elblandclinic | Bethge J.,University of Kiel | Arlt A.,University of Kiel | And 4 more authors.
Endoscopy | Year: 2013

Background and study aims: Insertion of a percutaneous endoscopic gastrostomy (PEG) is standard care for many patients with oropharyngeal (ENT) and esophageal malignancies in order to ensure enteral feeding. The current pull-through insertion technique involves direct contact with the tumor and case reports have demonstrated the presence of metastases at insertion sites. The aim of the current study was to prospectively evaluate the risk of malignant cell seeding and the development of abdominal wall metastases after PEG placement. Patients and methods: A total of 50 consecutive patients with ENT/esophageal tumors were included. After PEG placement (40 pull-through technique, 10 direct insertion), brush cytology was taken from the PEG tubing and the transcutaneous incision site. A second cytological assessment was performed after a follow-up period of 3 - 6 months. Results: In total, 26 patients with ENT cancer, 13 with esophageal cancer, and one with esophageal infiltration of lung cancer underwent pull-through PEG placement with no immediate complications. Cytology following brushing of tubing and incision sites demonstrated malignant cells in 9 /40 cases (22.5 %). Correlation analyses revealed a higher rate of malignant seeding in older patients and in those with higher tumor stages. At follow-up, cytology was undertaken in 32 /40 patients who had undergone pull-through PEG placement. Malignant cells were present in three on cytology, resulting in a metastatic seeding rate of 9.4 %. Conclusion: This study showed that malignant cells were present in 22.5 % of patients immediately after pull-through PEG placement; local metastases were verified at follow-up in 9.4 %, all of which were from esophageal squamous cell carcinoma. This risk is particularly high in the older age group and in patients with higher tumor stages. Therefore, pull-through PEG placement should be avoided in these patients and direct access PEG favored instead. © Georg Thieme Verlag KG · Stuttgart · New York.

Lezina L.,University of Leicester | Purmessur N.,University of Leicester | Antonov A.V.,MRC Toxicology Unit | Ivanova T.,University of Leicester | And 10 more authors.
Cell Death and Disease | Year: 2013

The tumour suppressor p53 is a crucial regulator of cell cycle arrest and apoptosis by acting as a transcription factor to regulate a variety of genes. At least in part, this control is exerted by p53 via regulating expression of numerous microRNAs. We identified two abundantly expressed microRNAs, miR-16 and miR-26a, whose expression is regulated by p53 during the checkpoint arrest induced by the genotoxic drug, doxorubicin. Importantly, among the targets of these miRs are two critical checkpoint kinases, Chk1 and Wee1. The p53-dependent augmentation of miR-16 and miR-26a expression levels led to the cell cycle arrest of tumour cells in G1/S and increased apoptosis. Strikingly, the bioinformatics analysis of survival times for patients with breast and prostate cancers has revealed that co-expression of mir-16 and miR-26a correlated with a better survival outcome. Collectively, our data provide a novel mechanism whereby p53 represses Chk1 and Wee1 expression, at least partially, via upregulation of miR-16 and miR-26a and thus sensitizes tumour cells to genotoxic therapies. © 2013 Macmillan Publishers Limited All rights reserved.

Lezina L.,University of Leicester | Aksenova V.,Saint Petersburg State Polytechnic University | Ivanova T.,University of Leicester | Purmessur N.,University of Leicester | And 9 more authors.
Cell Death and Differentiation | Year: 2014

During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.Cell Death and Differentiation advance online publication, 15 August 2014; doi:10.1038/cdd.2014.108.

Sulatskaya A.I.,Saint Petersburg State Polytechnic University | Kuznetsova I.M.,Institute of Cytology
Tsitologiya | Year: 2010

Benzthiazole dye thioflavin T (ThT) is widely used to study the formation and structure of amyloid fibrils. Nevertheless, till now there is no common opinion concerning molecular mechanisms of ThT binding to amyloid fibrils and the reasons of dramatic increase in its fluorescence quantum yield on incorporation into amyloid fibrils. Our data prove that ThT molecules incorporate in the amyloid fibrils in the monomeric form and there is no ground to suppose the formation of ThT dimers, eximers, or micells. It was shown that the increase in the quantum yield of ThT incorporated in amyloid fibrils was caused by restriction of benzthiazole and aminobenzene rings torsion fluctuations relative to each other. The use of equilibrium microdialysis allowed determining the absorption spectrum, the number of binding modes of ThT with insulin amyloid fibrils and for each mode determining the binding constants and the number of binding sites for each mode.

Chitikova Z.V.,Institute of Cytology | Gordeev S.A.,Institute of Cytology | Bykova T.V.,Institute of Cytology | Zubova S.G.,Institute of Cytology | And 2 more authors.
Cell Cycle | Year: 2014

Cells respond to genotoxic stress by activating the DNA damage response (DDR). When injury is severe or irreparable, cells induce apoptosis or cellular senescence to prevent transmission of the lesions to the daughter cells upon cell division. Resistance to apoptosis is a hallmark of cancer that challenges the efficacy of cancer therapy. In this work, the effects of ionizing radiation on apoptosis-resistant E1A + E1B transformed cells were investigated to ascertain whether the activation of cellular senescence could provide an alternative tumor suppressor mechanism. We show that irradiated cells arrest cell cycle at G2/M phase and resume DNA replication in the absence of cell division followed by formation of giant polyploid cells. Permanent activation of DDR signaling due to impaired DNA repair results in the induction of cellular senescence in E1A + E1B cells. However, irradiated cells bypass senescence and restore the population by dividing cells, which have near normal size and ploidy and do not express senescence markers. Reversion of senescence and appearance of proliferating cells were associated with downregulation of mTOR, activation of autophagy, mitigation of DDR signaling, and expression of stem cell markers. © 2014 Landes Bioscience.

Karitskaya I.,Russian Academy of Sciences | Aksenov N.,Russian Academy of Sciences | Vassilieva I.,Institute of Cytology | Zenin V.,Russian Academy of Sciences | Marakhova I.,Russian Academy of Sciences
Pflugers Archiv European Journal of Physiology | Year: 2010

The aim of the study was to elucidate the mechanism responsible for the proliferation-related regulation of Na,K-ATPase pump. Our data demonstrate that in mitogen-stimulated human blood lymphocytes, enhanced ouabain-sensitive Rb(K) fluxes in the middle/late stage of G0/G1/S transit are associated with the increased number of Na,K-ATPase pumps expressed at the cell surface (as determined by the [3H]ouabain binding). Analysis of total RNA (reverse transcription-polymerase chain reaction) and protein (Western blotting) showed a threefold increase in the level of Na,K-ATPase al-subunit and β1-subunit mRNAs and significant increase in the Na,K-ATPase al- subunit protein during the first day of mitogen-induced proliferation. The elevated K transport as well as the increased expression of Na,K-ATPase is closely associated with the IL-2-dependent stage of T-cell response. The pharmacological inhibition of IL-2-induced MEK/ERK or JAK/STAT cascades suppressed the IL-2-induced proliferation and reduced the functional and protein expressions of Na,K-ATPase. It is concluded that during the lymphocyte transition from resting stage to proliferation, (1) long-term activation of Na,K-ATPase pump is due to the enhanced expression of Na,K-ATPase protein and mRNA, and (2) the cytokine signaling via the IL-2 receptor is necessary for the cell cycle-associated upregulation of Na,K-ATPase. © Springer-Verlag 2010.

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