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Feasibility of personalized treatment concepts in gastrointestinal malignancies： Sub-group results of prospective clinical phase Ⅱ trial EXACT

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Chinese Journal of Cancer Research 2018年第5期30卷 508-515页

作者： Matthias Unseld Robert Mader Lukas Baumann Clarence Veraar Fritz Wrba Fredrik Waneck Markus Kieler Daniela Bianconi walter berger Maria Sibilia Leonhard Miillauer Christoph Zielinski Gerald W. Prager Department of Medicine I Division of Oncology Medical University of Vienna Vienna 1090 Austria Comprehensive Cancer Center Medical University Vienna - General Hospital Vienna 1090 Austria Department of Medical Statistics Medical University of Vienna Vienna 1090 Austria Clinical Institute of Pathology Medical University of Vienna Vienna 1090 Austria Department of Interventional Radiology Medical University of Vienna Vienna 1090 Austria Department of Medicine I Institute of Cancer Research Medical University of Vienna Vienna 1090 Austria

Objective： Advances in high-throughput genomic profiling and the development of new targeted therapies improve patient＇s survival. In gastrointestinal （GI） malignancies, the concept of personalized medicine （PM） was not investigated so far. The aim of this prospective study was to evaluate the efficacy of a personalized treatment in GI patients who failed standard treatment. Methods： Out of the original prospective clinical phase II EXACT trial, 21 （38%） GI cancer patients who had no further treatment options were identified. A molecular profile （MP） via a 50 gene next generation sequencing （NGS） panel in combination with immunohistochemistry （IHC） was conducted using real-time biopsy tumor material. Results were discussed by a multidisciplinary team （MDT） to translate the individual MP in an experimental treatment. Results： Of the 55 patients originally included in the EXACT trial, 21 （38%） suffered from GI malignancies. The final analysis showed that 15 （71%） patients had experienced a longer progression-free survival （PFS） upon experimental targeted treatment （124 d, quartiles 70/193 d）, when compared with the PFS achieved by the previous conventional therapy （62 d, quartiles 55/83 d）（P=0.014）. Thirteen （62%） patients receiving targeted treatment experienced a disease control according to Response Evaluation Criteria in Solid Tumors （RECIST）. Median overall survival （OS） from the start of experimental therapy to time of censoring or death was 193 d （quartiles 115/374 d）. Conclusions： PM was not investigated in GI malignancies so far in a prospective trial. This study shows that treatment based on real-time molecular tumor profiling led to a superior clinical benefit, and survival as well as response was significantly improved when compared with previous standard medications.

关键词： Personalized medicine gastrointestinal malignancies prospective trial next generations sequencing

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

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Nano Research 2017年第2期10卷 652-671页

作者： Svitlana Prylutska Rostyslav Panchuk Grzegorz Golunski Larysa Skivka Yuriy Prylutskyy Vasyl Hurmach Nadya Skorohyd Agnieszka Borowik Anna Woziwodzka Jacek Piosik Olena Kyzyma Vasil Garamus Leonid Bulavin Maxim Evstigneev Anatoly Buchelnikov Rostyslav Stoika walter berger Uwe Ritter Peter Scharff Taras Shevchenko National University of Kyiv 64 Volodymyrska Str. 01601 Kyiv Ukraine Institute of Cell Biology NAS of Ukraine 14-16 Drahomanov 5tr. 79005 Lviv Ukraine Laboratory of Biophysics Intercollegiate Faculty ofBiotechnology UG-MUG Abrahama 58 80-307 Gdansk Poland Joint Institute for Nuclear Research 6 Joliot-Curie Str. 141980 Dubna Moscow reg. Russia Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research 1 Max-Planck Str. 21502 Geesthacht Germany Belgorod State University 85 Pobedy Str. 308015 Belgorod Russia Institute of Cancer Research and Comprehensive Cancer Center Medical University Vienna 1090 8A Borschkegasse Vienna Austria Institute of Chemistry and Biotechnology Technical University ofllmenau 25 Weimarer Str. 98693 Ilmenau Germany

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin （Cis） with C60 fullerene （C60＋Cis complex） and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy- resistant human leukemia cell sublines （resistant to Adriamycin and Vinculin, respectively）. We discovered that the action of the C60＋Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma （LLC） C57BL/6J male mice showed that the C60＋Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein （P-gp）, multidrug resistance protein 1 （MRP-1）, and multidrug resistance protein 2 （MRP-2） molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60＋Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60＋Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60＋Cis complex might be a potential novel chemotherapy modification.

关键词： molecular docking,small-angle X-ray scattering,apoptosis,mutagenic activity lung carcinoma (LLC),cytotoxicity

Intraocular pressure before and after capsulorhexis using two viscoelastic substances and two surgical approaches in enucleated porcine eyes

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International Journal of Ophthalmology(English edition) 2024年第6期17卷 1156-1160页

作者： Chiraz Ben Abdallah walter Sekundo Markus SLadewig Daniel M.Handzel Augenzentrum Osthessen Fulda 36037Germany University Eye Hospital Philipps-University Marburg 35043Germany University Eye Hospital Philipps-University Campus FuldaFulda 36043Germany

AIM:To investigate the influence of ophthalmic viscoelastic devices(OVDs)and different surgical approaches on the intraocular pressure(IOP)before and after creation of the curvilinear circular capsulorhexis(CCC)as a measure for anterior chamber stability during this ***:Prospective experimental WetLab study carried out on enucleated porcine *** was measured before and after CCC with the iCare Rebound tonometer(iCare ic200;iCare Finland Oy,Vantaa,Finland).The OVDs used were a cohesive one[Z-Hyalin,Carl Zeiss Meditec AG,Germany;hyaluronic acid(HA)]and a dispersive[Z-Celcoat,Carl Zeiss Meditec AG,Germany;hydroxy propylmethylcellulosis(HPMC)].The CCC was created using Utrata forceps or 23 g microforceps in different combinations with the ***:Using the Utrata forceps the IOP dropped from 63.65±6.44 to 11.25±3.63 mm Hg during the *** use of different OVDs made no *** the 23 g microforceps the IOP dropped from 65.35±8.15 to 36.55±6.09 mm *** difference between IOP drop using either Utrata forceps or 23 g microforceps was highly significant regardless of the OVD ***:Using the sideport for the creation of the capsulorhexis leads to a lesser drop in IOP during this maneuver compared to the main incision in enucleated porcine *** use of different OVD has no significant influence on IOP drop.

关键词： cataract surgery ophthalmosurgical viscoelastic device intraocular pressure capsulorhexis enucleated porcine eye

Pumping-induced Well Hydraulics and Groundwater Budget in a Leaky Aquifer System with Vertical Heterogeneity in Aquitard Hydraulic Properties

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Acta Geologica Sinica(English Edition) 2024年第2期98卷 477-490页

作者： ZHUANG Chao LÜChenyang YAN Long LI Yabing ZHOU Zhifang WANG Jinguo DOU Zhi walter A.ILLMAN School of Earth Sciences and Engineering Hohai UniversityNanjing 211100China School of Geography Earth and Environmental SciencesUniversity of BirminghamBirmingham B152TTU.K. Department of Modern Mechanics University of Science and Technology of ChinaHefei 230027China Department of Earth and Environmental Sciences University of WaterlooOntario N2L 3G1Canada

In groundwater hydrology,aquitard heterogeneity is often less considered compared to aquifers,despite its significant impact on groundwater hydraulics and groundwater resources evaluation.A semi-analytical solution is derived for pumping-induced well hydraulics and groundwater budget with consideration of vertical heterogeneity in aquitard hydraulic conductivity(K)and specific storage(S_(s)).The proposed new solution is innovative in its partitioning of the aquitard into multiple homogeneous sub-layers to enable consideration of various forms of vertically heterogeneous K or S_(s).Two scenarios of analytical investigations are explored:one is the presence of aquitard interlayers with distinct K or S_(s) values,a common field-scale occurrence;another is an exponentially depth-decaying aquitard S_(s),a regional-scale phenomenon supported by statistical *** investigations reveal that a low-K interlayer can significantly increase aquifer drawdown and enhance aquifer/aquitard depletion;a high-S_(s) interlayer can noticeably reduce aquifer drawdown and increase aquitard *** of low-K or high-S_(s) interlayers also significantly impact well hydraulics and groundwater *** the context of an exponentially depth-decaying aquitard S_(s),a larger decay exponent can enhance aquifer *** using current models with a vertically homogeneous aquitard,half the sum of the geometric and harmonic means of exponentially depth-decaying aquitard S_(s) should be used to calculate aquitard depletion and unconfined aquifer leakage.

关键词： hydrogeology aquitard vertical heterogeneity semi-analytical solution well hydraulics groundwater budget

Activins and activin antagonists in hepatocellular carcinoma

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World Journal of Gastroenterology 2008年第11期14卷 1699-1709页

作者： Alev Deli Emanuel Kreidl Stefan Santifaller Barbara Trotter Katja Seir walter berger Rolf Schulte-Hermann Chantal Rodgarkia-Dara Michael Grusch Institute of Cancer Research Department of Medicine IMedical University of Vienna Borschkegasse 8aVienna A-1090Austria

In many parts of the world hepatocellular carcinoma (HCC)is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently *** is increasing evidence that activins,which are members of the transforming growth factorβ(TGFβ)superfamily of growth and differentiation factors,could play important roles in liver *** are disulphide-linked homo- or heterodimers formed from four differentβsubunits termedβA,βB,βC,andβE,*** A, the dimer of twoβA subunits,is critically involved in the regulation of cell growth,apoptosis,and tissue architecture in the liver,while the hepatic function of other activins is largely unexplored so *** regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG,and at the cell membrane antagonistic coreceptors like Cripto or ***,in the intracellular space inhibitory Smads can modulate and control activin *** data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation,fibrosis and development of *** current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

关键词：肝细胞癌生长因子治疗方法拮抗体

Between Quantum Mechanics and General Relativity

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Journal of Modern Physics 2024年第8期15卷 1199-1228页

作者： walter James Christensen Jr. Department of Physics and Astronomy Cal Poly Pomona University Pomona USA

The origin of elementary particle mass is considered as a function of n-valued graviton quanta. To develop this concept we begin in a cold region of “empty space” comprised of only microscopic gravitons oscillating at angular frequency ω. From opposite directions enters a pair of stray protons. Upon colliding, heat and energy are released. Customarily, this phase and what follows afterward would be described by Quantum Chromodynamics (QCD). Instead, we argue for an intermediary step. One in which neighboring gravitons absorb discrete amounts of plane-wave energy. Captured by the graviton, the planewave becomes a standing wave, whereupon its electromagnetic energy densities are converted into gravitational quanta. Immediately thereafter an elementary particle is formed and emitted, having both mass and spin. From absorption to conversion to emission occurs in less than 3.7 × 10−16 s. During this basic unit of hybrid time, general relativity and quantum physics unite into a common set of physical laws. As additional stray protons collide the process continues. Over eons, vast regions of spacetime become populated with low-mass particles. These we recognize to be dark matter by its effects on large scale structures in the universe. Its counterpart, dark energy, arises when the conversion of gravitational quanta to particle emission is interrupted. This causes the gravitational quanta to be ejected. It is recognized by its large scale effects on the universe.

关键词： Dark Matter and Energy Gravitational Quanta Graviton Standing Wave Schwarzschild Metric General Relativity Quantum Physics Unified Field Theory Blackholes

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways:Experimental and clinical evidence

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World Journal of Experimental Medicine 2024年第2期14卷 46-52页

作者： Raúl Lelio Sanz Sebastián García Menéndez Felipe Inserra Leon Ferder walter Manucha Department of Pathology Facultad de Ciencias MédicasUniversidad Nacional de CuyoMendoza 5500Argentina Department of Pharmacology Instituto de Medicina y Biología Experimental de CuyoCentro Científico TecnológicoMendoza 5500Argentina Department of Nephrology Universidad de MaimónidesCiudad Autónoma de Buenos Aires C1405Argentina Department of Cardiology Universidad de MaimónidesCiudad Autónoma de Buenos Aires C1405Argentina

Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and *** dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and *** II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS *** activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative *** of energy production by mitochondria is a common feature of all metabolic *** SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ***,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against *** cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these *** clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal ***2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen *** findings suggest that SGLT2i hold great potential for the treatment of ***,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.

关键词： Sodium-glucose cotransporter-2 inhibitors Cardiovascular diseases Sirtuins Oxidative stress Inflammation Mitochondrial dysfunction

Evaluating Methods of Visual Assistance for Workers to Improve Quality and Usability in Individualized Kitchen Cabinet Assembly

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Journal of Computer and Communications 2024年第2期12卷 156-172页

作者： Albert Eff Michael S. J. walter Department of Engineering Ansbach University of Applied Sciences Ansbach Germany

In times of digitalisation, visual assistance systems in assembly are increasingly important. The design of these assembly systems needs to be highly complex to meet the requirements. Due to the increasing number of variants in production processes, as well as shorter innovation and product life cycles, assistance systems should improve quality and reduce complexity of assembly processes. However, many large kitchen manufacturers still assemble kitchen cabinets manually, due to the high variety of components, such as rails and fittings. This paper focuses on the analysis and evaluation of virtual assistance systems to improve quality and usability in individualised kitchen cabinet assembly processes at a large German manufacturer. A solution is identified and detailed.

关键词： Digitalisation Assembly Process Visual Assistance Usability Human-Centred Assembly Design

Enhancing the stability of Ni Fe-layered double hydroxide nanosheet array for alkaline seawater oxidation by Ce doping

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Journal of Energy Chemistry 2024年第4期91卷 306-312页

作者： Yongchao Yao Shengjun Sun Hui Zhang Zixiao Li Chaoxin Yang Zhengwei Cai Xun He Kai Dong Yonglan Luo Yan Wang Yuchun Ren Qian Liu Dongdong Zheng Weihua Zhuang Bo Tang Xuping Sun Wenchuang(walter)Hu Department of Laboratory Medicine West China HospitalSichuan UniversityChengdu 610041SichuanChina College of Chemistry Chemical Engineering and Materials ScienceShandong Normal UniversityJinan 250014ShandongChina Institute of Fundamental and Frontier Sciences University of Electronic Science and Technology of ChinaChengdu 610054SichuanChina Institute for Advanced Study Chengdu UniversityChengdu 610106SichuanChina Laoshan Laboratory Qingdao 266237ShandongChina

Electrocatalytic hydrogen production from seawater holds enormous promise for clean energy ***,the direct electrolysis of seawater encounters significant challenges due to poor anodic stability caused by detrimental chlorine ***,we present our recent discovery that the incorporation of Ce into Ni Fe layered double hydroxide nanosheet array on Ni foam(Ce-Ni Fe LDH/NF)emerges as a robust electrocatalyst for seawater *** the seawater oxidation process,CeO_(2)is generated,effectively repelling Cl^(-)and inhibiting the formation of Cl O-,resulting in a notable enhancement in the oxidation activity and stability of alkaline *** prepared Ce-Ni Fe LDH/NF requires only overpotential of 390 m V to achieve the current density of 1 A cm^(-2),while maintaining long-term stability for 500 h,outperforming the performance of Ni Fe LDH/NF(430 m V,150 h)by a significant *** study highlights the effectiveness of a Ce-doping strategy in augmenting the activity and stability of materials based on Ni Fe LDH in seawater electrolysis for oxygen evolution.

关键词： Ce doping NiFe layered double hydroxide Seawater oxidation Electrocatalysis Cl^(-) repulsion