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Mechanisms underlying reversed TRAIL sensitivity in acquired bortezomib-resistant non-small cell lung cancer cells

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Cancer Drug Resistance 2024年第1期7卷 869-889页

作者： Leonie De Wilt Bartosz Kamil Sobocki gerrit jansen Hessan Tabeian Steven de Jong Godefridus J.Peters Frank Kruyt Department of Medical Oncology Amsterdam University Medical CentersLocation VUMCVrije Universiteit AmsterdamAmsterdam 1007MBthe Netherlands Department of Biochemistry Medical University of GdańskGdańsk 80-210Poland Department of Rheumatology Amsterdam University Medical CentersVrije Universiteit AmsterdamAmsterdam 1081 HVthe Netherlands Department of Medical Oncology University of GroningenUniversity Medical Center GroningenGroningen 9713 GZthe Netherlands

Aim:The therapeutic targeting of the tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL)death receptors in cancer,including non-small cell lung cancer(NSCLC),is a widely studied approach for tumor selective apoptotic cell death ***,apoptosis resistance is often *** main aim of this study was to investigate the apoptotic mechanism underlying TRAIL sensitivity in three bortezomib(BTZ)-resistant NSCLC variants,combining induction of both the intrinsic and extrinsic ***:Sensitivity to TRAIL in BTZ-resistant variants was determined using a tetrazolium(MTT)and a clonogenic assay.A RT-qPCR profiling mRNA array was used to determine apoptosis pathway-specific gene *** expression of these proteins was determined through ELISA assays and western Blotting,while apoptosis(sub-G1)and cytokine expression were determined using flow *** genes were silenced by specific *** rafts were isolated with fractional ***:A549BTZR(BTZ-resistant)cells were sensitive to TRAIL in contrast to parental A549 cells,which are resistant to ***-sensitive H460 cells remained equally sensitive for TRAIL as *** A549BTZR cells,we identified an increased mRNA expression of TNFRSF11B[osteoprotegerin(OPG)]and caspase-1,-4 and-5 mRNAs involved in cytokine activation and immunogenic cell *** the OPG,interleukin-6(IL-6),and interleukin-8(IL-8)protein levels were markedly enhanced(122-,103-,and 11-fold,respectively)in the A549BTZR cells,this was not sufficient to trigger TRAIL-induced apoptosis in the parental A549 *** the extrinsic apoptotic pathway,the A549BTZR cells showed TRAIL-R1-dependent TRAIL *** shift of TRAIL-R1 from non-lipid into lipid rafts enhanced TRAIL-induced *** the intrinsic apoptotic pathway,a strong increase in the mRNA and protein levels of the anti-apoptotic myeloid leukemia cell differentiation protein(Mcl-1)and B-cell

关键词： TRAIL bortezomib resistance sensitization Bcl-2 family lipid rafts cytokines

Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells

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Cancer Drug Resistance 2023年第3期6卷 430-446页

作者： gerrit jansen Marjon Al Yehuda G.Assaraf Sarah Kammerer Johan van Meerloo Gert J.Ossenkoppele Jacqueline Cloos Godefridus J.Peters Department of Rheumatology and Clinical Immunology Amsterdam Rheumatology and immunology CenterAmsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands The Fred Wyszkowsky Cancer Research Laboratory Faculty of BiologyThe Technion-Israel Institute of TechnologyHaifa 3200003Israel Department of Medical Oncology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Institute of Biotechnology Molecular Cell BiologyBrandenburg University of Technology Cottbus-SenftenbergSenftenberg 01968Germany Department of Hematology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Department of Biochemistry Medical University of GdanskGdansk 80-210Poland

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) ***: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR ***: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by ***: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

关键词： Aminopeptidase statins mevalonate pathway carboxyl esterase Rheb mTOR

Role of E3 ubiquitin ligases in lung cancer

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World Journal of Clinical Oncology 2013年第3期4卷 58-69页

作者： Barbara C Snoek Leonie HAM de Wilt gerrit jansen Godefridus J Peters Department of Medical Oncology VU University Medical Center1081 HV AmsterdamThe Netherlands Department of Rheumatology VU University Medical Center1081 HV AmsterdamThe Netherlands

E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S ***,E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation,proliferation and apoptosis.E3 ubiquitin ligases are often found overexpressed in human cancers,including lung cancer,and their deregulation has been shown to contribute to cancer ***,the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical *** this review,we focus on E3 ubiquitin ligases that have been found deregulated in lung ***,we discuss the processes in which they are involved and evaluate them as potential anti-cancer *** better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis,we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.

关键词： E3 ubiquitin ligases Lung cancer Ubiquitinproteasome system Proteasome inhibitors Bortezomib Apoptosis Gene regulation DNA repair

Flood events and their effects in a Himalayan mountain river: Geomorphological examples from the Buri Gandaki Valley, Nepal

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Journal of Mountain Science 2017年第7期14卷 1303-1316页

作者： gerrit TOMBRINK Institute of Geography University of Gottingen

This research examines flood events and related human interactions in the northwestern Himalayan Buri Gandaki Valley(Nepal). Past flood events that left traces at elevations between 3745 m to 780 m above sea level were investigated and reconstructed using morphometric and descriptive fluvial geomorphological analyses of historical flood markers and their related forms in the Buri Gandaki River system. Furthermore, the discharge of the Buri Gandaki River was measured, and infrastructure and permanent and temporary settlements potentially influenced by floods in the region due to their proximity to natural hazard areas were mapped. All reconstructed flood indicators have been documented with photographs that illustrate the evolution of the landscape over a short period in the Holocene. Moreover, satellite images have confirmed the morphological findings at the mesoscale and macroscale. An analysis of the flood levels showed that the high-water marks between 2160 m and 1710 m above sea level represented the highest reconstructed paleoflood stages. An intense flood hazard was observed in the upper stream of the Buri Gandaki near the Birendra Kund glacial lake and Samagaun settlement(3520 m above sea level). Further conclusions may be drawn from the anthropogenic reactions to flooding, such as those of the ethnic groups in this valley, who have used their local knowledge of floods and high discharge events along the Buri Gandaki River to takesafety precautions. Thus, local knowledge has reduced the social vulnerability in the settled areas of the valley. As a result of these local adaption strategies within the valley, we must rethink our implementation of protection and urbanisation strategies.

关键词： Floods Vulnerability Fluvialgeomorphology Himalaya Buri Gandaki River

Factors influencing the removal of fine non-cohesive sediment by vortex settling basin at small river abstraction works

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International Journal of Sediment Research 2021年第4期36卷 501-511页

作者： Kuria Kiringu gerrit Basson Department of Civil Engineering University of Stellenbosch

Diverted sediment causes a wide range of problems at small diversion works. The difference in water levels between low flows and floods, low investment capital and presence of cohesive sediment and fine non-cohesive sediment coupled with a requirement for a high level of supply assurance makes the design of such hydraulic structures complex. Vortex settling basins(VSBs) offer a promising alternative to conventional settling structures or hydro-cyclones. In the current study, parameters affecting the trapping of particles >75 mm were numerically investigated using ANSYS Fluent and were validated by physical modeling. It was established that the inlet velocity needs to be maintained at 0.26 m/s, the underflow to inflow ratio should be between 0.05 and 0.10, the cylinder height to cylinder diameter ratio should be greater than 0.5, and the positioning of the inlet pipe to cylinder height ratio should be greater than 0.7, with a cone of slope ratio of 2:1(V:H) and the cylinder diameter to inlet diameter ratio should be 8.2. These parameters form the basic design guidelines for VSB use at small diversion works(<100 L/s duty capacity).

关键词： Vortex settling basin Sediment trapping efficiency River diversion works ANSYS Fluent Numerical modeling

Impact of Crisis Communication Strategies on People's Attitudes toward Behavioral Guidelines Regarding COVID-19 and on Their Trust in Local Officials

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International Journal of Disaster Risk Science 2022年第4期13卷 495-506页

作者： gerrit Hirschfeld Meinald T.Thielsch Faculty of Business CareTech OWL–Center for HealthWelfare and TechnologyUniversity of Applied Sciences Bielefeld33619 BielefeldGermany Department of Psychology University of Münster48149 MünsterGermany

Situational Crisis Communication Theory(SCCT)guides responses of corporations in *** tested how COVID-19 related crisis communication strategies affect trust in mayors and the acceptance of behavioral measures.A total of 561 participants(53%female)with a mean age of 50 years took part in an online experiment in which we systematically manipulated the mayor's crisis communication strategy(deny crisis,diminish role in crisis,rebuild relationship after taking responsibility,bolster reputation,no response)and pre-crisis reputation(good past crisis management,bad past crisis management).Age,gender,and education served as *** also tested the predictive power of personal concern regarding the COVID-19 pandemic,as well as internal and external control *** our preregistered analysis,we found that crisis communication strategies had no significant effect on participants'ratings of behavioral measures,but they affected participants'trust in the *** deny crisis strategy resulted in the most unfavorable ratings,while the effects of the other strategies were moderated by the mayor's precrisis *** exploratory analyses showed that individual concern and trust were important predictors for the acceptance of behavioral *** though we did not find any effects of communication strategies on behavioral measures,our results support SCCT's utility in guiding communication strategy during a pandemic.

关键词： COVID-19 Crisis communication Germany Local officials Situational Crisis Communication Theory

Anisotropic magnetoresistance:A 170-year-old puzzle solved

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Science China(Physics,Mechanics & Astronomy) 2021年第1期64卷 120-121页

作者： gerrit E.W.Bauer Advanced Institute for Materials Research Institute for Materials ResearchTohoku UniversitySendai980-8577Japan Zernike Institute for Advanced Materials University of GroningenGroningen9747 AGNetherlands

Thomson[1],the later Lord Kelvin,reported an increased electric resistance in iron and nickel when the magnetization is parallel rather than normal to the current direction,an effect now called anisotropic magnetoresistance(AMR).The AMR allows sensing magnetic fields by simply measuring the resistance change when the magnetization *** the magnetoresistance of magnetic tunnel junctions is larger,AMR sensors are attractive by their simplicity and robustness.

关键词： resistance magnetoresistance magnetization

Chirality enables thermal magnon transistors

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Science China(Physics,Mechanics & Astronomy) 2024年第4期67卷 161-166页

作者： Tao Yu Chengyuan Cai gerrit E.W.Bauer School of Physics Huazhong University of Science and TechnologyWuhan 430074China .WPI-AIMR and Institute for Materials Research and SCIS Tohoku UniversitySendai 980-8577Japan Kavli Institute for Theoretical Sciences University of Chinese Academy of SciencesBeijing 100190China

We report a theory of thermal spin pumping into proximity magnets under a transverse-bias-driven heat flow of magnons in magnetic films when the dipolar coupling to the magnetic gate is tuned to be “chiral”. While there is no rectification of the magnon current in the film, we predict that chirality diverts a large percentage(50% for perfect chirality) of it into the gate. This transverse thermal spin pumping effect can be controlled by rotating the film magnetization and may help manage the heat flow in future magnonic circuits.

关键词： magnon chirality quantum transport transistor

Unmasking metabolic dependencies in pancreatic cancer: aberrant polyamine synthesis as a promising new therapeutic target

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5151-5152页

作者： gerrit Wolters-Eisfeld Thilo Hackert Cenap Güngör Department of General Visceral and Thoracic SurgeryUniversity Medical Center Hamburg-EppendorfHamburgGermany

In a recently published Nature article,Lee et *** distinct metabolic dependencies of pancreatic ductal adenocarcinoma(PDA)cells compared to normal tissue,and discovered that PDA cells exhibited a unique reliance on de novo ornithine synthesis from glutamine,rather than *** aberrant polyamine synthesis offers a promising therapeutic target for pancreatic cancer.

关键词： synthesis den depen