| 1. |
- Rozsas, Anita, et al.
(author)
-
Erythropoietin Receptor Expression Is a Potential Prognostic Factor in Human Lung Adenocarcinoma
- 2013
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
-
Journal article (peer-reviewed)abstract
- Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPO alpha were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPO alpha with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPO alpha treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPO alpha significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPO alpha treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.
|
|
| 2. |
- Biurrun, Idoia, et al.
(author)
-
Benchmarking plant diversity of Palaearctic grasslands and other open habitats
- 2021
-
In: Journal of Vegetation Science. - Oxford : John Wiley & Sons. - 1100-9233 .- 1654-1103. ; 32:4
-
Journal article (peer-reviewed)abstract
- Journal of Vegetation Science published by John Wiley & Sons Ltd on behalf of International Association for Vegetation Science.Aims: Understanding fine-grain diversity patterns across large spatial extents is fundamental for macroecological research and biodiversity conservation. Using the GrassPlot database, we provide benchmarks of fine-grain richness values of Palaearctic open habitats for vascular plants, bryophytes, lichens and complete vegetation (i.e., the sum of the former three groups). Location: Palaearctic biogeographic realm. Methods: We used 126,524 plots of eight standard grain sizes from the GrassPlot database: 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 and 1,000 m2 and calculated the mean richness and standard deviations, as well as maximum, minimum, median, and first and third quartiles for each combination of grain size, taxonomic group, biome, region, vegetation type and phytosociological class. Results: Patterns of plant diversity in vegetation types and biomes differ across grain sizes and taxonomic groups. Overall, secondary (mostly semi-natural) grasslands and natural grasslands are the richest vegetation type. The open-access file ”GrassPlot Diversity Benchmarks” and the web tool “GrassPlot Diversity Explorer” are now available online (https://edgg.org/databases/GrasslandDiversityExplorer) and provide more insights into species richness patterns in the Palaearctic open habitats. Conclusions: The GrassPlot Diversity Benchmarks provide high-quality data on species richness in open habitat types across the Palaearctic. These benchmark data can be used in vegetation ecology, macroecology, biodiversity conservation and data quality checking. While the amount of data in the underlying GrassPlot database and their spatial coverage are smaller than in other extensive vegetation-plot databases, species recordings in GrassPlot are on average more complete, making it a valuable complementary data source in macroecology. © 2021 The Authors.
|
|
| 3. |
- Patterson, Nick, et al.
(author)
-
Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
-
Journal article (peer-reviewed)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
|
|
| 4. |
- Tisza, Anna, et al.
(author)
-
Laser ablation-inductively coupled plasma-mass spectrometry analysis reveals differences in chemotherapeutic drug distribution in surgically resected pleural mesothelioma
- 2023
-
In: British Journal of Clinical Pharmacology. - 0306-5251. ; 89:11, s. 3364-3374
-
Journal article (peer-reviewed)abstract
- Aims: Pleural mesothelioma (PM) is a highly aggressive thoracic tumour with poor prognosis. Although reduced tissue drug accumulation is one of the key features of platinum (Pt) resistance, little is known about Pt distribution in human PM. Methods: We assessed Pt levels of blood samples and surgically resected specimens from 25 PM patients who had received neoadjuvant Pt-based chemotherapy (CHT). Pt levels and tissue distributions were measured by laser ablation-inductively coupled plasma-mass spectrometry and correlated with clinicopathological features. Results: In surgically resected PM specimens, mean Pt levels of nontumourous (fibrotic) areas were significantly higher (vs tumourous regions, P = 0.0031). No major heterogeneity of Pt distribution was seen within the tumourous areas. Pt levels correlated neither with the microvessel area nor with apoptosis rate in the tumourous or nontumourous regions. A significant positive correlation was found between serum and both full tissue section and tumourous area mean Pt levels (r = 0.532, P = 0.006, 95% confidence interval [95% CI] 0.161-0.771 and r = 0.415, P = 0.039, 95% CI 0.011-0.702, respectively). Furthermore, a significant negative correlation was detected between serum Pt concentrations and elapsed time from the last cycle of CHT (r = −0.474, P = 0.017, 95% CI −0.738-−0.084). Serum Pt levels correlated negatively with overall survival (OS) (P = 0.029). Conclusions: There are major differences in drug distribution between tumourous and nontumourous areas of PM specimens. Serum Pt levels significantly correlate with full section and tumourous area average Pt levels, elapsed time from the last CHT cycle, and OS. Further studies investigating clinicopathological factors that modulate tissue Pt concentration and distribution are warranted.
|
|
| 5. |
- Torok, Szilvia, et al.
(author)
-
Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors
- 2017
-
In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 7:2, s. 400-412
-
Journal article (peer-reviewed)abstract
- Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.
|
|
| 6. |
- Török, Szilvia, et al.
(author)
-
Localization of sunitinib, its metabolites and its target receptors in tumor bearing mice: a MALDI mass spectrometry imaging study
- 2015
-
In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 172:4, s. 1148-1163
-
Journal article (peer-reviewed)abstract
- A functional blood vessel network is essential for maintaining the necessary oxygen and nutrient levels in solid tumors. Thus, the inhibition of blood vessel growth by different antiangiogenic agents has become one of the most important topics in cancer research over the past few decades. The in vitro studies of these drugs are promising, but both the in vivo and the clinical experiences are controversial. Therefore, investigating the pharmacokinetic parameters of these compounds is a pivotal issue in drug development. In this study, the detection and the adsorption, distribution, metabolism, elimination (ADME) of the antiangiogenic receptor tyrosine kinase inhibitor (RTKI) sunitinib is analyzed in a subcutaneous syngeneic murine tumor model of colorectal cancer. The parent molecule of sunitinib was detected at m/z 399.218 with fragment ions at m/z 326.1 and 283.1 with matrix assisted laser desorption ionization (MALDI) technique. Metabolites of the drug were measured in blood samples and main metabolites were found in tumor, liver and kidney tissues at m/z 371.188, 397.203 and 415.214. Tissue distribution of the drug and its metabolites showed an overlapping pattern by MALDI imaging. The present study supports the role of the MALDI technique in the ADME characterization of drug candidates in preclinical drug development.
|
|
| 7. |
- Abahazi, Emese, et al.
(author)
-
Covalently immobilized Trp60Cys mutant of omega‰-transaminase from Chromobacterium violaceum for kinetic resolution of racemic amines in batch and continuous-flow modes
- 2018
-
In: Biochemical engineering journal. - : Elsevier. - 1369-703X .- 1873-295X. ; 132, s. 270-278
-
Journal article (peer-reviewed)abstract
- Covalent immobilization of an engineered omega-transaminase mutant Trp60Cys from Chromobacterium violaceum (CvTAW60C) was performed on bisepoxide-activated aminoalkyl resins. Activity of the various CvTAW60C preparations was evaluated in kinetic resolution of four racemic amines (rac-1a–d). The most active EA-G-CvTAW60C preparation (CvTAW60C attached to polymeric resin with ethylamine function activated with glycerol diglycidyl ether—EA-G) could perform the kinetic resolution of racemic 4-phenylbutan-2-amine (rac-1a) over 49% conversion up to 19 consecutive reaction cycles or in media containing up to 50% v/v DMSO as cosolvent in batch mode reactions. The immobilization process of CvTAW60C onto the EA-G resin filled in stainless steel bioreactors was also tested in flow-through mode. Kinetic resolution of three racemic amines containing aromatic moieties (rac-1a-c) was performed in continuous-flow mode resulting in easy-to-separate mixture of the corresponding ketone (2a–c) and the non-converted (R)-amine in high enantiopurity (ee(R)-1a-c ≥ 96%).
|
|
| 8. |
- Bencze, Janos, et al.
(author)
-
Comparison of Semi-Quantitative Scoring and Artificial Intelligence Aided Digital Image Analysis of Chromogenic Immunohistochemistry
- 2022
-
In: Biomolecules. - : MDPI AG. - 2218-273X. ; 12
-
Journal article (peer-reviewed)abstract
- Semi-quantitative scoring is a method that is widely used to estimate the quantity of proteins on chromogen-labelled immunohistochemical (IHC) tissue sections. However, it suffers from several disadvantages, including its lack of objectivity and the fact that it is a time-consuming process. Our aim was to test a recently established artificial intelligence (AI)-aided digital image analysis platform, Pathronus, and to compare it to conventional scoring by five observers on chromogenic IHC-stained slides belonging to three experimental groups. Because Pathronus operates on grayscale 0-255 values, we transformed the data to a seven-point scale for use by pathologists and scientists. The accuracy of these methods was evaluated by comparing statistical significance among groups with quantitative fluorescent IHC reference data on subsequent tissue sections. The pairwise inter-rater reliability of the scoring and converted Pathronus data varied from poor to moderate with Cohen's kappa, and overall agreement was poor within every experimental group using Fleiss' kappa. Only the original and converted that were obtained from Pathronus original were able to reproduce the statistical significance among the groups that were determined by the reference method. In this study, we present an AI-aided software that can identify cells of interest, differentiate among organelles, protein specific chromogenic labelling, and nuclear counterstaining after an initial training period, providing a feasible and more accurate alternative to semi-quantitative scoring.
|
|
| 9. |
- Bense, Laszlo, et al.
(author)
-
Right main bronchus perforation detected by 3D-image
- 2011
-
In: BMJ Case Reports. - : BMJ. - 1757-790X.
-
Journal article (peer-reviewed)abstract
- A male metal worker, who has never smoked, contracted debilitating dyspnoea in 2003 which then deteriorated until 2007. Spirometry and chest x-rays provided no diagnosis. A 3D-image of the airways was reconstructed from a high-resolution CT (HRCT) in 2007, showing peribronchial air on the right side, mostly along the presegmental airways. After digital subtraction of the image of the peribronchial air, a hole on the cranial side of the right main bronchus was detected. The perforation could be identified at the re-examination of HRCTs in 2007 and 2009, but not in 2010 when it had possibly healed. The occupational exposure of the patient to evaporating chemicals might have contributed to the perforation and hampered its healing. A 3D HRCT reconstruction should be considered to detect bronchial anomalies, including wall-perforation, when unexplained dyspnoea or other chest symptoms call for extended investigation.
|
|
| 10. |
- Berta, Judit, et al.
(author)
-
Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis
- 2021
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.
|
|
