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Povzetek: Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor–ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α–CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α–CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.
Ključne besede: glioblastoma, glioblastoma stem cells, niches, acute myeloid leukemia, hematopoietic stem cells, bone marrow, C-X-C receptor type 4, stromal-derived factor-1 ▫$[alpha]$▫, plerixafor
Objavljeno v DiRROS: 06.08.2024; Ogledov: 71; Prenosov: 121
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Povzetek: OBJECTIVE Increased levels of vascular endothelial growth factor (VEGF) in human plasma samples have suggested that circulating VEGF is a cause of endothelial dysfunction in diabetes mellitus. However, artificial release of VEGF from platelets as a source of VEGF in plasma samples, as also occurs in serum samples, has not been ruled out in these studies. RESEARCH DESIGN AND METHODS We determined VEGF levels in plasma collected in both citrate and PECT, a medium that inactivates platelets, in a cross-sectional cohort of 21 healthy subjects and 64 patients with type 1 diabetes. In addition, we evaluated whether VEGF levels in both types of plasma correlated with the presence of diabetes, glycemic control, markers of in vivo or ex vivo platelet activation, and degree of diabetic retinopathy and nephropathy. RESULTS VEGF levels were invariably low in PECT plasma of both nondiabetic and diabetic subjects and were unrelated to any other diabetes-related variable studied. In contrast, VEGF levels in citrate plasma were 150% higher in diabetic patients than in control subjects and correlated with diabetes-related variables. Multiple linear regression analysis showed that levels of platelet factor 4, a marker for ex vivo platelet activation, and HbA1c were the independent predictors of VEGF levels in citrate plasma. Platelet activation, in vivo and ex vivo, was similar in diabetic persons and control subjects. CONCLUSIONS Like serum, citrate plasma is not suitable for reliable measurements of circulating VEGF. The low levels of VEGF in vivo, as represented by measurements in PECT plasma in our study, do not support a role of circulating VEGF in endothelial dysfunction in type 1 diabetes. Higher levels of VEGF in citrate plasma samples of diabetic persons do not represent the in vivo situation, but mainly originate from higher artificial ex vivo release from platelets correlating with the degree of glycemic control.
Ključne besede: vascular endothelial growth factor, VEGF, diabetes mellitus
Objavljeno v DiRROS: 02.08.2024; Ogledov: 128; Prenosov: 63
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Povzetek: Background. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, routine clinical practice is different between countries/institutions. Patients and methods. The REFLECT study (NCT04031898) is a retrospective medical chart review that explored real-life treatment and outcomes of EGFRm NSCLC patients receiving first-line (1L) first-/second-generation (1G/2G) EGFR TKIs in 8 countries. This study included adult patients with documented advanced/metastatic EGFRm NSCLC with 1L 1G/2G EGFR TKIs initiated between Jan 2015 – Jun 2018. We reviewed data on clinical characteristics, treatments, EGFR/T790M testing patterns, and survival outcomes. Here, we report data from 120 medical charts in 3 study sites from Slovenia. Results. The Slovenian cohort (median age 70 years, 74% females) received 37% erlotinib, 32% afatinib, 31% gefitinib. At the time of data collection, 94 (78%) discontinuations of 1L TKI, and 89 (74%) progression events on 1L treatment were reported. Among patients progressing on 1L, 73 (82%) were tested for T790M mutation yielding 50 (68%) positive results, and 62 (85%) received 2L treatment. 82% of patients received osimertinib. Attrition rate between 1L and 2L was 10%. The median (95% CI) real-world progression free survival on 1L EGFR TKIs was 15.6 (12.6, 19.2) months; median overall survival (95% CI) was 28.9 (25.0, 34.3) months. Conclusions. This real-world study provides valuable information about 1G/2G EGFR TKIs treatment outcomes and attrition rates in Slovenian EGFRm NSCLC patients. The reduced attrition rate and improved survival outcomes empha-size the importance of 1L treatment decision.
Ključne besede: real-world study, non-small cell lung cancer, epidermal growth factor receptor, lung cancer
Objavljeno v DiRROS: 25.07.2024; Ogledov: 98; Prenosov: 41
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Povzetek: Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.
Ključne besede: CAR-T cells, TCR, inducible, transcription factor, NFAT, single lentiviral expression system, IL-6, IL-12, CRS, armored
Objavljeno v DiRROS: 18.07.2024; Ogledov: 142; Prenosov: 25
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Povzetek: The fungus Phyllosticta citricarpa is a quarantine pathogen in the EU and is of high economic importance in many parts of the world where favourable climate conditions drive the development of citrus black spot (CBS) disease. Disease symptoms include necrotic lesions on leaves and fruits. Low disease pressure can reduce crop market-ability, while higher disease pressure can cause premature fruit drop, significantly increasing crop losses. The wind-dispersed spores of P. citricarpa are especially prob-lematic for rapid pathogen dispersal, but also provide an opportunity for early detec-tion of the disease spreading into a new area. In this study we have developed and validated a quantitative PCR (qPCR) assay based on the TEF1-α sequence. Specificity testing demonstrated that it is currently the only qPCR assay that does not cross- react with closely related Phyllosticta species. The assay is sensitive and can detect a single copy of the TEF1 gene in a reaction, it is highly repeatable and reproducible and can be used for testing of the sticky tapes from spore traps as well as citrus fruit sam-ples. High-throughput sequencing (HTS) of the DNA barcodes ITS1 and TEF1 was also explored for the detection and discrimination of P. citricarpa. The limit of detection of the HTS was 1000 spores on a daily spore trap tape. This study makes an important improvement to the diagnostics of the CBS and the methods developed can also be applied to improve the surveillance and early detection of the pathogen when linked to spore samplers in the field.
Ključne besede: detection, fungal spore sampling, internal transcribed region (ITS), translation elongation factor 1-α (TEF1)
Objavljeno v DiRROS: 12.07.2024; Ogledov: 133; Prenosov: 152
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