Genetische versus epigenetische BRCA1-Stummschaltungswege: klinische Effekte bei Patienten mit primärem Ovarialkarzinom

Objectives: The objective of this thesis is to investigate the incidence and clinical impact of both BRCA1 germline and epigenetic silencing mechanisms in a large patient cohort of primary epithelial ovarian cancer (PEOC). Methods: 188 primary PEOC patients treated between 2000 and 2011 at Charité University Hospital of Berlin were included in the current study. Patients’ tumor tissues and blood samples were retrieved from the Tumor Ovarian Cancer (TOC) Network (www.toc-network.de). Sanger sequencing of BRCA1 gene exon11 was carried out to detect germline mutations. Tumor biopsies were investigated for BRCA1 gene promoter hypermethylation using bisulphite-converted methylation-specific polymerase chain reaction. Clinicopathological variables and survival of the patients were compared according to the BRCA1 genetic constellations. Results: 21 (11.2%) patients were positive for hypermethylation in BRCA1 promoter (HMB), 18 (9.6%) patients possessed germline mutations in BRCA1 exon 11 (GMB). HMB patients presented a significantly younger age at diagnosis compared to BRCA1 wild type (BWT) patients (54y vs 61y, p=0.045), and both GMB and HMB patients were more likely to show high grade serous ovarian cancer (HGSOC) (76.2% and 77.8% vs 52.7%, p=0.043 and p=0.043). Positive family history of ovarian and breast cancers was more frequently observed among GMB patients compared to BWT patients (44.4% vs 13.5%, p=0.003). No significant difference in terms of tumor dissemination pattern, surgical outcomes, platinum-response or survival were observed among GMB, HMB and BWT patients. Multivariate analysis showed that neither GMB nor HMB was identified as independent prognostic factor for ovarian cancer patients. Conclusions: HMB is associated with earlier-onset of ovarian cancer. The coexistence of both GBM and HMB occurred in 0.5% of ovarian cancer patients and is identified as an infrequent event. Compared to BWT, silencing of BRCA1 through germline mutation and hypermethylation confers to different clinical characteristics of ovarian cancer patients, but similar clinical outcome.Ziele: Ziel der vorliegenden Studie war es, in einer großen Kohorte von Patientinnen mit primär epithelialem Ovarialkarzinom (EOC) die Inzidenz und den klinischen Einfluss von genetischen und epigenetischen Silencing-Mechanismen des BRCA1-Gens zu untersuchen. Methode: 188 primäre EOC-Patientinnen wurden rekrutiert, die zwischen 2000 und 2011 an der Charité-Universitätsmedizin Berlin behandelt wurden. Die Tumor- und Blutproben der Patientinnen stammen vom Tumor Bank Ovarian Cancer (TOC)- Netzwerk (www.toc-network.de). Die direkte Sequenzierung des BRCA1-Gens Exon11 wurde durchgeführt, um Keimbahnmutationen nachzuweisen, während Tumorproben auf die BRCA1-Genpromotor-Hypermethylierung durch Bisulfit-konvertierte methylierungsspezifische Polymerasekettenreaktion untersucht wurden. Basierend auf ihrem BRCA1-Genstatus wurden die Patienten hinsichtlich klinisch-pathologischer Variablen und des Überlebens verglichen. Ergebnisse: Es zeigten 21 Patientinnen (11,2 %) eine Hypermethylierung im BRCA1-Promotor (HMB) und 18 Patientinnen (9,6 %) Keimbahnmutationen in BRCA1 Exon11 (GMB). HMB-Patienten wiesen bei der Diagnose ein signifikant jüngeres Alter im Vergleich zu BRCA1-Wildtyp-Patientinnen (BWT) auf (54y gegenüber 61y, p = 0,045). Sowohl GMB- als auch HMB-Patientinnen hatten mit höherer Wahrscheinlichkeit ein seröses Ovarialkarzinom (HGSOC) (76,2 % und 77,8 % gegenüber 52,7 %, p = 0,043 und p = 0,043). Eine positive Familienanamnese bezüglich Brust- oder Ovarialkarzinom wurde häufiger bei GMB-Patientinnen als bei BWT-Patientinnen berichtet (44,4 % gegenüber 13,5 %, p = 0,003). GMB-, HMB- und BWT-Patientinnen zeigten keine signifikanten Unterschiede in Bezug auf Tumorausbreitungsmuster, chirurgische Ergebnisse, Antwort auf Platinum-basierte Chemotherapie und Gesamtüberleben. Weder Mutation noch Hypermethylierung des BRCA1-Genestatus wurden als unabhängige prognostische Faktoren für Patientinnen mit Ovarialkarzinom gefunden. Schlussfolgerungen: HMB ist mit einem früheren Auftreten eines Ovarialkarzinoms assoziiert. Darüber hinaus ist die Koexistenz von GBM und HMB ein seltenes Ereignis, das bei 0,5 % der Ovarialkarzinomfälle auftritt. Das Silencing von BRCA1 durch Mutation und Hypermethylierung verleiht den klinischen Charakteristika von Patientinnen mit Ovarialkarzinom einen ähnlichen klinischen Befund wie BWT-Patientinnen

RMSE-ELM: Recursive Model based Selective Ensemble of Extreme Learning Machines for Robustness Improvement

Extreme learning machine (ELM) as an emerging branch of shallow networks has shown its excellent generalization and fast learning speed. However, for blended data, the robustness of ELM is weak because its weights and biases of hidden nodes are set randomly. Moreover, the noisy data exert a negative effect. To solve this problem, a new framework called RMSE-ELM is proposed in this paper. It is a two-layer recursive model. In the first layer, the framework trains lots of ELMs in different groups concurrently, then employs selective ensemble to pick out an optimal set of ELMs in each group, which can be merged into a large group of ELMs called candidate pool. In the second layer, selective ensemble is recursively used on candidate pool to acquire the final ensemble. In the experiments, we apply UCI blended datasets to confirm the robustness of our new approach in two key aspects (mean square error and standard deviation). The space complexity of our method is increased to some degree, but the results have shown that RMSE-ELM significantly improves robustness with slightly computational time compared with representative methods (ELM, OP-ELM, GASEN-ELM, GASEN-BP and E-GASEN). It becomes a potential framework to solve robustness issue of ELM for high-dimensional blended data in the future.Comment: Accepted for publication in Mathematical Problems in Engineering, 09/22/201

A study on improving the performance of control charts under non-normal distributions

Master'sMASTER OF ENGINEERIN

A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes.

Insulin-stimulated glucose uptake in fat and muscle is mediated by the major facilitative glucose transporter Glut4. Insulin controls the trafficking of Glut4 to the plasma membrane via regulation of a series of small G proteins, including RalA and Rab10. We demonstrate here that Rab10 is a bona fide target of the GTPase-activating protein AS160, which is inhibited after phosphorylation by the protein kinase Akt. Once activated, Rab10 can increase the GTP binding of RalA by recruiting the Ral guanyl nucleotide exchange factor, Rlf/Rgl2. Rab10 and RalA reside in the same pool of Glut4-storage vesicles in untreated cells, and, together with Rlf, they ensure maximal glucose transport. Overexpression of membrane-tethered Rlf compensates for the loss of Rab10 in Glut4 translocation, suggesting that Rab10 recruits Rlf to membrane compartments for RalA activation and that RalA is downstream of Rab10. Together these studies identify a new G protein cascade in the regulation of insulin-stimulated Glut4 trafficking and glucose uptake

Laser tuning parameters and concentration retrieval technique for wavelength modulation spectroscopy based on the variable-radius search artificial bee colony algorithm

A novel wavelength modulation spectroscopy (WMS) laser tuning parameters and concentration retrieval technique based on the variable-radius-search artificial bee colony(VRS-ABC) algorithm is proposed. The technique imitates the foraging behavior of bees to achieve the retrieval of gas concentration and laser tuning parameters in a calibration-free WMS system. To address the problem that the basic artificial bee colony(ABC) algorithm tends to converge prematurely, we improve the search method of the scout bee. In contrast to prior concentration retrieval methods that utilized the Levenberg-Marquardt algorithm, the current technique exhibits a reduced dependence on the pre-characterization of laser parameters, leading to heightened precision and reliability in concentration retrieval. We validated the simulation with the VRS-ABC-based technique and the LM-based technique for the target gas C2H2. The simulation results show that the VRS-ABC-based technique performs better in terms of convergence speed and fitting accuracy, especially in the multi-parameter model without exact characterization

Dichlorido[2,3,5,6-tetra­fluoro-4-(tri­fluoro­meth­yl)phenyl-κC 1]bis­(tri­methyl­phosphine-κP)cobalt(III)

In the title compound, [Co(C7F7)Cl2(C3H9P)2], the CoIII atom displays a trigonal–bipyramidal coordination geometry, with the two Cl ligands and the C atom of the perfluoro­tolyl ligand in the equatorial plane and the two phosphine ligands occupying axial positions. The mol­ecule has an approximate C 2v symmetry. The trifluoro­methyl group is disordered over two positions, with nearly equal occupancies

Concentration retrieval in a calibration-free wavelength modulation spectroscopy system using particle swarm optimization algorithm

This paper develops a spectral fitting technology based on the particle swarm optimization (PSO) algorithm, which is applied to a calibration-free wavelength modulation spectroscopy system to achieve concentration retrieval. As compared with other spectral fitting technology based on the Levenberg-Marquardt (LM) algorithm, this technology is relatively weakly dependent on the pre-characterization of the laser parameters. The gas concentration is calculated by fitting the simulated spectra to the measured spectra using the PSO algorithm. We validated the simulation with the LM algorithm and PSO algorithm for the target gas C2H2. The results showed that the convergence speed of the spectral fitting technique based on the PSO algorithm was about 63 times faster than the LM algorithm when the fitting accuracy remained the same. Within 5 seconds, the PSO algorithm can produce findings that are generally consistent with the values anticipated.Comment: arXiv admin note: text overlap with arXiv:2210.1654