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Changes of protein expression during tumorosphere formation of small cell lung cancer circulating tumor cells

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Oncology Research 2023年第1期31卷 13-22页

作者： SANDRA STICKLER barbara rath MAXIMILIAN HOCHMAIR CLEMENS LANG LUKAS WEIGL GERHARD HAMILTON Institute of Pharmacology Medical University of ViennaViennaAustria Karl Landsteiner Institute of Lung Research and Pulmonary Oncology Klinik FloridsdorfViennaAustria Department of Trauma Surgery Sozialmedizinisches Zentrum OstDonauspitalViennaAustria Division of Special Anesthesia and Pain Medicine Medical University of ViennaViennaAustria

Small cell lung cancer(SCLC)is frequently disseminated and has a dismal prognosis with survival times of approximately two *** cancer responds well to initial chemotherapy but recurs within a short time as a globally chemoresistant *** tumor cells(CTCs)are held responsible for metastasis,the extremely high numbers of these cells in advanced SCLC allowed us to establish several permanent CTC cell *** CTCs are distinguished by the spontaneous formation of large spheroids,termed tumorospheres,in regular tissue *** contain quiescent and hypoxic cells in their interior and are associated with high chemoresistance compared to single cell *** CTC lines were compared for their expression of 84 proteins associated with cancer either as single cells or in the form of tumorospheres in Western blot *** the exception of the UHGc5 line,all other CTC lines express EpCAM and lack a complete EpCAM-negative,vimentin-positive epithelial-mesenchymal transition(EMT)*** formation of tumorospheres the expression of EpCAM,that mediates cell-cell adhesion is markedly *** such as E-Cadherin,p27 KIP1,Progranulin,BXclx,Galectin-3,and Survivin showed variable changes for the distinct CTC cell *** conclusion,EpCAM presents the most critical marker for individual SCLC CTCs and the assembly of highly chemoresistant tumorospheres.

关键词： SCLC Spheroid Chemoresistance EpCAM Topotecan Epirubicin

Role of circulating tumor cell spheroids in drug resistance

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Cancer Drug Resistance 2019年第3期2卷 762-772页

作者： Gerhard Hamilton barbara rath Department of Surgery Medical University of ViennaVienna A-1090Austria

Cancer cell spheroids are used for drug screening as these three-dimensional(3D)assemblies recapitulate tumors more realistic than the widely employed 2D in vitro *** drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug *** tumor cells(CTCs)effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer(SCLC)and in other cancer patients with high tumor *** are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal *** may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic *** our lab we have obtained 9 permanent SCLC CTC cell lines(BHGc7,BHGc10,BHGc16,BHGc26,BHGc27,BHGc50,BHGc59,BHGc71,and UHGc5)of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids,termed *** aggregates were shown to exhibit high drug resistance compared to the corresponding single cell *** increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in *** drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low ***,we have detected such tumorospheres in non-small-cell lung cancer(NSCLC)patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

关键词： Cancer spheroid circulating tumor cells small cell lung cancer non-small-cell lung cancer transformation dormancy

Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

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Cancer Drug Resistance 2020年第2期3卷 171-178页

作者： barbara rath Adelina Plangger Gerhard Hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1090Austria

Mutated or rearranged driver kinases in non-small cell lung cancer(NSCLC)cells are clinically amenable to treatment with tyrosine kinase inhibitors(TKIs)resulting in prolonged survival and significant benefit compared to cytotoxic *** most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase,which can be blocked by a range of specific TKIs in *** clinics,resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases(on-target)or alternative pathways circumventing the original kinase(off-target)alterations.A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer(SCLC)in up to 14%of cases,which,in general,is accompanied by resistance to the original *** transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive *** transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug *** conclusion,the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

关键词： Lung cancer non-small cell lung cancer small cell lung cancer transformation epidermal growth factor receptor tyrosine kinase inhibitor chemotherapy drug resistance

Protection of small-cell lung cancer circulating tumor cells by cellular fragmentation

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 345-354页

作者： barbara rath Adelina Plangger Doris Moser Maximilian Hochmair Ernst Ulsperger Gerhard Hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1190Austria Department of Cranio-Maxillofacial and Oral Surgery Medical University of ViennaVienna A-1090Austria Hospital Floridsdorf Vienna A-1210Austria Hospital Horn Horn A-3580Austria

Aim:Small-cell lung cancer(SCLC)disseminates aggressively and may exhibit high chemoresistance and poor survival *** this study,we aimed to investigate a new mechanism of drug resistance for SCLC circulating tumor cells(CTCs).Methods:SCLC CTC cell lines(n=4)which shed cellular fragments(MAT),as demonstrated by light and scanning electron microscopy,are compared to permanent SCLC *** proteins are detected by proteome arrays and the functional impact of MAT is studied using cytotoxicity tests involving cisplatin and ***:The SCLC CTC lines revealed layers of attached cellular fragments with a range of decreasing sizes from intact cells(approximately 12μm)down to small debris(approximately 2μm)which are not detectable in permanent SCLC *** SCLC CTC clusters represent cores of these fragment-coated *** profiling of MAT revealed a protein pattern similar to intact *** tests employing SCLC and SCLC CTC lines with chemotherapeutics used in therapy of SCLC demonstrated an inhibitory activity of MAT on the resulting ***:Generation of cell-associated debris by SCLC CTCs offers protective effects against cytotoxic drugs,representing a novel mechanism allowing survival of SCLC CTCs in patients.

关键词： Small cell lung cancer circulating tumor cells shedding topotecan

Heterogeneous patterning of blood-brain barrier and adaptive myelination as renewing key in gray and white matter

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Neural Regeneration Research 2024年第3期19卷 481-482页

作者： barbara Pavan Department of Neuroscience and Rehabilitation University of Ferraravia L BorsariFerraraItalyCenter for Translational Neurophysiology of Speech and Communication(CTNSC)Italian Institute of Technology(IIT)via Fossato di MortaraFerraraItaly

Background:Development and homeostasis of the brain are enabled through the precise control of the cell microenvironment by the blood-brain barrier(BBB),which interfaces between the brain parenchyma and the lumen of blood microvessels,and by the blood-cerebrospinal fluid barrier,which separates the cerebrospinal fluid from the blood vessels of the choroid plexus(Villabona-Rueda et al.,2019).Here,the focus will be on the BBB,the impairment of which is considered the earliest common denominator in neurovascular diseases.

关键词： homeostasis blood

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

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Journal of Cancer Metastasis and Treatment 2016年第1期2卷 446-452页

作者： Gerhard Hamilton barbara rath Society for Research on Biology and Treatment of Cancer A-1160 ViennaAustria

Despite the fact that the majority of cancer patients succumb to metastatic disease,most aspects of tumor metastasis are not understood in detail at *** biologic steps of dissemination are difficult to characterize in human tumors and research is in large part confined to cell line and experimental animal ***-mesenchymal transition(EMT),intravasation of malignant cells,dissemination as circulating tumor cells(CTCs)and eventually mesenchymal-epithelial transition(MET)at distal sites are steps believed to be involved in *** cell lung cancer(SCLC)is distinguished by early dissemination and excessive numbers of CTCs,which allowed for the ex vivo expansion of six permanent CTC lines taken from relapsed *** exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large *** cells may have invaded without undergoing EMT,the role of MET is *** SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells;these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases,leading in turn to resistance and failure of *** characterization of these lines is expected to provide the markers to find the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence.

关键词： Cancer metastasis small cell lung cancer circulating tumor cells epithelial-mesenchymal transition tumorosphere chemotherapy drug resistance

Commentary on "Association of daily sitting time and leisure-time physical activity with body fat among ***"

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Journal of Sport and Health Science 2024年第2期13卷 127-129页

作者： barbara E.Ainsworth School of Exercise and Health Shanghai University of SportShanghai 200438China

In their study,association of daily sitting time and leisure-time physical activity (LTPA) with body fat among ***,Liao et al.^(1) analyzed data from the 2011-2018 National Health and Examination Survey to examine associations between h/day sitting,meeting (or not meeting) the *** Activity Guidelines of≥150 min/week of moderate-and vigorous-intensity LTPA,and combinations of sitting time and LTPA on totaland trunk percent body fat (BF%).

关键词： U.S. adult among

Does ash dieback affect the reproductive ecology of Fraxinus excelsior L.?

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Journal of Forestry Research 2024年第2期35卷 54-69页

作者： Anna‑Katharina Eisen Lisa Buchner barbara Fussi Susanne Jochner‑Oette Physical Geography/Landscape Ecology and Sustainable Ecosystem Development Catholic University of Eichstätt-Ingolstadt85072 EichstättGermany Bavarian Office for Forest Genetics(AWG) 83317 TeisendorfGermany

Forest tree species reproduction is a key factor in maintaining the genetic diversity of future generations and the stability of forest *** ongoing ash dieback disease could affect the reproductive ecology of Fraxinus excelsior *** have a major impact on the quantity and quality of pollen and *** this study,we investigated pollen production and viability of pollen and seeds of ash trees with different health status from 2018 to *** were collected from 105 trees(pollen production),pollen from 125 trees(pollen viability),and seeds from 53 trees(seed quality)in two seed orchards and in one floodplain forest in southern *** all parameters were examined at every site every *** average pollen production per tree was estimated at 471.2±647.9 billion pollen *** addition,we found that a high number of inflorescences did not equate to high pollen production per *** production of healthy and diseased trees did not differ significantly,although only 47%of severely diseased male trees(vs.72%for healthy trees)produced *** regards to pollen viability,the TTC test showed an average viability of 73%±17%.Overall,there was a slight tendency for diseased trees to have less viable ***,a significant difference could only be calculated for trees in the floodplain *** percentage of germinable seeds in 2018 was 38%in the floodplain forest and 57%in one of the seed *** percentage of viable seeds(TTC test)ranged from 17 to 22%in the orchards in ***-viable seeds were usually heavily infested by *** general,seed quality was not significantly different between healthy and diseased *** results indicate that ash dieback affects flower formation and pollen viability but not pollen production or seed ***,the fact that hardly any flowering was observed,especially for trees that were seriously affected,suggests a negative effect of ash dieback on reproductive per

关键词： Common ash Seed orchard Floodplain forest Pollen production Viability TTC test Seed stratification Phenology

Nonuniform Dependence on the Initial Data for Solutions of Conservation Laws

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Communications on Applied Mathematics and Computation 2024年第1期6卷 489-500页

作者： John M.Holmes barbara Lee Keyfitz Department of Mathematics The Ohio State UniversityColumbusOH43210USA

In this paper,we study systems of conservation laws in one space *** prove that for classical solutions in Sobolev spaces H^(s),with s>3/2,the data-to-solution map is not uniformly *** results apply to all nonlinear s... 详细信息

关键词： Conservation laws Data-to-solution map Nonuniform dependence