88 results on '"Stege G"'
Search Results
2. Mini-review of waste sector greenhouse gas and short-lived climate pollutant emissions in Tyre Caza, Lebanon, using the Solid Waste Emissions Estimation Tool (‘SWEET’)
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Alexander Stege, G, primary, James Law, H, additional, Ramola, Aditi, additional, and Mazo-Nix, Sandra, additional
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- 2022
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3. Changes in Physico-Chemical Properties of Iron-Based Fischer–Tropsch Catalyst Induced by SiO2 Addition
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Dlamini, H., Motjope, T., Joorst, G., ter Stege, G., and Mdleleni, M.
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- 2002
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4. Sleep and the use of sleep medication in chronic obstructive pulmonary disease
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Stege, G., Dekhuijzen, P.N.R., Elshout, F.J.J. van den, Vos, P.J.E., Heijdra, Y.F., and Radboud University Nijmegen
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Pathogenesis and modulation of inflammation [N4i 1] ,Poverty-related infectious diseases Aetiology, screening and detection [N4i 3] - Abstract
Contains fulltext : 117662.pdf (Publisher’s version ) (Open Access) Radboud Universiteit Nijmegen, 15 mei 2013 Promotor : Dekhuijzen, P.N.R. Co-promotores : Elshout, F.J.J. van den, Vos, P.J.E., Heijdra, Y.F.
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- 2013
5. Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease
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Stege, G., Vos, P.J.E., Dekhuijzen, P.N.R., Hilkens, P.H., Ven, M.J.T. van de, Heijdra, Y.F., Elshout, F.J.J. van den, Stege, G., Vos, P.J.E., Dekhuijzen, P.N.R., Hilkens, P.H., Ven, M.J.T. van de, Heijdra, Y.F., and Elshout, F.J.J. van den
- Abstract
Item does not contain fulltext, PURPOSE: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis. METHODS: In a retrospective study, the full-night polysomnographic recordings of patients with and without COPD were analyzed automatically by Matrix Sleep Analysis software and manually. The outcomes of manual and automated analyses in both groups were compared using Bland-Altman plots and Students' paired t tests. RESULTS: Fifty PSGs from patients with COPD and 57 PSGs from patients without COPD were included. In both study groups, agreement between manual and automated analysis was poor in nearly all sleep and respiratory parameters, like total sleep time, sleep efficiency, sleep latency, amount of rapid eye movement sleep and other sleep stages, number of arousals, apnea-hypopnea index, and desaturation index. CONCLUSION: Automated analysis of PSGs by the studied automated system in patients with COPD has poor agreement with manual analysis when looking at sleep and respiratory parameters and should, therefore, not replace the manual analysis of PSG recordings in patients with COPD.
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- 2013
6. Sleep and the use of sleep medication in chronic obstructive pulmonary disease
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Dekhuijzen, P.N.R., Elshout, F.J.J. van den, Vos, P.J.E., Heijdra, Y.F., Stege, G., Dekhuijzen, P.N.R., Elshout, F.J.J. van den, Vos, P.J.E., Heijdra, Y.F., and Stege, G.
- Abstract
Radboud Universiteit Nijmegen, 15 mei 2013, Promotor : Dekhuijzen, P.N.R. Co-promotores : Elshout, F.J.J. van den, Vos, P.J.E., Heijdra, Y.F., Contains fulltext : 117662.pdf (Publisher’s version ) (Open Access)
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- 2013
7. Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD.
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Stege, G., Heijdra, Y.F., Elshout, F.J.J. van den, Ven, M.J.T. van de, Bruijn, P.J. de, Sorge, A.A. van, Dekhuijzen, P.N.R., Vos, P.J.E., Stege, G., Heijdra, Y.F., Elshout, F.J.J. van den, Ven, M.J.T. van de, Bruijn, P.J. de, Sorge, A.A. van, Dekhuijzen, P.N.R., and Vos, P.J.E.
- Abstract
1 april 2010, Contains fulltext : 89034.pdf (publisher's version ) (Closed access), BACKGROUND: Benzodiazepines can improve sleep quality, but are also thought to cause respiratory depression in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the effects of temazepam on indices of circadian respiratory function, dyspnea, sleep quality, and sleepiness in patients with severe COPD and insomnia. METHODS: In a double-blind, randomized, placebo-controlled, cross-over study in 14 stable patients with COPD (mean FEV(1) 0.99+/-0.3L) with insomnia, polysomnography with continuous transcutaneous capnography and oximetry, arterial gas sampling, hypercapnic ventilatory response, multiple sleep latency test, Epworth Sleepiness Scale, dyspnea and sleep visual analogue scales (VAS) were performed at baseline, after one week of temazepam 10mg at bedtime and after one week of placebo. RESULTS: Temazepam did not cause statistically significant changes in mean transcutaneous carbon dioxide tension during sleep compared to placebo (5.9+/-1.0 kPa vs. 6.3+/-1.4 kPa, p-value 0.27), nor in mean oxygen saturation (92+/-3% vs. 92+/-2%, p-value 0.31), nor in any of the other investigated variables, except for the total sleep time and sleep latency VAS, which improved with temazepam. CONCLUSIONS: One week usage of temazepam 10mg does not influence circadian respiratory function, dyspnea, and sleepiness in patients with stable, severe, normocapnic COPD and insomnia and it improves total sleep time and subjective sleep latency. However, this is a preliminary explorative study for assessing the feasibility to perform a larger study on this topic. The clinical implications of this study are very limited.
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- 2010
8. Accuracy of transcutaneous carbon dioxide tension measurements during cardiopulmonary exercise testing.
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Stege, G., Elshout, F.J.J. van den, Heijdra, Y.F., Ven, M.J.T. van de, Dekhuijzen, P.N.R., Vos, P.J.E., Stege, G., Elshout, F.J.J. van den, Heijdra, Y.F., Ven, M.J.T. van de, Dekhuijzen, P.N.R., and Vos, P.J.E.
- Abstract
Contains fulltext : 79575.pdf (publisher's version ) (Closed access), BACKGROUND: Measurements of transcutaneous carbon dioxide tension (PtcCO(2)) with current devices are proven to provide clinically acceptable agreement with measurements of partial arterial carbon dioxide tension (PaCO(2)) in several settings but not during cardiopulmonary exercise testing (CPET). OBJECTIVES: The primary objective of this study was to investigate the agreement between PaCO(2) and PtcCO(2) measurements (using a Tosca 500 with a Tosca sensor 92) during CPET. A secondary objective was to investigate the agreement between arterial and transcutaneous oxygen saturation (SaO(2), SpO(2)) as measured with this sensor during CPET. METHODS: In patients with various pulmonary diseases, PtcCO(2) and SpO(2) were continuously measured and compared with arterial blood gas samples during CPET. A maximum bias of 0.5 kPa and 95% limits of agreement (LOA) of 1 kPa between carbon dioxide pressure (PCO(2)) measurements were determined as clinically acceptable. RESULTS: In total 101 'paired' arterial and transcutaneous measurements were obtained from 21 patients. Bias between PaCO(2) and PtcCO(2) was -0.03 kPa with LOA from -0.78 to 0.71 kPa. Bias between SaO(2) and SpO(2) was -1.0% with LOA from -2.83 to 0.83%. CONCLUSIONS: Transcutaneous estimations of PCO(2) and SpO(2) are accurate and can be used in CPET, circumvening the need for arterial cannulation.
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- 2009
9. Sleep, hypnotics and chronic obstructive pulmonary disease.
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Stege, G., Vos, P.J.E., Elshout, F.J.J. van den, Dekhuijzen, P.N.R., Ven, M.J.T. van de, Heijdra, Y.F., Stege, G., Vos, P.J.E., Elshout, F.J.J. van den, Dekhuijzen, P.N.R., Ven, M.J.T. van de, and Heijdra, Y.F.
- Abstract
Contains fulltext : 70998.pdf (publisher's version ) (Closed access), The quality of sleep is significantly compromised in many patients with chronic obstructive pulmonary disease (COPD) and may be further diminished when certain comorbidities are present. A reduced sleep quality is associated with daytime consequences like fatigue, psychiatric problems and an impaired quality of life. Sleep induces physiologic alterations in respiratory function, which can become pathologic and may provoke or worsen hypoxemia and hypercapnia in COPD. Dyspnea, cough and excessive mucus production should be optimised to minimise causes for sleep disturbance. Pharmacological therapy may be helpful; sedatives like benzodiazepines and non-benzodiazepine benzodiazepine-receptor agonists (NBBRAs) are (equally) effective in improving sleep quality. Whether or not these hypnotics produce serious adverse respiratory effects during sleep, remains unclear due to opposing studies. Therefore, their use should be as short as possible.
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- 2008
10. The CTLA-4 +49GG genotype is associated with susceptibility for nephrotic kidney diseases
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Spink, C., primary, Stege, G., additional, Tenbrock, K., additional, and Harendza, S., additional
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- 2013
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11. Intracellular free calcium concentrations in cell suspensions during hyperthermia
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Wierenga, P. K., Stege, G. J., Kampinga, H. H., and Konings, A. W.
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INDICATORS ,FURA-2 ,FURA-2/AM ,DEATH ,INTRACELLULAR FREE CALCIUM ,MICROSCOPY ,HYPERTHERMIA ,HEAT ,CYTOSOLIC FREE CA-2+ ,FLUORESCENCE - Abstract
The aim of this study was to explore the possibility that heat-induced alterations in calcium homeostasis are the cause of hyperthermic cell killing. Therefore, the intracellular free calcium concentration ([Ca2+](i)) was determined spectrofluorometrically, using the fluorescent calcium probe fura-2/acetoxy methylester (AM), at both physiological and hyperthermic temperatures in cell suspensions from six different tumor cell lines. For all cell lines fura-2 leakage appears to contribute to a change in the fluorescence signal and hence leads to a false indication of an increase in [Ca2+](i), especially at the hyperthermic temperature. Two methods were introduced that circumvent this problem and results in true values of [Ca2+](i). Also, measurements of [Ca2+](i) in single cells using a fluorescent microscopical technique (not affected by dye leakage) were used for comparison. All three ap preaches show that a hyperthermic treatment that kills >90% of the cells does not lead to changes in the [Ca2+](i) in most cell lines. Therefore, heat-induced alterations of calcium homeostasis cannot be considered the general cause for hyperthermic cell killing.
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- 1994
12. Heat shock, but not the reactive state per se, induces increased expression of the small stress proteins hsp25 and αB-crystallin in glial cells in vitro
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Brzyska, M, primary, Stege, G J. J., additional, Renkawek, K, additional, and Bosman, G J. C. G. M., additional
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- 1998
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13. Thermotolerance and nuclear protein aggregation: Protection against initial damage or better recovery?
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Stege, G. J. J., primary, Brunsting, J. F., additional, Kampinga, H. H., additional, and Konings, A. W. T., additional
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- 1995
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14. On the role of hsp72 in heat-induced intranuclear protein aggregation
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Stege, G. J. J., primary, Li, G. C., additional, Li, L., additional, Kampinga, H. H., additional, and Konings, A. W. T., additional
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- 1994
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15. Synergistic action of calcium-lonophores and hyperthermia is best interpreted as thermal enhancement of calcium toxicity
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Stege, G. J. J., primary, Wierenga, P. K., additional, Konings, A. W. T., additional, and Kampinga, H. H., additional
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- 1993
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16. Heat-induced Intranuclear Protein Aggregation and Thermal Radiosensitization.
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Stege, G. J. J., Kampinga, H. H., and Konings, A. W. T.
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- 1995
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17. Hyperthermia, Intracellular Free Calcium and Calcium Ionophores.
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Stege, G. J. J., Wierenga, P. K., Kampinga, H. H., and Konings, A. W. T.
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- 1993
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18. Changes in Physico-Chemical Properties of Iron-Based FischerTropsch Catalyst Induced by SiO2 Addition
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Dlamini, H., Motjope, T., Joorst, G., Stege, G. ter, and Mdleleni, M.
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The effect of adding SiO to a precipitated Fe-based FischerTropsch catalyst was investigated. Silica was added to the catalyst either during or after precipitation. The iron-based FischerTropsch catalysts were studied using Mössbauer spectroscopy, BET surface area, XRD and SEM characterization methods. Adding SiO to the catalyst during precipitation or immediately after precipitation (i.e., precipitated SiO) results in the formation of Fe crystallites with an average diameter less than 3 nm, which have high surface areas and exhibit a strong interaction with the SiO matrix. Consequently, these crystallites are resistant to reduction and carburisation. When SiO was added to the catalyst after heat treatment (i.e., binder SiO), the resulting catalyst was observed to consist of segregated SiO-rich and Fe-rich phases. The distribution of KO in both these phases indicates that the amount of effective KO, i.e., that associated with Fe, is less when SiO is added as a binder. The low extent of reduction and carburisation observed with catalysts that contain precipitated SiO results in catalysts with low % CO conversion. A positive correlation between the amount of iron carbides present in the catalyst and the % CO conversion was observed in these studies.
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- 2002
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19. Differential expression of stress proteins in human adult astrocytes in response to cytokines
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Bajramovic, J. J., Bsibsi, M., Geutskens, S. B., Hassankhan, R., Verhulst, K. C., Stege, G. J., Groot, C. J. de, and Noort, J. M. van
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- 2000
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20. β-Aspartylpeptidase activity, a microflora associated characteristic (MAC); Its presence in different strains of anaerobic bacteria
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Welling, G. W., Stege, G. J. J., and Meijer-severs, G. J.
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β-Aspartylglycine can adequately be used as an indicator of colonisation-resistance as its presence reflects the absence of β-aspartylpeptide-degrading activity originating from a substantial number of different strains of anaerobic bacteria. In this study, 14 strains of anaerobic bacteria were isolated from human faeces and the β-aspartyl-peptide-degrading activity in these bacteria was determined by a high-performance liquid chromatography assay. In 12 of 14 strains this activity was present, which indicates that its absence indeed reflects a substantial disturbance of the anaerobic bacterial flora. In addition, the assay was used to determine β-aspartylpeptidase activity in faecal supernatants of healthy volunteers and decontaminated patients.
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- 1988
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21. Heat shock but not the reactive state per seinduces increased expression of the small stress proteins hsp25 and αBcrystallin in glial cells in vitro
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Brzyska, M, Stege, G J. J., Renkawek, K, and Bosman, G J. C. G. M.
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The stress proteins hsp25 αB-crystallin are found in increased concentrations in reactive astrocytes of brains undergoing neurodegeneration. In order to characterize this reaction, we investigated the expression of hsp25 and αB-crystallin during growth and after stress (heat shock) in glial cells in vitro. In primary rat brain cultures, hsp25 was present in actively dividing astrocytes that were positive for glial fibrillary acidic protein. αB-crystallin was found predominantly in oligodendrocytes. Heat shock resulted in increased concentrations of hsp25 and αB-crystallin in astrocytes, without any detectable changes in intracellular localization, as detectable with confocal laser microscopy. These results indicate that a neurodegeneration-related increase of the small stress proteins in astrocytes is independent of gliosis per se, and may be a disease-related event.
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- 1998
22. Focused attention in ADHD
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Tollenaar, M. S., John Stins, Jc, Tinca Polderman, Ter Stege, G. E., and Boomsma, Dorret I.
23. Genetics of Attention, aim & design of this study
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Tinca Polderman, John Stins, Ter Stege, G. E., Tollenaar, M. S., Boomsma, Dorret I., and Verhulst, F. C.
24. The ‘Flight of colours’ test in multiple sclerosis, retrobulbar neuritis and healthy controls
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Smits, M.Y., primary, Minderhoud, J.M., additional, Boonstra, S., additional, Kuks, J., additional, and Ter Stege, G., additional
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- 1984
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25. β-Aspartylpeptidase activity, a microflora associated characteristic (MAC); Its presence in different strains of anaerobic bacteria
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Welling, G. W., primary, Stege, G. J. J., additional, and Meijer-Severs, G. J., additional
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- 1988
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26. An evaluation of air and greenhouse gas emissions and methane-recovery potential from bioreactor landfills
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Sullivan, Pat and Stege, G. Alexander
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- 2000
27. Strengths and challenges in current lung cancer care: Timeliness and diagnostic procedures in six Dutch hospitals.
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Genet SAAM, Visser E, Youssef-El Soud M, Belderbos HNA, Stege G, de Saegher MEA, Westeinde SCV', Brunsveld L, Broeren MAC, van de Kerkhof D, Eduati F, van den Borne BEEM, and Scharnhorst V
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- Humans, Artificial Intelligence, Prospective Studies, Hospitals, Lung, Lung Neoplasms diagnosis, Lung Neoplasms therapy, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung therapy, Carcinoma, Neuroendocrine
- Abstract
Objectives: Timely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed., Materials and Methods: 1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis., Results: The majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures., Conclusion: These insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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28. Liquid biopsy-based decision support algorithms for diagnosis and subtyping of lung cancer.
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Visser E, Genet SAAM, de Kock RPPA, van den Borne BEEM, Youssef-El Soud M, Belderbos HNA, Stege G, de Saegher MEA, van 't Westeinde SC, Brunsveld L, Broeren MAC, van de Kerkhof D, Deiman BALM, Eduati F, and Scharnhorst V
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- Humans, Prospective Studies, Biomarkers, Tumor, Phosphopyruvate Hydratase, Liquid Biopsy, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology
- Abstract
Objectives: Pathologic subtyping of tissue biopsies is the gold standard for the diagnosis of lung cancer (LC), which could be complicated in cases of e.g. inconclusive tissue biopsies or unreachable tumors. The diagnosis of LC could be supported in a minimally invasive manner using protein tumor markers (TMs) and circulating tumor DNA (ctDNA) measured in liquid biopsies (LBx). This study evaluates the performance of LBx-based decision-support algorithms for the diagnosis of LC and subtyping into small- and non-small-cell lung cancer (SCLC and NSCLC) aiming to directly impact clinical practice., Materials and Methods: In this multicenter prospective study (NL9146), eight protein TMs (CA125, CA15.3, CEA, CYFRA 21-1, HE4, NSE, proGRP and SCCA) and ctDNA mutations in EGFR, KRAS and BRAF were analyzed in blood of 1096 patients suspected of LC. The performance of individual and combined TMs to identify LC, NSCLC or SCLC was established by evaluating logistic regression models at pre-specified positive predictive values (PPV) of ≥95% or ≥98%. The most informative protein TMs included in the multi-parametric models were selected by recursive feature elimination., Results: Single TMs could identify LC, NSCLC and SCLC patients with 46%, 25% and 40% sensitivity, respectively, at pre-specified PPVs. Multi-parametric models combining TMs and ctDNA significantly improved sensitivities to 65%, 67% and 50%, respectively., Conclusion: In patients suspected of LC, the LBx-based decision-support algorithms allowed identification of about two-thirds of all LC and NSCLC patients and half of SCLC patients. These models therefore show clinical value and may support LC diagnostics, especially in patients for whom pathologic subtyping is impossible or incomplete., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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29. Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer.
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Visser E, de Kock R, Genet S, Borne BVD, Soud MY, Belderbos H, Stege G, de Saegher M, 't Westeinde SV, Broeren M, Eduati F, Deiman B, and Scharnhorst V
- Abstract
Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis. This prospective, multicenter study establishes the diagnostic value of ctDNA analysis by droplet digital PCR (ctDNA-ddPCR) in patients with primary lung cancer. CtDNA from 458 primary lung cancer patients was analyzed using a panel of multiplex ddPCRs for EGFR (Ex19Del, G719S, L858R, L861Q and S768I), KRAS G12/G13 and BRAF V600 mutations. For 142 of 175 advanced stage non-squamous NSCLC patients tDNA-NGS results were available to compare to ctDNA-ddPCR. tDNA-NGS identified 98 mutations, of which ctDNA-ddPCR found 53 mutations (54%), including 32 of 45 (71%) targetable driver mutations. In 2 of these 142 patients, a mutation was found by ctDNA-ddPCR only. In 33 advanced stage patients lacking tDNA-NGS results, ctDNA-ddPCR detected 15 additional mutations, of which 7 targetable. Overall, ctDNA-ddPCR detected 70 mutations and tDNA-NGS 98 mutations in 175 advanced NSCLC patients. Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies., (Copyright © 2022. Published by Elsevier Inc.)
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- 2023
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30. Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients.
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de Kock R, Borne BVD, Soud MY, Belderbos H, Stege G, de Saegher M, van Dongen-Schrover C, Genet S, Brunsveld L, Scharnhorst V, and Deiman B
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- Aged, Disease Progression, Female, Humans, Male, Middle Aged, Prospective Studies, Biomarkers, Tumor metabolism, Liquid Biopsy methods, Lung Neoplasms therapy
- Abstract
Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression. Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.3, Cyfra 21-1, HE4, NSE, proGRP and SCCA) using electrochemiluminescence immunoassays. Biomarker concentration changes were compared with the outcome of CT-scans during therapy. The median difference of the concentration of ctDNA, CA125 and Cyfra21-1 was significantly lower in patients with partial response (PR) compared to patients with progressive disease (PD) on the first evaluation CT-scan (P<0.001, P=0.042 and P=0.020, respectively). A substantial agreement between ctDNA or CA125 response and radiographic response was observed (k=0.692 and k=0.792, respectively). The median difference of the concentration of ctDNA and Cyfra21-1 was also significantly lower in PR patients compared to PD patients at the last CT-scan during therapy (P<0.001 and P=0.026, respectively). An almost perfect agreement between ctDNA and radiographic response (k=0.827) and a moderate agreement between Cyfra21-1 response and radiographic response was observed (k=0.553). Serial testing of the concentration of ctDNA, Cyfra21-1, and possibly CA125 could be a useful added tool for monitoring therapy response and early detection of disease progression in lung cancer patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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31. Pragmatic trial on inhaled corticosteroid withdrawal in patients with COPD in general practice.
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van den Bemt L, van den Nieuwenhof L, Rutjes A, van der Meer V, Stege G, Wensing M, Teichert M, and Schermer T
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- Administration, Inhalation, Adrenal Cortex Hormones administration & dosage, Aged, Bronchodilator Agents administration & dosage, Bronchodilator Agents adverse effects, Dyspnea epidemiology, Dyspnea etiology, Female, Health Status, Humans, Male, Quality of Life, Withholding Treatment, Adrenal Cortex Hormones therapeutic use, Bronchodilator Agents therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
The therapeutic value of inhaled corticosteroids (ICSs) for COPD is limited. In published RCTs, ICS could be withdrawn in COPD patients without increasing exacerbation risk when bronchodilator treatment is optimized. Here we report on the feasibility and risks of ICS withdrawal in Dutch general practice for COPD patients without an indication for ICSs. In our pragmatic trial, general practitioners decided autonomously which of their COPD patients on ICS treatment could stop this, how this was done, and whether additional bronchodilator therapy was needed. We recruited 62 COPD patients (58 analysed) who were eligible for ICS withdrawal in 79 practices. In 32 patients (55.2%, 95% CI: 42.5-67.3%) ICS was withdrawn successfully, 19 (32.8%, 95% CI: 22.1-45.6%) restarted ICS treatment within six months, 12 patients (20.7%, 95% CI: 12.3-32.8%) had a moderate exacerbation, and one patient had a severe exacerbation. ICS withdrawal was successful in just over half of the patients with COPD without an indication for ICS.
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- 2020
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32. Correction of the NSE concentration in hemolyzed serum samples improves its diagnostic accuracy in small-cell lung cancer.
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Genet SAAM, Visser E, van den Borne BEEM, Soud MY, Belderbos HNA, Stege G, de Saegher MEA, Eduati F, Broeren MAC, van Dongen J, Brunsveld L, van de Kerkhof D, and Scharnhorst V
- Abstract
Neuron-specific enolase (NSE) is a well-known biomarker for the diagnosis, prognosis and treatment monitoring of small-cell lung cancer (SCLC). Nevertheless, its clinical applicability is limited since serum NSE levels are influenced by hemolysis, leading to falsely elevated results. Therefore, this study aimed to develop a hemolysis correction equation and evaluate its role in SCLC diagnostics. Two serum pools were spiked with increasing amounts of hemolysate obtained from multiple individuals. A hemolysis correction equation was obtained by analyzing the relationship between the measured NSE concentration and the degree of hemolysis. The equation was validated using intentionally hemolyzed serum samples, which showed that the correction was accurate for samples with an H-index up to 30 μmol/L. Correction of the measured NSE concentration in patients suspected of lung cancer caused an increase in AUC and a significantly lower cut-off value for SCLC detection when compared to uncorrected results. Therefore, a hemolysis correction equation should be used to correct falsely elevated NSE concentrations. Results of samples with an H-index above 30 μmol/L should not be reported to clinicians. Application of the equation illustrates the importance of hemolysis correction in SCLC diagnostics and questions the correctness of the currently used diagnostic cut-off value., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
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- 2020
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33. CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN.
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Brix SR, Stege G, Disteldorf E, Hoxha E, Krebs C, Krohn S, Otto B, Klätschke K, Herden E, Heymann F, Lira SA, Tacke F, Wolf G, Busch M, Jabs WJ, Özcan F, Keller F, Beige J, Wagner K, Helmchen U, Noriega M, Wiech T, Panzer U, and Stahl RA
- Subjects
- Aged, Animals, Biomarkers blood, Chemokine CCL8 genetics, Chemokine CCL8 metabolism, Chemokines, CC analysis, Dendritic Cells chemistry, Female, Glomerulonephritis pathology, Glomerulonephritis physiopathology, Humans, Macrophages chemistry, Male, Mice, Middle Aged, Prospective Studies, Protein Array Analysis, Receptors, CCR8 genetics, Receptors, CCR8 metabolism, Up-Regulation, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Chemokines, CC blood, Glomerulonephritis etiology, Glomerulonephritis metabolism
- Abstract
ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18(+) cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8(-/-) mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8(-/-) mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
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34. CXCL5 drives neutrophil recruitment in TH17-mediated GN.
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Disteldorf EM, Krebs CF, Paust HJ, Turner JE, Nouailles G, Tittel A, Meyer-Schwesinger C, Stege G, Brix S, Velden J, Wiech T, Helmchen U, Steinmetz OM, Peters A, Bennstein SB, Kaffke A, Llanto C, Lira SA, Mittrücker HW, Stahl RA, Kurts C, Kaufmann SH, and Panzer U
- Subjects
- Animals, Chemokine CXCL1 metabolism, Chemokines metabolism, Disease Models, Animal, Epithelial Cells cytology, Female, Glomerulonephritis metabolism, Glomerulonephritis microbiology, Inflammation, Interleukin-17 metabolism, Kidney metabolism, Kidney Tubules metabolism, Male, Mice, Mice, Knockout, Mice, Transgenic, Neutrophil Infiltration immunology, Up-Regulation, Chemokine CXCL5 metabolism, Glomerulonephritis pathology, Neutrophils metabolism, Th17 Cells cytology
- Abstract
Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens., (Copyright © 2015 by the American Society of Nephrology.)
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- 2015
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35. MicroRNA-155 drives TH17 immune response and tissue injury in experimental crescentic GN.
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Krebs CF, Kapffer S, Paust HJ, Schmidt T, Bennstein SB, Peters A, Stege G, Brix SR, Meyer-Schwesinger C, Müller RU, Turner JE, Steinmetz OM, Wolf G, Stahl RA, and Panzer U
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Glomerulonephritis pathology, Humans, Immunity, Humoral immunology, Immunophenotyping, Male, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Mutant Strains, MicroRNAs genetics, Neutrophils cytology, Neutrophils immunology, Spleen cytology, Spleen immunology, Th17 Cells cytology, Glomerulonephritis genetics, Glomerulonephritis immunology, MicroRNAs immunology, Th17 Cells immunology
- Abstract
CD4(+) T cells play a pivotal role in the pathogenesis of autoimmune disease, including human and experimental crescentic GN. Micro-RNAs (miRs) have emerged as important regulators of immune cell development, but the impact of miRs on the regulation of the CD4(+) T cell immune response remains to be fully clarified. Here, we report that miR-155 expression is upregulated in the kidneys of patients with ANCA-associated crescentic GN and a murine model of crescentic GN (nephrotoxic nephritis). To elucidate the potential role of miR-155 in T cell-mediated inflammation, nephritis was induced in miR-155(-/-) and wild-type mice. The systemic and renal nephritogenic TH17 immune response decreased markedly in nephritic miR-155(-/-) mice. Consistent with this finding, miR-155-deficient mice developed less severe nephritis, with reduced histologic and functional injury. Adoptive transfer of miR-155(-/-) and wild-type CD4(+) T cells into nephritic recombination activating gene 1-deficient (Rag-1(-/-)) mice showed the T cell-intrinsic importance of miR-155 for the stability of pathogenic TH17 immunity. These findings indicate that miR-155 drives the TH17 immune response and tissue injury in experimental crescentic GN and show that miR-155 is a potential therapeutic target in TH17-mediated diseases.
- Published
- 2013
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36. Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease.
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Stege G, Vos PJ, Dekhuijzen PN, Hilkens PH, van de Ven MJ, Heijdra YF, and van den Elshout FJ
- Subjects
- Aged, Arousal physiology, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Polysomnography methods, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive physiopathology, Signal Processing, Computer-Assisted, Sleep Apnea, Obstructive diagnosis, Sleep Apnea, Obstructive physiopathology
- Abstract
Purpose: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis., Methods: In a retrospective study, the full-night polysomnographic recordings of patients with and without COPD were analyzed automatically by Matrix Sleep Analysis software and manually. The outcomes of manual and automated analyses in both groups were compared using Bland-Altman plots and Students' paired t tests., Results: Fifty PSGs from patients with COPD and 57 PSGs from patients without COPD were included. In both study groups, agreement between manual and automated analysis was poor in nearly all sleep and respiratory parameters, like total sleep time, sleep efficiency, sleep latency, amount of rapid eye movement sleep and other sleep stages, number of arousals, apnea-hypopnea index, and desaturation index., Conclusion: Automated analysis of PSGs by the studied automated system in patients with COPD has poor agreement with manual analysis when looking at sleep and respiratory parameters and should, therefore, not replace the manual analysis of PSG recordings in patients with COPD.
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- 2013
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37. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.
- Author
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Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, Harendza S, Helmchen UM, and Stahl RA
- Subjects
- Adult, Aged, Biomarkers blood, Biopsy, Case-Control Studies, Creatinine blood, Female, Glomerulonephritis, Membranous genetics, Glomerulonephritis, Membranous pathology, Humans, Immunohistochemistry, Kidney Glomerulus pathology, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Proteinuria blood, Proteinuria immunology, RNA, Messenger analysis, Receptors, Phospholipase A2 genetics, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Autoantibodies blood, Glomerulonephritis, Membranous blood, Glomerulonephritis, Membranous immunology, Kidney Glomerulus chemistry, Kidney Glomerulus immunology, Receptors, Phospholipase A2 analysis, Receptors, Phospholipase A2 immunology
- Abstract
The M-type phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy with detectable autoantibodies in the serum of up to 70% of patients. In retrospective studies, the PLA2R-autoantibody titer in the serum was sometimes negative indicating their measurement alone may be inconclusive. In order to better differentiate between primary and secondary membranous nephropathy, we conducted a prospective study that included 88 patients with a histologic diagnosis of membranous nephropathy. Immunohistochemical analysis for PLA2R was faintly positive in kidneys from normal individuals and patients with various other glomerular injuries. In 61 of the 88 patients, PLA2R expression was strongly positive in glomeruli, and in 60 of these patients PLA2R autoantibodies were also detected in the serum. The 27 patients negative for serum PLA2R autoantibodies were faintly positive for PLA2R staining in glomeruli and in 15 of these patients a secondary cause was found. The remaining 12 patients have a yet undetected secondary cause of membranous nephropathy or have different glomerular antigens other than PLA2R. Thus, increased staining for PLA2R in glomeruli of renal biopsies tightly correlates with the presence of PLA2R autoantibodies in the serum and this may help discriminate between primary and secondary membranous nephropathy.
- Published
- 2012
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38. Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD.
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Stege G, Heijdra YF, van den Elshout FJ, van de Ven MJ, de Bruijn PJ, van Sorge AA, Dekhuijzen PN, and Vos PJ
- Subjects
- Cross-Over Studies, Double-Blind Method, Female, Humans, Hypercapnia drug therapy, Hypercapnia physiopathology, Male, Middle Aged, Netherlands, Oximetry, Polysomnography, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Gas Exchange physiology, Sleep Apnea Syndromes physiopathology, Treatment Outcome, Dyspnea drug therapy, Hypnotics and Sedatives therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy, Pulmonary Gas Exchange drug effects, Sleep Apnea Syndromes drug therapy, Temazepam therapeutic use
- Abstract
Background: Benzodiazepines can improve sleep quality, but are also thought to cause respiratory depression in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the effects of temazepam on indices of circadian respiratory function, dyspnea, sleep quality, and sleepiness in patients with severe COPD and insomnia., Methods: In a double-blind, randomized, placebo-controlled, cross-over study in 14 stable patients with COPD (mean FEV(1) 0.99+/-0.3L) with insomnia, polysomnography with continuous transcutaneous capnography and oximetry, arterial gas sampling, hypercapnic ventilatory response, multiple sleep latency test, Epworth Sleepiness Scale, dyspnea and sleep visual analogue scales (VAS) were performed at baseline, after one week of temazepam 10mg at bedtime and after one week of placebo., Results: Temazepam did not cause statistically significant changes in mean transcutaneous carbon dioxide tension during sleep compared to placebo (5.9+/-1.0 kPa vs. 6.3+/-1.4 kPa, p-value 0.27), nor in mean oxygen saturation (92+/-3% vs. 92+/-2%, p-value 0.31), nor in any of the other investigated variables, except for the total sleep time and sleep latency VAS, which improved with temazepam., Conclusions: One week usage of temazepam 10mg does not influence circadian respiratory function, dyspnea, and sleepiness in patients with stable, severe, normocapnic COPD and insomnia and it improves total sleep time and subjective sleep latency. However, this is a preliminary explorative study for assessing the feasibility to perform a larger study on this topic. The clinical implications of this study are very limited., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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39. Accuracy of transcutaneous carbon dioxide tension measurements during cardiopulmonary exercise testing.
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Stege G, van den Elshout FJ, Heijdra YF, van de Ven MJ, Dekhuijzen PN, and Vos PJ
- Subjects
- Aged, Electrocardiography, Female, Heart Rate, Humans, Male, Middle Aged, Prospective Studies, Blood Gas Monitoring, Transcutaneous, Exercise Test
- Abstract
Background: Measurements of transcutaneous carbon dioxide tension (PtcCO(2)) with current devices are proven to provide clinically acceptable agreement with measurements of partial arterial carbon dioxide tension (PaCO(2)) in several settings but not during cardiopulmonary exercise testing (CPET)., Objectives: The primary objective of this study was to investigate the agreement between PaCO(2) and PtcCO(2) measurements (using a Tosca 500 with a Tosca sensor 92) during CPET. A secondary objective was to investigate the agreement between arterial and transcutaneous oxygen saturation (SaO(2), SpO(2)) as measured with this sensor during CPET., Methods: In patients with various pulmonary diseases, PtcCO(2) and SpO(2) were continuously measured and compared with arterial blood gas samples during CPET. A maximum bias of 0.5 kPa and 95% limits of agreement (LOA) of 1 kPa between carbon dioxide pressure (PCO(2)) measurements were determined as clinically acceptable., Results: In total 101 'paired' arterial and transcutaneous measurements were obtained from 21 patients. Bias between PaCO(2) and PtcCO(2) was -0.03 kPa with LOA from -0.78 to 0.71 kPa. Bias between SaO(2) and SpO(2) was -1.0% with LOA from -2.83 to 0.83%., Conclusions: Transcutaneous estimations of PCO(2) and SpO(2) are accurate and can be used in CPET, circumvening the need for arterial cannulation.
- Published
- 2009
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40. Sleep, hypnotics and chronic obstructive pulmonary disease.
- Author
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Stege G, Vos PJ, van den Elshout FJ, Richard Dekhuijzen PN, van de Ven MJ, and Heijdra YF
- Subjects
- Humans, Hypnotics and Sedatives therapeutic use, Respiratory Mechanics drug effects, Respiratory Mechanics physiology, Sleep physiology, Sleep Wake Disorders drug therapy, Hypnotics and Sedatives adverse effects, Pulmonary Disease, Chronic Obstructive complications, Sleep Wake Disorders etiology
- Abstract
The quality of sleep is significantly compromised in many patients with chronic obstructive pulmonary disease (COPD) and may be further diminished when certain comorbidities are present. A reduced sleep quality is associated with daytime consequences like fatigue, psychiatric problems and an impaired quality of life. Sleep induces physiologic alterations in respiratory function, which can become pathologic and may provoke or worsen hypoxemia and hypercapnia in COPD. Dyspnea, cough and excessive mucus production should be optimised to minimise causes for sleep disturbance. Pharmacological therapy may be helpful; sedatives like benzodiazepines and non-benzodiazepine benzodiazepine-receptor agonists (NBBRAs) are (equally) effective in improving sleep quality. Whether or not these hypnotics produce serious adverse respiratory effects during sleep, remains unclear due to opposing studies. Therefore, their use should be as short as possible.
- Published
- 2008
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41. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia.
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Stege G, Fenton A, and Jaffray B
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple epidemiology, Abnormalities, Multiple mortality, Abnormalities, Multiple therapy, Cohort Studies, Fetal Death epidemiology, Hernia, Diaphragmatic epidemiology, Hernia, Diaphragmatic therapy, Humans, Incidence, Infant, Newborn, Infant, Newborn, Diseases diagnosis, Infant, Newborn, Diseases epidemiology, Infant, Newborn, Diseases mortality, Infant, Newborn, Diseases therapy, Neonatal Screening methods, Neonatal Screening trends, Prenatal Diagnosis statistics & numerical data, Prenatal Diagnosis trends, Retrospective Studies, Survival Analysis, Survival Rate, Hernia, Diaphragmatic mortality, Hernias, Diaphragmatic, Congenital, Infant Mortality trends
- Abstract
Objective: Reported survival in congenital diaphragmatic hernia (CDH) fails to allow for case selection bias. This study reports the incidence of CDH in a geographically defined population over 11 years and assesses the effect of new therapies (high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, inhaled nitric oxide, and delayed surgery) on survival when case selection is avoided., Methods: A retrospective review of cases from a regional case registry, the Northern Region Congenital Anomaly Survey, was conducted., Results: A total of 185 cases were identified. Mortality was 62% and did not vary significantly during the study period. Mortality was unaffected by the introduction of new therapies. There was a significant inverse correlation between the rate of elective termination and survival of live borns. The presence of an additional anomaly increased mortality to 79%., Conclusions: The mortality of CDH when complete case ascertainment is achieved is unaffected by new therapies. The survival rate is principally determined by the rate of antenatal termination and the incidence of associated anomalies. Reports of improved survival of CDH should be interpreted with caution, as variations in outcome are more likely to be explained by case selection artifact.
- Published
- 2003
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42. The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity.
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Stege GJ, Renkawek K, Overkamp PS, Verschuure P, van Rijk AF, Reijnen-Aalbers A, Boelens WC, Bosman GJ, and de Jong WW
- Subjects
- Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Animals, Animals, Newborn, Apoptosis drug effects, Benzothiazoles, Cell Survival drug effects, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Hippocampus, Neurons drug effects, Neurons metabolism, Neurons ultrastructure, Peptide Fragments metabolism, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Plaque, Amyloid ultrastructure, Protein Binding drug effects, Protein Structure, Secondary drug effects, Rats, Thiazoles, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides toxicity, Crystallins pharmacology, Molecular Chaperones pharmacology, Neurons pathology, Peptide Fragments chemistry, Peptide Fragments toxicity, Plaque, Amyloid drug effects
- Abstract
Amyloid beta (Abeta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD). As a result of conformational changes, Abeta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alphaB-crystallin and Hsp27 occur at increased levels and colocalize with these plaques. In vitro, sHsps act as molecular chaperones that recognize unfolding peptides and prevent their aggregation. The presence of sHsps in AD brains may thus reflect an attempt to prevent amyloid fibril formation and toxicity. Here we report that alphaB-crystallin does indeed prevent in vitro fibril formation of Abeta(1-40). However, rather than protecting cultured neurons against Abeta(1-40) toxicity, alphaB-crystallin actually increases the toxic effect. This indicates that the interaction of alphaB-crystallin with conformationally altering Abeta(1-40) may keep the latter in a nonfibrillar, yet highly toxic form., (Copyright 1999 Academic Press.)
- Published
- 1999
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43. Dementia, gliosis and expression of the small heat shock proteins hsp27 and alpha B-crystallin in Parkinson's disease.
- Author
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Renkawek K, Stege GJ, and Bosman GJ
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease pathology, Brain metabolism, Brain pathology, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles pathology, Parkinson Disease pathology, Plaque, Amyloid pathology, Reference Values, Crystallins metabolism, Dementia etiology, Gliosis etiology, Heat-Shock Proteins metabolism, Parkinson Disease complications, Parkinson Disease metabolism
- Abstract
Cognitive impairment and dementia are common in the later stages of Parkinson's disease (PD). Neuropathological examination of demented PD (PDD) patients often reveals changes that are typical of Alzheimer's disease (AD). In AD, there is a massive reactive gliosis and increased expression of the small heat shock proteins (hsp) hsp27 and alpha B-crystallin. Since these proteins are characteristic for reactive astrocytes in AD, we investigated their expression in the brains of PDD patients. The results were compared with those obtained in the brains of non-demented PD patients. We found (1) no detectable expression of hsp in PD without dementia, and low expression in PD with mild dementia; (2) reactive gliosis and increased expression of hsp in the cortex of PDD brains; (3) a strong association between hsp immunoreactivity and the severity of the AD-specific changes, especially with the number of tangles in the hippocampus; (4) a distinct immunoreaction of alpha B-crystallin in microglia in the substantia nigra and in the hippocampus in PDD. These results indicate that astrocytes react to the disease conditions in AD and in PDD in a similar way, namely by the increased expression of small heat shock proteins, and present additional evidence for the thesis that the pathology of the dementia in PD is related to that in AD.
- Published
- 1999
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44. The short 5' untranslated region of the betaA3/A1-crystallin mRNA is responsible for leaky ribosomal scanning.
- Author
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Werten PJ, Stege GJ, and de Jong WW
- Subjects
- 5' Untranslated Regions genetics, 5' Untranslated Regions physiology, Animals, Base Sequence, CHO Cells, Codon, Initiator genetics, Cricetinae, Crystallins analysis, DNA, Recombinant, Gene Expression physiology, Genetic Vectors, RNA, Messenger genetics, Transcription, Genetic, Crystallins genetics, Protein Biosynthesis physiology, Protein Isoforms genetics, Untranslated Regions physiology
- Abstract
Leaky ribosomal scanning allows the expression of multiple proteins from a single mRNA by occasionally skipping the first start codon, and initiating translation at a subsequent one. BetaA3- and betaA1-crystallin, two members of the beta-crystallin family of vertebrate eye lens proteins, are produced via this mechanism, of which, until now, only very few examples have been found in eukaryotic genes. Since the two start codons on the betaA3/A1 messenger lie in the same reading frame, the two translated proteins are identical, except for the 17 residues shorter N-terminal extension of betaA1-crystallin. It has been suggested that the very short leader (5-7 nucleotides) of the betaA3/A1 messenger might cause slippage at the first start codon, although the unfavorable context of this start codon might also be responsible. Using transient transfections, we now demonstrate that increasing the length of the leader sequence to 67 nucleotides indeed completely abolishes translation initiation at the second start codon, and thus expression of the betaA1-crystallin protein. Messengers having a leader of 5, 7 or 14 nucleotides all express both betaA3- and betaA1-crystallin at very similar relative levels.
- Published
- 1999
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45. The biochemistry of Alzheimer's disease.
- Author
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Stege GJ and Bosman GJ
- Subjects
- Alzheimer Disease pathology, Amyloid metabolism, Animals, Apolipoproteins E metabolism, Apoptosis, Humans, Membrane Proteins metabolism, Presenilin-1, Alzheimer Disease metabolism
- Abstract
In the course of the biochemical efforts devoted to elucidation of the cause(s) and mechanism(s) of neurodegeneration in Alzheimer's disease (AD), much attention has been given to the processes by which amyloid is generated from amyloid precursor protein, notwithstanding the finding that mutations in 2 other proteins, presenilin 1 and 2, are associated with early-onset, familial AD in the majority of patients. In addition, the reason why the apolipoprotein E epsilon4 allele is over-represented in patients with the sporadic form of AD is unknown. Furthermore, the degree of dementia is clearly associated more with the degree of neurofibrillary pathology than with the amyloid plaque burden. In general, amyloid formation may very well be at the end of a pathophysiological cascade, set in motion by many different triggers. This cascade could involve excessive apoptosis, followed by necrosis and inflammation. In this process, microglia as well as astrocytes are involved. Disturbance of I or more critical signal transduction processes, especially at the level of the plasma membrane, may be an important trigger. The pathogenesis of AD is complicated, but further identification of the processes of neurodegeneration will also lead to identification of the factors that make specific neurons vulnerable and, hopefully, point the way to a means to prevent neuronal degeneration at an early stage.
- Published
- 1999
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46. Rat Hsp20 confers thermoresistance in a clonal survival assay, but fails to protect coexpressed luciferase in Chinese hamster ovary cells.
- Author
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van de Klundert FAJM, van den IJssel PRLA, Stege GJ, and de Jong WW
- Subjects
- Animals, CHO Cells, Cell Survival genetics, Cricetinae, HSP20 Heat-Shock Proteins, Heat-Shock Proteins biosynthesis, Luciferases biosynthesis, Phosphoproteins biosynthesis, Rats, Temperature, Transfection, Gene Expression Regulation, Heat-Shock Proteins genetics, Luciferases genetics, Phosphoproteins genetics
- Abstract
Hsp20 is a mammalian small heat shock protein with some deviating in vitro characteristics. We now compare the in vivo cellular thermoprotective abilities of Hsp20 with those of its direct relative, alphaB-crystallin. In a clonal survival assay Chinese hamster ovary (CHO) cells stably overexpressing Hsp20 survive equally well as alphaB-crystallin-expressing cells, after a heat shock. In a transient assay, however, overexpression of Hsp20 did not result in an enhanced recovery of coexpressed firefly luciferase after heat shock, in contrast to alphaB-crystallin. This might indicate that these highly homologous stress proteins are involved in at least partially distinct protective activities in cultured cells., (Copyright 1999 Academic Press.)
- Published
- 1999
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47. Heat shock, but not the reactive state per se, induces increased expression of the small stress proteins hsp25 and alpha B-crystallin in glial cells in vitro.
- Author
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Brzyska M, Stege GJ, Renkawek K, and Bosman GJ
- Subjects
- Aging metabolism, Animals, Animals, Newborn, Astrocytes cytology, Biomarkers analysis, Brain cytology, Brain growth & development, Cells, Cultured, Glial Fibrillary Acidic Protein analysis, HSP27 Heat-Shock Proteins, Hot Temperature, Kinetics, Molecular Chaperones biosynthesis, Neuroglia cytology, Rats, Rats, Wistar, Time Factors, Astrocytes metabolism, Brain metabolism, Crystallins biosynthesis, Gene Expression Regulation, Heat-Shock Proteins biosynthesis, Neoplasm Proteins biosynthesis, Neuroglia metabolism
- Abstract
The stress proteins hsp25 and alpha B-crystallin are found in increased concentrations in reactive astrocytes of brains undergoing neurodegeneration. In order to characterize this reaction, we investigated the expression of hsp25 and alpha B-crystallin during growth and after stress (heat shock) in glial cells in vitro. In primary rat brain cultures, hsp25 was present in actively dividing astrocytes that were positive for glial fibrillary acidic protein. alpha B-crystallin was found predominantly in oligodendrocytes. Heat shock resulted in increased concentrations of hsp25 and alpha B-crystallin in astrocytes, without any detectable changes in intracellular localization, as detectable with confocal laser microscopy. These results indicate that a neurodegeneration-related increase of the small stress proteins in astrocytes in independent of gliosis per se, and may be a disease-related event.
- Published
- 1998
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48. Thermal protein denaturation and protein aggregation in cells made thermotolerant by various chemicals: role of heat shock proteins.
- Author
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Kampinga HH, Brunsting JF, Stege GJ, Burgman PW, and Konings AW
- Subjects
- Arsenites pharmacology, Diamide pharmacology, Ethanol pharmacology, HeLa Cells, Heat-Shock Proteins chemistry, Humans, Protein Conformation drug effects, Protein Denaturation drug effects, Sodium Compounds pharmacology, Temperature, Heat-Shock Proteins physiology, Proteins chemistry
- Abstract
Thermotolerance (TT) induced by sodium arsenite (A-TT: 100 microM, 1 h, 37 degrees C) was compared to heat-induced thermotolerance (H-TT: 15 min, 44 degrees C) using HeLa S3 cells. All four pretreatments led to comparable levels of thermotolerance and also induced resistance to arsenite-, ethanol-, and diamide-induced toxicity (clonogenic ability). Stress-induced expression of the major heat shock proteins (hsp27, hsc70(p73), hsp70(p72), and hsp90) was generally highest in H-TT cells and lowest in A-TT cells. Interestingly, the four types of TT cells showed distinct differences in certain aspects of resistance against thermal protein damage. Thermal protein denaturation and aggregation determined in isolated cellular membrane fractions was found to be attenuated when they were isolated from H-TT and A-TT cells but not when isolated from E-TT and D-TT cells. The heat resistance in the proteins of the membrane fraction corresponded with elevated levels of hsp70(p72) associated with the isolated membrane fractions. In the nuclear fraction, only marginal (not significant) attenuation of the formation of protein aggregates (as determined by TX-100 (in)solubility) was observed. However, the postheat recovery from heat-induced protein aggregation in the nucleus was faster in H-TT, E-TT, and D-TT cells, but not in A-TT cells. Despite the fact that elevated levels of hsp27, hsp70(p73), and hsp70(p72) were found in the TX-100 insoluble nuclear fraction derived from all TT cells, no correlation was found with the degree of resistance in terms of the accelerated recovery from nuclear protein aggregation. The only correlation between accelerated recovery from nuclear protein aggregates was that with total cellular levels of hsp27. The data indicate that heat-induced loss of clonogenic ability may be a multitarget rather than a single target event. A threshold of damage may exist in cells after exposure to heat; multiple sets of proteins in (different compartments of) the cell need to be damaged before this threshold is exceeded and the cell dies. As a consequence, stabilization of only one of these sets of proteins is already sufficient to render cells thermotolerant at the clonogenic level.
- Published
- 1995
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49. Cells overexpressing Hsp27 show accelerated recovery from heat-induced nuclear protein aggregation.
- Author
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Kampinga HH, Brunsting JF, Stege GJ, Konings AW, and Landry J
- Subjects
- Animals, Cell Line, Clone Cells, Cricetinae, Heat-Shock Proteins biosynthesis, Hot Temperature, Humans, Protein Denaturation, Recombinant Proteins biosynthesis, Recombinant Proteins metabolism, Cell Nucleus metabolism, Cell Survival physiology, Heat-Shock Proteins physiology, Nuclear Proteins metabolism, Transfection
- Abstract
Protein denaturation/aggregation upon cell exposure to heat shock is a likely cause of cell death. In the nucleus, protein aggregation has often been correlated to inhibition of nuclear located processes and heat-induced cell killing. In Chinese hamster O23 cells made thermotolerant by a prior heating (20'44 degrees C + 10h 37 degrees C) which induces the whole spectrum of heat shock proteins (hsps), the extent of nuclear protein aggregation during heat shock is reduced and the rate of recovery from aggregation after heat shock is enhanced. In contrast, a heat resistant Chinese hamster cell line overexpressing only hsp27 shows an unaltered sensitivity to formation of nuclear protein aggregates by heat, but shows the same enhanced rate of recovery from nuclear protein aggregation as thermotolerant cells. This suggests that accelerated recovery of protein aggregation could be partly responsible for hsp27-mediated thermoprotection.
- Published
- 1994
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50. Importance of the ATP-binding domain and nucleolar localization domain of HSP72 in the protection of nuclear proteins against heat-induced aggregation.
- Author
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Stege GJ, Li L, Kampinga HH, Konings AW, and Li GC
- Subjects
- Adaptation, Biological, Adenosine Triphosphate metabolism, Animals, Base Sequence, Cell Compartmentation, Cell Line, Cell Nucleolus physiology, HSP72 Heat-Shock Proteins, Heat-Shock Proteins genetics, Hot Temperature adverse effects, Humans, Molecular Sequence Data, Protein Denaturation, Rats, Recombinant Proteins metabolism, Structure-Activity Relationship, Heat-Shock Proteins physiology, Nuclear Proteins physiology
- Abstract
Heat treatment of cells results in an increased protein content of nuclei when isolated after the heat treatment (intranuclear protein aggregation). In a previous study, the role of HSP72 was investigated using Rat-1 fibroblasts stably transfected with the human HSP72 gene. It was observed that the expression of human HSP72 in Rat-1 cells (HR cells) confers heat resistance. The initial heat-induced increase in the nuclear protein content was lower in HR cells as compared to the parent Rat-1 cells. In the present communication, the effects of overexpression of intact or mutant human HSP72 in Rat-1 cells on heat-induced increase in intranuclear protein aggregation and their relationship to cells' thermal sensitivity were examined. Four closely related cell lines were used for this study: Rat-1 cells which constitutively expressed the intact human HSP72, or mutant human HSP72 either missing its ATP-binding domain or nucleolar localization domain, and wild type Rat-1 cells. Our results show that expression of the intact human HSP72 or mutant human HSP72 missing its ATP-binding domain confers heat resistance and protects cells against heat-induced intranuclear protein aggregation. On the other hand, cells expressing mutant human HSP72 missing its nucleolar localization domain demonstrated heat shock responses similar to control Rat-1 cells.
- Published
- 1994
- Full Text
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