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Berlin, Germany

Banning A.,Justus Liebig University | Regenbrecht C.R.A.,University Hospital Berlin | Tikkanen R.,Justus Liebig University
Cellular Signalling | Year: 2014

Flotillins are highly conserved and widely spread proteins that function in receptor tyrosine kinase signaling and membrane trafficking processes. Flotillin-1 and flotillin-2 have been shown to form both homo- and hetero-oligomers, and their cellular localization changes during signaling. Increased expression of flotillins has been detected in several types of cancer and shown to correlate with poor survival. Consistently, flotillin-2 knockout mice show a reduced formation of metastases in a breast cancer animal model. Our recent data have shown that flotillin-1 depletion results in diminished activation of the epidermal growth factor receptor and impairs its downstream signaling towards the mitogen activated protein kinases and the respective transcriptional response. Here we show that genetic ablation of flotillin-2 in a mouse model or its knockdown in cultured cells increases extracellular signal regulated kinase (ERK) activation. Furthermore, the downstream transcriptional targets of ERK and p53 are upregulated at both mRNA and protein levels. These data suggest that opposite effects are obtained upon ablation of one of the two flotillins, with flotillin-2 knockout/knockdown enhancing and flotillin-1 knockdown inhibiting ERK signaling. Due to their overexpression in cancers, flotillins may be considered as cancer therapy targets. However, our findings suggest that care needs to be taken when interfering with flotillin function, as undesired effects such as deregulation of growth-associated genes may emerge in certain cell types. © 2013 Elsevier Inc.

Hartwig I.R.V.,University of Hamburg | Pincus M.K.,University Hospital Berlin | Diemert A.,University of Hamburg | Hecher K.,University of Hamburg | Arck P.C.,University of Hamburg
Human Reproduction | Year: 2013

Study Question Are maternal progesterone levels in early pregnancy associated with fetal birthweight? Summary Answer Low levels of first-trimester maternal progesterone are significantly associated with a reduction in birthweight in girls, but not boys. What is Already KnownProgesterone in the third trimester of pregnancy has previously been related to birthweight in humans. Study Design, Size, Duration Pregnant women between gestational weeks 4 and 12 were recruited by 99 obstetricians in private practice and enrolled in a prospective cohort study. A follow-up took place at birth. Women younger than 18 years, who had undergone fertility treatments or were diagnosed with infectious diseases, were excluded from the study. A subgroup of 906 participants in whom progesterone had been measured was then selected retrospectively based on the following criteria: no miscarriages, elective abortions or pregnancy complications, infections or multiple births. Data from the follow-up were available for 623 women, who were included in the analyses. Participants/ Materials, Setting, Methods The study was coordinated at the Charité University Medicine in Berlin, Germany. Anthropometric, medical and psychosocial information were collected and serum progesterone and estradiol levels were measured in women during the first trimester of pregnancy, followed by the documentation of the pregnancy outcome at birth. Univariable and multivariable regression analyses were performed to identify maternal markers, among them progesterone, affecting birthweight and to determine environmental and maternal factors that are associated with maternal progesterone levels during pregnancy. Main Results AND THE ROLE OF CHANCEIn the multivariable regression model, each increase in maternal progesterone by 1 ng/ml during the first trimester increased girls' birthweight by 10.17 g (95% CI: 2.03-18.31 g). If the mother carried a boy, maternal smoking and perceived worries during early pregnancy predicted a reduced birthweight, irrespective of progesterone levels. Maternal body mass index over 25 and maternal age <21 years significantly correlated with the reduced levels of progesterone. Correlations between environmental challenges and maternal progesterone did not reach levels of significance. Since the analyses were exploratory, the likelihood that results may be due to chance is increased. Limitations, Reasons for Caution Due to the exploratory nature of the analyses, results need to be independently confirmed in a larger sample. Furthermore, our findings pertain to pregnant women without pregnancy complications or fertility treatments. Wider Implications of the Findings Maternal progesterone during early pregnancy is an indicator of subsequent fetal development in female children. Future studies should confirm this relationship and determine whether maternal progesterone is a useful tool in predicting pregnancies at risk resulting in the birth of a girl with low birthweight. Detailed identification of environmental factors modulating maternal progesterone levels should be addressed in future studies. Study Funding/Potential Competing InterestsFinancial support was provided by the Alexander von Humboldt Foundation, Excellence Initiative of the Hamburg Foundation for Research and the Association for Prevention and Information for Allergy and Asthma (Pina e.V.). The authors have no conflict of interest. © 2012 The Author.

Arsenic R.,University Hospital Berlin
Diagnostic Pathology | Year: 2014

Background: 3-phosphoinositide-dependent protein kinase-1 (PDK1) functions downstream of phosphoinositide 3-kinase (PIK3) and activates members of the AGC family of protein kinases that are known to play crucial roles in physiological processes associated with cell metabolism, growth, proliferation and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human disease, including cancer.Methods: We used immunohistochemical analysis to determine PDK1 expression in 241 tumors from patients with breast cancer in which we had previously analyzed PIK3CA mutation status.Results: Moderate or high expression of PDK1 was observed in 213 of the 241 cases (88%). There was no correlation between PIK3CA mutation status and PDK1 overexpression.Conclusion: Our findings indicate that PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway, suggesting that PDK1 plays a specific and distinct role from the canonical PIK3/Akt pathway and promotes oncogenesis independently of AKT. Our data implicate PDK-1 and downstream components of the PDK-1 signaling pathway as promising therapeutic targets for the treatment of breast cancer. © 2014 Arsenic; licensee BioMed Central Ltd.

Chantraine F.,CHR Citadelle | Chantraine F.,University of Liege | Braun T.,University Hospital Berlin | Gonser M.,Horst Schmidt Kliniken | And 3 more authors.
Acta Obstetricia et Gynecologica Scandinavica | Year: 2013

Objective Abnormally invasive placenta (AIP) poses diagnostic and therapeutic challenges. We analyzed clinical cases with confirmed placenta increta or percreta. Design Retrospective case series. Setting Multicenter study. Population Pregnant women with AIP. Methods Chart review. Main outcome measures Prenatal detection rates, treatment choices, morbidity, mortality and short-term outcome. Results Sixty-six cases were analyzed. All women and all but three fetuses survived; 57/64 women (89%) had previous uterine surgery. In 26 women (39%) the diagnosis was not known before delivery (Group 1), in the remaining 40 (61%) diagnosis had been made between 14 and 37 weeks of gestation (Group 2). Placenta previa was present in 36 women (54%). In Groups 1 and 2, 50% (13/26) and 62% (25/40) of the women required hysterectomy, respectively. In Group 1 (unknown at the time of delivery) 69% (9/13) required (emergency) hysterectomy for severe hemorrhage in the immediate peripartum period compared with only 12% (3/25) in Group 2 (p = 0.0004). Mass transfusions were more frequently required in Group 1 (46%, 12/26 vs. 20%, 8/40; p = 0.025). In 18/40 women (45%) from Group 2 the placenta was intentionally left in situ; secondary hysterectomies and infections were equally frequent (18%) among these differently treated women. Overall, postpartum infections occurred in 11% and 20% of women in Groups 1 and 2, respectively. Conclusions AIP was known before delivery in more than half of the cases. Unknown AIP led to significantly more emergency hysterectomies and mass transfusions during or immediately after delivery. Prenatal diagnosis of AIP reduces morbidity. Future studies should also address the selection criteria for cases appropriate for leaving the placenta in situ. © 2013 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.

Matziolis G.,University Hospital Berlin | Mehlhorn S.,University Hospital Berlin | Schattat N.,University Hospital Berlin | Diederichs G.,University Medicine Berlin | And 3 more authors.
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2012

Purpose: There are two different techniques for retaining the posterior cruciate ligament (PCL) in total knee arthroplasty. The attachment of the PCL can be spared during resection of the tibial plateau, so that a small posterior bone block remains. In contrast to this, many surgeons resect the tibial plateau completely and detach a part of the tibial PCL attachment from the resected material. The objective of this study was to determine how big this part is in an anatomical resection of the tibial plateau with 0° and 7° slope and whether it is gender-dependent. Methods: Two hundred consecutive patients who had undergone MRI of a knee joint were included. Patients were excluded if they were younger than 18 years or had dysplasia of the knee joint or injuries of the posterior cruciate ligament. The MRIs of 182 knees that fulfilled the inclusion criteria were analysed. For each knee, an anatomical tibial resection with 0° and 7° posterior slope was simulated, and the parts of the tibial PCL attachment that were resected and retained were determined. Results: Given a measured tibial resection with 0° slope, 45 ± 28% of the tibial PCL attachment was removed in the men, compared with 46 ± 30% in the women (n. s.). Given a resection with 7° slope, 69 ± 24% of the tibial PCL attachment was removed in the men and 67 ± 25% in the women. This corresponded to a complete resection in 19 men (20%) and 16 women (24%). Conclusions: Independently of gender, the anatomical resection of the tibia leads to the removal of a considerable part of the tibial PCL attachment, if this is not spared in the form of a bone block during resection. This becomes increasingly relevant with higher posterior slope of the resection plane. In the case of a cruciate-retaining surgical technique, the retention of the posterior tibial cortical bone in the area of attachment of the PCL is therefore strongly recommended. Level of evidence: II. © 2011 Springer-Verlag.

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