| 1. |
- Kamposioras, Konstantinos, et al.
(författare)
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Synthesis of Recommendations From 25 Countries and 31 Oncology Societies : How to Navigate Through Covid-19 Labyrinth
- 2020
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Ingår i: Frontiers in Oncology. - : Frontiers. - 2234-943X. ; 10
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Pandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak.Methods: We did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies.Results: By synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis.Conclusions: In an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally.
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| 2. |
- Koutsioumpa, Marina, et al.
(författare)
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Interplay between αvβ3 Integrin and Nucleolin Regulates Human Endothelial and Glioma Cell Migration
- 2013
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:1, s. 343-354
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Tidskriftsartikel (refereegranskat)abstract
- The multifunctional protein nucleolin (NCL) is overexpressed on the surface of activated endothelial and tumor cells and mediates the stimulatory actions of several angiogenic growth factors, such as pleiotrophin (PTN). Because α(v)β(3) integrin is also required for PTN-induced cell migration, the aim of the present work was to study the interplay between NCL and α(v)β(3) by using biochemical, immunofluorescence, and proximity ligation assays in cells with genetically altered expression of the studied molecules. Interestingly, cell surface NCL localization was detected only in cells expressing α(v)β(3) and depended on the phosphorylation of β(3) at Tyr(773) through receptor protein-tyrosine phosphatase β/ζ (RPTPβ/ζ) and c-Src activation. Downstream of α(v)β(3,) PI3K activity mediated this phenomenon and cell surface NCL was found to interact with both α(v)β(3) and RPTPβ/ζ. Positive correlation of cell surface NCL and α(v)β(3) expression was also observed in human glioblastoma tissue arrays, and inhibition of cell migration by cell surface NCL antagonists was observed only in cells expressing α(v)β(3). Collectively, these data suggest that both expression and β(3) integrin phosphorylation at Tyr(773) determine the cell surface localization of NCL downstream of the RPTPβ/ζ/c-Src signaling cascade and can be used as a biomarker for the use of cell surface NCL antagonists as anticancer agents.
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| 3. |
- Lampropoulou, Evgenia, et al.
(författare)
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Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTP beta/zeta) and alpha(nu)beta(3) integrin. Screening for proteins that interact with RPTP beta/zeta and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclindependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTP beta/zeta interaction and revealed the molecular association of CDK5 and RPTP beta/zeta. In endothelial cells, PTN activates CDK5 in an RPTP beta/zeta- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, alpha(nu)beta(3) and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-alpha] carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTP beta/zeta-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties.
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| 4. |
- Papadimitriou, Elsa, et al.
(författare)
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TGFβ-induced early activation of the small GTPase RhoA is Smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2
- 2011
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Ingår i: Cellular Physiology and Biochemistry. - Basel : Karger. - 1015-8987 .- 1421-9778. ; 28:2, s. 229-238
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Tidskriftsartikel (refereegranskat)abstract
- TGFβ has been shown to induce short- and long-term actin reorganization controlled by Rho-GTPase signaling. A number of direct Smad target genes, rapidly activated by TGFβ, have been previously reported to control the long-term Rho activation and actin reorganization. However, the molecular mechanisms that regulate the prompt stimulation of Rho GTPases by TGFβ remain unknown. In the present study we report that TGFβ rapidly stimulated RhoA and RhoB activation in JEG3 choriocarcinoma cells that lack endogenous Smad3. Inhibition of Smad2 expression via siRNA-mediated silencing or by blocking its phosphorylation using the TβRI inhibitor SB431542 did not prevent the early RhoA/B activation by TGFβ indicating that this effect is Smad2/3-independent. Pre-treatment of the cells with the general tyrosine kinase inhibitor Genistein blocked the TGFβ-induced early RhoA activation. In line with this finding, TGFβ-stimulation resulted in a quick activation of the non-receptor tyrosine kinase Src, followed by activation of the guanine nucleotide exchange factor (GEF) Vav2. Inhibition of Src kinase by the selective inhibitor of the Src family tyrosine kinases PP2 totally blocked the early TGFβ-induced RhoA activation. Similarly, Vav2 silencing via siRNA reduced the TGFβ-induced RhoA activation implying that the rapid Src/Vav2 stimulation was effective in regulating RhoA activation. Our present findings provide for the first time a clear evidence for the role of Src and Vav2-GEF in the early Smad2/3-independent Rho activation by TGFβ.
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| 5. |
- Sarris, Theodore E., et al.
(författare)
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Daedalus MASE (mission assessment through simulation exercise): A toolset for analysis of in situ missions and for processing global circulation model outputs in the lower thermosphere-ionosphere
- 2023
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Ingår i: Frontiers in Astronomy and Space Sciences. - : Frontiers Media SA. - 2296-987X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Daedalus MASE (Mission Assessment through Simulation Exercise) is an open-source package of scientific analysis tools aimed at research in the Lower Thermosphere-Ionosphere (LTI). It was created with the purpose to assess the performance and demonstrate closure of the mission objectives of Daedalus, a mission concept targeting to perform in-situ measurements in the LTI. However, through its successful usage as a mission-simulator toolset, Daedalus MASE has evolved to encompass numerous capabilities related to LTI science and modeling. Inputs are geophysical observables in the LTI, which can be obtained either through in-situ measurements from spacecraft and rockets, or through Global Circulation Models (GCM). These include ion, neutral and electron densities, ion and neutral composition, ion, electron and neutral temperatures, ion drifts, neutral winds, electric field, and magnetic field. In the examples presented, these geophysical observables are obtained through NCAR’s Thermosphere-Ionosphere-Electrodynamics General Circulation Model. Capabilities of Daedalus MASE include: 1) Calculations of products that are derived from the above geophysical observables, such as Joule heating, energy transfer rates between species, electrical currents, electrical conductivity, ion-neutral collision frequencies between all combinations of species, as well as height-integrations of derived products. 2) Calculation and cross-comparison of collision frequencies and estimates of the effect of using different models of collision frequencies into derived products. 3) Calculation of the uncertainties of derived products based on the uncertainties of the geophysical observables, due to instrument errors or to uncertainties in measurement techniques. 4) Routines for the along-orbit interpolation within gridded datasets of GCMs. 5) Routines for the calculation of the global coverage of an in situ mission in regions of interest and for various conditions of solar and geomagnetic activity. 6) Calculations of the statistical significance of obtaining the primary and derived products throughout an in situ mission’s lifetime. 7) Routines for the visualization of 3D datasets of GCMs and of measurements along orbit. Daedalus MASE code is accompanied by a set of Jupyter Notebooks, incorporating all required theory, references, codes and plotting in a user-friendly environment. Daedalus MASE is developed and maintained at the Department for Electrical and Computer Engineering of the Democritus University of Thrace, with key contributions from several partner institutions.
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| 6. |
- Tabernero, Josep, et al.
(författare)
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A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer : The AGENT Trial
- 2024
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Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 4:1, s. 28-37
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin).Experimental Design:AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR).Results:Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin.Conclusions:The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes.Significance:This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.
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