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Inhibition of histone deacetylase for the treatment of biliary tract cancer:A new effective pharmacological approach

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World Journal of Gastroenterology 2007年第35期13卷 4761-4770页

作者： Thilo Bluethner Manuel Niederhagen Karel Caca Frederik Serr helmut Witzigmann Christian Moebius Joachim Mossner Marcus Wiedmann Department of Internal Medicine Ⅱ University of LeipzigPhilipp-Rosenthal-Str.27Leipzig 04103Germany Institute of Pathology University of LeipzigLiebigstr.26Leipzig 04103Germany Department of Internal Medicine Ⅰ Klinikum LudwigsburgPosilipostr.4Ludwigsburg 71640Germany Department of Surgery Ⅱ University of LeipzigLiebigstrasse 20a04103 LeipzigGermany

AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

关键词： Histone deacetylase inhibitor Biliary tract cancer Cholangiocarcinoma NVP-LAQ824 NVP-LBH589

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Time-Neutrality of Natural Laws Challenged: Time Is Not an Illusion but Ongoing Energy-Driven Information Loss

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Journal of Modern Physics 2021年第3期12卷 300-327页

作者： helmut Tributsch Institute for physical and theoretical Chemistry Free University Berlin Germany Helmholtz Centre Berlin for Materials and Energy Berlin Germany

It is shown that the time of entropy increase, here called action time, is caused by a dynamically understood energy. It drives time by decreasing its presence per state, that is by abandoning order, information, and creating entropy. This mechanism can be derived from basic principles via the Lagrange-Euler formalism, just considering the properties of really experienced, oriented time and thus abandoning the paradigm of time neutrality. It describes nature driven by a dynamically understood principle of least action, which is identified as manifestation of fundamental irreversibility in nature. This readily explains the second law of thermodynamics and also yields the entropy law for non-linear irreversible thermodynamics: maximum entropy production within the restraints of the system. Dynamic energy-driven time, action time, and time asymmetry is generated via the process of erasing information and liberating its energy irreversibly as heat. It is not an illusion but information-based reality. It is the loss of information to the past and different from clock-time, which is just an artificial scale, using information for tracking real time, action time. Energy-driven fundamental irreversibility of nature can better describe experienced reality and opens the way to understand and finally imitate the self-organizing creativity in nature. It also draws far reaching consequences for understanding quantum physics, gravitation and cosmology as well as biology. From the point of view of irreversibility, nature turns out to be more elegant, simpler and rationally understandable. For the first time, it can be explained in a few words what energy and nature basically represent and why it must have been information, which has started the universe.

关键词： Time-Invariance Energy Time Entropy Information Irreversibility Self-Organization Nature

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Effective transport width——A methodology to describe the spatial variability of bedload transport

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International Journal of Sediment Research 2023年第2期38卷 294-301页

作者： Rolf Rindler Sabrina Schwarz Marcel Liedermann Dorian Shire-Peterlechner Andrea Kreisler Johann Aigner Michael Tritthart helmut Habersack Institute of Hydraulic Engineering and River Research Department of Water Atmosphere and Environment University of Natural Resources and Life Sciences

The monitoring of bedload transport processes in rivers is a still challenging task in research and the parameter effective transport width(ETW) allows, for the first time, a process description of the local variability of the bedload transport. In this paper, the distribution of bedload transport over a river crosssection was studied by statistically analyzing long-term monitoring data. Using an innovative integrated measurement system, combining geophones distributed over the river width with bedload traps and basket sampling, allows for continuous, high-resolution, long-term monitoring data of bedload transport characteristics to be generated. Geophone data can be used to record and describe bedload transport processes such as intensity, temporal variability, and local variability. One parameter observed was the ETW, which describes the width where bedload transport is taking place for different discharge classes in gravel bed rivers. With the help of a data series recorded over more than a decade, it is now possible, for the first time, to statistically describe the continuously and directly measured ETW. Hence, it became evident that the effective bedload transport width depends on the discharge rate and local transport capacity, and that bedload transport over the entire river width only occurs at high flows that prevail a few days a year.

关键词： Bedload transport Spatial distribution Effective transport width Plate geophones

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Natural orifice transluminal endoscopic surgery in pancreatic diseases

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World Journal of Gastroenterology 2010年第31期16卷 3859-3864页

作者： Sonja Gillen Jrg Kleeff Michael Kranzfelder Shailesh V Shrikhande helmut Friess Hubertus Feussner Department of Surgery Tech-nische Universitt München Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgery Tata Memorial Hospital

Natural orifice transluminal endoscopic surgery (NOTES) is a surgical technique that has received considerable interest in recent years. Although minimal access surgery has increasingly replaced traditional open abdominal surgical approaches for a wide spectrum of indications, in pancreatic diseases its widespread use is limited to few indications because of the challenging and demanding nature of major pancreatic operations. Nonetheless, there have been attempts in animal models as well as in the clinical setting to perform diag- nostic and resectional NOTES for pancreatic diseases. Here, we review and comment upon the available data regarding currently analyzed and performed pancreatic NOTES procedures. Potential indications for NOTES include peritoneoscopy, cyst drainage, and necrosectomy, palliative procedures such as gastroenterostomy, as well as resections such as distal pancreatectomy or enucleation. These procedures have already been shown to be technically feasible in several studies in animal models and a few clinical trials. In conclusion, NOTES is a rapidly developing concept/technique that could potentially become an integral part of the armamentarium dealing with surgical approaches to pancreatic diseases.

关键词： Natural orifice transluminal endoscopic surgery Pancreatic disease Chronic pancreatitis Pancreatic resection Pancreatic drainage

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Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

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World Journal of Gastroenterology 2004年第13期10卷 1918-1922页

作者： Hans U.Kasper Hella Wolf Uta Drebber helmut K.Wolf Michael A.Kern Department of Pathology University of CologneGermany Department of Pathology University of MagdeburgGermany Department of Pathology Johannes-GutenbergUniversity of MainzGermany

AIM:Cydooxygenases (COX) are key enzymes for conversion of arachidonic acid to *** oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible *** inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis,tumorigenesis and inflammatory *** study was to clarify their role in pancreatic adenocarcinomas. METHODS:We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocardnomas of different grade and *** results were compared with microvessel density and dinicopathological data. RESULTS:Twenty-one (52.5%) of the cases showed iNOS expression,15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the *** intensity was different between the *** correlation between iNOS and COX-2 expression was *** was no relationship with microvessel density. However,iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 *** was no correlation with other clinicopathological data. CONCLUSION:Approximately half of the cases expressed iNOS and *** two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic *** to a low prevalence of COX-2 expression,chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.

关键词： Adenocarcinoma Aged Aged, 80 and over Cyclooxygenase 2 Female Humans Immunohistochemistry Isoenzymes Male Membrane Proteins Microcirculation Middle Aged Nitric Oxide Synthase Nitric Oxide Synthase Type II Pancreas Pancreatic Neoplasms Prostaglandin-Endoperoxide Synthases

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In operando study of orthorhombic V_(2)O_(5) as positive electrode materials for K-ion batteries

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Journal of Energy Chemistry 2021年第11期30卷 627-636,I0015页

作者： Qiang Fu Angelina Sarapulova Lihua Zhu Georgian Melinte Alexander Missyul Edmund Welter Xianlin Luo Michael Knapp helmut Ehrenberg Sonia Dsoke Institute for Applied Materials(IAM) Karlsruhe Institute of Technology(KIT)Hermann-von-Helmholtz-Platz 1D-76344 Eggenstein-LeopoldshafenGermany Helmholtz Institute Ulm for Electrochemical Energy Storage(HIU) Helmholtzstrasse 1189081 UlmGermany Institute of Nanotechnology(INT) Karlsruhe Institute of Technology(KIT)Hermann-von-Helmholtz-Platz 1D-76344 Eggenstein-LeopoldshafenGermany CELLS-ALBA Synchrotron E-08290 Cerdanyola del VallesBarcelonaSpain Deutsches Elektronen-Synchrotron DESY Notkestraße 85D-22607 HamburgGermany

Herein, the electrochemical performance and the mechanism of potassium insertion/deinsertion in orthorhombic V_(2)O_(5) nanoparticles are studied. The V2O5 electrode displays an initial potassiation/depotassiation capacity of 200 mAh g^(−1)/217 mAh g^(−1) in the voltage range 1.5–4.0 V vs. K^(+)/K at C/12 rate, suggesting fast kinetics for potassium insertion/deinsertion. However, the capacity quickly fades during cycling, reaching 54 mAh g^(−1) at the 31st cycle. Afterwards, the capacity slowly increases up to 80 mAh g^(−1) at the 200th cycle. The storage mechanism upon K ions insertion into V2O5 is elucidated. In operando synchrotron diffraction reveals that V_(2)O_(5) first undergoes a solid solution to form K_(0.6)V_(2)O_(5) phase and then, upon further K ions insertion, it reveals coexistence of a solid solution and a two-phase reaction. During K ions deinsertion, the coexistence of solid solution and the two-phase reaction is identified together with an irreversible process. In operando XAS confirms the reduction/oxidation of vanadium during the K insertion/extraction with some irreversible contributions. This is consistent with the results obtained from synchrotron diffraction, ex situ Raman, X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). Moreover, ex situ XPS confirms the “cathode electrolyte interphase” (CEI) formation on the electrode and the decomposition of CEI film during cycling.

关键词： Orthorhombic V_(2)O_(5) In operando synchrotron diffraction In operando X-ray absorption spectroscopy K-ion batteries

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欧洲大陆法律心理学述评

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心理学报 1996年第1期28卷 104-109页

作者：吴宗宪 helmut Kury 司法部犯罪与改造研究所北京100029 Max-Planck-Institut Freiburg Germany

对欧洲大陆国家的法律心理学发展状况作了述评。全文包括３部分：对相关概念（犯罪心理学、审判心理学、法律心理学、司法心理学）的辨析；欧洲大陆国家法律心理学的现状；简要评价。

关键词：欧洲大陆法律心理学述评。

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Analysis of the Navier-Stokes Equations

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Journal of Applied Mathematics and Physics 2014年第10期2卷 938-947页

作者： helmut Martin Institute of Hydraulic Engineering and Technical Hydromechanics Technische Universitat Dresden Dresden Germany

The Navier-Stokes equations for incompressible fluid flows with impervious boundary and free surface are analyzed by means of a perturbation procedure involving dimensionless variables and a dimensionless perturbation parameter which is composed of kinematic viscosity of fluid, the acceleration of gravity and a characteristic length. The new dimensionless variables are introduced into the equation system. In addition, the perturbation parameter is introduced into terms for deriving approximations systems of different orders. Such systems are obtained by equating coefficients of like powers of perturbation parameter for the successive coefficients in the series. In these systems several terms are analyzed with regards to size and significance. Based on those systems, suitable solutions of NS equations can be found for different boundary conditions. For example, a relation for stationary channel flow is obtained as approximation to the NS equations of the lowest order after transformation back to dimensional variables.

关键词： Navier-Stokes Equations Incompressible Flow Perturbation Theory Stationary Open Channel Flow

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Different profiles of cytokine expression during mild and severe acute pancreatitis

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World Journal of Gastroenterology 2010年第15期16卷 1845-1853页

作者： Zilvinas Dambrauskas Nathalia Giese Antanas Gulbinas Thomas Giese Pascal O Berberat Juozas Pundzius Giedrius Barauskas helmut Friess Laboratory for Research of Digestive System Institute for Biomedical ResearchEiveniu Str. 2 50009 Kaunas Lithuania Department of Surgery Kaunas University of MedicineEiveniu Str. 2 50009 Kaunas Lithuania Department of Surgery Heidelberg UniversityIm Neuenheimer Feld 110D-69120 Heidelberg Germany Institute for Immunology Heidelberg UniversityIm Neuenheimer Feld 305D-69120 Heidelberg Germany Department of Surgery University of Technology MunichIsmaninger Str. 2281675 Munich Germany Department of Surgery Kaunas University of MedicineEiveniu Str. 250009 Kaunas Lithuania

AIM:To study secretion patterns of proand anti-in-flammatory cytokines, and activation of various cellular subsets of leukocytes in peripheral ***: We have conducted a prospective obser-vational study. One hundred and eight patients with a diagnosis of acute pancreatitis and onset of the disease within last 72 h were included in this study. The mRNA expression of 25 different types of cytokines in white blood cells was determined by quantitative real time polymerase chain reaction. Levels of 8 different cytokines in blood serum were measured by enzymelinked immunosorbent assay. Clinical data and cytokine expression results were subjected to statistical ***: Severe and necrotizing acute pancreatitis (AP) is characterized by the significant depletion of circulating lymphocytes. Severe acute pancreatitis is as-sociated with a typical systemic inflammatory response syndrome and over-expression of pro-inflammatory cy-tokines [interleukin (IL)-6, IL-8, macrophage migration inhibitory factor (MIF)]. Serum IL-6 and MIF concentra-tions are the best discriminators of severe and necrotiz-ing AP as well as possible fatal outcome during the early course of the disease. CONCLUSION: Deregulation of cellular immune sys-tem is a key event leading to severe and necrotizing AP. IL-6 and MIF could be used as early predictors of complications.

关键词： Acute pancreatitis Cytokines Prognostic factors

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Contractual or Legal Rules for Groups of Companies?

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商事法论集 2012年第1期 253-259页

作者： helmut Kohl Goethe-University

*** As a general rule,corporate law focuses on the single,independent *** this basic"ideal"model that the legislator originally had in mind and which for many decades was in the center of academic discussion-in theory-all shareholders have the same interests-they want a stable,growing company and high returns on their *** course,this model is far distant from *** already is true in the independent corporation where in the real world we frequently find investors with very differing aims and hopes for the *** can be taken for granted that indeed all shareholders will be interested in high yields on their investments,but their time horizon might differ tremendously.

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