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British Journal of Cancer Apr 2020Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach...
BACKGROUND
Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.
METHODS
Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).
RESULTS
ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.
CONCLUSION
Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Chick Embryo; Deoxyglucose; Energy Metabolism; Glioblastoma; Glycolysis; Humans; Imidazoles; Oxidative Phosphorylation; Pyridines; Pyrimidines
PubMed: 32115576
DOI: 10.1038/s41416-020-0759-0 -
Journal of Cardiac Surgery Nov 2022The introduction of the frozen elephant trunk (FET) technique for total arch replacement (TAR) has revolutionized the field of aortovascular surgery. However, although... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The introduction of the frozen elephant trunk (FET) technique for total arch replacement (TAR) has revolutionized the field of aortovascular surgery. However, although FET yields excellent results, the risk of certain complications requiring secondary intervention remains present, negating its one-step hybrid advantage over conventional techniques. This systematic review and meta-analysis sought to evaluate controversies regarding the incidence of FET-related complications, with a focus on aortic remodeling, distal stent-graft induced new entry (dSINE) and endoleak, in patients with type A aortic dissection (TAAD) and/or thoracic aortic aneurysm.
MATERIALS AND METHODS
A comprehensive literature search was conducted using multiple electronic databases including EMBASE, Scopus, and PubMed/MEDLINE to identify evidence on TAR with FET in patients with TAAD and/or aneurysm. Studies published up until January 2022 were included, and after applying exclusion criteria, a total of 43 studies were extracted.
RESULTS
A total of 5068 patients who underwent FET procedure were included. The pooled estimates of dSINE and endoleak were 2% (95% confidence interval [CI] 0.01-0.06, I = 78%) and 3% (95% CI 0.01-0.11, I = 89%), respectively. The pooled rate of secondary thoracic endovascular aortic repair (TEVAR) post-FET was 7% (95% CI 0.05-0.12, I = 89%) while the pooled rate of false lumen thrombosis at the level of stent-graft was 91% (95% CI 0.75-0.97, I = 92%). After subgroup analysis, heterogeneity for distal stent-graft induced new entry (dSINE) and endoleak resolved among European patients, where Thoraflex Hybrid (THP) and E-Vita stent-grafts were used (both I = 0%). In addition, heterogeneity for secondary TEVAR after FET resolved among Asians receiving Cronus (I = 15.1%) and Frozenix stent-grafts (I = 1%).
CONCLUSION
Our results showed that the FET procedure in patients with TAAD and/or aneurysm is associated with excellent results, with a particularly low incidence of dSINE and endoleak as well as highly favorable aortic remodeling. However the type of stent-graft and the study location were sources of heterogeneity, emphasizing the need for multicenter studies directly comparing FET grafts. Finally, THP can be considered the primary FET device choice due to its superior results.
Topics: Aortic Dissection; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Azides; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Deoxyglucose; Endoleak; Humans; Retrospective Studies; Stents; Treatment Outcome
PubMed: 36069163
DOI: 10.1111/jocs.16918 -
Cancer Biotherapy & Radiopharmaceuticals May 2023In the past decade, the implementation of immunotherapy with checkpoint inhibitors has determined a major change in the management of oncological patients. The...
In the past decade, the implementation of immunotherapy with checkpoint inhibitors has determined a major change in the management of oncological patients. The challenges associated to the new therapeutic regimen have promoted adapted criteria for response assessment to interpret imaging findings and atypical patterns of response. Parallel to the new morphological criteria, also fluoro-deoxyglucose positron emission/computed tomography imaging has required novel approaches and specific guidelines on how to perform, interpret, and report the scan in patients with solid tumors under immune checkpoint inhibitors therapy. A summary of the novelties related to the new joint international European Association of Nuclear Medicine (EANM)/Society of Nuclear Medicine and Molecular Imaging (SNMMI)/Australian and New Zealand Society of Nuclear Medicine (ANZSNM) guidelines on immunotherapy is provided herein to elucidate most critical aspects in image interpretation.
Topics: Humans; Nuclear Medicine; Fluorodeoxyglucose F18; New Zealand; Australia; Positron-Emission Tomography; Immunotherapy; Molecular Imaging; Positron Emission Tomography Computed Tomography
PubMed: 36730788
DOI: 10.1089/cbr.2022.0091 -
American Journal of Physiology. Cell... Feb 2024Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously...
Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1 Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD. The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.
Topics: Humans; Mice; Animals; Complement Pathway, Alternative; Matrix Metalloproteinase 2; Aortic Aneurysm, Thoracic; Aortic Dissection; Inflammation; Azides; Deoxyglucose
PubMed: 38189133
DOI: 10.1152/ajpcell.00210.2023 -
Journal of Nuclear Medicine : Official... Aug 2021
Topics: Fluorodeoxyglucose F18; Humans; Inflammation; Middle Aged; Positron-Emission Tomography
PubMed: 33893189
DOI: 10.2967/jnumed.121.262446 -
PLoS Genetics Jul 2020Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the...
Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA abundance that were greatly reduced in the 2DG resistant strains. These findings suggest the common adaptive response to 2DG is to limit the magnitude of the response. Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.
Topics: Deoxyglucose; Endocytosis; Energy Metabolism; Gene Expression Regulation, Fungal; Glucose; Glucose Transport Proteins, Facilitative; Hexokinase; Humans; Mutation; Phosphoric Monoester Hydrolases; Protein Phosphatase 1; Protein Serine-Threonine Kinases; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Whole Genome Sequencing
PubMed: 32673313
DOI: 10.1371/journal.pgen.1008484 -
Bioelectrochemistry (Amsterdam,... Oct 2022Diabetes is one of metabolic diseases affecting major human health. The early diagnosis and treatment of diabetes have significant benefits. 1,5-anhydroglucitol (1,5-AG)...
Diabetes is one of metabolic diseases affecting major human health. The early diagnosis and treatment of diabetes have significant benefits. 1,5-anhydroglucitol (1,5-AG) accurately reflects a patient's average blood glucose level for the past 3-7 days and becomes a promising marker for real-time detection of diabetes. In this study, a novel biosensor for determination 1,5-AG is constructed using reduce graphene oxide-carboxymethylated chitosan-hemin@platinum nanocomposites (rGO-CMC-H@Pt NCs) nanozyme and pyranose oxidase (PROD) enzyme as the electrochemical biosensing platform. The rGO-CMC-H@Pt NCs nanozyme has good electro-conductibility, high specific surface area, and admirable peroxide-like catalysis effect to enhance the electrochemical response. 1,5-AG is catalyzed by PROD and produces hydrogen peroxide (HO), which in turn can be decomposed by rGO-CMC-H@Pt NCs and produce a current signal recorded by differential pulse voltammetry (DPV) technique. Under optimal conditions, the response currents have a linear relationship in the 1,5-AG concentration of 0.1-2.0 mg/mL with R of 0.9869. The sensitivity is 2.1895 μA/μg·mL and the limit of detection (LOD) is 38.2 μg/mL (S/N = 3). In addition, the specificity, reproducibility, stability and recovery (94.5-107.6%) of 1,5-AG biosensors all exhibit good performance. Therefore, the designed 1,5-AG biosensor has a good effect and can be used for the diagnosis of diabetes.
Topics: Biosensing Techniques; Chitosan; Cytochrome P-450 CYP2B1; Deoxyglucose; Electrochemical Techniques; Graphite; Hemin; Humans; Hydrogen Peroxide; Limit of Detection; Platinum; Reproducibility of Results
PubMed: 35839688
DOI: 10.1016/j.bioelechem.2022.108204 -
Biomedicine & Pharmacotherapy =... Sep 2019Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show F-FDG activity. Caution in the interpretation must be... (Review)
Review
Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show F-FDG activity. Caution in the interpretation must be taken to avoid the misdiagnosis of malignancy. Utilization of both CT findings as well as patient history can help differentiate benign infectious and inflammatory processes from malignancy, although occasionally additional work-up may be required. This article discusses the mechanism of F-FDG uptake in infection and inflammation with illustrative examples.
Topics: Animals; Fluorodeoxyglucose F18; Humans; Infections; Inflammation; Neoplasms; Positron Emission Tomography Computed Tomography
PubMed: 31334700
DOI: 10.1016/j.biopha.2019.109168 -
Journal of Pharmacological Sciences Sep 2021We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by...
We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone. 2DG/rotenone reduced ATP levels and increased mitochondrial superoxide production, causing mitochondrial swelling and necrotic death in various cancer cell lines. 2DG/rotenone failed to increase proautophagic beclin-1 and autophagic flux in melanoma cells despite the activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). 3MA, but not autophagy inhibition with other PI3K and lysosomal inhibitors, attenuated 2DG/rotenone-induced mitochondrial damage, oxidative stress, ATP depletion, and cell death, while antioxidant treatment mimicked its protective action. The protection was not mediated by autophagy upregulation via class I PI3K/Akt inhibition, as it was preserved in cells with genetically inhibited autophagy. 3MA increased AMPK and mTORC1 activation in energy-stressed cells, but neither AMPK nor mTORC1 inhibition reduced its cytoprotective effect. 3MA reduced JNK activation, and JNK pharmacological/genetic suppression mimicked its mitochondria-preserving and cytoprotective activity. Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.
Topics: AMP-Activated Protein Kinases; Adenine; Animals; Autophagy; Cell Death; Deoxyglucose; JNK Mitogen-Activated Protein Kinases; Mechanistic Target of Rapamycin Complex 1; Melanoma; Melanoma, Experimental; Mice, Inbred C57BL; Mitochondria; Mitochondrial Swelling; Necrosis; Oxidative Stress; Phosphatidylinositol 3-Kinases; Rotenone; Mice
PubMed: 34294367
DOI: 10.1016/j.jphs.2021.06.003 -
Tomography (Ann Arbor, Mich.) Mar 2023We have integrated a compact and lightweight PET with an existing CT image-guided small animal irradiator to enable practical onboard PET/CT image-guided preclinical...
We have integrated a compact and lightweight PET with an existing CT image-guided small animal irradiator to enable practical onboard PET/CT image-guided preclinical radiation therapy (RT) research. The PET with a stationary and full-ring detectors has ~1.1 mm uniform spatial resolution over its imaging field-of-view of 8.0 cm diameter and 3.5 cm axial length and was mechanically installed inside the irradiator in a tandem configuration with CT and radiation unit. A common animal bed was used for acquiring sequential dual functional and anatomical images with independent PET and CT control and acquisition systems. The reconstructed dual images were co-registered based on standard multi-modality image calibration and registration processes. Phantom studies were conducted to evaluate the integrated system and dual imaging performance. The measured mean PET/CT image registration error was ~0.3 mm. With one-bed and three-bed acquisitions, initial tumor focused and whole-body [F]FDG animal images were acquired to test the capability of onboard PET/CT image guidance for preclinical RT research. Overall, the results have shown that integrated PET/CT/RT can provide advantageous and practical onboard PET/CT image to significantly enhance the accuracy of tumor delineation and radiation targeting that should enhance the existing and enable new and potentially breakthrough preclinical RT research and applications.
Topics: Animals; Positron Emission Tomography Computed Tomography; Radiation Oncology; Fluorodeoxyglucose F18; Phantoms, Imaging
PubMed: 36961005
DOI: 10.3390/tomography9020046