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Outcome Results of Treatment with Selective Internal Radiation Therapy (SIRT) in Patients with Hepatocellular Carcinoma: A Single Center Experience  [PDF]
Jan Pfeiffenberger, Tatjana Zimmermann, Daniel N. Gotthardt, Christoph Springfeld, Wolfgang Stremmel, Peter Schirmacher, Henning Schulze-Bergkamen, Arianeb Mehrabi, Christoph W. Michalski, Katrin Hoffmann, Nikolas Kortes, Boris Radeleff, Uwe Haberkorn, Clemens Kratochwil, Karl Heinz Weiss, Carsten Grüllich
Journal of Cancer Therapy (JCT) , 2017, DOI: 10.4236/jct.2017.84031
Abstract: Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in patients with HCC treated with SIRT, to stratify patients with tumor vascularization and analyze the impact of sequential sorafenib treatment. Methods: Thirty-nine patients who received SIRT for HCC between 2010 and 2013 at our center were included in this retrospective analysis. Tumor vascularization was assessed using a combination of MRI, MAA-scintigraphy and angiography. Tumor vascularization was correlated with survival. Subgroups are treated with two commercially available 90Y-labeled products SIR-Spheres (n = 16) and TheraSpheres (n = 23) and sequential therapy with sorafenib compared to SIRT only was analyzed. Results: Adverse events occurred in 49% of patients with only four grade 3 and no grade 4 event. Median survival for all patients was 12.5 months (95% CI: 8.7 - 16.3). No significant differences were detectable between Thera Spheres or SIR Spheres. Survival was shorter in patients with low tumor vascularization score (OS: 3.8 months (95% CI 0 - 15.0), p = 0.043). Survival was longer with sorafenib upon progression after SIRT (n=16) with an OS of 17.4 months (95% CI: 12.1 – 22.7) compared to no sorafenib (n = 13; 9.1 months; 95% CI: 3.0 - 15.1) or progression upon sorafenib before SIRT (n = 10; 8.6 months; 95% CI: 5.5 - 11.7). Conclusions: SIRT is safe in HCC patients. Tumor vascularization by radiography and scintigraphy may predict survival benefit. Sorafenib is active after SIRT and significantly prolongs survival.
Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction
Henning Schulze-Bergkamen, Binje Fleischer, Marcus Schuchmann, Achim Weber, Arndt Weinmann, Peter H Krammer, Peter R Galle
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-232
Abstract: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively.Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition.Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies.The incidence of hepatocellular carcinoma (HCC) in Western countries has experienced a significant increase over recent years. Currently, HCC ranks among the five most important causes of cancer-related mortality worldwide [1]. In Western countries, HCC occurs mainly in patients with liver cirrhosis and has an annual incidence of about 2–4 cases per 100,00
TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies
Bruno Christian Koehler, Toni Urbanik, Binje Vick, Regina Johanna Boger, Steffen Heeger, Peter R Galle, Marcus Schuchmann, Henning Schulze-Bergkamen
World Journal of Gastroenterology , 2009,
Abstract: AIM: To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors, in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL), on overcoming TRAIL resistance in hepatocellular carcinoma (HCC) and to study the efficacy of agonistic TRAIL antibodies, as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis.METHODS: Surface expression of TRAIL receptors (TRAIL-R1-4) and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting, respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs. HCC cells were treated with kinase inhibitors and chemotherapeutic drugs. Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: TRAIL-R1 and -R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However, treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates. Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002 [inhibition of phosphoinositol-3-kinase (PI3K)], AG1478 (epidermal growth factor receptor kinase), PD98059 (MEK1), rapamycin (mammalian target of rapamycin) and the multi-kinase inhibitor Sorafenib. Furthermore, the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance: knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells. Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION: Our data identify the blockage of survival kinases, combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
Beyond Cell Death – Antiapoptotic Bcl-2 Proteins Regulate Migration and Invasion of Colorectal Cancer Cells In Vitro
Bruno Christian Koehler, Anna-Lena Scherr, Stephan Lorenz, Toni Urbanik, Nicole Kautz, Christin Elssner, Stefan Welte, Justo Lorenzo Bermejo, Dirk J?ger, Henning Schulze-Bergkamen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076446
Abstract: Migration and invasion of malignant cells are prerequisites for cancer progression and metastasis. The Bcl-2 family of proteins consists of about 25 members and has been extensively studied in the context of apoptosis. Despite the fact that small molecules targeting Bcl-2 proteins have already entered clinical trials, very few studies investigated a role of antiapoptotic Bcl-2 proteins beside cell death in the context of metastasis. The aim of this study was to dissect a potential role of the antiapoptotic Bcl-2 proteins Mcl-1, Bcl-2 and Bcl-xL on migration and invasion of colorectal cancer cells independent of their cell death control function. We used migration and invasion assays as well as three dimensional cell cultures to analyze colorectal cancer cell lines (HT29 and SW480) after siRNA mediated knockdown or overexpression of Mcl-1, Bcl-2 or Bcl-xL. We observed neither spontaneous cell death induction nor impaired proliferation of cells lacking Mcl-1, Bcl-2 or Bcl-xL. In contrast, knockdown of Mcl-1 led to increased proliferation. Strikingly, we demonstrate a profound impairment of both, migration and invasion, of colorectal cancer cells after Mcl-1, Bcl-2 or Bcl-xL knockdown. This phenotype was completely revised in cells overexpressing Mcl-1, Bcl-2 or Bcl-xL. The most pronounced effect among the investigated proteins was observed for Bcl-2. The data presented indicate a pivotal role of Mcl-1, Bcl-2 and Bcl-xL for migration and invasion of colorectal cancer cells independent of their known antiapoptotic effects. Thus, our study illustrates novel antitumoral mechanisms of Bcl-2 protein targeting.
Bcl-x and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells
Henning Schulze-Bergkamen, Roland Ehrenberg, Lothar Hickmann, Binje Vick, Toni Urbanik, Christoph C Schimanski, Martin R Berger, Arno Schad, Achim Weber, Steffen Heeger, Peter R Galle, Markus Moehler
World Journal of Gastroenterology , 2008,
Abstract: AIM: To explore the role of Bcl-xL and Myeloid cell leukaemia (Mcl)-1 for the apoptosis resistance of colorectal carcinoma (CRC) cells towards current treatment modalities.METHODS: Bcl-xL and Mcl-1 mRNA and protein expression were analyzed in CRC cell lines as well as human CRC tissue by Western blot, quantitative PCR and immunohistochemistry. Bcl-xL and Mcl-1 protein expression was knocked down or increased in CRC cell lines by applying specific siRNAs or expression plasmids, respectively. After modulation of protein expression, CRC cells were treated with chemotherapeutic agents, an antagonistic epidermal growth factor receptor (EGFR1) antibody, an EGFR1 tyrosine kinase inhibitor, or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed.RESULTS: Here we show that in human CRC tissue and various CRC cell lines both Bcl-xL and Mcl-1 are expressed. Bcl-xL expression was higher in CRC tissue than in surrounding non-malignant tissue, both on protein and mRNA level. Mcl-1 mRNA expression was significantly lower in malignant tissues. However, protein expression was slightly higher. Viability rates of CRC cells were significantly decreased after knock down of Bcl-xL expression, and, to a lower extent, after knock down of Mcl-1 expression. Furthermore, cells with reduced Bcl-xL or Mcl-1 expression was more sensitive towards oxaliplatin- and irinotecan-induced apoptosis, and in the case of Bcl-xL also towards 5-FU-induced apoptosis. On the other hand, upregulation of Bcl-xL by transfection of an expression plasmid decreased chemotherapeutic drug-induced apoptosis. EGF treatment clearly induced Bcl-xL and Mcl-1 expression in CRC cells. Apoptosis induction upon EGFR1 blockage by cetuximab or PD168393 was increased by inhibiting Mcl-1 and Bcl-xL expression. More strikingly, CD95- and TRAIL-induced apoptosis was increased by Bcl-xL knock down.CONCLUSION: Our data suggest that Bcl-xL and, to a lower extent, Mcl-1, are important anti-apoptotic factors in CRC. Specific downregulation of Bcl-xL is a promising approach to sensitize CRC cells towards chemotherapy and targeted therapy.
Unilateral Auditory Cortex Lesions Impair or Improve Discrimination Learning of Amplitude Modulated Sounds, Depending on Lesion Side
Holger Schulze, Anke Deutscher, Konstantin Tziridis, Henning Scheich
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087159
Abstract: A fundamental principle of brain organization is bilateral symmetry of structures and functions. For spatial sensory and motor information processing, this organization is generally plausible subserving orientation and coordination of a bilaterally symmetric body. However, breaking of the symmetry principle is often seen for functions that depend on convergent information processing and lateralized output control, e.g. left hemispheric dominance for the linguistic speech system. Conversely, a subtle splitting of functions into hemispheres may occur if peripheral information from symmetric sense organs is partly redundant, e.g. auditory pattern recognition, and therefore allows central conceptualizations of complex stimuli from different feature viewpoints, as demonstrated e.g. for hemispheric analysis of frequency modulations in auditory cortex (AC) of mammals including humans. Here we demonstrate that discrimination learning of rapidly but not of slowly amplitude modulated tones is non-uniformly distributed across both hemispheres: While unilateral ablation of left AC in gerbils leads to impairment of normal discrimination learning of rapid amplitude modulations, right side ablations lead to improvement over normal learning. These results point to a rivalry interaction between both ACs in the intact brain where the right side competes with and weakens learning capability maximally attainable by the dominant left side alone.
Bayesian analysis of exoplanet and binary orbits
Tim Schulze-Hartung,Ralf Launhardt,Thomas Henning
Physics , 2012, DOI: 10.1051/0004-6361/201219074
Abstract: We introduce BASE (Bayesian astrometric and spectroscopic exoplanet detection and characterisation tool), a novel program for the combined or separate Bayesian analysis of astrometric and radial-velocity measurements of potential exoplanet hosts and binary stars. The capabilities of BASE are demonstrated using all publicly available data of the binary Mizar A.
Auditory Cortical Contrast Enhancing by Global Winner-Take-All Inhibitory Interactions
Simone Kurt, Anke Deutscher, John M. Crook, Frank W. Ohl, Eike Budinger, Christoph K. Moeller, Henning Scheich, Holger Schulze
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001735
Abstract: Brains decompose the world into discrete objects of perception, thereby facing the problem of how to segregate and selectively address similar objects that are concurrently present in a scene. Theoretical models propose that this could be achieved by neuronal implementations of so-called winner-take-all algorithms where neuronal representations of objects or object features interact in a competitive manner. Here we present evidence for the existence of such a mechanism in an animal species. We present electrophysiological, neuropharmacological and neuroanatomical data which suggest a novel view of the role of GABAA-mediated inhibition in primary auditory cortex (AI), where intracortical GABAA-mediated inhibition operates on a global scale within a circular map of sound periodicity representation in AI, with functionally inhibitory projections of similar effect from any location throughout the whole map. These interactions could underlie the proposed competitive “winner-take-all” algorithm to support object segregation, e.g., segregation of different speakers in cocktail-party situations.
A Planetary Companion around a Metal-Poor Star with Extragalactic Origin
J. Setiawan,R. Klement,T. Henning,H. -W. Rix,B. Rochau,T. Schulze-Hartung,J. Rodmann
Physics , 2011, DOI: 10.1063/1.3570972
Abstract: We report the detection of a planetary companion around HIP 13044, a metal-poor star on the red Horizontal Branch. The detection is based on radial velocity observations with FEROS, a high-resolution spectrograph at the 2.2-m MPG/ESO telescope, located at ESO La Silla observatory in Chile. The periodic radial velocity variation of P = 16.2 days can be distinguished from the periods of the stellar activity indicators. We computed a minimum planetary mass of 1.25 MJup and an orbital semi-major axis of 0.116 AU for the planet. This discovery is unique in three aspects: First, it is the first planet detection around a star with a metallicity much lower than few percent of the solar value; second, the planet host star resides in a stellar evolutionary stage that is still unexplored in the exoplanet surveys; third, the star HIP 13044 belongs to one of the most significant stellar halo streams in the solar neighborhood, implying an extragalactic origin of the planetary system HIP 13044 in a disrupted former satellite of the Milky Way.
Untangling Phase and Time in Monophonic Sounds  [PDF]
Henning Thielemann
Journal of Signal and Information Processing (JSIP) , 2010, DOI: 10.4236/jsip.2010.11001
Abstract: We are looking for a mathematical model of monophonic sounds with independent time and phase dimensions. With such a model we can resynthesise a sound with arbitrarily modulated frequency and progress of the timbre. We propose such a model and show that it exactly fulfils some natural properties, like a kind of timeinvariance, robustness against non-harmonic frequencies, envelope preservation, and inclusion of plain resampling as a special case. The resulting algorithm is efficient and allows to process data in a streaming manner with phase and shape modulation at sample rate, what we demonstrate with an implementation in the functional language Haskell. It allows a wide range of applications, namely pitch shifting and time scaling, creative FM synthesis effects, compression of monophonic sounds, generating loops for sampled sounds, synthesise sounds similar to wavetable synthesis, or making ultrasound audible.
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