1,721,297 research outputs found
Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells
No full textChromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth
The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability
No full textBRCA1 is a tumor-suppressor gene associated with, but not restricted to, breast and ovarian cancer and implicated in various biological functions. During mitosis, BRCA1 and its positive regulator Chk2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability. However, the function of BRCA1 during mitosis has not been defined mechanistically. To gain insights into the mitotic role of BRCA1 in regulating microtubule assembly, we systematically identified proteins interacting with BRCA1 during mitosis and found the centrosomal protein Cep72 as a novel BRCA1-interacting protein. CEP72 is frequently upregulated in colorectal cancer tissues and overexpression of CEP72 mirrors the consequences of BRCA1 loss during mitosis. In detail, the overexpression of CEP72 causes an increase in microtubule plus end assembly, abnormal mitotic spindle formation and the induction of chromosomal instability. Moreover, we show that high levels of Cep72 counteract Chk2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly. Thus, CEP72 represents a putative oncogene in colorectal cancer that might negatively regulate the mitotic function of BRCA1 to ensure chromosomal stability.Deutsche Forschungsgemeinschaft; DF
Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma
No full textHead and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p = 0.006) as well as progression-free survival (p = 0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities
Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20⁒
No full textSomatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.Modern Pathology advance online publication, 6 January 2017; doi:10.1038/modpathol.2016.217
Fokal segmentale Glomerulosklerose und juxtaglomerulärer Apparat der hypertensiven "fawn-hooded" Ratte
Get PDFIn dieser Arbeit wurden 8 und 16 Wochen alte, hypertensive "fawn-hooded" Ratten (FHH8, FHH16) mit genetisch ähnlichen 16 Wochen alten "fawn-hooded" Ratten mit nur geringgradiger Blutdruckerhöhung (FHL16, Kontrollgruppe) hinsichtlich der pathologisch-anatomischen Veränderungen der Nierenmorphologie und hinsichtlich der Expression von NO-Synthase-1 (NOS1), Cyclooxygenase-2 (COX-2) und Renin am juxtaglomerulären Apparat (JGA) verglichen. Die histopathologischen Veränderungen bei FHH16 umfassten die klassischen Schädigungszeichen der fokal segmentalen Glomerulosklerose (FSGS) mit fokaler Überexpression von Kollagen IV und eine moderate Arteriolopathie. Bei FHH8 ließen sich, wie bei FHL16 keine morphologischen Schädigungen nachweisen. Die NOS1-Aktivität an der Macula densa, untersucht mittels der NADPH-Diaphorasereaktion und die NOS1 mRNA Expression waren bei FHH8 (+153 and +88%; P < 0.05) und FHH16 (+93 and +98%; P < 0.05) im Vergleich zu FHL16 signifikant erhöht. Eine gleichgerichtete signifikante Erhöhung zeigte sich für die COX-2-Expression an der Macula densa von FHH8 (+166%; P < 0.05) und FHH16 (+157%; P < 0.05) im Vergleich zu FHL16. Des weiteren ließ sich eine signifikante, ebenfalls gleichgerichtete Überexpression von Renin in der afferenten Arteriole auf Protein- und mRNA-Ebene bei FHH8 (+51 and +166%; P < 0.05) und FHH16 (+105 and +136%; P < 0.05) im Vergleich zu FHL16 nachweisen. Somit konnte gezeigt werden, dass die gleichgerichtete Überexpression von NOS1, COX-2 und Renin am JGA bei der FHH-Ratte der Entwicklung einer fokal segmentalen Glomerulosklerose vorausgeht und damit möglicherweise pathogenetische Bedeutung für die Entstehung der Nierenschädigung bei diesem Rattenstamm hat.This study describes elevated histochemical signals for nitric oxide synthase-1 (NOS1) and cyclooxygenase-2 (COX-2) in juxtaglomerular apparatus (JGA) and adjacent thick ascending limb of the kidney of fawn-hooded hypertensive rats (FHH). Two different age groups of FHH (8 and 16 wk; FHH8 and FHH16, respectively) were compared with genetically related fawn-hooded rats with close to normal blood pressure (FHL) that served as controls. Histopathological changes in FHH16 comprised focal segmental glomerulosclerosis (FSGS), focal matrix overexpression (mainly of collagen IV), and a moderate arteriolopathy with hypertrophy of the media, enhanced immunoreactivity for alpha-smooth muscle actin, and altered distribution of myofibrils. Macula densa NOS activity, as expressed by NADPH-diaphorase staining, and NOS1 mRNA abundance were significantly elevated in FHH8 (+153 and +88%; P < 0.05) and FHH16 (+93 and +98%; P < 0.05), respectively. Even higher elevations were registered for COX-2 immunoreactivity in FHH8 (+166%; P < 0.05) and FHH16 (+157%; P < 0.05). The intensity of renin immunoreactivity and renin mRNA expression in afferent arterioles was also elevated in FHH8 (+51 and +166%; P < 0.05) and FHH16 (+105 and +136%; P < 0.05), respectively. Thus we show that coordinate upregulation of tubular NOS1, COX-2, and renin expression precedes, and continues after, the manifestation of glomerulosclerotic damage in FHH. These observations may have implications in understanding the role of local paracrine mediators in glomerular disease
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Characterization of paraganglioma-like neuroendocrine tumors of the pancreas
No full textDas Ziel dieser Doktorarbeit ist die ausführliche Charakterisierung von paragangliomartigen neuroendokrinen Tumoren des Pankreas. Dabei soll untersucht werden, inwiefern ein paragangliomartiges Wachstumsmuster von pankreatischen neuroendokrinen Tumoren (PanNETs) mit der Produktion von Hormonen assoziiert ist. Es handelt sich um eine experimentelle Studie mit insgesamt 68 Fällen. Zusammenfassend kann gesagt werden, dass PanNETs mit einem paragangliomartigen Wachstumsmuster statistisch signifikant mit der Produktion von Somatostatin assoziiert sind.The aim of this thesis is to present a detailed characterization of paraganglioma-like neuroendocrine tumors of the pancreas, and to investigate to what extent a paraganglioma-like growth pattern of pancreatic neuroendocrine tumors (PanNETs) is associated with the production of hormones. It is an experimental study with a total of 68 cases. In summary, PanNETs with a paraganglioma-like growth pattern are statistically significantly associated with the production of somatostatin
Prognostic significance of polo like kinase isoforms in solid human tumors - implications for novel chemotherapeutic treatment strategies
No full textHabilitationsschrift komplett
Titelblatt, Inhaltsverzeichnis und Danksagung
Einleitung
Zielstellung
Ergebnisse
Diskussion
Zusammenfassung
LiteraturverzeichnisMaligne Tumorerkrankungen nehmen in den Mortalitätsstatistiken
industrialisierter Länder seit Jahrzehnten den zweiten Rang ein. Trotz
Fortschritten in der Behandlung einiger dieser Erkrankungen hat sich die
Gesamttumormortalität in den letzten Jahrzehnten nicht wesentlich verändert,
so dass nach wie vor dringender Bedarf nach neuen Behandlungsstrategien
besteht. Als neue, nicht interventionelle Therapieoption rückte in den letzten
Jahren die Behandlung maligner Tumoren durch eine gezielte Ausschaltung
einzelner Proteine und Proteingruppen, die so genannte zielgerichtete
Chemotherapie , in den Fokus des medizinischen Interesses. Als mögliche
Zielproteine kommen vor allem solche Proteine in Frage, die eine Rolle in der
Regulation malignitätsdefinierender Zelleigenschaften spielen. Die Familie der
Polokinase (PLK) Isoformen spielt eine zentrale Rolle in der Mitoseregulation
normaler und maligner Zellen. Weiterhin ist bekannt, dass eine Hemmung
einzelner PLK-Isoformen in vitro und in vivo zu einer Arretierung von
Tumorzellen in der Mitose, zur Apoptoseinduktion und zu einer Verminderung des
Tumorwachstums führt. In den vorliegenden Studien wurde der Expressionsstatus
von Polokinase-Isoformen in verschiedenen Kohorten von Karzinompatienten
erhoben und mit klinisch-pathologischen und zytogenetischen Daten sowie mit
dem Patientenüberleben korreliert. Zusätzlich wurde die Assoziation der PLK-
Isoform-Expression mit der proliferativen Aktivität von Tumoren und
Tumorzelllinien untersucht. Zwischen 26% und 67% der untersuchten Karzinome
der Brust, des Magens, des Kolorektums, der Ovarien, des Pankreas und der
Prostata zeigten eine verstärkte PLK1-Expression im Vergleich zum jeweils
korrespondierenden, nicht-transformierten Ausgangsgewebe. Zusätzlich konnte
eine verstärkte Expression der PLK3-Isoform in malignen Tumoren des Ovars und
der Brust nachgewiesen werden. In einigen Tumoren ließ sich eine Assoziation
von proliferativer Aktivität und PLK-Isoform-Überexpression darstellen, eine
strikte Begrenzung der PLK-Expression auf proliferierende Tumorzellen lag
nicht vor. Die Expression beider PLK-Isoformen korrelierte regelmäßig mit
klinisch-pathologischen Parametern, die die Ausdehnung des Tumors und die
Tumoraggressivität beschreiben. Zusätzlich ergab sich für die PLK-Isoform-
Expression in einigen, aber nicht allen untersuchten Tumoren eine teilweise
unabhängige, prognostische Relevanz. Die erhobenen Daten legen unter
Berücksichtigung von Daten aus funktionellen Studien nahe, dass die Inhibition
von PLK-Isoformen als ein interessanter neuer Ansatz für eine gezielte
Chemotherapie in einer Vielzahl von humanen Karzinomen in Frage kommt.Malignant tumors rank second only to cardiovascular disease in mortality
statistics in industrialized countries. Despite undeniable improvements in the
treatment of some of these diseases, overall cancer mortality has changed
little over the last decades. Based on these epidemiologic data it is obvious
that there is an urgent need for novel therapeutic approaches in the treatment
of human malignancies. Research on non-interventional treatment strategies for
human tumors in the last years concentrated on the development of substances
selectively targeting specific proteins and protein families. These so called
targeted therapy approaches mainly focus on genetically altered as well as
aberrantly expressed proteins known to contribute to malignant cell behaviour.
Genetic alterations typically associated with a malignant cell phenotype often
affect proteins involved in DNA repair, apoptosis, cell adhesion, invasion,
angiogenesis and, finally, cell proliferation and cell cycle control. The
protein family of polo like kinases (PLK) is known to play an outstanding role
in the regulation of mitosis in normal and malignant cells. Inhibition of PLK
isoforms in vitro and in vivo led to a mitotic arrest and an induction of
apoptosis in malignant cells, which resulted in a strong inhibition of tumor
growth. In the studies presented here, expression of PLK isoforms in several
large and well-characterized cohorts of human tumors was investigated.
Expression data were correlated to clinicopathological and cytogenetic tumor
characteristics and to patient survival. Furthermore, the association of PLK
expression and cell proliferation was assessed in cancer cell lines and
primary human tumors. Between 26% and 67% of carcinomas of the breast, the
stomach, the colorectum, the ovaries, the pancreas and the prostate were found
to show enhanced expression of PLK1 when compared to the respective non-
transformed tissue of origin. In addition, in ovarian cancer as well as in
breast cancer high expression of PLK3 was observed in a subset of tumors . In
some of the tumor entities investigated a positive association of PLK isoform
expression with cell proliferation was found, although PLK expression was not
strictly confined to cycling cells. Expression of PLK1 and PLK3 usually was
elevated in highly aggressive locally advanced tumors when compared to their
low grade locally restricted counterparts. Interestingly, in some but not all
tumor entities high PLK isoform expression had significant partly independent
negative prognostic impact. The data presented here, if interpreted in the
context of recently published functional data, suggest that inhibition of PLK
isoforms might represent an interesting new targeted chemotherapeutic approach
for the treatment of a variety of human carcinomas
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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